Despite the improved short-term outcomes of kidney transplantation, more than 50% of kidney allografts are lost by 10 years after transplant. The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors. Cellular and/or antibody-mediated rejection (ABMR) was the leading culprit of IFTA followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity. Acute rejection is less common after the first year of transplant. The most common type of rejection after the first year of transplant is chronic rejection, which is defined as a prolonged cellular and/or antibody mediated immune response against the transplanted organ. Risk of graft failure is significantly higher in patients with DSA, C4d staining or both. Both pretransplant and de novo DSA are associated with significant graft loss, development of de novo DSA is associated with significant worse 10-year graft survival. Although transplant glomerulopathy is one of the predominant findings on chronic ABMR, it is not specific to rejection since other causes of chronic endothelial injury may lead to similar pattern of injury including thrombotic microangiopathy, recurrent autoimmune glomerulonephritis and hepatitis C-related glomerulonephritis. At 10 years after transplant, glomerular disease recurrence was the third leading cause of graft loss. Focal segmental glomerulosclerosis (FSGS) tends to recur early after transplant with massive proteinuria and is associated with graft loss in 50%–80% of cases. a potential circulating factor that leads to podocyte injury is highly suspected. Atypical hemolytic-uremic syndrome has also a high rate of recurrence (30%–90%) depending on the underlying complement abnormalities. IgA nephropathy has a high recurrence rate (up to 40%), commonly may exacerbate with reduction of immunosuppression late after transplantation. BK nephropathy has become a major cause of both acute and chronic allograft dysfunction. BK infection follows a predictable pattern with initial viruria followed by viremia and then nephropathy. Patients with greater than 10,000 copies of BK and allograft dysfunction are likely to have BK nephropathy, although it should be confirmed by renal biopsy. CMV infection is one of the most common opportunistic infections after kidney transplantation. CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility for infection and rejection. Direct involvement of CMV infection on the kidney is rare and may present with necrotizing crescentic glomerulonephritis with viral inclusions. CNI is known to have significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy. CNI withdrawal are associated with high rate of de novo DSA formation. One study revealed that chronic CNI nephrotoxicity was considered the culprit in only 1% of cases when protocol biopsies were performed. The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities (e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults. A significant mismatch between donor and recipient size (kidney weight/recipient weight b2.3 g/kg) is associated with a higher rate of hypertension, proteinuria and lower graft survival. Renal artery stenosis may lead to graft ischemia and injury. It occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation. Ureteral obstruction due to anastomotic stenosis or ureter ischemia (fragile vasculature of ureter) may lead to significant hydronephrosis and graft injury. The management of patients with chronic allograft injury depends primarily in the underlying cause of injury. Urinalysis with sediment visualization may help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy, respectively. Noninvasive biomarkers have the potential to earlier identify ongoing graft injury as well as predict response to treatment. protein and mRNA levels of CXCL9 was shown to be a great predictor of rejection with an elevation in levels detected 30 days before a biopsy-proven rejection. A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection. In a recent study, a high percentage of NKG2A+ cells after kidney transplantation correlated with the presence of DSA, cABMR and worse graft function. C1q-fixing DSA and IgG3 showing worse outcome. Since creatinine is a late marker of kidney dysfunction and in the absence of any noninvasive biomarker to monitor kidney injury in transplantation, longitudinal surveillance biopsies have emerged in few centers as a critical monitoring tool of kidney recipients. Preventive strategies Belatacept, a CTLA4Ig fusion protein that blocks the CD80/CD86 interaction with CD28 preventing T cell activation, is developed in an attempt to reduce CNI nephrotoxicity. Its use is associated with high rate of acute cellular rejection in first year post transplant. Its utilization is contraindicated in EBV negative patients because of higher risk of PTLD. Other CNI-sparing agents such as mTOR inhibitors have not shown a benefit in improving long-term graft survival Treatment strategies The most significant risk factor for chronic ABMR is acute ABMR, so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients. Bortezomib and Eculizumab have been used as alternatives. Appropriate treatment of primary glomerulonephritis recurrence is warranted.
MICHAEL Farag
2 years ago
Summarize this article
. Introduction
Cellular and/or antibody-mediated rejection (ABMR) was the leading culprit of IFTA
followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity However, the revised Banff 2005 classification system renamed CAN to IFTA.
Diagnostic strategies
The management of patients with chronic allograft injury depends primarily in the underlying cause of injury. Therefore, obtaining a careful history in regards to the primary renal disease, the early posttransplant course (e.g. severe delayed graft function might indicate significant irreversible early allograft damage), episodes of acute rejection (if any), degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important. The likelihood of different causes of graft injury is strongly influenced by the timing after transplantation.
– Urinalysis with sediment visualization may help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy, respectively.
– A kidney ultrasound may exclude mechanical complications such as ureteric obstruction and vascular stenosis.
– a kidney biopsy should be performed in the majority of patients with dysfunction and no clear reversible factor present or if other worrisome features such as significant proteinuria or cellular casts are present.
– The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA
Preventive strategies
– Alternatives to CNI: costimulatory blockade agent belatacept but not in clinical practice because of its potential risk to develop acute cellular rejection in the first year after transplantation and contraindicated in patients with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder.Other CNI-sparing agents such as mTOR inhibitors have not shown a benefit in improving long-term graft survival.
– Better controlling blood pressure post-transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant.
– Preventing non-compliance
Treatment strategies
The most significant risk factor for chronic ABMR is acute ABMR, so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients. Potential alternatives to rituximab to reduce antibody production include bortezomib. In severe cases of ABMR, eculizumab that inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy.
Assafi Mohammed
2 years ago
This review article, give a view on the pathogenesis and treatment strategies of chronic allograft injury.
Chronic allograft injury; Etiology : 1.Immunological causes in a form of rejection; cellular, anti-body mediated or mix pattern of rejection. Non-compliance is one of the major risk factors for chronic allograft injury. DSA has a role in graft dysfunction which is increasingly recognized. mechanism of chronic injury:
antibody-mediated injury to the endothelium( vascular beds; glomeruli, PTC and small-medium sized vessels).
cellular hypertrophy, expansion and duplication of the basement membrane and some podocyte injury.
2. Glomerular disease recurrence : recurrence was the third leading cause of graft loss
FSGS tends to recur early after transplant with massive proteinuria and is associated with graft loss in 50%–80% of cases
Atypical hemolytic-uremic syndrome has also a high rate of recurrence (30%–90%).
IgA nephropathy has a high recurrence rate (up to 40%).
3.Infections (viral/bacterial)
Both viral and bacterial infections may lead to kidney allograft injury.
BK is a major cause of acute and chronic allograft injury, with the intensity of immunosuppression is a predictable risk factor for infection. 30 to 65% of patients with BK virus associated nephropathy tend to lose their graft within a year.
CMV affects the allograft in different ways; from CMV syndrome(fever, weakness and myalgia) to end organ disease(colitis ,pneumonitis, hepatitis)and through immunomodulatory mechanisms. Direct involvement to the kidney by the virus is rare.
UTI may lead to chronic allograft injury through direct invasion and spread of infection or via triggering of immune response and hence rejection.
4. Non-immunological causes
CNI nephrotoxicity; from renal vasoconstriction to IFTA and TMA.
Poor quality donor grafts after the expansion of the donor pool to retrieve kidney from cardiac-death patients, elderly and those with comorbidities.
Renal artery stenosis; occurs in 5% of KTRs and should be suspected in few years post transplant in those with flash pulmonary edema, Uncontrolled HTN or acute elevation of the BP.
Urinary tract obstruction; due to uretral stenosis at the anastomotic site or to ureteric ischemia because of fragile ureter.
Chronic allograft injury; Diagnostic strategies
1.Obtaining careful history in regards to the primary renal disease, the early post- transplant course, episodes of acute rejection, degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important.
2.Urinalysis with sediment visualization.
3.A kidney ultrasound may exclude mechanical complications such as ureteric obstruction and vascular stenosis.
4.Kidney biopsy is indicated when there is no clear reversible factor or when there is worrisome features(proteinuria or cellular cast). Longitudinal surveillance biopsies(protocol biopsy) have emerged as a critical monitoring tool of kidney recipients as creatinine is a late marker of kidney dysfunction. Justifications for Protocol biopsies: according to Loupy et al. study on 1001 unsensetized patients
(a) creatinine is a late marker of kidney dysfunction.
(b) subclinical AMR was associated with a worse 8- year outcome (56%), compared to CMR(88%) and non-rejection group (88%).
(c) detection of specific and unsuspected graft injury that may have consequent change in management. It helps selecting the most effective therapeutic strategy.
5.Noninvasive biomarkers : are currently not in clinical use outside of the research setting.
(a) protein and mRNA levels of CXCL9.
(b) a urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA.
(c) NK cell immunophenotyping. NKG2A+ cells after kidney transplantation correlated with the presence of DSA, cABMR and worse graft function.
(d) The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA for the prediction of antibody-mediated rejection.
Chronic allograft injury; Preventive strategies
1.Alternatives to CNI eg; Belatacept and mTORi.
Belatacept is contraindicated in seronegative EBV status as it causes PTLD. The high rate of associated acute CMR in the first post transplant period limit the use of Belatacept.
mTOR inhibitors have not shown a benefit in improving long-term graft survival with specific concerning side.
2.Preventing non-compliance: Risk factors and clues for noncomplicance: poor social support, missed appointments, fluctuating drug levels, differences between drug prescribed and dispensed, unexpected late rejection, psychiatric disorder, substance abuse, adolescence, increased time since transplant and financial crisis.
Chronic allograft injury; Treatment strategies
Management of chronic rejection through prevention of ABMR and early treatment it, using plasmapheresis plus Rituximab and IVIG. Bortezomib is an alternative to rituximab while eculizumab is used in severe cases.
Management of recurrent primary glomerulonephritis:
Alyaa Ali
2 years ago
By 10 years post-transplant ,10% of kidney allografts are lost.the causes of allograft loss include immunological and non immunological causes. Immunological causes
Allo-MHC molecules in the donor kidney leads to a life-long low-grade exposure to foreign antigens that may lead to chronic immunologically mediated injury( cellular , antibody mediated or mixed)
Acute rejection is less common after the first year of transplant,but the rate of late acute rejection is about 5% per year . The most common type of rejection after the first year of transplant is chronic rejection, which is defined as a prolonged cellular and/or antibody mediated immune response against the transplanted organ .
Donor-specific antibodies (DSA) are a major cause of graft loss late after transplantation may develop due to non compliance .
Both pretransplant and de novo DSA are associated with significant graft loss . The rate of de novo DSA ranges between 15% and 20% at 5 years post-transplant in unsensitized recipients and development of de novo DSA is associated with significant worse 10-year graft survival The mechanism of chronic injury frequently involves primarily an antibody-mediated injury to the endothelium of multiple vascular beds including glomeruli, peritubular capillaries and small-medium sized vessels leads to cellular hypertrophy,
expansion and duplication of the basement membrane and some podocyte injury,with the pathologic appearance of transplant glomerulopathy on kidney biopsy. Glomerular disease recurrence
At 10 years after transplant, recurrence was the third leading cause of graft loss
some forms of primary kidney disease are related to high-risk of recurrence and graft loss early after transplant, others may be associated with a delayed presentation and slowly progressive course.
(FSGS) tends to recur early after transplant with massive proteinuria and is associated with graft loss in 50%–80% of cases .
Atypical hemolytic-uremic syndrome has also a high rate of recurrence (30%–90%)
IgA nephropathy has a high recurrence rate (up to 40%) but rarely causes early graft loss. Infection
Both viral and bacterial infections may lead to kidney allograft injury.With the increased use of more potent immunosuppressive drugs in the past 15 years, BK nephropathy has become a major cause of both acute and chronic allograft dysfunction .Also,kidney recipients that developed CMV post-transplant have significantly worse graft and patient survival . Non-immunological causes CNI toxicity
CNI has significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy.
long-termallograft fibrosis was primarily related to chronic CNI toxicity that led to IFTA, glomerulosclerosis and arteriolar hyalinosis Poor quality donor grafts
The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities (e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults . Renal artery stenosis and urinary tract obstruction
Renal artery stenosis may lead to graft ischemia and injury. This condition occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation. Underlying etiology includes stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant
artery. Diagnostic strategy
Urinalysis with sediment visualization may help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy, respectively.
A kidney ultrasound may exclude mechanical complications such as ureteric obstruction and vascular stenosis.
A kidney biopsy should be performed in the majority of patients with dysfunction and no clear reversible factor present or if other worrisome features such as significant proteinuria or cellular casts are present
Since creatinine is a late marker of kidney dysfunction , longitudinal surveillance biopsies have been used in few centers as a critical monitoring tool of kidney recipients for detection of specific, unsuspected, graft injury with consequent change in management.
Non invasive biomarkers:The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA for the prediction of antibody-mediated rejection.
Preventive strategies
Alternatives to CNI
Better control of blood pressure
Techniques to better preserve the donor kidney after retrieval have been explored. In particular, the use of a machine perfusion has demonstrated a greater benefit in 3-year graft survival in particular in expanded-criteria donor kidneys when compared to cold static storage
prevention of non compliance
Treatment strategies
chronic ABMR is an important cause of late graft loss, the most significant risk factor for
chronic ABMR is acute ABMR
to prevent it we use combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin in sensitized patients .Potential alternatives to rituximab
to reduce antibody production include bortezomib . In severe cases of ABMR, eculizumab that inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy
The FDA currently has no approved therapy for chronic ABMR [84] and mechanistic interventional clinical trials are needed to address the safety and efficacy of B cell and DSA depleting strategies for chronic rejection.
Management strategy for FSGS may include high dose steroids and cyclosporine aiming podocyte stabilization, in combination with plasma exchanges to remove circulating humoral factors.
recurrent IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor blockers , but specific protocols for recurrence management are lacking. Following recommendations for native IgA nephropathy, oral prednisone (1 mg/mg 2 months and
then slow taper) may be advisable .
Recurrent membranous nephropathy may be managed with rituximab,
The treatment of recurrent membranoproliferative GN (MPGN) : recurrent type I or idiopathic cases successfully treated with rituximab
C3 glomerulopathy and dense deposit disease have been recently managed with
eculizumab, with variable responses
Sahar elkharraz
2 years ago
Chronic allograft dysfunction still remain problems despite improving of immunosuppressive therapy post transplant.
Chronic allograft rejection always occurring 5 years post transplant.
It’s mainly due to immunological and non immunological factors.
The most common cause of graft loss are death with function graft .
The second cause are chronic allograft proved by renal biopsy due to recurrence of glomerular disease and chronic rejection of cellular and AMR.
Other causes are infection and drug toxicity.
Immunological causes:
It’s due to presence of alloantibodies which lead to chronic immunological mediated injury.
It’s manifested by renal biopsy to tubular atrophy. It’s carrying high risk of graft loss even discovered early by renal biopsy protocol.
The most common of chronic graft injury is non compliance and non adherence to immunosuppressive therapy.
Causes of chronic allograft dysfunction are DM / HTN/ Hyperlipidemia / infection and drug toxicity/
Recurrence of de novo glomerular disease
Donor kidney disease.
Presence of DSA appear pre and post transplant and rarely chronic allograft dysfunction appear in one year post transplant.
Presence of de novo DSA appear 10 years post transplant.
The appearance of transplant glomerulopathy by renal biopsy prove presence of chronic allograft dysfunction which shows swelling in endothelial cell and doubling of basement membrane and disruptive of podocytes.
Risk of recurrence of glomerular disease post transplant by 100% are:
Systemic primary oxalosis
Diabetic Nephropathy
Fabry disease
DDD
Atypical HUS disease
Risk of recurrence of glomerular disease post transplant by 75% to 50% are:
IgA nephropathy
SLE
ANCS vasculitis
Amylidosis
Scleroderma
Anti GBM disease
Recurrence less than 20% are infection
Bacterial and viral infection are risk of graft loss.
Serial serum PCR routine done post transplant.
If BK PCR high so reduction of immunosuppressive therapy is mandatory.
PCR of CMV infection
Symptoms of CMV infection range from fever/ weakness myalgia to end organ infection pneumonitis/ colitis and hepatitis.
If vermia high are assistant with necrotizing crescent glomerulonephritis and viral inclusion.
Non immunological factors:
CNI toxicity
poor quality of donor
Vascular stenosis
Diagnosis of chronic allograft dysfunction:
Good history of date of transplant and serial monitoring of drug level and serial PCR of any evidence of previous infection and previous rejection and fallow up chart and compliance of patient and adherence to drug. History of hypertension and DM and there control .
Urine analysis to rule out cellular cast and granular cast, presence of proteinuria and leukocytes in urine.
USS of kidney for any mechanical obstruction and vascular stenosis.
Non invasive bio markers:
mRNA level of CXCL9 predict rejection which appear 30 days before biopsy proven rejection.
Urinary mRNA include CD3E / CXCL 10 185 ribosomal RNA. It’s may increase in patients with CMV & BK infection.
Increase level of NKG2A associated with presence of DSA , CABMR worse graft function.
Anti HLA DSA is predicted AMR.
Protocol renal biopsy shows early sub clinical inflammation associated with worse graft.
Preventive strategies:
Alternative to CNI are Co-stimulatory blocked agents belatacept are CTLA4 Ig fusion protein blocks CD8/CD86 interaction with CD28 preventing T cell activity. Initially every 2 weeks and then monthly but it has high rate of rejection in first year post transplant.
Another alternative are mTor inhibitors
ACEI and ARBC inhibitors there is no evidence of benefit post transplant and also have side effects like anemia and decrease GFR and hyperkalemia.
Non compliance:
miss fallow up
non adherence to immunosuppressive agents
poor social support
drug addicted
Treatment of chronic allograft dysfunction:
The main cause are acute ABMR
So management are plasma exchange plus Rituximab and Intravenous immunoglobulin in sensitised patients.
alternative to rituximab are bortezomib.
In severe cases can be use eculizumab .
Use of steroid with intravenous immunoglobulin plus plasma exchange may reduce risk of graft loss. If no response use rituximab.
Mohammed Sobair
2 years ago
Introduction:
Despite the improved short-term outcomes of kidney transplantation, more than 50% of
kidney allografts are lost by 10 years after transplantation.
Causes of chronic allograft loss are multifactorial, common:
Careful history in regards to the primary renal disease, the early posttransplant course.
Urine analysis.
Biopsy.
Ultrasound.
Noninvasive biomarkers:
Anti-HLA DSA for the prediction of antibody-mediated rejection
Protein and mRNA levels of CXCL9.
CD3E, CXCL10 and 18S ribosomal RNA also associated with rejection.
NK cell immunophenotyping.
Preventive strategies:
Alternatives to CNI: to minimize IF/TA associated with CNI.
Both mTOR and Belatacept is promising but still not used widely.
Better controlling blood pressure.
Preventing non-compliance.
Treatment strategies:
Management of chronic rejection:
Management and prevention of acute ABMR, so prevention strategies have been
focused on avoiding it. Preventive combined therapies including plasmapheresis,
rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients.
Potential alternatives to rituximab to reduce antibody production include Bortezomib.
In severe cases of ABMR, Eculizumab.
Management of recurrent primary glomerulonephritis:
FSGS recurrence, high dose steroids and cyclosporine , in combination with plasma
exchanges .
Recurrent IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor
blockers, but specific protocols for recurrence management are lacking.
Following recommendations for native IgA nephropathy, oral prednisone (1 mg/mg 2
months and then slow taper) may be advisable.
Recurrent membranous nephropathy may be managed with rituximab, and some patients
respond to therapy up to one year after treatment.
The treatment of recurrent membranoproliferative GN (MPGN) is based in underlying
etiological factors.
For the idiopathic cases related to immune complexes, no consensus exists, and
steroids, cyclophosphamide and/or plasma exchanges have been unsuccessful.
Some recurrent type I or idiopathic cases successfully treated with rituximab.
Conclusion:
Chronic allograft injury can significantly affect long-term graft survival.
Therefore, prevention of injury should be a major focus of caring of transplant
recipients. Based on the heterogeneity of causes of injury strategies may include CNI
minimization, better preservation of the allograft after retrieval, use of protocol biopsies,
active noncompliance screening, measurement of DSA post-transplant and other
potential novel biomarkers of graft injury, BK surveillance and aggressive treatment of
hypertension, hyperglycemia and hyperlipidemia.
mai shawky
2 years ago
Summary: chronic allograft injury
• Chronic graft damage eventually leads to graft loss years post transplantation.
• May be immunologically and non immunologically mediated.
• Surveillance biopsies revealed glomerular disease (37%), tubular atrophy/ tubular atrophy (IFTA; 30.7%) and acute rejection (12% of cases).
• Glomerular diseases either transplant glomerulopathy or recurrence of glomerular diseases.
• The main causes behind graft scarring were recurrent rejection episodes, infections as BK nephropathy and recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity, complications of systemic diseases as uncontrolled DM, hypertension and dyslipidemia and recurrent or de novo glomerular diseases.
• Untreated/ or inadequately treated acute rejection turns into chronic rejection that eventually cause scarring and IFTA. In addition, non adherence to therapy and development of de novo DSA leads to late and chronic active ABMR.
• Glomerular diseases with high risk of recurrence and graft loss are:
o Dense deposit disease (DDD) 80%–100%
o FSGS 20%–50% (up to 80% if prior graft loss)
o Atypical HUS (depending on underlying mutation) 30%–90%
o C3 glomerulonephritis 65% 50%
o MPGN (C3+ Ig+): infection, monoclonal gammopathy, autoimmune dz (variable) 30%–50% 15%
o IgA nephropathy 20%–40% 5%–15%
o Membranous GN 10%–40% 10%–15%
o Anti GBM disease
• systemic diseases with high risk of recurrence and graft loss are
o Oxalosis (consider combined liver/kidney) 100% 50%
o Cystinosis (if on enzyme replacement)
o Scleroderma (little data) 20% 50%
o Immunoglobulin deposition diseases 50%–75% 30%
o Amyloidosis 20%–40% 20%
o ANCA vasculitis 15%–20% 6%–8% SLE 2%–10% 2%–7%
o Diabetic nephropathy 100%
o Fabry disease (if on enzyme replacement) 100%
• Diagnostic strategies:
o Urine analysis and active sediment for recurrent nephritis.
o DSA and protocol biopsy for rejection.
o Early detection of rejection and diagnosis of infection, prevention of none adherence
• Treatment is directed to the treatment of the cause
• Antirejection therapy is combined steroid pulses, ivig and plasmapheresis and optimization of the maintenance therapy.
_ prevention of chronic graft damage by ensuring drug compliance, minimization of CNI induced nephrotoxicity and appropriate treatment of acute rejection is best strategy to prevent graft loss.
Last edited 2 years ago by mai shawky
Wael Jebur
2 years ago
This article is casting light on the contentious issue of managing the chronic allograft injury.Elaborating on the causes , etiology and prospective management.
Before Banff meeting on the year 2005 , the term chronic allograft nephropathy CAN was over-zealously echoed to describe unclassified deterioration of allograft function.But, due to its non-specificity,and being rather an ambiguous term, it was replaced by the mentioned meeting to IFTA, (stand for interstitial fibrosis and tubular atrophy) which was entirely descriptive and non diagnostic, larger studies such as Dekafe study performed to explore the potential causes of this commonly encountered pathological finding on allograft biopsy.
The paradigm was shifted from mainly Cni related nephrotoxicity to focus on chronic ABMR, BKPN, recurrent glomerular disease and interstitial nephritis.Non-compliance was the main culprits in precipitating the immunologic reaction and chronic ABMR as the main underlying etiology . Chronic ABMR:
Was considered the predominant causes of chronic allograft dysfunction, IFTA, chronic rejection and failure.
The HLA incompatability is the major trigger for immunologic reaction with both TCMR and ABMR can be precipitated , the first year is associated with heightened incidence of both types of rejection, the late acute rejection is usually associated ABMR, that potentially progress to chronic rejection.
Features associated with high risk of progression include De novo DSAs, complement fixing DSAs tested by C1q testing and the phenotype of IgG antibodies particularly IgG3.
DSAs against Type II HLA antigen. with MFI of more than 2500 are usually associated with increased risk of cABMR.
Presentation of cABMR:
progressive long term deterioration of allograft function with proteinuria.
pathogenesis: Its principally resultant from the interaction of DSAs with HLA antigens on the endothelial cells in glomeruli and peritubular capillaries featuring transplant glomerulopathy and peritubular capillaritis.
Treatment:
Its dependent on the time of diagnosis , duration since transplantation,
IVIG, methylprednnisolon and Rituximab were recommended and plasma pheresis if it happened in the first year post transplantation .Bortizomibe,to deplete Plasma cells as a source of DSAs, and Eculizumab to mitigate C5 complement component which is part of complement mediated ABMR.
Optimization of immunosuppression with adding of CNi if not yet on the same , and shifting of Cyclosporin to Tacrolimus and keeping the trough level at its upper site. Similarly prednisolon has to be initiated if its not yet in the medication list.
CNi nephrotoxicity is another important underlying etiology of IFTA, usually with stripped phenotype. Strategies to minimize the toxicity include CNi avoidance protocol, replacement with mTORi , however, the reported outcome was not significantly different, Nevertheless, a protocol involved mTORi with minimized dose of CNi was showing promising result and the result of TRANSFORM study is pending to explore this potential.
Ahmed Omran
2 years ago
10 year graft loss is more than 50% due to immunological and non-immunological causes. Interstitial fibrosis and tubular atrophy may be due to rejection, recurrent pyelonephritis, BK virus nephropathy ureteral stenosis and CNI nephrotoxicity.
Immunological causes: include : Chronic injury can occur by DSA, resulting in chronic rejection with proteinuria and /or elevated serum creatinine. Late rejection episode increase risk of chronic graft dysfunction. Increased DSA levels and/or C4d positivity increase graft failure risk. FSGS with recurrence rate of 20-80% has 50-80% graft loss. IgA nephropathy with 20-40% recurrence rate has 5-15% graft loss. BK viral infection results in chronic graft injury and 30-65% patients lose graft within 1.CMV infection, leads to increased rejection and poor graft survival. UTI can lead to rejection through activating innate immune system.
CNI nephrotoxicity:
Donor graft of low quality could be a cause of chronic graft injury. RAS and ureteral stenosis could lead to chronic graft injury. Diagnosis :includes history taking, and investigations including urine analysis, US and biopsy .Biomarkers eg: DSA with IgG isotyping ,DSA c1q fixation properties, protein and mRNA levels of CXCL9,…. have increased association with chronic graft injury. Grafts with subclinical AMR have worse outcomes.
Preventive measures: include blood pressure control, drug compliance and CNI alternatives; belatacept,( co-stimulatory blockade agent) which is associated with increased ACR in first year, with better long-term graft and patient survival.
Treatment includes prevention and management of acute AMR. Treatment of subclinical rejection with de novo DSA. Patients with higher risk of graft loss should be treated with augmentation of IS and use of steroids & IVIG. Without poor prognostic factors, management should include ATG ;if cellular component is present, plasmapheresis, rituximab, bortezomib & eculizumab if refractory to treatment. FSGS recurrence to be managed with high dose steroids, IVIG & PE. IgA N recurrence needs ACEI or ARBs with oral steroids. Membranous nephropathy needs rituximab In case of graft loss, second transplantation with a live donor avoidance of HLA mismatch as the preferred option.
ahmed saleeh
2 years ago
Causes of CAN
previously was the first 1 CNI Toxicity
Now multiple other causes e.g Non compliance (up to 40%) , Rejection , Infections , medical causes and CNI toxicity
1. Immunological causes of allograft rejection:
Probability of graft failure was significantly higher in patients with DSA, C4d staining or both, and the severity ​of clinical injury directly correlated with the intensity of the antibody ​response .
5 years post-transplant in unsensitized recipients and develop​ment of de novo DSA is associated with significant worse 10-year graft ​survival 57% compared to 96% in patients without de novo DSA
The mechanism of chronic injury frequently involves primarily ​an antibody-mediated injury to the endothelium of multiple vascular ​beds including glomeruli,peritubular capillaries and small-medium ​sized vessels , This endothelium injury leads to cellular hypertro​phy, expansion and duplication of the basement membrane and some ​podocyte injury, with the pathologic appearance of transplant glomeru​lopathy on kidney biopsy .
2. Recurrence of Original GN e.g FSGS (early with bad prognosis) , IgA nephropathy (better prognosis with ACE-I)
3. Infections
BK
is a ubiquitous ​virus that is tropic to the kidney tubules and may proliferate out of ​control in the setting of immunosuppression. Donor and recipient BK ​serologies do not predict the risk of infection and the intensity of immu​nosuppression seems to be the predominant risk factor .
30%– ​65% of patients that develop BK-associated nephropathy lose their kid​ney allograft withi 1 year of diagnosis . BK infection does ​not have any systemic symptoms, which significantly delays the diag​nosis.
surveillance of ​BK with serum PCR has become routine in most transplant centers
biopsy is important to confirm the diagnosis with SV40 staining for ​the BK virus and exclusion of any other etiology of graft dysfunction.
CMV
infections such as urinary tract ​infections may also lead to chronic injury either due to direct injury to ​the allograft in the setting of an infection affecting the kidney or ​indirectly, through triggering a rejection process due to the activation ​of innate immune system with increased
expression of costimulatory ​molecules and lowering of the threshold for T cell activation ​and proliferation.
CNI exposure:
current protocols ​using lower dosage and exposure to CNI in kidney transplant recipients ​do not seem to be the primary
culprit of many of the graft deteriorations ​that occur and avoidance of CNI
without any substitute agent will lead ​to poor outcomes.
low to
moderate-dose tacrolimus (target 3–7 ng/mL, ​median 7 ng/mL achieved, range
4.3–10.0 ng/mL) in combination with ​mycophenolate and steroids was associated with the best outcomes in​cluding lower rejection rate, lowerfibrosis and improved renal function ​at one year of follow-up .Extension of follow-up to 3 years failed to ​confirm that improvement
Poor quality donors :
the expansion of the donor pool to include kidneys from do​nors after cardiac death, elderly donors or those with comorbidities ​(e.g. diabetes and hypertension) may
significantly affect the allograft ​survival due to presence of preexisting injury, lower nephron mass ​and greater susceptibility of new insults
Renal artery stenosis may lead to graft ischemia and injury ,Gold-standard imaging
for diagnosis is arteriography ​though a Doppler ultrasound is frequently used as a screening method ​in suspected cases.
ureteral obstruction due to anastomotic ​stenosis or ureter ischemia (fragile vasculature of ureter) may lead to ​significant hydronephrosis and graft injury
based on the heterogene​ity of causes of late graft dysfunction, a kidney biopsy should be ​performed in the majority of
patients with dysfunction and no clear re​versible factor present or if other
worrisome features such as significant ​proteinuria or cellular casts are
present.
the distinction among the ​different DSA IgG isotypes seems to be relevant, with IgG3 showing ​worse outcomes .
Best way to avoid CAN is to prevent ABMR and early treat ABMR if occurred .
CARLOS TADEU LEONIDIO
2 years ago
· Summarize this article
INTRODUTION
The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors. In the largest longitudinal surveillance biopsy study available, El-Zoghby et al, they observed that death with a functioning graft was the most common cause of graft loss.
IMMUNOLOGICAL CAUSES
The persistent presence of allo-MHC molecules in the donor kidney leads to a life-long low-grade exposure to foreign antigens that may lead to chronic immunologically mediated injury. This process may take the form of cellular, antibody-mediated or a mix rejection. Diagnosis of chronic ABMR requires a kidney biopsy to exclude other potential causes.
Risk of subsequent graft failure was significantly higher in patients with DSA, C4d staining or both, and the severity of clinical injury directly correlated with the intensity of the antibody response. The recognition of alloantibodies as a major cause of chronic rejection has also been driven by the development of novel techniques that allowed better identification and quantification of anti-HLA DAS, histologic assessment of injury through C4d staining, electron microscopy and gene profiling of kidney biopsies.
The mechanism of chronic injury frequently involves primarily an antibody-mediated injury to the endothelium of multiple vascular beds including glomeruli, peritubular capillaries and small-medium sized vessels. This endothelium injury leads to cellular hypertrophy, expansion and duplication of the basement membrane and some podocyte injury, with the pathologic appearance of transplant glomerulopathy on kidney biopsy.
GLOMERULAR DISEASE RECURRENCE
No clear risk factors were identified that predicted recurrence risk and other trials failed to demonstrate a direct association of type of immunosuppression. The importance of recurrence of native kidney disease in the allograft has changed with recent longitudinal protocol biopsy studies demonstrating their significant impact on graft injury.
While some forms of primary kidney disease are associated with high-risk of recurrence and graft loss early after transplant, others may be associated with a delayed presentation and slowly progressive course: (A) – focal segmental glomerulosclerosis (FSGS); (B) – Atypical hemolytic-uremic syndrome; (C) – IgA nephropathy.
Many patients do not have a established etiology of their primary kidney disease (e.g. presumed hypertension) and recurrence of disease could be a significant unexpected complication.
Infections (viral/bacterial)
Both viral and bacterial infections may lead to kidney allograft injury. BK nephropathy has become a major cause of both acute and chronic allograft dysfunction. Donor and recipient BK serologies do not predict the risk of infection and the intensity of immunosuppression seems to be the predominant risk fator. The greatest challenge in regards to BK is that 30%– 65% of patients that develop BK-associated nephropathy lose their kidney allograft within 1 year of diagnosis. Therefore, surveillance of BK with serum PCR has become routine in most transplant centers since early detection of a rise in BK viral load may drive reduction of immunosuppression. This is particularly important since BK infection does not have any systemic symptoms, which significantly delays the diagnosis.
CMV infection is one of the most common opportunistic infections after kidney transplantation and may lead to a range of clinical presentations, from CMV syndrome (fever, weakness, myalgia) to end-organ disease (colitis, pneumonitis, hepatitis). In addition, CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility for infection and rejection. Indeed, kidney recipients that developed CMV post-transplant have significantly worse graft and patient survival.
Non-immunological causes
CNI nephrotoxicity
CNI is known to have significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy. the Symphony study that compared tacrolimus-based regimens (high-dose vs. low dose) with either cyclosporine or CNI-free, sirolimus-based therapy. Their results revealed that low to moderate-dose tacrolimus (target 3–7 ng/mL, median 7 ng/mL achieved, range 4.3–10.0 ng/mL) in combination with mycophenolate and steroids was associated with the best outcomes including lower rejection rate, lower fibrosis and improved renal function at one year of follow-up. Despiste this, one of the major limitations of the hypothesis of CNI nephrotoxicity is that the CNI-related histologic lesions in the kidney are relatively nonspecific.
Poor quality donor grafts
The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities (e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults.
Renal artery stenosis and urinary tract obstruction
Renal artery stenosis may lead to graft ischemia and injury. This condition occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation. Underlying etiology includes stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant artery. Gold-standard imaging for diagnosis is arteriography though a Doppler ultrasound is frequently used as a screening method in suspected cases
DIAGNOSTIC STRATEGIES
The management of patients with chronic allograft injury depends primarily in the underlying cause of injury. Therefore obtaining a careful history in regards to the primary renal disease, the early posttransplant course (e.g. severe delayed graft function might indicate significant irreversible early allograft damage), episodes of acute rejection (if any), degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important. The likelihood of different causes of graft injury is strongly influenced by the timing after transplantation.
Some tests can be used as screening to differentiate the etiologies: Urinalysis, kidney ultrasound and kidney biopse.
Noninvasive biomarkers
Noninvasive biomarkers have the potential to earlier identify ongoing graft injury as well as predict response to treatment, helping the clinician to individualize immunosuppression and provide earlier intervention prior to clinically evident dysfunction. For examples, levels of : CXCL9, CD3E, CXCL10 and 18S ribosomal RNA. Although, none of the above biomarkers are currently in clinical use outside of the research setting.
Protocol biopsies
The justification to perform those protocol biopsies includes the detection of specific, often unsuspected, graft injury with consequent change in management.
PREVENTIVE STRATEGIES
Alternatives to CNI
The research for alternatives to CNI to minimize nephrotoxicity has led to the development of the costimulatory blockade agent belatacept. Your regimen suggest a significant better graft function and survival in patients on belatacept when compared to cyclosporine, which may result in significant changes in practice . Belatacept is contraindicated in patients with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder and is associated high rate of acute cellular rejection in the first year after transplantation has limited the wide use of this agente.
Other CNI-sparing agents such as mTOR inhibitors have not shown a benefit in improving long-term graft survival with specific concerning side.
Better controlling blood pressure post-transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant. Furthermore, each 20-mmHg increase in systolic blood pressure in kidney transplant recipients is associated with a 32% increased risk of cardiovascular disease and 13% increased risk of death.
Techniques to better preserve the donor kidney after retrieval have been explored. In particular, the use of a machine perfusion has demonstrated a greater benefit in 3-year graft survival in particular in expanded-criteria donor kidneys when compared to cold static storage.
Preventing non-compliance
Risk factors and clues for noncomplicance include poor social support, missed appointments, fluctuating drug levels, differences between drug prescribed and dispensed, unexpected late rejection, psychiatric disorder, substance abuse, adolescence, increased time since transplant and financial crisis.
TREATMENT STRATEGIES
Management of chronic rejection
The most significant risk factor for chronic ABMR is acute ABMR, so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients. Potential alternatives to rituximab to reduce antibody production include bortezomib. In severe cases of ABMR, eculizumab that inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy.
While various approaches have been used to treat acute ABMR, few have been tested in chronic ABMR . The allografts treated with IVIG and rituximab or rituximab alone or Thymoglobulin® to steroids/IVIG did not improve graft survival significantly.
Management of recurrent primary glomerulonephritis
FSGS probably has podocyte dysregulation and circulating humoral involved, so therapeutic strategies may include high dose steroids and cyclosporine aiming podocyte stabilization, in combination with plasma exchanges to remove circulating humoral factors.
Recurrent IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor blockers.
Recurrent membranous nephropathy may be managed with rituximab, and some patients respond to therapy up to one year after treatment
CONCLUSION
Chronic allograft injury can significantly affect long-term graft survival. Therefore, prevention of injury should be a major focus of caring of transplant recipients. Based on the heterogeneity of causes of injury, strategies may include CNI minimization, better preservation of the allograft after retrieval, use of protocol biopsies, active noncompliance screening, measurement of DSA post-transplant and other potential novel biomarkers of graft injury, BK surveillance and aggressive treatment of hypertension, hyperglycemia and hyperlipidemia.
Ibrahim Omar
2 years ago
Summarize this article :
despite renal transplantation is the best available treatment for ESRD patients, the long-term graft survival is somewhat limited as the great majority of renal grafts are being lost within 10 years after transplantation.
this limited long-term graft survival is predominantly caused by chronic allograft injury (CAI).
CAI is caused by many variable causes, including many immunological and also non-immunological causes.
immunological causes includes mainly the variable types of rejection ( as antibody mediated, cellular mediated, mixed, acute, chronic, subacute ) recurrent glomerular diseases, de novo glomerular diseases,…. etc.
non-immunlogical causes include the variable types of infections ( as reactivation of latent infections, superinfection, great susceptibility to community and hospital acquired infections ) drug nephrotoxicities (as CNI), worsening and new development of traditional vascular risk factors ( DM, HTN, dyslipidemia, hyperuricemia….) as well as the variable surgical causes of early and late graft dysfunction.
the accurate diagnosis of the major causes of graft dysfunction is of a high importance and remains a hopeful challenge that a timely specific therapeutic intervention can improve the long-term graft survival.
the current strategies for managing CAI and so improving the long-term graft survival, include the following :
1- Better preservation of allografts after retrieval.
2- CNI minimization.
3- DSA monitoring.
4- Other potential novel biomarkers of CAI.
5- Protocol biopsies.
6- BK surveillance.
7- Aggressive ttt of traditional vascular risk factors.
8- Active non-compliance screening.
Theepa Mariamutu
2 years ago
Chronic allograft injury: Mechanisms and potential treatment targets 
KTX has good short-term outcomes, but the long-term outcomes are still haven’t achieve a good outcome. 10-year graft loss of more than half, resulting from both immunological and non-immunological causes. Interstitial fibrosis and tubular atrophy on biopsy may be due to rejection (both cellular and antibody mediated), BK virus nephropathy, recurrent pyelonephritis, non-standard donor kidney, ureteral stenosis and CNI nephrotoxicity.
Immunological causes:
Chronic injury can occur by antibodies acting on foreign antigens in the donor kidney (DSA), leading to chronic rejection leads to presenting with proteinuria or impaired sr creatinine.
Late acute rejection – increase the risk of chronic graft dysfunction
Risk of graft failure is high in patients with increased DSA levels and/or C4d positivity on kidney biopsy.
Recurrence of glomerular disease
FSGS has recurrence of 20-80% with 50-80% graft loss.
IgA nephropathy has 20-40% recurrence rates with 5-15% graft loss.
Infections
BK virus (>10,000) -30-65% patients having BK virus nephropathy losing graft within 1 year of diagnosis
CMV infection, due to immunomodulatory mechanism, leads to increased rejection with poorer graft survival.
UTI – trigger a rejection process by activating innate immune system
Non-immunological causes:
Calcineurin inhibitor (CNI) nephrotoxicity
if high levels are maintained for longer duration although the changes seen in biopsy are non-specific and it has been seen that CNI elimination has worse graft outcomes.
Poor quality of donor graft – extended criteria donors, increased cold ischemia time and significant donor/recipient size mismatch (>2.3g/kg)
Renal artery stenosis leading to graft injury
ureteral obstruction due to ureteral stenosis or ischemia may responsible for chronic graft injury.
Diagnostic strategies
Thorough history
-primary disease
comorbidities – diabetes and hypertension, previous rejection episodes
underimmunosuppression due to non-adherence or physician advised
CNI drug levels.
Investigations
urine examination
ultrasound graft kidney
kidney biopsy
Non-invasive biomarkers
anti-HLA DSA with IgG isotyping (IgG3 showing worse outcomes)
DSA c1q fixation properties
protein and mRNA levels of CXCL9
urinary CD3E
CXCL10
18S ribosomal RNA
NK cell immunophenotyping with increased NKG2A+
Protocol biopsies – subclinical AMR have worse outcomes than those without rejection or with subclinical cellular rejection.
Preventive strategies
Drug adherence
CNI alternatives:
Belatacept, a co-stimulatory blockade agent which is associated with increased acute cellular rejection in first year, but better long-term graft and patient survival.
mTOR inhibitors have not shown benefit in long-term outcomes.
Blood pressure control – has role in preventing chronic graft.
Treatment strategies
Subclinical rejection should be treated in presence of de novo DSA
Patients with chronicity score >8, DSA MFI >2500, serum creatinine >3mg/dl and urinary protein creatinine ratio >1g/g -higher risk of graft loss – should be managed with augmentation of immunosuppression -steroids and IVIG
In the absence of the poor prognostic markers- should be additionally treated with ATG (if cellular component is present), plasmapheresis, rituximab, bortezomib and eculizumab if refractory to initial treatment.
Recurrence of the primary glomerular disease must be treated.
FSGS recurrence can be managed with high dose steroids, IVIG and plasma exchange.
IgA nephropathy recurrence may need ACE inhibitors or ARBs with oral steroids.
Recurrent membranous nephropathy may need rituximab for treatment.
Last edited 2 years ago by Theepa Mariamutu
amiri elaf
2 years ago
## Summarize this article
* There are many causes of chronic allograft loss , including both immunological and non-immunological factors .
*El-Zoghby et al. evaluated 1317 kidney transplant recipients with protocol biopsies at time 0, 4 months, 1, 2 and 5 years post-transplant, with a mean follow up of 50 months, they conducted that:
*Most common cause of graft loss was death with a functioning graft .
*Patient with 5 years graft survival protocol biopsies showed glomerular disease in the form of recurrent glomerular disease and transplant glomerulopathy (37%).
*(IFTA; 30.7%) and acute rejection (12% of cases
# Immunological causes
*Allo MHC molecules leads to chronic immunologically mediated injury( cellular, ABMR or a mix rejection).
*Acute rejection is less common after the first year, but the rate of late acute rejection is about 5% per year.
*It result from prolonged cellular and/or antibody mediated immune response directed to the transplanted organ
*The patient presented with rise in creatinine and/or proteinuria.
*The (DSA) as a major cause of graft dysfunction late after transplant.
*The risk factors are, non compliance affecting more than 40% of kidney recipients and more than half of cases with late rejection & graft loss .
*Diagnosis of chronic ABMR by biopsy exclusion.
*DeKAF conducted that the risk of graft failure was higher in patients with DSA, C4d staining or both & the severity of injury correlated with intensity of the antibody
response.
*Both pretransplant and de novo DSA are associated with significant graft loss.
* The mechanism of chronic injury due to antibody mediated injury to the endothelium of multiple vascular beds( glomeruli, peritubular capillaries and small-medium sized vessels ), this injury leads to cellular hypertrophy, Expansion, duplication of the basement membrane, podocyte injury and finally transplant glomerulopathy.
# Glomerular disease recurrence
*Some types of primary kidney disease (FSGS) has early recurrence and graft loss after transplant (50%–80% ) , while others with a delayed presentation and slowly progression, IgA nephropathy has a high recurrence rate ( 40%), but rarely causes early graft loss and exacerbate with reduction of immunosuppression late after transplantation
* Atypical hemolytic-uremic syndrome rate of recurrence (30%–90%).
# Infections (viral/bacterial)
* lead to kidney allograft injury, associated with the increased use of potent immunosuppressive
* BK nephropathy is a major cause of acute and chronic allograft dysfunction.
* 30%– 65% of patients with BK nephropathy lose their kidney allograft within 1 year of diagnosis.
* Early detection BKV load with serum PCR is mandatory with reduction of immunosuppression.
*CMV may cause injury through an immunomodulatory mechanism leading to
higher susceptibility for infection and rejection.
*CMV post-transplant have significantly worse graft and patient survival.
*UTI lead to chronic inj ury either due to direct injury to the allograft in the setting of an infection affecting the kidney or indirectly, through triggering a rejection process by activation of innate immune system.
# Non-immunological causes
CNI have nephrotoxicity (ranging from vasoconstriction, to tubular, vascular injury and TMA.
# Poor quality donor grafts
*The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors, those with comorbidities, genetic susceptibility in kidney donors and mismatch between donor and recipient size all these affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults .
# Renal artery stenosis and urinary tract obstruction
* lead to graft ischemia and injury.
*It occurs in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after
transplantation.
*The etiology includes stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant artery.
*Diagnosis by arteriography though a doppler ultrasound
*Ureteral obstruction due to anastomotic stenosis or ureter ischemia
# Diagnostic strategies
*The management of patients with chronic allograft injury depends in the underlying cause of injury careful history, degree of hypertension/blood sugar , CNI levels and noncompliance is important.
*Urinalysis with sediment visualizationmay
*kidney ultrasound to exclude mechanical complications ( ureteric obstruction and vascular stenosis).
*Kidney biopsy the justification to perform protocol biopsies includes the detection of specific, unsuspected, graft injury with consequent change in management.
# Noninvasive biomarkers
*It identify earlier ongoing graft injury, predict response to treatment, helping
to individualize immunosuppression and provide earlier intervention prior to clinically evident dysfunction.
# Preventive strategies
* Alternatives to CNI
Researches was done for alternatives to CNI to reduce nephrotoxicity :
-Belatacept( co stimulatory blockade agent )
-mTOR inhibitors have not shown a benefit in improving long-term graft survival
-Everolimus with CNI minimization
-Controlling blood pressure post transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant
-ACEI inhibitors/ARBs no randomized trial has yet demonstrated a benefit in renal transplantation
# Preventing non-compliance
Risk factors include( poor social support, missed appointments, fluctuating drug levels, differences between drug prescribed and dispensed, unexpected late rejection, psychiatric disorder, substance abuse, adolescence, increased time since transplant and financial crisis) so screening at every clinic visit is important
# Treatment strategies
Management of chronic rejection
*Prevention by combined therapies including plasmapheresis, rituximab and (IVIG) in sensitized patients alternatives to rituximab is bortezomib.
*Eculizumab In severe cases of ABMR, eculizumab, inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be
considered as an adjuvant therapy.
*Adequate treatment of acute ABMR.
* Management of recurrent primary glomerulonephritis, FSGS with high dose steroids, cyclosporine andplasma exchanges to remove circulating humoral factors. *IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor blockers, but specific protocols for recurrence management are lacking.
for native IgA nephropathy, oral prednisone may be advisable.
*Recurrent membranous nephropathy managed with rituximab.
*The treatment of recurrent (MPGN) according to under lying etiological factors.
Zahid Nabi
2 years ago
Despite the improved short-term outcomes of kidney transplantation, more than 50% of kidney allografts are lost by 10 years after transplant. This paper has explored the mechanisms leading to graft injury and what could be its remedy.
Immunological causes
The persistent presence of allo-MHC molecules in the donor kidney leads to a life-long low-grade exposure to foreign antigens that may lead to chronic immunologically mediated injury.
Both pretransplant and de novo DSA are associated with significant graft loss . The rate of de novo DSA ranges between 15% and 20% at 5 years post-transplant in unsensitized recipients and develop- ment of de novo DSA is associated with significant worse 10-year graft survival (57% compared to 96% in patients without de novo DSA)
Glomerular disease recurrence
Non-immunological causes
CNI nephrotoxicity
Poor quality donor grafts
Renal artery stenosis and urinary tract obstruction
Infections( viral/ bacterial)
BKV
CMV
UTI
All can lead to graft failure
Diagnostic strategies
The management of patients with chronic allograft injury depends primarily in the underlying cause of injury .
Noninvasive biomarkers
Can help to identify injury early
Protocol biopsies
Can be considered once strongly indicated
Preventive strategies
Alternatives to CNI
Preventing non-compliance
Treatment strategies
Management of chronic rejection
Management of recurrent primary glomerulonephritis
Chronic allograft injury can significantly affect long-term graft survival. Therefore, prevention of injury should be a major focus of caring of transplant recipients. Based on the heterogeneity of causes of injury , strategies may include
CNI minimization,
better preservation of the allograft after retrieval, use of protocol biopsies,
active noncompliance screening,
measurement of DSA post-transplant and other potential novel biomarkers of graft injury,
BK surveillance
aggressive treatment of hypertension, hyperglycemia and hyperlipidemia.
Filipe prohaska Batista
2 years ago
This paper describes potential mechanisms and treatments for chronic graft injury, after all, 50% of transplants do not exceed ten years for various reasons, including immunological or non-immunological factors.
Immunologic causes tend to be cellular, antibody or mixed mediated. The presence of increased creatinine or proteinuria suggests rejection. DSA and/or C4d deposits are also risk factors. The increase in DSA promotes glomerulitis, capillaritis, and other endothelial lesions.
Recurrent glomerular disease, viral (mainly BK and CMV), bacterial, fungal infections are non-immunological causes that can lead to graft loss. Calcineurin inhibitor-induced nephrotoxicity, graft quality, clinical conditions, ischemia time, and veno-occlusive obstruction are other forms of chronic graft injury.
Diagnostic strategies are highly variable and depend heavily on the availability and standardization of each service. Histopathological tends to follow the pattern established by the BAANF.
The main risk factors are poor social support, frequent absences, fluctuating drug levels, psychiatric illness, adolescence, illicit drug use, and long transplant times. Chronicity, DSA MFI > 2500, and elevated proteinuria are laboratory markers that complement the clinical findings.
Ahmed Abd El Razek
2 years ago
Introduction
The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors. Death with a functioning graft was the most common cause of graft loss. For those patients that survived up to 5 years after transplant, the predominant findings on protocol biopsies were glomerular disease (37%), tubular atrophy/tubular atrophy (IFTA; 30.7%) and acute rejection (12% of cases).
Cellular and/or antibody-mediated rejection (ABMR) was the leading culprit of IFTA followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity.
Immunological causes
The most common type of rejection after the first year of transplant is chronic rejection, defined as a prolonged cellular and/or antibody mediated immune response against the graft that may present with either a rise in creatinine and/or proteinuria.
The role of donor-specific antibodies (DSA) as a major cause of graft dysfunction late after transplant in being increasingly determined.
Noncompliance may be a major culprit, affecting up to 40% of kidney recipients and associated with more than half of cases of late rejection leading to graft loss.
Diagnosis of chronic ABMR requires a kidney biopsy to exclude other potential causes.
Risk of subsequent graft failure was significantly higher in patients with DSA, C4d staining or both, and the severity of clinical injury directly correlated with the intensity of the antibody response.
Both pretransplant and de novo DSA are associated with significant graft loss. The rate of de novo DSA ranges between 15% and 20% at 5 years post-transplant in unsensitized recipients and development of de novo DSA is associated with significant worse 10-year graft survival (57% compared to 96% in patients without de novo DSA).
Transplant glomerulopathy is one of the predominant findings on chronic ABMR,but it is not specific to rejection as other causes of chronic endothelial injury may lead to similar pattern of injury including thrombotic microangiopathy, recurrent autoimmune glomerulonephritis and hepatitis C-related glomerulonephritis.
Glomerular disease recurrence
Recurrence was the third leading cause of graft loss.
Focal segmental glomerulosclerosis (FSGS) tends to recur early after transplant with massive proteinuria and is associated with graft loss in 50%–80% of cases. Atypical hemolytic-uremic syndrome has also a high rate of recurrence (30%–90%).IgA nephropathy has a high recurrence rate (up to 40%) but rarely causes early graft loss and commonly may exacerbate with reduction of immunosuppression late after transplantation.
Early recognition and intervention of recurrence may potentially improve long-term graft survival.
Infections (viral/bacterial)
With the increased use of more potent immunosuppressive drugs in the past 15 years, BK nephropathy has become a major cause of both acute and chronic allograft dysfunction. Donor and recipient BK serologies do not predict the risk of infection and the intensity of immunosuppression seems to be the predominant risk factor. The challenge in regards to BK is that 30%–65% of patients that develop BK-associated nephropathy lose their kidney allograft within 1 year of diagnosis, so surveillance of BK with serum PCR has become routine in most transplant centers since early detection of a rise in BK viral load may drive reduction of immunosuppression.
Patients with greater than 10,000 copies of BK and allograft dysfunction are likely to have BK nephropathy, biopsy is important to confirm the diagnosis with SV40 staining for the BK virus.
CMV infection is one of the most common opportunistic infections after kidney transplantation. CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility for infection and rejection. Direct involvement of CMV infection on the kidney is demonstrated by necrotizing crescentic glomerulonephritis with viral inclusions.
General infections such as urinary tract infections may also lead to chronic injury either due to direct injury to the allograft or indirectly, through triggering a rejection process due to the activation of innate immune system with increased expression of costimulatory molecules and lowering of the threshold for T cell activation and proliferation.
Non-immunological causes
CNI nephrotoxicity
It has significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy. Long-term allograft fibrosis was related to chronic CNI toxicity that led to IFTA, glomerulosclerosis and arteriolar hyalinosis.
Poor quality donor grafts
The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities(e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults.
Subsequent graft insults may come on the form of ischemic injury such as during prolonged cold ischemic time after kidney retrieval, poor blood pressure or blood sugar control post-transplant, infections and/or superimposed alloimmune injury.
Renal artery stenosis and urinary tract obstruction
It occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation.
Gold-standard imaging for diagnosis is arteriography though a Doppler ultrasound is frequently used as a screening method.
Ureteral obstruction due to anastomotic stenosis or ureter ischemia may lead to significant hydronephrosis and graft injury.
Diagnostic strategies
Urinalysis with sediment visualization may help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy.
Ultrasound may exclude mechanical complications such as ureteric obstruction and vascular stenosis.
Biopsy should be performed in the majority of patients with dysfunction and no clear reversible factor present or if other worrisome features such as significant proteinuria or cellular casts are present.
Noninvasive biomarkers: protein and mRNA levels of CXCL9 was shown to be a great predictor of rejection. A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection. NK cell immunophenotyping
The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA for the prediction of antibody-mediated rejection. The distinction among the different DSA IgG isotypes seems to be relevant, with IgG3 showing worse outcomes.
Protocol biopsies
Treatment strategies
Preventative measures (controlling blood pressure, Techniques to better preserve the donor kidney after retrieval, preventing non-compliance to medications).
Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients.
Management of recurrent primary glomerulonephritis.
Conclusion
Chronic allograft injury can significantly affect long-term graft survival.
Strategies may include CNI minimization, better preservation of the allograft after retrieval, use of protocol biopsies, active noncompliance screening, measurement of DSA post-transplant and other potential novel biomarkers of graft injury, BK surveillance and aggressive treatment of hypertension, hyperglycemia and hyperlipidemia.
saja Mohammed
2 years ago
Summarize this article Abstract:
Despite improvement of the short term graft survival after kidney transplant still long term graft survival hampered by many immunological and non-immunological factors that lead to progressive allograft injury and loss , this review study focus on identification of the pathogenesis of the different factors and treatment options.
According to the evidence from reviewing the protocol biopsies over different follow up time from day 0,1month, 4month 1,2 years and up to 5 years mean fu 50 months mainly from registry studies and the finding as follows.
Death with functioning graft is the most common cause of graft loss
5 years post-transplant protocol biopsies findings:
Acute rejection in 12% only while late acute rejection after 1 year reported in 5%.
After 1 year most common type of rejection is chronic ABMR which typically characterized by graft dysfunction and proteinuria and positive DSAs
Recurrence or denovo glomerulonephritis in 37%
IFTA found in 30.7%, which is nonspecific sign of chronic graft injury is just replaced the previous term of chronic allograft nephropathy as per the Banff classification since 2005 and IFTA could be part of chronic TCMR and CAMR, or chronic CNI toxicity, BKV Nephropathy, pyelonephritis, ureteral obstruction and part of ECD with poor quality of the donor kidney.
The DeKAF study reported the histological finding after 7 years FU for chronic graft injury includes Rejection CABMR ,which significantly correlated with C4D staining , clinical proteinuria, and the level of DSA and main risk factor for chronic rejection is the nonadherence to immunotherapy which was reported in 40% of cases either intentional immunosuppressive reduction in case of serious infection or malignancy or due other personal strain like mental stress ,cost, its more in young recipients . Immunological factors:
Poor HLA match,Prior sensitization, new alloantibodies, non-compliance ,rejection episode both performed and denovo DSA associated with chronic rejections, denovo DSA associated with poor 10 years graft survival. Transplant glomerulopathy nonspecific to chronic graft rejection and can be seen in chronic TMA, chronic HCV glomerulopathy or autoimmune glomerulopathy which characterized by chronic endothelial injury . Non immunological factors : Infections like BKV, CMV, pyelonephritis, sepsis Recipients related factors associated with chronic allograft injury includes
Cni toxicity, Ischemic heart disease, Hypertension, renal artery stenosis, Diabetes Dyslipidemia Drug induced interstitial nephritis Glomerular or denovo recurrence of glomerular diseases is the 3rd leading cause of chronic graft injury as per Australian registry data some of glomerular disease relapse early post-transplant like FSGS, ahus, IgA nephropathy and some they have lower rate and slower progression like MGN early recognition and intervention is the key to prevent graft loss. Many donors related risk factors of chronic allograft injury:
ECD from old patients with comorbid disease, DCD, small nephron mass, long cold ischemia, DGF, IRP, and size mismatch.
Management of chronic graft injury :
No specific protocol or guideline for management of chronic allo graft injury and the best strategy is to focus on prevention by identification of the risk factors and work on minimization or avoidance improved compliance with medication and diagnostic tools like using DSA monitoring, protocol biopsies and adopt new novel molecular biomarkers that would help in early diagnosis , better selection of the donors and avoid repeat mismatches, treatment of non-immunological medical conditions like control of DM , heart disease ,HTN , proteinuria ,dyslipidemia, infections , drug toxicity .
Manal Malik
2 years ago
Chronic allograft injury: Mechanisms and potential treatment targetsintroduction
after 10 years of transplant >50% of kidney allograft have been lost.
immunological factors is leading cause of graft loss.
causes of IFTA:
1)cellular and or antibody -mediated rejection.
2)BK virus.
3) recurrent pyelonephritis.
4)poor quality donor kidney.
5)ureteral stenosis.
6)CNI nephrotoxicity.
Banff 2005 classification system renamed CAN to IFTA.
this article will highlight details the pathogenesis and treatment strategies of chronic allograft injury. immunological causes
chronic immunological induced injury is result from lifelong low grate exposure to foreign antigens.
it is unclear if subclinical inflammation is related to cellular -mediated rejection or other process.
chronic rejection is common after one year of transplant and mainly result from DSA.
chronic ABMR diagnosis by kidney biopsy.
10 year graft survival has worse outcome in the patient has develop of de novo DSA.
late allograft failure result from alloimmune response which is mainly caused by DSA. glommular disease recurrence:
at 10 years after transplant recurrence disease was the third leading cause of graft loss
FSGS recurrence and associated with graft loss in 50 to 80 % of cases..
Atypical HUS 30 to 90% rate of recurrence
overall recurrence disease posttransplant is heterogenous process with variable consequence.
early recognize and intervention may improve long term graft survival. Infection(viral /bacterial)
allograft injury maybe caused by bacterial or viral infection.
BK virus major cause of graft and chronic allograft dysfunction.
risk factor for BK virus is the intensity of immunosuppression.
30 to 65% of patients develop BK -associated nephropathy loose their kidney allograft within 1 years of diagnosis.
surveillance of BK PCR to detect early the risk of BK viral load may drive reduction of immunosuppression.
BK virus >10000 copies of BK virus and allograft dysfunction are likely to have BK nephropathy.
so renal biopsy is important to confirm diagnosis with SV40 stanning for the BK virus.
CMV infection is one of the most common opportunistic infection after kidney transplant.
recipient whom develop CMV posttransplant have worse graft and patient survival. NON Immunological CNI nephrotoxicity
mechanism of CNI nephropathy
1)vasoconstriction
2)acute tubular injury.
3)vascular injury.
4)TMA is rare.
CNI regimen still the best over others and this supported by:
1)combination of CNI with other standard immunosuppression regimen is out come after 3 years follow up is lower rate of rejection ,lower fibrosis and improved renal function..
2)premature randomized trial CNI withdrawal there is high rate of development of dnDSA. Poor quality donor graft
factors associated with worse graft outcome:
1)deceased donor from cardiac death
2)elderly donors.
3)comorbidities DM, HTN.
4)Genetic susceptibility in kidney donor (two high risk alleles for APOL1).:
5)significant mismatching between donor and recipient size (kidney weight /recipient weight <2.3g/kg) .
6)prolong cold ischemia
Renal artery stenosis and urinary tract obstruction.
RAS result in graft ischemia and injury
present by :
1)persistent uncontrolled HTN.
2)Flash pulmonary oedema.
3)acute elevation of Bp with few years after transplant.
ureteric obstruction
due to:
1)anastomotic stenosis.
2)ureteric ischemia.
lead to hydronephrosis and graft injury.
diagnostic strategies:
management of chronic allograft injury depend on primary underlying cause of injury . Non invasive biomarker
non-invasive biomarker is detected ongoing graft injury and response to treatment
make timely decision to clinician to avoid clinical evident of graft dysfunction e.g protein and mRNA level of CXCL9 is predictor of rejection detected 30 days before biopsy proven rejection.
anti HLA DSA is best non-invasive biomarker clinically available. although not all patients with DSA carry worse prognosis .
DSA IgG3 showing worse outcome. Protocol biopsies
protocol biopsy used to detected specific ,unsuspected graft injury with consequent change in management.
subclinical rejection need to specific the cause of subclinical inflammation to select appropriate effective therapy . Preventive strategies alternative to CNI
Research for alternative to CNI to minimize nephrotoxicity has led to development of costimulatory blocker agent(beltacept).
beltacept first given every 2 week then monthly as an infusion in place of CNI
despite approval of FDA but its use is limited as associated with high rate of acute cellular rejection in the first year of transplant.
Bp controlled posttransplant is associated with an improvement in graft survival in 1 and 3 years posttransplant
preventing non compliance:
detect the risk of non compliance is crucial such as :
1)poor social support
2)psychiatric illness
3)substance abuse and others. management of chronic rejection
most common cause of chronic ABMR is acute ABMR.
prevention is use plasmapheresis ,rituximab or bortezomib and IVIG in sensitized patient
eculizumab in sever ABMR can be adjuvant therapy
FDA has no approval therapy for chronic ABMR.
clinical trials are needed to address the safety and efficacy of B cell and DSA depleting strategies in chronic rejection
poor prognostic marker of CABMR:
1)serum creatinine >3mg/dl
2)protein /creatinine ratio>1g/day
3)Banff>8
4)DSA>2500MFI
increase immunosuppression and consider steroid and IVIG.
if no poor prognostic marker in cABMR treatment as follow:
Step1
1)increase immunosuppression baseline
2)steroid /IVIG
3)Thymoglobulin .
Step2
1)Adjuvant therapy with pp/rituximab( low grate evidence)
2)protease inhibitor or eculizumab(very low grate evidence)
prepare patient for next transplant:
1)do not stop all immunosuppression after graft fail
2)avoid repeat HLA mismatch if possible management of recurrent Primary GN
recurrent FSGS treatment with steroid ,cyclosporin and PLEX has better result comparing group without plasma exchange.
recurrent IgA treated with ACE but no specific treatment for recurrent I
recurrent MN treated with Rituximab.
MPGN treatment:
secondary MPGN treat the cause
primary MPGN no consensuses exists
some of type 1MPGN recurrent
cases successfully treated with rituximab.
recurrent c3 glomerulopathy and dense deposit disease treated by eculizumab with variable response Conclusion
chronic allograft injury affect long term graft survival
strategies to prevent Chronic allograft injury:
1)CNI minimization
2)prevention of the allograft after retvieral
3)use of protocol biopsy.
4)active non compliance screening.
5)measurement of DSA posttransplant
6)protentional novel biomarker of graft injury
7)BK virus surveillance and aggressive treatment of HTN ,DM and hyperlipemia.
.
Kidney transplantation is the best treatment for end stage renal disease. Short term outcomes of graft and patient survival, are successfully achieved. However, long-term outcomes are suboptimal.
The graft survival on the long term is affected by several factors including immunological and immunological causes.
Interstitial fibrosis and tubular atrophy in chronic allograft nephropathy are the cornerstone of diagnosis. This could be due to:
– Rejection (both cellular and antibody mediated)
– Viral infection namely BK virus nephropathy
– Recurrent pyelonephritis
– EDK criteria
– Ureteral stenosis
– CNI nephrotoxicity
Immunological vs non-immunological
Immunological causes: activation of immune response due to the presence of foreign antigen resulting in the formation of de novo DSA, which manifest clinically in proteinuria and slowly progressive renal failure.
Risk of graft failure:
– High DSA level
– C4d positivity on kidney biopsy
Another major immunological cause is recurrence of glomerular disease which requires early diagnosis and management.
– FSGS has recurrence of 20-80% with 50-80% graft loss.
– IgA nephropathy has 20-40% recurrence rates with 5-15% graft loss.
– Infections like BK virus causes chronic graft injury in 30-65% patients.
– CMV infection, due to immunomodulatory mechanism, leads to increased rejection with poorer graft survival.
– Urinary tract infections can also trigger a rejection process by activating innate immune system.
Non-immunological causes:
– CNI nephrotoxicity when exposure to high levels for prolonged periods.
– Poor quality of donor graft due to extended criteria donor
– Increased cold ischemia time
– Donor/recipient size mismatch
– Renal artery stenosis
– Ureteral obstruction
Early diagnosis of chronic allograft injury is required as early interventions may be helpful. Diagnostic strategies for chronic graft injury include:
– Comorbidities as diabetes, hypertension and ASCVD
– Adequate history about the primary disease
– Previous rejection episodes including biopsy results
– Non-adherence
– CNI levels.
Required investigations
– Urinalysis
– Renal imaging with graft ultrasound
– Kidney biopsy
Preventive strategies
– Maintaining therapeutic CNI levels
– Blood pressure control
– Early identification of rejection episodes (including subclinical rejections in protocol biopsies for previously sensitized patients)
– Early identification and treatment of infectious complications
Chronic Allograft Nephropathy was defined as dysfunctional kidney grafts without clear cause, which was later replaced by IFTA in the revised Banff 2005 classification. There are multiple causative factors of chronic graft loss and one of the study showed the commonest cause of graft loss is the death with a functioning graft and almost 50% of allografts failed within 10years post transplant. Immunological Causes of IFTA
Lifelong low grade exposure to foreign antigens resulting in antibody-mediated, cellular or mixed rejection.
Late onset acute Rejection
Infections Non Immunological causes
CNI toxicity
Poor donor selection
Renal artery stenosis
TMA
Post renal urinary obstruction Diagnosis ; Careful detailed history including the primary disease, comorbidities like diabetes and hypertension, previous rejection episodes, under immunosuppression due to non-adherence or asking about the CNI drug levels should be taken. Investigations like urinalysis to check for cast and proteinuria , Doppler ultrasound of the grafted kidney as well as allograft biopsy including the protocol biopsies should be part of the center protocol. Non-invasive biomarkers like anti-HLA DSA with IgG isotyping (IgG3 showing worse outcomes), mRNA levels of CXCL9, urinary mRNA signatures of CD3E,CXCL10, 18S ribosomal RNA and NK cell immuno-phenotyping e.g NKG2A(45,46, 47)have shown increased correlation with chronic graft injury. Treatment of chronic ABMR
Treatment of chronic active ABMR is difficult since it is associated with irreversible tissue damage and no proper FDA approved treatment mentioned in the literature for chronic active ABMR, Current treatment is directed against the following: Main therapy
High dose Methylprednisolone -Decreasing inflammation produced by rejection
IVIG -Decreasing production of antibodies
Intensify baseline immunosuppression
ATG if associated with cellular rejection Second line agents in case of refractory chronic ABMR (poor evidence)
Rituximab- Depleting B cells only if there is biopsy evidence of active microvascular inflammation and given 1 week after completion of IVIG
Plasmapharesis- Removing DSA play no rule in chronic active ABMR Third-line agents (very poor evidence)
Bortezomib and eculizumab showed no benefit in treatment of chronic active ABMR
In case of graft failure, it is recommended not to stop immunosuppression in order to prepare the patient to the next transplant to avoid rebound of DSA
III. Chronic allograft injury: Mechanisms and potential treatment targetsï‚· Summarize this article Chronic allograft injury can result from both immunological & non-immunological factors. 1. Immunological causes: Chronic immunologically mediated injury results from life-long exposure to foreign allo-HLA molecules in the donor kidney. This injury could be cellular, antibody-mediated or a mix rejection. The rate of late acute rejection is about 5%/year. It is the most common type of rejection after the 1st year of transplant; it presents with either a rise in creatinine &/or proteinuria. The role of DSA as a major cause of graft dysfunction late after transplant is being increasingly recognized. Risk factors include noncompliance, affecting up to 40% of recipients & associated with more than half of cases of late rejection leading to graft loss. Diagnosis of CABMR requires a biopsy to exclude other potential causes. In DeKAF, the risk of graft failure was significantly higher in patients with DSA, C4d or both, & the severity of clinical injury directly correlated with the intensity of the antibody response. Both preformed & dnDSA are associated with significant graft loss. The mechanism of injury involves an antibody-mediated injury to the endothelium of glomeruli, PTCs & small-medium sized vessels. The endothelial injury leads to cellular hypertrophy, expansion & duplication of the BM & some podocyte injury, with the pathologic appearance of TG on biopsy. TG is, however, not specific; it can be seen in TMA, recurrent autoimmune GN & HCV-related GN. —————————————————————– 2. Glomerular disease recurrence: At 10 years after transplant, recurrence was the 3rd leading cause of graft loss (Australia/New Zealand registry). No clear risk factors were identified that predicted recurrence risk. FSGS recurs early after transplant with massive proteinuria & is associated with graft loss in 50%–80% of cases. Atypical HUS has also a high recurrence rate (30%–90%) depending on the underlying complement abnormality. IgA nephropathy has a high recurrence rate (up to 40%) but rarely causes early graft loss & commonly may exacerbate with reduction of IS late after transplantation. Early recognition & intervention potentially improve long-term graft survival. ———————————————————— 3. Infections (viral/bacterial) BK nephropathy: A major cause of both acute & chronic graft dysfunction. The intensity of IS is the main risk factor. Viruria is followed by viremia & then nephropathy. A 30%–65% of patients lose their graft within 1 year of BK nephropathy. Surveillance with serum PCR is important(early detection mandate reduction of IS). Biopsy is needed to confirm the diagnosis & to exclude any other etiology of graft dysfunction. CMV infection: A common post-transplant infection. Presentations include: – CMV syndrome (fever, weakness, myalgia) – Colitis – Pneumonitis – Hepatitis – Higher susceptibility for infection & rejection through immunomodulatory mechanisms. Recipients who developed CMV post-transplant have significantly worse graft & patient survival. General infections such as UTIs may lead to chronic injury either due to direct injury to the allograft or indirectly, through triggering a rejection process due to the immunological activation. ================================ 4. Non-immunological causes CNI nephrotoxicity Ranges from vasoconstriction to tubular & vascular injury, & rarely TMA. Multiple trials tested the hypothesis that CNI minimization or avoidance could reduce graft injury & improve long-term graft survival. However, studies failed to confirm this benefit on long term follow up. CNI cause significant nephrotoxicity,particularly with high maintenance levels. Current protocols of lower CNI exposure do not seem to be the primary cause of many of the graft deteriorations that occur & avoidance of CNI without any substitute agent will lead to poor outcomes. Poor quality donor grafts – DCD, elderly donors or those with comorbidities(e.g. DM & hypertension) affect graft survival due to presence of preexisting injury & lower nephron mass. – Presence of genetic susceptibility in kidney donors (e.g. 2 high-risk alleles for APOL1) is associated with worse graft survival. – Significant mm between donor & recipient size is associated with a higher rate of hypertension, proteinuria & lower graft survival. Renal artery stenosis RAS may lead to graft ischemia & injury. It occurs in up to 5% of kidney recipients & is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in BP within the 1st few years after transplantation. It is caused by stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant artery. Diagnosis by arteriography; Doppler ultrasound is an screening test. Urinary tract obstruction Is due to anastomotic stenosis or ureter ischemia & may cause significant hydronephrosis & graft injury. Ultrasound would identify an obstruction & fluoroscopy would identify the exact obstructed site. Diagnostic strategies H/O the primary renal disease, the early post-transplantcourse & events e.g. severe DGF, episodes of acute rejection, degree of hypertension/blood sugar control, CNI levels over time & noncompliance is important. Urinalysis: cellular casts, granular casts or significant proteinuria may indicate an active GN, ATN or TG, respectively. Ultrasound may exclude ureteric obstruction & vascular stenosis. A kidney biopsy should be performed in the majority of patients with dysfunction and no clear reversible factor present; it is also indicated if there is significant proteinuria or cellular casts. Noninvasive biomarkers Mostly restricted to research setting. Measurement of anti-HLA DSA for the prediction of AMR is the best noninvasive biomarker clinically available. Testing for DSA C1q fixation properties are of limited value in predicting future chronic injury. Differential DSA IgG isotypes is helpful, with IgG3 showing worse outcomes. Protocol biopsies May detect specific, often unsuspected, graft injury with consequent change in management. 25% of biopsies may lead to change in management (Henderson et al). Preventive strategies Alternatives to CNI 1. Belatacept (co-stimulatory blockade): It is a CTLA4Ig fusion protein that blocks the CD80/CD86 interaction with CD28 preventing T cell activation. Contraindicated in EBV-ve status(higher risk of PTLD) High rates of ACR in the 1st post-transplant year has limited its use. Data of 7-year follow-up with belatacept regimen suggest a significant better graft function & survival when compared to cyclosporine; not compared to the most commonly used tacrolimus. 2. mTOR inhibitors: Do not improve long-term graft survival. The potential role of everolimus with CNI minimization is promising. TRANSFORM is an ongoing randomized trial comparing minimized CNI plus everolimus vs. standard CNI plus MMF. 3. ACEI inhibitors/ARBs: No randomized trial has yet shown a benefit in renal transplant. Significant S/E (e.g. anemia, hyperkalemia & GFR reduction) has limited its broad use. Preventing non-compliance – Screening at every clinic visit is important – More frequent monitoring of drug levels & kidney function in high-risk patients. – Address complexity of the drug regimen & financial issues Treatment strategies Management of chronic rejection: Focused on avoiding acute ABMR as it is the most significant risk factor for chronic ABMR. PP, rituximab & IVIG are used in sensitized patients. Bortezomib is a potential alternative to rituximab to reduce antibody production. Eculizumab used as adjunctive in severe cases of ABMR. Treating acute ABMR avoids CABMR, however, >40% of cases do not resolve after standard treatment with rituximab. Only few treatments have been tested in CABMR. In the largest study of CABMR published to date(123 patients with BP-CABMR followed for a median of 9.5 years pos-transplant & 4.3 years after CABMR), the addition of rituximab or ATG to steroids/IVIG did not improve graft survival significantly. Management of recurrent primary GN Recurrent FSGS: High dose steroids & cyclosporine aiming podocyte stabilization, combined with PP to remove circulating humoral factors. Better results seen with this regimen compared to historical control group without PP. Recurrent IgA nephropathy: May be treated with ACE i or ARBs; specific protocols for management are lacking. Oral prednisone may be advisable. Recurrent membranous nephropathy: May be managed with rituximab; some patients respond to therapy up to 1 year after treatment.
Recurrent MPGN: No consensus exists for the idiopathic cases related to immune complexes, & steroids, cyclophosphamide &/or PP have been unsuccessful. Rituximab was successful in some recurrent type I or idiopathic disease. MPGN due to dysregulation of alternative complement pathway, C3 glomerulopathy & DDD have been recently managed with eculizumab, with variable responses.
Thank You, this is massive. Try to make your summary shorter Dr Mohamed
Huda Al-Taee
2 years ago
Summary:
Despite the improvement in short term outcomes of kidney transplantation, many grafts are lost 10 years post-transplantation.
The causes of chronic allograft loss are multifactorial including both immunological and non-immunological causes.
Five years post-transplantation, the predominant feature in graft biopsy are IFTA, glomerular disease, and acute rejection.
Chronic Allograft Nephropathy was used to describe dysfunctional kidney grafts of unclear cause, then it was replaced by the term IFTA by the revised Banff 2005 classification.
Immunological causes:
The presence of allo-MHC molecules in the donor’s kidney leads to chronic immunologically mediated injury ( chronic rejection).
Chronic injury presented usually with either rise in serum creatinine or proteinuria.
The role of DSA and non-compliance are increasingly recognized.
The importance of recurrence of native kidney disease in the allograft has changed by the protocol biopsy studies as they demonstrate their significant impact on graft injury. While some forms of primary kidney disease are associated with a high risk of recurrence and graft loss early after transplant, others may be associated with a delayed presentation and slowly progressive course such as FSGS may recur early after transplantation and is associated with early graft loss while IgA nephropathy has a high recurrence rate (up to 40%) but rarely causes early graft loss.
Both viral and bacterial infections may lead to kidney allograft injury such as BK virus infection, as 30-65% of patients that develop BK nephropathy lose their allograft within 1 year of diagnosis.In addition, CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility to infection and rejection. General infections such as urinary tract infections may also lead to chronic injury either due to direct injury to the allograft or indirectly, through triggering a rejection process.
Non-immunological causes:
CNI toxicity
poor quality grafts
Renal a. stenosis and urinary tract obstruction
Diagnostic strategies:
careful history
GUE
Abdominal US
Graft biopsy
Noninvasive biomarkers:
Noninvasive biomarkers have the potential to earlier identify ongoing graft injury as well as predict response to treatment.
Protein and mRNA levels of CXCL9 were shown to be a great predictor of rejection with an elevation in levels detected 30 days before a biopsy-proven rejection. A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection. All these biomarkers are used only in research settings.
The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA for the prediction of antibody-mediated rejection with C1q binding and IgG3 subclass shown to be associated with worse allograft survival.
Preventive strategies:
Alternatives to CNI: belatacept Despite getting the FDA approval for kidney transplantation as a potential CNI-sparing agent in kidney transplantation in 2011, is associated high rate of acute cellular rejection in the first year after transplantation and this limits its use in addition to the risk of PTLD in EBV negative patients.
Preventing non-compliance: Screening at every clinic visit is critical and more frequent monitoring of drug levels and kidney function may be warranted in high-risk patients.
Treatment strategies:
Management of chronic rejection:
Avoiding Acute ABMR as it is a significant risk factor for chronic ABMR, using combined PP, IVIG and rituximab in sensitized patients, an alternative to rituximab is bortezomib, and in severe cases, eculizumab may be used.
Management of recurrent glomerular disease:
recurrent FSGS: PP+ steroids (high dose)+ cyclosporin
recurrent IgA: ACEi or ARB, oral prednisolone for 1-2 months may be advisable. no specific protocol for treatment.
recurrent MN: rituximab
recurrent MPGN: according to the aetiology
According to Elzoghby et al (n =1317 transplanted patients) , death with a functioning graft was the most common cause of graft loss among transplanted recipients with protocol biopsies at different times up to 5 years post-transplant.
Other main risk factors and causes of chronic allograft injury include:
vAlloimmune :
1- Poor HLA match
2- Prior sensitization
3- New alloantibodies
4- Non compliance
5- Rejection episode:
Chronic rejection in form of prolonged cellular and/or antibody mediated immune response against transplanted organ leading to increased creatinine and/or proteinuria.
vRecurrence of de novo glomerular disease:
1- FSGS: has 20 to 50 % of recurrence and 50 to 80% risk of graft loss.
2- Atypical HUS
3- Dense Deposit Disease
4- C3 glomerulopathy
5- IgA nephropathy
6- Membranous GN
Also systemic diseases like oxalosis, scleroderma, SLE, ANCA vasculitis, diabetic nephropathy …etc
vRecipient related causes:
1- CNI nephrotoxicity
2- Diabetes
3- Hypertension
4- Renal artery stenosis
5- Ureteral obstruction
6- Heart failure
7- Drug induced acute interstitial nephritis
vDonor related:
1- Poor quality donor kidney: kidneys from donors after cardiac death, elderly donors or with comorbidities.
2- Prolonged ischemia
3- Delayed graft function
4- Significant size mismatch
vInfections :
1- BK nephropathy:
It is a major cause of both acute and chronic allograft dysfunction. It found in renal tubule and with the use of strong immunosuppressant it will replicate largely causing viruria, viremia and then nephropathy.
30 to 65% of patients with BK nephropathy lose their kidney allograft within 1 year of diagnosis.
2- CMV infection:
It can lead to end organ disease (pneumonitis, colitis, hepatitis) and may cause injury through immunomodulatory mechanism leading to high risk of infection and rejection.
Direct kidney affection is rare causing necrotizing crescentic glomerulonephritis.
3- Recurrent pyelonephritis
4- Sepsis Diagnostic strategies:
Careful history taking of the primary cause.
Control of diabetes and hypertension
Urine analysis
Kidney ultrasound with Doppler
Kidney biopsy
Investigations for BK and CMV infection
Anti-HLA DSA and its isotype
Protocol biopsies Preventive strategies:
1- Alternatives to CNI: use of Belatacept which blocks the CD80/CD86 interaction with CD28 preventing T cell activation.
2- Preventing non-compliance: with social, psychological and financial support.
Continuous education and warning in each follow up visit. Treatment strategies:
1- Proper management of chronic rejection
2- Management of recurrent primary cause
3- Aggressive management of infection
4- Modulation and reduction of immunosuppression drugs for the most common viral infections.
Thank You Naglaa Nice to see your active contributions
MOHAMMED GAFAR medi913911@gmail.com
2 years ago
The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors .
the term chronic allograft nephropathy (CAN) was used to encompass dysfunctional kidney grafts of unclear cause. However, the revised Banff 2005 classification system renamed CAN to IFTA without evidence of any specific etiology .
The persistent presence of allo-MHC molecules in the donor kidney leads to a life-long low-grade exposure to foreign antigens that may lead to chronic immunologically mediated injury .
some forms of primary kidney disease are associated with high-risk of recurrence and graft loss early after transplant, others may be associated with a delayed presentation and slowly progressive course ,FSGS recurrent rate is about 50-80%,aHUS 30-90%,ig A nephropathy 40% rarely cause graft loss.
Both viral and bacterial infections may lead to kidney allograft injury ,K nephropathy has become a major cause of both acute and chronic allograft dysfunction ,The greatest challenge in regards to BK is that 30%– 65% of patients that develop BK-associated nephropathy lose their kidney allograft within 1 year of diagnosis ,Direct involvement of CMV infection on the kidney is rare .
CNI is known to have significant nephrotoxicity ranging from vaso- constriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy ,CNI toxicity that led to IFTA, glomerulosclerosis and arteriolar hyalinosis .
the expansion of the donor pool to include kidneys from do- nors after cardiac death, elderly donors or those with comorbidities (e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults .
Renal artery stenosis may lead to graft ischemia and injury. This con- dition occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation .
since creatinine is a late marker of kidney dysfunction and in the absence of any solid noninvasive biomarker to monitor kidney injury in transplantation,protocol bobisies can solve this issues, justification to perform those protocol biopsies includes the detection of specific, often unsuspected, graft injury with consequent change in management .
belatacept used to minimize cni toxicity,given initially every 2 weeks and then monthly as an infusion in place of a CNI agent. Belatacept is contra- indicated in patients with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder .
poor socio economic satus is assciated with higher incidence of rejection rates,Screening at every clinic visit is critical and more frequent monitoring of drug levels and kidney function may be warranted in high-risk patients.
prevention strategies have been focused on avoiding AMBMR, including PLEX with iv igg and RTX,as it is the main cause of CABMR with late graft dysfunction.
1- Chronic glomerular injury proved by mesangial sclerosis and basement membrane duplication and it is cause by the following diseases: a- DM, HTN
b- recurrent GN like FSGS, immune complex deposition
disease
c- AMR
d-TMA
2- Chronic endothelial/vascular injury proved by basement membrane duplication, arterial wall thickening and hyalinosis…this caused by AMR, cellular rejection, TMA, CNI toxicity
3- Chronic tubulointerstitial injury proved by IF/TA interstitial fibrosis and tubular atrophy and caused by CNI toxicity, BK nephropathy, rejection and recurrent UTI and obstruction.
Treatment target of chronic graft injury is based on
1- Prevention kidney protection from the start of process old age kidney, DCD,ECD, also try to minimize cold and warm ischemia so try to protect kidney, also identification of high risk patients, intensify immunosuppression, desensitization program.
2- Early detection and diagnosis of high bl.p and bl.glucose so optimization of the treatment is important, detection of CNI toxicity and recurrent GN , BK nephropathy and UT obstruction and infection
3- Early diagnosis and management of chronic AMR
4- Prepare for next transplant before going to dialysis
. -50% of kidney allografts are lost by 10 years after transplant.
-The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors.
-Death with a functioning graft was the most common cause of graft loss.
– For those patients that survived up to 5 years after transplant, the predominant findings on protocol biopsies were glomerular disease (37%), tubular atrophy/
tubular atrophy (IFTA; 30.7%) and acute rejection (12% of cases).
-Glomerular diseases can be recurrent glomerular disease or transplant
glomerulopathy.
– Causes of IFTA: Cellular and/or antibody-mediated rejection (ABMR) followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis, and calcineurin inhibitor (CNI) nephrotoxicity.
-The persistent presence of allo-MHC molecules in the donor’s kidney leads to chronic immunologically mediated injury that may take the form of cellular, antibody-mediated, or a mix rejection.
-The kidney graft inflammation detected early on surveillance biopsies that do not fit the criteria of rejection has been associated with the development of tubular atrophy and/or graft loss.
-The most common type of rejection after the first year of transplant is chronic
rejection, which is defined as a prolonged cellular and/or antibody-mediated
immune response against the transplanted organ that may present with either a rise in creatinine and/or proteinuria.
– Noncompliance may be a major cause, affecting up to 40% of kidney recipients and associated with more than half of cases of late rejection leading to graft loss.
-Risk of subsequent graft failure was significantly higher in patients with DSA, C4d staining, or both, and the severity of clinical injury directly correlated with the intensity of the antibody response.
-Both pretransplant and de novo DSA are associated with significant
graft loss.
– Transplant glomerulopathy is one of the predominant findings on chronic ABMR, it is not specific to rejection since other causes of chronic endothelial injury may lead to a similar pattern of injury including thrombotic microangiopathy,
recurrent autoimmune glomerulonephritis and hepatitis C-related
glomerulonephritis
-Some forms of primary kidney disease are associated with a high risk of recurrence and graft loss early after transplant, and others are associated with a delayed presentation and slowly progressive course.
-Both viral and bacterial infections may lead to kidney allograft
injury.
-With the increased use of more potent immunosuppressive
drugs in the past 15 years, BK nephropathy has become a major cause
of both acute and chronic allograft dysfunction.
-30%–65% of patients that develop BK-associated nephropathy lose their kidney
allograft within 1 year of diagnosis
-CMV infection is one of the most common opportunistic infections
after kidney transplantation and may lead to a range of clinical presentations,
from CMV syndrome (fever, weakness, myalgia) to end-organ
disease (colitis, pneumonitis, hepatitis).
-kidney recipients that developed CMV post-transplant have significantly worse
graft and patient survival .
-General infections such as urinary tract infections may also lead to chronic injury either due to direct injury to the allograft in the setting of an infection affecting the kidney or indirectly, through triggering a rejection process due to the activation of innate immune system with increased expression of costimulatory
molecules and lowering of the threshold for T cell activation and proliferation.
-One study suggests that some of the allograft changes presumed to be
related to CNI are actually from other etiologies.
– CNI canbe associated with significant nephrotoxicity, in particular if high levels
of CNI are maintained post-transplant.
-The expansion of the donor pool to include kidneys from donors
after cardiac death, elderly donors or those with comorbidities
(e.g. diabetes and hypertension) may significantly affect the allograft
survival due to presence of preexisting injury, lower nephron mass
and greater susceptibility of new insults.
-A significant mismatch between donor and recipient size (kidney weight/recipient weight b2.3 g/kg) is associated with a higher rate of hypertension, proteinuria and lower graft survival .
-Renal artery stenosis occurs in up to 5% of kidney recipients and is suspected in patientswith persistent uncontrolled hypertension, flash pulmonary edema, or
an acute elevation in blood pressure within the first few years after
transplantation.
-Ureteral obstruction due to anastomotic stenosis or ureter ischemia (fragile vasculature of ureter) may lead to significant hydronephrosis and graft injury.
–The management of patients with chronic allograft injury :
1.careful history in regards to the primary renal disease
2.The early posttransplant course (e.g. severe delayed graft functionmight indicate significant irreversible early allograft damage).
3.episodes of acute rejection(if any) .
4.degree of hypertension/blood sugar control.
5. CNI levels over time and noncompliance are important.
6. Urinalysis with sediment visualization may help in the identification
of potential etiologies as cellular casts, granular casts, or significant
proteinuria indicative of active glomerulonephritis, acute
tubular necrosis or transplant glomerulopathy, respectively.
7. A kidney ultrasound: exclude mechanical complications such as ureteric obstruction and vascular stenosis.
8. kidney biopsy: should be performed in the majority of patients with dysfunction and no clear reversible factor present or if other worrisome features such as significant proteinuria or cellular casts are present.
-Protein and mRNA levels of CXCL9 were shown to be a great predictor of rejection
(AUC 0.88) with an elevation in levels detected 30 days before a
-A urinary mRNA signature that includes CD3E, CXCL10, and 18S ribosomal RNA
was associated with rejection (AUC 0.85).
-NK cell immunophenotyping correlated with the presence of DSA, cABMR, and worse graft function.
-The distinction among the different DSA IgG isotypes seems to be relevant, with IgG3 showing worse outcomes.
-Protocol biopsies can detect specific, often unsuspected, graft injury with the consequent change in management.
-The research for alternatives to CNI tominimize nephrotoxicity has led to the development of the costimulatory blockade agent belatacept .
-Belatacept is contraindicated in patients with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder.
-Belatacept-associated high rate of acute cellular rejection in the first year after transplantation has limited the widespread use of this agent.
-The data of 7-year follow-up with a belatacept regimen suggest a significant
better graft function and survival in patients on belatacept when
compared to cyclosporine.
-mTOR inhibitors have not shown a benefit in improving
long-term graft survival with specific concerning sides.
-Better controlling blood pressure post-transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant.
-Risk factors and clues for noncompliance include poor social support,
missed appointments, fluctuating drug levels, differences between
drug prescribed and dispensed, unexpected late rejection, psychiatric
disorder, substance abuse, adolescence, increased time since transplant
and financial crisis.
–Management of chronic rejection
-The most significant risk factor for chronic ABMR is acute ABMR so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab, and intravenous immunoglobulin (IVIG) are
used in sensitized patients.
-Potential alternatives to rituximab to reduce antibody production include bortezomib.
-In severe cases of ABMR, eculizumab can be considered an adjuvant therapy
Thank You, Reem; this is massive. You need to shorten your summary
Amit Sharma
2 years ago
Summarize this article
Kidney transplants have achieved good short-term outcomes, but the long-term outcomes are still unsatisfactory with 10 year graft loss of more than 50%, resulting from both immunological as well as non-immunological causes. Interstitial fibrosis and tubular atrophy on biopsy may be due to rejection (both cellular and antibody mediated), BK virus nephropathy, recurrent pyelonephritis, non-standard donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity.
Immunological causes: Chronic injury can occur by antibodies acting on foreign antigens in the donor kidney (DSA), leading to chronic rejection presenting with proteinuria or elevated serum creatinine. Late acute rejection episodes also increase the risk of chronic graft dysfunction. Risk of graft failure is high in patients with increased DSA levels and/or C4d positivity on kidney biopsy. Recurrence of glomerular disease is another major immunological cause of chronic graft injury which requires early identification and treatment. FSGS has recurrence of 20-80% with 50-80% graft loss. IgA nephropathy has 20-40% recurrence rates with 5-15% graft loss. Infections like BK virus also lead to chronic graft injury with 30-65% patients having BK virus nephropathy losing graft within 1 year of diagnosis. CMV infection, due to immunomodulatory mechanism, leads to increased rejection with poorer graft survival. Urinary tract infections can also trigger a rejection process by activating innate immune system.
Non-immunological causes: Calcineurin inhibitor (CNI) nephrotoxicity has been seen if high levels are maintained for prolonged periods although the changes seen in biopsy are non-specific and it has been seen that CNO elimination has worse graft outcomes. Poor quality of donor graft due to extended criteria donors, increased cold ischemia time and significant donor/recipient size mismatch is another cause of chronic graft injury. Renal artery stenosis leading to graft injury and ureteral obstruction due to ureteral stenosis or ischemia is also responsible for chronic graft injury.
Diagnostic strategies for chronic graft injury include detailed history including the primary disease, comorbidities like diabetes and hypertension, previous rejection episodes, underimmunosuppression due to non-adherence or physician advised and the CNI drug levels. Investigations like urine examination, ultrasound graft kidney as well as kidney biopsy give important clues. Non-invasive biomarkers like anti-HLA DSA with IgG isotyping (IgG3 showing worse outcomes), DSA c1q fixation properties, protein and mRNA levels of CXCL9, urinary CD3E, CXCL10 and 18S ribosomal RNA, NK cell immunophenotyping with increased NKG2A+ cells have shown increased correlation with chronic graft injury. Protocol biopsies have shown that grafts with subclinical AMR have worse outcomes than those without rejection or with subclinical cellular rejection.
Preventive strategies include emphasis on maintaining drug compliance and CNI alternatives including belatacept, a co-stimulatory blockade agent which is associated with increased acute cellular rejection in first year, but better long-term graft and patient survival. mTOR inhibitors have not shown benefit in long-term outcomes. Blood pressure control also has a role in preventing chronic graft.
Treatment strategies include prevention and adequate treatment of acute AMR. Subclinical rejection should be treated in presence of de novo DSA. Patients with chronicity score >8, DSA MFI >2500, serum creatinine >3mg/dl and urinary protein creatinine ratio >1g/g have higher risk of graft loss. Such patients should be managed with augmentation of immunosuppression as well as use of steroids and IVIG. In the absence of the poor prognostic markers, patients should be additionally treated with ATG (if cellular component is present), plasmapheresis, rituximab, bortezomib and eculizumab if refractory to initial treatment. Recurrence of the primary glomerular disease must be treated. FSGS recurrence can be managed with high dose steroids, IVIG and plasma exchange. IgA nephropathy recurrence may need ACE inhibitors or ARBs with oral steroids. Recurrent membranous nephropathy may need rituximab for treatment. In the unfortunate event of graft loss, re-transplantation with a live donor avoiding repeat HLA mismatch as the preferred choice should be planned.
Chronic allograft injury: Mechanisms and potential treatment targets
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
▪︎Chronic allograft nephropathy (CAN) was
used to define dysfunctional kidney grafts of unclear cause and renamed by Banff 2005 classification system  to tubular atrophy (IFTA), without evidence of any specific etiology. Â
☆Immunological causes:
__________________________
▪︎ Chronic rejection is the most common type of rejection after the first year of transplant.
▪︎ DSA is  as a major cause of  late graft dysfunction
☆Mechanism of chronic injury:
__________________
▪︎ There is an antibody-mediated injury to the endothelium of multiple vascular beds which cause cellular hypertrophy,
☆Glomerular disease recurrence after transplant
___________
(A) Primary renal diseases:
1) FSGS: tends to recur early
2)Â Atypical hemolytic-uremic syndrome.
3) IgA nephropathy 4)Dense deposit disease
5) C3 GN 6) MPGN (C3+ Ig+) 7) IgA nephropathy 8)Â Membranous GN
9)Â Anti GBM disease( Rare)
(B) Systemic disease:
Oxalosis ,Scleroderma, Immunoglobulin deposition, Amyloidosis, ANCA vasculitis, SLE (2%–7%) and Fabry disease.
☆Infections (viral/bacterial):
_____________________________
â—‡BK infection:
▪︎ BK nephropathy is a major cause of acute and chronic allograft dysfunction.
▪︎BK is tropic to the kidney tubules.
▪︎ It follows a predictable pattern (viruria →viremia →nephropathy).
▪︎ Does not have any systemic symptoms, which significantly delays the diagnosis.
▪︎ Biopsy is imp. to confirm the diagnosis.
â—‡CMV infection:
▪︎ One of the most common opportunistic infections after kidney transplantation.
▪︎Cause a range of clinical presentations
▪︎Direct involvement of CMV infection on the kidney is rare. But, it exert injury through an immunomodulatory mechanism
â—‡UTI:
▪︎ Can cause  direct or indirect injury (by activation of innate immune system).
☆Non-immunological causes:
_______________________________
â—‡CNI nephrotoxicity
▪︎ Range from vasoconstriction to tubular and vascular injury, and in rare cases TMA.
▪︎ CNI-related histologic lesions in the kidney are relatively nonspecific.
☆Poor quality donor grafts:
______________________________
Graft survival may be affected by:
1) Kidneys from donors after cardiac death, elderly or those with comorbidities
2) Presence of genetic susceptibility in kidney donors.
3) A significant mismatch between donor and recipient size.
4) A graft insults.
☆Renal artery stenosis(RAS) and urinary tract obstruction:
___________
▪︎RAS may lead to graft ischemia & injury.
▪︎ Gold-standard imaging for diagnosis is arteriography though a Doppler ultrasound
▪︎ Ureteral obstruction may lead to significant hydronephrosis and graft injury.
☆Diagnostic strategies of Chronic allograft injury: by:
________
1. Careful history in regards to the primary renal disease, the early posttransplant course, episodes of acute rejection (if any), degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important.
2.The time of transplantation
3. Urinalysis with sediment visualization.
4. US may to mechanical complications
5. A kidney biopsy
6. Noninvasive biomarkers: predict ongoing graft injury and response to treatment
7. Protocol biopsies: have emerged in few centers as a critical monitoring tool.
☆Preventive strategies:
_________________________
1. Alternatives to CNI:
▪︎Belatacept.
▪︎mTOR inhibitors
▪︎ everolimus with CNI minimization.
2. Better controlling blood pressure
3. Limit the use of ACEI inhibitors/ARBs.
4. Use of techniques to better preserve the donor kidney after retrieval ( eg: a machine perfusion)
5. Â Preventing non-compliance.
☆Treatment strategies
1. Management of chronic rejection
▪︎Preventive combined therapies including plasmapheresis, rituximab (Bortezomib is an alternative), IVIG are used in sensitized patients.
▪︎ In severe cases of ABMR, eculizumab.
▪︎ Adequate treatment of acute ABMR.
2. Management of recurrent GN:
▪︎FSGS: high dose steroids, cyclosporine and plasma exchanges
▪︎No specific treatment of recurrent IgA nephropathy.
▪︎ Recurrent membranous nephropathy may be treated with rituximab.
▪︎Recurrent MPGN: Treatment is based in underlying cause.
Recent developments in transplantation have contributed to better graft outcomes in the short term. However, there was still a significant problem with long-term graft survival owing to the fact that more than fifty per cent of allografts fail within ten years after the transplantation due to chronic allograft damage. This article sheds light on the genesis of chronic allograft nephropathy as well as the therapeutic strategy for this condition.
Immunological factors include a high HLA mismatch, TCMR, AMR or mixed rejection, and non-compliance (40 per cent of cases).
-Recurrent or de novo glomerular disease; diseases with a high recurrence rate include FSGS (with rates ranging from 20 to 30 per cent), atypical HUS (with rates ranging from 15 to 80 per cent), MPGN (with rates ranging from 80 to 100 per cent), and IgA nephropathy (with rates ranging from 20 to 40 per cent).
-Risk factors and causes of chronic allograft injury. • Alloimmune Poor HLA match Prior sensitization New alloantibodies Non-compliance Rejection episode • Recurrent or de novo glomerular disease • Recipient-related: CNI nephrotoxicity Diabetes Hypertension Renal artery stenosis Ureteral obstruction Heart failure Drug-induced acute interstitial nephritis • Donor-related Poor quality donor kidney Prolonged ischemia Delayed graft function Significant size mismatch • Infections BK nephropathy CMV infection Recurrent pyelonephritis Sepsis.
-Diagnosis:
Consequently, it is essential to collect a comprehensive history regarding the primary renal disease, the early posttransplant course (for example, severely delayed graft function could indicate significant irreversible early allograft damage), CNI levels over time, and noncompliance.
. Urinalysis with sediment visualization has the potential to assist in the identification of potential causes, such as cellular casts, granular casts, or significant proteinuria, each of which is indicative of active glomerulonephritis, acute tubular necrosis, or transplant glomerulopathy, respectively. Ultrasonography of the kidney might potentially rule out the presence of mechanical problems including ureteric blockage and vascular stenosis.
. Additionally, a kidney biopsy should be performed if other concerning characteristics, such as significant proteinuria or cellular casts, are present.
-Preventive strategies:
Different Options for CNI
A CTLA4Ig fusion protein called belatacept is responsible for blocking the CD80/CD86 interaction with CD28, which in turn prevents T cell activation.
Because of the increased likelihood of a post-transplant lymphoproliferative disease, it is not administered to patients with a negative EBV status.
There is insufficient evidence to determine if belatacept improves graft survival over the long term.
mTOR inhibitors did not result in an increase in graft survival over the long run.
The results of research evaluating the effect of everolimus on CNI reduction are encouraging.
Avoidance of noncompliance with regulations
-The management of persistent instances of rejection:
Taking into account that chronic ABMR is a significant contributor to late graft loss, it is reasonable to make treating this disease a high priority for developing preventative and therapeutic measures. Acute ABMR is the most important risk factor for developing chronic ABMR, and as a result, preventative methods have concentrated on avoiding getting acute ABMR.
Patients who have been sensitized to the virus are candidates for preventative combination therapy. These therapies include plasmapheresis, rituximab, and intravenous immunoglobulin (IVIG).
Bortezomib is one of the potential alternatives to rituximab that may be used to decrease antibody production. Eculizumab, which blocks one of the primary effector activities of the anti-HLA antibody, the complement activation, might be regarded as an adjuvant treatment for severe instances of ABMR. This is because complement activation is one of the most important functions of the anti-HLA antibody.
The long term outcome of kidney transplantation is still unsatisfactory as 50% of allografts are lost within 10 years post transplant.
Chronic allograft loss is multifactorial and a study showed that death with a functioning graft is the commonest cause. Immunological causes of chronic allograft nephropathy (CAN): Chronic rejection:
The most common type of rejection one year post transplant, non compliance is considered a major risk factor for late rejection and graft loss.
DSA has a significant role in late allograft failure, pre transplant and de novo DSA are associated with significantly higher risk of graft loss. Glomerular disease recurrence:
The risk of recurrence of primary kidney disease or systemic disease is variable with different consequences
Some glomerular disease are associated with high risk of recurrence while others are associated with delayed presentation Infections: BK nephropathy:
A major cause of acute and chronic graft dysfunction and leads to graft loss in 30-65% of patients within one year.
It has no systemic symptoms so surveillance of BK with serum PCR allows early detection, however, a biopsy is still needed to confirm the diagnosis and to exclude other causes. CMV infection:
The most common opportunistic infection post transplant, varies from CMV syndrome to end-organ disease and has an immunomodulatory effect.
Patients with CMV post transplant have worse patient and graft survival. General infection as UTI may also lead to chronic injury. Non immunological causes of CAN: CNI nephrotoxicity:
CNIs are known to cause vasoconstriction, tubular and vascular injury.
High levels of CNI post transplant are associated with significant nephrotoxicity, however, avoidance of CNI without any substitute resulted in poor outcome. Poor quality donor graft:
Kidneys from donors after cardiac death, elderly donors or those with comorbidities.
Donors with genetic susceptibility
Significant mismatch between donor and recipient size. Renal artery stenosis and urinary tract obstruction:
Renal artery stenosis leads to graft ischemia, suspected in patients with uncontrolled HTN or with flash pulmonary edema.
Ureteral obstruction may lead to significant hydronephrosis and graft injury. Diagnostic strategies:
Careful history, urinalysis,kidney ultrasound and graft biopsy are needed to determine the cause of graft injury. Non invasive biomarkers:
Are still under investigation, may help in early identification of graft injury before being clinically evident.
The clinically used biomarker is anti-HLA DSA, used for prediction of AMR and the results should be carefully interpreted. Protocol biopsies:
Longitudinal surveillance biopsies are used to detect unsuspected graft injury allowing early intervention. Preventive strategies: Alternatives to CNI: Belatacept, A co-stimulatory blockade agent, used as CNI sparing drug, associated with high rate of acute cellular rejection in the first year post transplant, long term trials are needed to determine its beneficial effect compared to tacrolimus. mTORi, didn’t show significant benefit, however, everolimus is promising and is still under investigation. Better control of HTN is associated with better graft survival. Using machine perfusion was also associated with better graft survival in expanded criteria donor kidneys compared to cold static storage. Preventing noncompliance through screening at clinic visits and monitoring of drug levels with explanation of potential consequences of non adherence. Treatment strategies: Management of chronic rejection
Prevention of acute AMR as it is a major risk factor through combine plasmapheresis, rituximab and IVIG.
There is no approved therapy for chronic AMR and interventional clinical trials are needed to determine safety and efficacy of B cell and DSA depleting strategies. Management of recurrent primary GN: FSGS, High dose steroid, cyclosporine and plasma exchange showed better results compared to same regimen without plasma exchange IgA nephropathy, No specific protocols are available, ACE inhibitors or ARBs with oral steroids may be used. MPGN, treatment varies according to the etiology.
The chronic allograft loss causes are multiple, including both immunological and non-immunological factors.
El-Zoghby et al. concluded that death with a functioning graft was the most common cause of graft loss. Immunological causes
chronic rejection is the most common rejection type after the first year of transplantation in the forum of prolonged cellular and/or antibody mediated immune response against the transplanted organ that may present with either a rise in creatinine and/or proteinuria.
DSA is a major risk factor in graft dysfunction.
Chronic ABMR requires a kidney biopsy to be diagnosed in order to exclude other potential causes.
Transplant glomerulopathy is a predominant feature of chronic ABMR,but it is not specific to rejection as it can be associated with thrombotic microangiopathy, recurrent autoimmune glomerulonephritis and hepatitis C-related glomerulonephritis. Glomerular disease recurrence
Some primary kidney diseases are associated with high-risk of recurrence and graft loss early after transplant, others can present later with slowly progressive course.
focal segmental glomerulosclerosis (FSGS) and atypical HUS can recur early after transplantation .IgA nephropathy has a high recurrence rate and commonly may exacerbate with reduction of immunosuppression late after transplantation. Infections
BK nephropathy has become a major cause of both acute and chronic allograft dysfunction due to the potent immunosuppressive drugs use causing graft loss within 1year of detection.
Biopsy with SV40 staining is needed for diagnosis.
CMV infection is frequent post transplantation ranging from CMV syndrome to end organ disease Non immunological causes CNI nephrotoxicity
Long-term allograft fibrosis was related to chronic CNI toxicity that led to IFTA, glomerulosclerosis and arteriolar hyalinosis.
A study concluded that low to moderate-dose tacrolimus with mycophenolate and steroids was associated with lower rate of rejection and better graft survival for 1 year follow up. Poor graft quality
A graft taken from a cadaver ,elderly donors or those with comorbidities ,mismatched kidney size affect the allograft survival RAS and urinary tract obstruction
RAS is suspected by persistent elvation of bp and flash pulmonary oedema , the diagnostic imaging is arteriography though a Doppler ultrasound.
A bedside ultrasound usually identifies obstruction and flouoroscopy detect exact site. Diagnostic strategies Non invasive biomarkers
Detection of DSA IgG isotypes seems to be relevant, with IgG3 giving the worst outcome.
A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was associated with rejection
NKG2A+ cells in high levels after kidney transplantation correlate with the presence of DSA, cABMR Protocol biopsies
To detect specific graft injuries with individualisation of management accordingly. Preventive strategies Alternatives to CNI
Belatacept is a CTLA4Ig fusion protein that blocks the CD80/CD86 interaction with CD28 preventing T cell activation.
It is not given with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder.
Betalacept effect on long term graft survival is not definite
mTOR inhibitors didnot improve long-term graft survival
A study testing everolimus with CNI minimization is promising . Avoidence of non compliance Treatment protocols Management of chronic rejection
Preventive mixed therapies including plasmapheresis, rituximab and IVIG are used in sensitized patients
Bortezomib and Eculizumab are other alternatives
Treatment of acute ABMR.
There is no approved therapy for chronic ABMR. Management of recurrent primary glomerulonephritis
For recurrent FSGS plasma exchange , high dose steroids and cyclosprorine
For recurrent Ig A nephropathy ACEI ,orARBS and oral steroids
Recurrent membranous can be treated with rituximab
Recurrent MPGN varies according to the cause
C3 glomerulopathy and dense deposit disease was treated with eculizumab. Conclusion
Prevention of allograft injury need to be the main target
More than 50% of graft are lost by 10 years and death censored attritition rates have unchanged over the last 25years. TG is the most common finding on biopsy in chronic allograft injury in patients with glomerular diseases. IFTA is a non specific finding and causes of this can be Acute antibody mediated or cellular rejection, Infections. poor donor selection, BK nephropathy, immunosuppressive agents toxicity or surgical factors. Immunological Causes of IFTA
Lifelong low grade exposure to foreign antigens resulting in antibody mediated, cellular or mixed rejection.
Late onset acute Rejection
Infections Non Immunological causes
CNI toxicity
Poor donor selection
Renal artery stenosis
TMA
Post renal urinary obstruction Diagnostic strategies
Biomarkers- in research settings
Protocol biopsies Prevention Strategies
Alternatives to CNI-Betacept, god control of hypertension
Prevent non adherence -provide social support to avoid missed appointment, better communication, Financial support, monitor drug levels Management Strategies Management of chronic rejection
Prevent acute ABMR, and treatment in the form of IVIG PP, Rituximab. In severe cases Ecluzimab.
Control medical conditions
Monitor DSA Management of recurrent primary glomerulonephritis.
The summary is OK but you need to add most discussion to the diagnostic and prevention strategies. The discussion is thin on words.
Ben Lomatayo
2 years ago
Introduction ;
Transplantation advances helped to improved short term graft outcomes. However long-term graft survival remained a huge challenge because > 50% of the allogarft are failed by 10 years after transplantation due chronic allograft injury(2). This article gives an insight about etiology and management approach for chronic allograft nephropathy
Immunological causes ; High HLA mismatch,TCMR, AMR or mixed rejection, non-compliance(40% of cases)
Recurrent or de novo glomerular disease ; Diseases with high recurrence rate are FSGS(20 -30%), atypical HUS(15-80%), MPGN(80%-100%)IgA nephropathy20-40%).(25).
It is wroth mentioned that recurrence disease is generally less aggressive with low rates of graft loss except in cases of FSGS(26,27%)
Infections ;
BK nephropathy; screening is essential due to high rate of graft loss after one year of BK nephropathy(30-65%).(29)
CMV ; increases risks of other infections and rejection through immunomodulatory pathway and associated with poor outcomes of both patient & graft survival.(30)
Urinary tract infections ; This leads to direct allograft injury or it activates the innate immunity and accelerate rejection process
Poor quality of the donated kidney ; DCD, elderly donor with comorbidities(HTN,DM),& size mismatch(38,39,40,41)
Surgical ; e.g. Renal artery stenosis(Difficult hypertension), ureteric stenosis( hydro-nephrosis)
Diagnosis ; Careful & detailed clinical history is essential
Urinalysis ; cast, proteinuria = active GN, ATN, or TG
Allograft biopsy including protocol biopsies
Non-invasive ; mRNA levels of CXCL9, urinary mRNA signatures of CD3E,CXCL10, 18S ribosomal RNA and NK cell immuno-phenotyping e.g NKG2A(45,46, 47)
DSAs
Prevention ;
1.Alternative to CNIs ; this was not successful up to date(55,57)
Fusion inhibitors ; e.g Belatacept, high rates of rejection & PTLPD
mTOR inhibitors ; e.g Sirolimus, Everolimus , again high rates of acute rejections
2.Prevent non-compliance ; early screening and frequent monitoring for those at high risks e.g poor social conditions, adolescence, mental problems, substance abuse and financial issues.
3.Blood pressure control ; trial of ACE-i/ ARBs
4.Better techniques for organ preservation after retrieval ; Machine perfusion
Treatment strategies ;
Chronic rejection
Prevention acute AMR is the most important thing here because evidence for treatment of Chronic rejection is not robust.
Recurrent primary Disease ; Mostly treated in the way as the native disease
Conclusion ;
Chronic allograft injury is associated with poor graft outcomes and it is essential to the identify the causes for better management outcomes. Since the diagnosis and treatment of chronic allograft injury can be very difficult, prevention of this condition is of paramount importance.
Nearly half of kidney transplant recipients loose there graft after 10 years
The most common cause of graft failure is death with functioning graft
Causes of chronic allograft dysfunction can be classified into
Tubulointerstitial (IFTA) causes :
Chronic CNI toxicity: It is suggested that the primary event responsible for acute or chronic damage related to CNI is vascular lesions, subsequent tubular ischemia, injury, atrophy and interstitial fibrosis, moreover TMA rarely can occur
Chronic rejection (CMR, ABMR, mixed rejection), it occurs after 1 year of transplantation due to mainly of either non compliance or planned subtherabiotic reduction of immunsoupressive drugs due to infection or malignancy, all these leads to the development of denovo DSA with subsequent development of rejection, the incidence of late rejection (> 1 year) is estimated to be 5% per year, diagnosis depends on histological features of rejection plus either C4d staining of the presence of DSA
Hypertension,
Infections including BK, CMV and recurrent pyelonephritis , the most important in BK nephropathy which is strongly associated with the intensity of immunosuppression, and its importance rely in about third to more than half of patietns diagnosed as BK nephropathy will have graft loss after 1 year of diagnosis,
Poor quality of the donor kidney which is related to the use of ECD who are deceased donors that are not ideal donors for kidney transplantation, ECD include elderly parients > 60 years, those with history of hypertension, or who died from cerebrovascular stroke, or those with an elevated serum creatinine. Moreover sometimes poor quality occur due to mismatch in the size between both donor and recipient, so if donor kidney is small in relation to the recipient size this may lead to the development of hyperfiltration and secondary FSGS, also prolonged cold ischemia time may alter quality of donor kidney
Glomerular causes:
Recurrence of primary glomerular disease, constitutes the third most common cause of graft loss after 1o0 years post transplantation, the frequency differ between types of glomerular diseases, which is 100% in case of diabetic nephropathy, oxalosis and fabry disease, frequent in cases with FSGS, DDD, C3 glomerulopathy amyloidosis, immunoglobulin deposition disease and atypical HUS, less frequent in immune complex MPGN, MN, IgA nephropathy, SLE, and ANCA vasculitis and rare in anti GBM (for example diabetic nephropathy, FSGS). Recurrence of primry glomerular disease can cause graft loss which occur more commonly in patients with FSGS, Oxalosis, C3 glomerulopathy, DDD and Atypical HUS, on the other hand IgA nephropathy, MN, SLE, ANCA vasculitis rarely causes graft loss
Denovo glomerular disease
Transplant glomerulopathy which is not specific for transplantation, picture of doubling of basement membrane can be seen in MPGN and TMA
Vascular causes
Microvascular including recurrent or denovo TMA
Renal artery stenosis due to either stenosis or athersclerosis
Post renal causes:
Ureteral stenosis
Diagnosis of chronic graft dysfunction
Detailed history taking including history of primary renal; disease, history of DM, HTN, history of rejection episodes, compliance on medications, monitoring of CNI, side effects , if there is planned reduction of the dose of CNI
Laboratory investigations including urine analysis, CNI level, urinary protein measurement, full renal function, serum uric acid, lipid profile, BK, CMV PCR, CBC, detection of DSA using luminex
US kidney for assessment of obstruction, vascular assessment
Renal biopsy either protocol biopsy in high risk transplant recipients or indication biopsy if the cause of renal dysfunction is not clear
Prevention of chronic graft dysfunction
Use of CNI sparing regimens using either belatacept or mTORS but both may be associated with higher incidence of rejection and side effects.
Ensuring the importance of compliance and addressing the cause of non compliance if present during each clinic visit
BP control since each 20 mmHg increase in BP is associated with worse graft survival at 1 and 3 years post transplantation
Use of techniques to preserve the donor kidney and reduce cold ischemia time such as the use of machine perfusion
Treatment of chronic ABMR
Treatment of chronic active ABMR is difficult since there it is associated with irreversible tissue damage
No optimal FDA approved treatment is set for chronic active ABMR, Current treatment is directed against the following:
Main therapy
Decreasing inflammation produced by rejection (high dose methylprednisolone)
Decreasing production of antibodies (IVIG)
Increase baseline immunosuppression
ATG if associated with cellular rejection
Second line agents in case of refractory chronic ABMR (poor evidence)
Depleting B celLs (rituximab) only if there is biopsy evidence of active microvascular inflammation and given 1 week after completion of IVIG
Removing DSA (plasmapharesis) play no rule in chronic active ABMR
Third-line agents (very poor evidence)
Bortezomib and eculizumab showed no benefit in treatment of chronic active ABMR
In case of graft failure, it is recommended not to stop immunosuppression in order to prepare the patient to the next transplant to avoid rebound of DSA
Summery:
50% of renal graft lost by 10 years post transplant. Chronic graft loss can result from immune or non immune cause. TG is the most common finding of protocol biopsy ( in glomerular disease). IFTA can a sequel of :
cellular &/or AMR.
recurrent pyelonephritis
BK nephropathy
poor quality donor kidney
uretral stenosis
CNI nephrotoxicity.
Immunological causes:
life long low grade exposure to donor Ags my lead to chronic immunological injury
late onset acute rejection ( non adherence & dnDSA)
infections ( chronic graft injury lead to direct & indirect activation of innate immune response).
Chronic injury commonly involve Ab-mediated endothelial injury ( glomeruli, PTC, small & medium size vessels), persistent endothelial injury lead to duplication of peritubular basement membrane to give TG.
TG is non specific finding can occur in ABMR, TMA, recurrent autoimmune GN, & hepatitis-C related GN.
Recurrence of glomerular disease is a frequent cause of graft loss 10 years after transplantation. FSGS can recur in early post transplant period with graft loss in 50-80% of cases, aHUS recurrence differ according to complement abnormality( 15% in MCP mutation, & 80% in circulatory protein mutation), but IgA nephropathy can recur in 40% of cases nut graft loss is uncommon early. So through protocol biopsy & early diagnosis & proper treatment can improve long term graft survival.
poor quality donor graft: due to expansion of donor pool that include kidneys from donor after cardiac death, elderly, or co-morbidities ( HT, DM) can affect graft survival due to pre-existing injury, low nephron mass, mismatch between donor & recipient size.
protocol biopsy : important for detection of early changes without clinical evidence of graft dysfunction.
Prevention:
Using alternative to CNI e.g. belatacept, mTOR-I, in addition to good control of blood pressure.
prevention of non adherence ( risk factors for non adherence include poor social support, missed appointment, fluctuated drug level, differences between prescribed & dispensed drug, unexpected late reaction, psychiatric diseases, substance abuse, adolescent, increased time since transplantation & financial crises.
Management:
prevention of chronic rejection: ( prevention of acute rejection & proper treatment of acute rejection( PP, IVIG+ rituximab, bortezumib, eculizumab).
Management depends on underlying cause of allograft injury.
History of primary renal disease
early post transplant course
acute rejection episodes
degree of hypertension or blood control
CNI levels over time
Recognition of non-compliance
Urinanalysis with sediment visualization
kidney ultrasound – to detect mechanical complications such as obstruction or stenosis
kidney biopsy in suspicion of dysfunction
Non-invasive bio markers – mRNA levels of CXCL9 – predictor of rejection with elevated levels a month before biopsy proven rejection.
Protocol biopsies help to identify unsuspected graft injury
Preventive care
Alternatives to CNI such as co-stimulators blockade agent belatacept, initially given every 2 weeks and then monthly. It is contraindicated in negative EBV patients because of risk of PTLD.
Preventing non-compliance
Screen at every visit for non compliance
address complexity of drug regimen
discuss financial burden
create awareness about consequences of non-adherence to immunosuppression.
Treatment strategies
Combination of plasmapheresis, rituximab, IVIG.
Alternative to rituximab is Bortezomib.
Eculizumab for severe ABMR.
Monitor DSA and treat sub clinical rejection if de novo DSA.
If poor prognostic markers are identified, then increase immunosuppression and consider administration of steroids or IVIG.
In case of need for re-transplant then do not stop immunosuppression after graft failure, and avoid repeat HLA mismatch in possible scenarios.
Aggressive treatment of hypertension, hyperglycemia and hyperlipidemia.
This article winds around identifying sources of threats to long term graft surival in renal transplant recipients. CNIs which have been long villainized in the transplant community as the cause of graft damage in the long term have been mentioned, and replaced with other factors as the major cause of graft damage or reduced graft survival. These factors include non-adherence to medication, BK nephropathy, disease recurrence, and antibody mediated injury.
Furthermore, the pathogenesis of chronic allograft nephropathy and associated treatment methods have been discussed,
Contents of this article can be subdivided as follows :
Causes of CAN; immunological and non-immunological, occurrence of glomerular disease and infections.
Diagnosis of chronic allograft injury
Preventive measures
Treatment strategy
Causes
Immunological causes
Inflammation of kidney graft
allo – MHC molecules from donor kidney
DSA – pretransplant and de novo DSA
Non-compliance, which could be intentional due to side effects, or accidental due to life event or financial trouble.
Alloimmune response due to DSA is a major cause of chronic allograft injury.
Mechanism of chronic injury involves antibody mediated injury to endothelium of various different vessels of glomeruli, peritubular capillaries and small to medium size vessels. The endothelium injury results in cellular hypertrophy, basement membrane duplication, podocyte injury. This can appear similar to transplant glomerulopathy on biopsy.
Recurrence of glomerular disease
Recurrence of disease is the third leading cause of loss of graft at 10 years post transplant. The time of graft loss after kidney transplant depends on the specific disease that is recurring. Some primary kidney disease that recur cause graft loss early after transplant, while others can be slow and cause graft loss late after transplant, more than 10 years post surgery.
For instance, FSGS recurs early after transplant with significant proteinuria and causes graft loss in 50% patients. On the other hand, IgA nephropathy recurs late after renal transplant and causes graft loss.
The mechanism of graft loss caused by recurrence of glomerular disease is unclear, however suspicion is toward circulating factors that result in podocyte injury.
Viral and bacterial infections can also cause damage to renal allograft. The major infections affecting the renal graft outcome post transplant include
BK nephropathy
CMV infection
Urinary tract infection
BK nephropathy occurs due to infection by BK virus. This virus colonizes the tubules of the kidney. The patient remains without any symptoms and hence serum PCR has to be done as part of routine check to ensure absence of infection. Aggressive immunosuppression is the major risk factor for BK virus. Early detection is key since most patients lose graft within one year of BK diagnosis.
CMV infection can cause graft loss. CMV syndrome involving fever, weakness and myalgia, as well as end organ disease including but not limited to colitis, pneumonia and hepatitis.
Urinary tract infection is another chronic cause of graft damage. It can affect the graft directly through infection of kidney or indirectly by activating the innate immune system.
Non-immunological causes
CNI nephrotoxicity
Poor quality of donor graft
Renal artery stenosis and urinary tract obstruction
CNI nephrotoxicity ranges from tubular to vascular injury. CNI regimen has been associated with fibrosis leading to IFTA in the long term. CNI minimization or elimination was attempted to find out if there is better outcome. However, protocol biopsies show that chronic CNI nephrotoxicity is not the main culprit for graft loss in long term in most patients. Hence, avoiding CNI may not lead to better outcome, but, in fact, may lead to a worse outcome. However, maintenance of high doses of CNIs post transplant for long periods of time causes significant nephrotoxicity.
Poor quality of donor pool can lead to graft insult and injury resulting in poor outcome. There are different factors that can lead to poor graft quality, such as :
Kidney from donor who died due to cardiac causes
elderly donor
donor with comorbidities such as diabetes and hypertension
genetic susceptibility of donor
donor recipient kidney size mismatch
prolonged CIT
Renal artery stenosis and urinary tract obstruction can lead to graft ischemia and injury. It is more seen in patients with
Persistent uncontrolled hypertension
pulmonary edema
acute elevation of blood pressure in the first two years post kidney transplant
Despite the improved short-term outcomes of kidney transplantation, more than 50% of kidney allografts are lost by 10 years after transplant.
The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors.
Cellular and/or antibody-mediated rejection (ABMR) was the leading culprit of IFTA followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity.
Acute rejection is less common after the first year of transplant. The most common type of rejection after the first year of transplant is chronic rejection, which is defined as a prolonged cellular and/or antibody mediated immune response against the transplanted organ. Risk of graft failure is significantly higher in patients with DSA, C4d staining or both.
Both pretransplant and de novo DSA are associated with significant graft loss, development of de novo DSA is associated with significant worse 10-year graft survival.
Although transplant glomerulopathy is one of the predominant findings on chronic ABMR, it is not specific to rejection since other causes of chronic endothelial injury may lead to similar pattern of injury including thrombotic microangiopathy, recurrent autoimmune glomerulonephritis and hepatitis C-related glomerulonephritis.
At 10 years after transplant, glomerular disease recurrence was the third leading cause of graft loss. Focal segmental glomerulosclerosis (FSGS) tends to recur early after transplant with massive proteinuria and is associated with graft loss in 50%–80% of cases. a potential circulating factor that leads to podocyte injury is highly suspected. Atypical hemolytic-uremic syndrome has also a high rate of recurrence (30%–90%) depending on the underlying complement abnormalities. IgA nephropathy has a high recurrence rate (up to 40%), commonly may exacerbate with reduction of immunosuppression late after transplantation.
BK nephropathy has become a major cause of both acute and chronic allograft dysfunction. BK infection follows a predictable pattern with initial viruria followed by viremia and then nephropathy.
Patients with greater than 10,000 copies of BK and allograft dysfunction are likely to have BK nephropathy, although it should be confirmed by renal biopsy.
CMV infection is one of the most common opportunistic infections after kidney transplantation. CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility for infection and rejection. Direct involvement of CMV infection on the kidney is rare and may present with necrotizing crescentic glomerulonephritis with viral inclusions.
CNI is known to have significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy. CNI withdrawal are associated with high rate of de novo DSA formation. One study revealed that chronic CNI nephrotoxicity was considered the culprit in only 1% of cases when protocol biopsies were performed.
The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities (e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults.
A significant mismatch between donor and recipient size (kidney weight/recipient weight b2.3 g/kg) is associated with a higher rate of hypertension, proteinuria and lower graft survival.
Renal artery stenosis may lead to graft ischemia and injury. It occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation.
Ureteral obstruction due to anastomotic stenosis or ureter ischemia (fragile vasculature of ureter) may lead to significant hydronephrosis and graft injury.
The management of patients with chronic allograft injury depends primarily in the underlying cause of injury. Urinalysis with sediment visualization may help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy, respectively.
Noninvasive biomarkers have the potential to earlier identify ongoing graft injury as well as predict response to treatment. protein and mRNA levels of CXCL9 was shown to be a great predictor of rejection with an elevation in levels detected 30 days before a biopsy-proven rejection. A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection. In a recent study, a high percentage of NKG2A+ cells after kidney transplantation correlated with the presence of DSA, cABMR and worse graft function. C1q-fixing DSA and IgG3 showing worse outcome.
Since creatinine is a late marker of kidney dysfunction and in the absence of any noninvasive biomarker to monitor kidney injury in transplantation, longitudinal surveillance biopsies have emerged in few centers as a critical monitoring tool of kidney recipients.
Preventive strategies
Belatacept, a CTLA4Ig fusion protein that blocks the CD80/CD86 interaction with CD28 preventing T cell activation, is developed in an attempt to reduce CNI nephrotoxicity. Its use is associated with high rate of acute cellular rejection in first year post transplant. Its utilization is contraindicated in EBV negative patients because of higher risk of PTLD.
Other CNI-sparing agents such as mTOR inhibitors have not shown a benefit in improving long-term graft survival
Treatment strategies
The most significant risk factor for chronic ABMR is acute ABMR, so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients. Bortezomib and Eculizumab have been used as alternatives.
Appropriate treatment of primary glomerulonephritis recurrence is warranted.
. Introduction
Cellular and/or antibody-mediated rejection (ABMR) was the leading culprit of IFTA
followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity However, the revised Banff 2005 classification system renamed CAN to IFTA.
Diagnostic strategies
The management of patients with chronic allograft injury depends primarily in the underlying cause of injury. Therefore, obtaining a careful history in regards to the primary renal disease, the early posttransplant course (e.g. severe delayed graft function might indicate significant irreversible early allograft damage), episodes of acute rejection (if any), degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important. The likelihood of different causes of graft injury is strongly influenced by the timing after transplantation.
– Urinalysis with sediment visualization may help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy, respectively.
– A kidney ultrasound may exclude mechanical complications such as ureteric obstruction and vascular stenosis.
– a kidney biopsy should be performed in the majority of patients with dysfunction and no clear reversible factor present or if other worrisome features such as significant proteinuria or cellular casts are present.
– The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA
Preventive strategies
– Alternatives to CNI: costimulatory blockade agent belatacept but not in clinical practice because of its potential risk to develop acute cellular rejection in the first year after transplantation and contraindicated in patients with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder. Other CNI-sparing agents such as mTOR inhibitors have not shown a benefit in improving long-term graft survival.
– Better controlling blood pressure post-transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant.
– Preventing non-compliance
Treatment strategies
The most significant risk factor for chronic ABMR is acute ABMR, so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients. Potential alternatives to rituximab to reduce antibody production include bortezomib. In severe cases of ABMR, eculizumab that inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy.
This review article, give a view on the pathogenesis and treatment strategies of chronic allograft injury.
Chronic allograft injury; Etiology :
1.Immunological causes in a form of rejection; cellular, anti-body mediated or mix pattern of rejection. Non-compliance is one of the major risk factors for chronic allograft injury. DSA has a role in graft dysfunction which is increasingly recognized.
mechanism of chronic injury:
2. Glomerular disease recurrence : recurrence was the third leading cause of graft loss
3.Infections (viral/bacterial)
4. Non-immunological causes
Chronic allograft injury; Diagnostic strategies
1.Obtaining careful history in regards to the primary renal disease, the early post- transplant course, episodes of acute rejection, degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important.
2.Urinalysis with sediment visualization.
3.A kidney ultrasound may exclude mechanical complications such as ureteric obstruction and vascular stenosis.
4.Kidney biopsy is indicated when there is no clear reversible factor or when there is worrisome features(proteinuria or cellular cast). Longitudinal surveillance biopsies(protocol biopsy) have emerged as a critical monitoring tool of kidney recipients as creatinine is a late marker of kidney dysfunction.
Justifications for Protocol biopsies: according to Loupy et al. study on 1001
unsensetized patients
(a) creatinine is a late marker of kidney dysfunction.
(b) subclinical AMR was associated with a worse 8- year outcome (56%), compared to CMR(88%) and non-rejection group (88%).
(c) detection of specific and unsuspected graft injury that may have consequent change in management. It helps selecting the most effective therapeutic strategy.
5.Noninvasive biomarkers : are currently not in clinical use outside of the research setting.
(a) protein and mRNA levels of CXCL9.
(b) a urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA.
(c) NK cell immunophenotyping. NKG2A+ cells after kidney transplantation correlated with the presence of DSA, cABMR and worse graft function.
(d) The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA for the prediction of antibody-mediated rejection.
Chronic allograft injury; Preventive strategies
1.Alternatives to CNI eg; Belatacept and mTORi.
2.Preventing non-compliance:
Risk factors and clues for noncomplicance: poor social support, missed appointments, fluctuating drug levels, differences between drug prescribed and dispensed, unexpected late rejection, psychiatric disorder, substance abuse, adolescence, increased time since transplant and financial crisis.
Chronic allograft injury; Treatment strategies
By 10 years post-transplant ,10% of kidney allografts are lost.the causes of allograft loss include immunological and non immunological causes.
Immunological causes
Allo-MHC molecules in the donor kidney leads to a life-long low-grade exposure to foreign antigens that may lead to chronic immunologically mediated injury( cellular , antibody mediated or mixed)
Acute rejection is less common after the first year of transplant,but the rate of late acute rejection is about 5% per year . The most common type of rejection after the first year of transplant is chronic rejection, which is defined as a prolonged cellular and/or antibody mediated immune response against the transplanted organ .
Donor-specific antibodies (DSA) are a major cause of graft loss late after transplantation may develop due to non compliance .
Both pretransplant and de novo DSA are associated with significant graft loss . The rate of de novo DSA ranges between 15% and 20% at 5 years post-transplant in unsensitized recipients and development of de novo DSA is associated with significant worse 10-year graft survival The mechanism of chronic injury frequently involves primarily an antibody-mediated injury to the endothelium of multiple vascular beds including glomeruli, peritubular capillaries and small-medium sized vessels leads to cellular hypertrophy,
expansion and duplication of the basement membrane and some podocyte injury,with the pathologic appearance of transplant glomerulopathy on kidney biopsy.
Glomerular disease recurrence
At 10 years after transplant, recurrence was the third leading cause of graft loss
some forms of primary kidney disease are related to high-risk of recurrence and graft loss early after transplant, others may be associated with a delayed presentation and slowly progressive course.
(FSGS) tends to recur early after transplant with massive proteinuria and is associated with graft loss in 50%–80% of cases .
Atypical hemolytic-uremic syndrome has also a high rate of recurrence (30%–90%)
IgA nephropathy has a high recurrence rate (up to 40%) but rarely causes early graft loss.
Infection
Both viral and bacterial infections may lead to kidney allograft injury.With the increased use of more potent immunosuppressive drugs in the past 15 years, BK nephropathy has become a major cause of both acute and chronic allograft dysfunction .Also,kidney recipients that developed CMV post-transplant have significantly worse graft and patient survival .
Non-immunological causes
CNI toxicity
CNI has significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy.
long-termallograft fibrosis was primarily related to chronic CNI toxicity that led to IFTA, glomerulosclerosis and arteriolar hyalinosis
Poor quality donor grafts
The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities (e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults .
Renal artery stenosis and urinary tract obstruction
Renal artery stenosis may lead to graft ischemia and injury. This condition occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation. Underlying etiology includes stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant
artery.
Diagnostic strategy
Preventive strategies
Treatment strategies
chronic ABMR is an important cause of late graft loss, the most significant risk factor for
chronic ABMR is acute ABMR
to prevent it we use combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin in sensitized patients .Potential alternatives to rituximab
to reduce antibody production include bortezomib . In severe cases of ABMR, eculizumab that inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy
The FDA currently has no approved therapy for chronic ABMR [84] and mechanistic interventional clinical trials are needed to address the safety and efficacy of B cell and DSA depleting strategies for chronic rejection.
Management strategy for FSGS may include high dose steroids and cyclosporine aiming podocyte stabilization, in combination with plasma exchanges to remove circulating humoral factors.
recurrent IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor blockers , but specific protocols for recurrence management are lacking. Following recommendations for native IgA nephropathy, oral prednisone (1 mg/mg 2 months and
then slow taper) may be advisable .
Recurrent membranous nephropathy may be managed with rituximab,
The treatment of recurrent membranoproliferative GN (MPGN) : recurrent type I or idiopathic cases successfully treated with rituximab
C3 glomerulopathy and dense deposit disease have been recently managed with
eculizumab, with variable responses
Chronic allograft dysfunction still remain problems despite improving of immunosuppressive therapy post transplant.
Chronic allograft rejection always occurring 5 years post transplant.
It’s mainly due to immunological and non immunological factors.
The most common cause of graft loss are death with function graft .
The second cause are chronic allograft proved by renal biopsy due to recurrence of glomerular disease and chronic rejection of cellular and AMR.
Other causes are infection and drug toxicity.
Immunological causes:
It’s due to presence of alloantibodies which lead to chronic immunological mediated injury.
It’s manifested by renal biopsy to tubular atrophy. It’s carrying high risk of graft loss even discovered early by renal biopsy protocol.
The most common of chronic graft injury is non compliance and non adherence to immunosuppressive therapy.
Causes of chronic allograft dysfunction are DM / HTN/ Hyperlipidemia / infection and drug toxicity/
Recurrence of de novo glomerular disease
Donor kidney disease.
Presence of DSA appear pre and post transplant and rarely chronic allograft dysfunction appear in one year post transplant.
Presence of de novo DSA appear 10 years post transplant.
The appearance of transplant glomerulopathy by renal biopsy prove presence of chronic allograft dysfunction which shows swelling in endothelial cell and doubling of basement membrane and disruptive of podocytes.
Risk of recurrence of glomerular disease post transplant by 100% are:
Systemic primary oxalosis
Diabetic Nephropathy
Fabry disease
DDD
Atypical HUS disease
Risk of recurrence of glomerular disease post transplant by 75% to 50% are:
IgA nephropathy
SLE
ANCS vasculitis
Amylidosis
Scleroderma
Anti GBM disease
Recurrence less than 20% are infection
Bacterial and viral infection are risk of graft loss.
Serial serum PCR routine done post transplant.
If BK PCR high so reduction of immunosuppressive therapy is mandatory.
PCR of CMV infection
Symptoms of CMV infection range from fever/ weakness myalgia to end organ infection pneumonitis/ colitis and hepatitis.
If vermia high are assistant with necrotizing crescent glomerulonephritis and viral inclusion.
Non immunological factors:
CNI toxicity
poor quality of donor
Vascular stenosis
Diagnosis of chronic allograft dysfunction:
Good history of date of transplant and serial monitoring of drug level and serial PCR of any evidence of previous infection and previous rejection and fallow up chart and compliance of patient and adherence to drug. History of hypertension and DM and there control .
Urine analysis to rule out cellular cast and granular cast, presence of proteinuria and leukocytes in urine.
USS of kidney for any mechanical obstruction and vascular stenosis.
Non invasive bio markers:
mRNA level of CXCL9 predict rejection which appear 30 days before biopsy proven rejection.
Urinary mRNA include CD3E / CXCL 10 185 ribosomal RNA. It’s may increase in patients with CMV & BK infection.
Increase level of NKG2A associated with presence of DSA , CABMR worse graft function.
Anti HLA DSA is predicted AMR.
Protocol renal biopsy shows early sub clinical inflammation associated with worse graft.
Preventive strategies:
Alternative to CNI are Co-stimulatory blocked agents belatacept are CTLA4 Ig fusion protein blocks CD8/CD86 interaction with CD28 preventing T cell activity. Initially every 2 weeks and then monthly but it has high rate of rejection in first year post transplant.
Another alternative are mTor inhibitors
ACEI and ARBC inhibitors there is no evidence of benefit post transplant and also have side effects like anemia and decrease GFR and hyperkalemia.
Non compliance:
miss fallow up
non adherence to immunosuppressive agents
poor social support
drug addicted
Treatment of chronic allograft dysfunction:
The main cause are acute ABMR
So management are plasma exchange plus Rituximab and Intravenous immunoglobulin in sensitised patients.
alternative to rituximab are bortezomib.
In severe cases can be use eculizumab .
Use of steroid with intravenous immunoglobulin plus plasma exchange may reduce risk of graft loss. If no response use rituximab.
Introduction:
Despite the improved short-term outcomes of kidney transplantation, more than 50% of
kidney allografts are lost by 10 years after transplantation.
Causes of chronic allograft loss are multifactorial, common:
Before 5 years:
Death with functioning graft.
After 5 years:
Glomerular disease (37%), tubular atrophy/ tubular atrophy (IFTA; 30.7%) and acute
rejection (12% of cases).
Diagnostic strategies:
Careful history in regards to the primary renal disease, the early posttransplant course.
Urine analysis.
Biopsy.
Ultrasound.
Noninvasive biomarkers:
Anti-HLA DSA for the prediction of antibody-mediated rejection
Protein and mRNA levels of CXCL9.
CD3E, CXCL10 and 18S ribosomal RNA also associated with rejection.
NK cell immunophenotyping.
Preventive strategies:
Alternatives to CNI: to minimize IF/TA associated with CNI.
Both mTOR and Belatacept is promising but still not used widely.
Better controlling blood pressure.
Preventing non-compliance.
Treatment strategies:
Management of chronic rejection:
Management and prevention of acute ABMR, so prevention strategies have been
focused on avoiding it. Preventive combined therapies including plasmapheresis,
rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients.
Potential alternatives to rituximab to reduce antibody production include Bortezomib.
In severe cases of ABMR, Eculizumab.
Management of recurrent primary glomerulonephritis:
FSGS recurrence, high dose steroids and cyclosporine , in combination with plasma
exchanges .
Recurrent IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor
blockers, but specific protocols for recurrence management are lacking.
Following recommendations for native IgA nephropathy, oral prednisone (1 mg/mg 2
months and then slow taper) may be advisable.
Recurrent membranous nephropathy may be managed with rituximab, and some patients
respond to therapy up to one year after treatment.
The treatment of recurrent membranoproliferative GN (MPGN) is based in underlying
etiological factors.
For the idiopathic cases related to immune complexes, no consensus exists, and
steroids, cyclophosphamide and/or plasma exchanges have been unsuccessful.
Some recurrent type I or idiopathic cases successfully treated with rituximab.
Conclusion:
Chronic allograft injury can significantly affect long-term graft survival.
Therefore, prevention of injury should be a major focus of caring of transplant
recipients. Based on the heterogeneity of causes of injury strategies may include CNI
minimization, better preservation of the allograft after retrieval, use of protocol biopsies,
active noncompliance screening, measurement of DSA post-transplant and other
potential novel biomarkers of graft injury, BK surveillance and aggressive treatment of
hypertension, hyperglycemia and hyperlipidemia.
Summary: chronic allograft injury
• Chronic graft damage eventually leads to graft loss years post transplantation.
• May be immunologically and non immunologically mediated.
• Surveillance biopsies revealed glomerular disease (37%), tubular atrophy/ tubular atrophy (IFTA; 30.7%) and acute rejection (12% of cases).
• Glomerular diseases either transplant glomerulopathy or recurrence of glomerular diseases.
• The main causes behind graft scarring were recurrent rejection episodes, infections as BK nephropathy and recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity, complications of systemic diseases as uncontrolled DM, hypertension and dyslipidemia and recurrent or de novo glomerular diseases.
• Untreated/ or inadequately treated acute rejection turns into chronic rejection that eventually cause scarring and IFTA. In addition, non adherence to therapy and development of de novo DSA leads to late and chronic active ABMR.
• Glomerular diseases with high risk of recurrence and graft loss are:
o Dense deposit disease (DDD) 80%–100%
o FSGS 20%–50% (up to 80% if prior graft loss)
o Atypical HUS (depending on underlying mutation) 30%–90%
o C3 glomerulonephritis 65% 50%
o MPGN (C3+ Ig+): infection, monoclonal gammopathy, autoimmune dz (variable) 30%–50% 15%
o IgA nephropathy 20%–40% 5%–15%
o Membranous GN 10%–40% 10%–15%
o Anti GBM disease
• systemic diseases with high risk of recurrence and graft loss are
o Oxalosis (consider combined liver/kidney) 100% 50%
o Cystinosis (if on enzyme replacement)
o Scleroderma (little data) 20% 50%
o Immunoglobulin deposition diseases 50%–75% 30%
o Amyloidosis 20%–40% 20%
o ANCA vasculitis 15%–20% 6%–8% SLE 2%–10% 2%–7%
o Diabetic nephropathy 100%
o Fabry disease (if on enzyme replacement) 100%
• Diagnostic strategies:
o Urine analysis and active sediment for recurrent nephritis.
o DSA and protocol biopsy for rejection.
o Early detection of rejection and diagnosis of infection, prevention of none adherence
• Treatment is directed to the treatment of the cause
• Antirejection therapy is combined steroid pulses, ivig and plasmapheresis and optimization of the maintenance therapy.
_ prevention of chronic graft damage by ensuring drug compliance, minimization of CNI induced nephrotoxicity and appropriate treatment of acute rejection is best strategy to prevent graft loss.
This article is casting light on the contentious issue of managing the chronic allograft injury.Elaborating on the causes , etiology and prospective management.
Before Banff meeting on the year 2005 , the term chronic allograft nephropathy CAN was over-zealously echoed to describe unclassified deterioration of allograft function.But, due to its non-specificity,and being rather an ambiguous term, it was replaced by the mentioned meeting to IFTA, (stand for interstitial fibrosis and tubular atrophy) which was entirely descriptive and non diagnostic, larger studies such as Dekafe study performed to explore the potential causes of this commonly encountered pathological finding on allograft biopsy.
The paradigm was shifted from mainly Cni related nephrotoxicity to focus on chronic ABMR, BKPN, recurrent glomerular disease and interstitial nephritis.Non-compliance was the main culprits in precipitating the immunologic reaction and chronic ABMR as the main underlying etiology .
Chronic ABMR:
Was considered the predominant causes of chronic allograft dysfunction, IFTA, chronic rejection and failure.
The HLA incompatability is the major trigger for immunologic reaction with both TCMR and ABMR can be precipitated , the first year is associated with heightened incidence of both types of rejection, the late acute rejection is usually associated ABMR, that potentially progress to chronic rejection.
Features associated with high risk of progression include De novo DSAs, complement fixing DSAs tested by C1q testing and the phenotype of IgG antibodies particularly IgG3.
DSAs against Type II HLA antigen. with MFI of more than 2500 are usually associated with increased risk of cABMR.
Presentation of cABMR:
progressive long term deterioration of allograft function with proteinuria.
pathogenesis: Its principally resultant from the interaction of DSAs with HLA antigens on the endothelial cells in glomeruli and peritubular capillaries featuring transplant glomerulopathy and peritubular capillaritis.
Treatment:
Its dependent on the time of diagnosis , duration since transplantation,
IVIG, methylprednnisolon and Rituximab were recommended and plasma pheresis if it happened in the first year post transplantation .Bortizomibe,to deplete Plasma cells as a source of DSAs, and Eculizumab to mitigate C5 complement component which is part of complement mediated ABMR.
Optimization of immunosuppression with adding of CNi if not yet on the same , and shifting of Cyclosporin to Tacrolimus and keeping the trough level at its upper site. Similarly prednisolon has to be initiated if its not yet in the medication list.
CNi nephrotoxicity is another important underlying etiology of IFTA, usually with stripped phenotype. Strategies to minimize the toxicity include CNi avoidance protocol, replacement with mTORi , however, the reported outcome was not significantly different, Nevertheless, a protocol involved mTORi with minimized dose of CNi was showing promising result and the result of TRANSFORM study is pending to explore this potential.
10 year graft loss is more than 50% due to immunological and non-immunological causes. Interstitial fibrosis and tubular atrophy may be due to rejection, recurrent pyelonephritis, BK virus nephropathy ureteral stenosis and CNI nephrotoxicity.
Immunological causes: include : Chronic injury can occur by DSA, resulting in chronic rejection with proteinuria and /or elevated serum creatinine. Late rejection episode increase risk of chronic graft dysfunction. Increased DSA levels and/or C4d positivity increase graft failure risk. FSGS with recurrence rate of 20-80% has 50-80% graft loss. IgA nephropathy with 20-40% recurrence rate has 5-15% graft loss. BK viral infection results in chronic graft injury and 30-65% patients lose graft within 1.CMV infection, leads to increased rejection and poor graft survival. UTI can lead to rejection through activating innate immune system.
CNI nephrotoxicity:
Donor graft of low quality could be a cause of chronic graft injury. RAS and ureteral stenosis could lead to chronic graft injury. Diagnosis :includes history taking, and investigations including urine analysis, US and biopsy .Biomarkers eg: DSA with IgG isotyping ,DSA c1q fixation properties, protein and mRNA levels of CXCL9,…. have increased association with chronic graft injury. Grafts with subclinical AMR have worse outcomes.
Preventive measures: include blood pressure control, drug compliance and CNI alternatives; belatacept,( co-stimulatory blockade agent) which is associated with increased ACR in first year, with better long-term graft and patient survival.
Treatment includes prevention and management of acute AMR. Treatment of subclinical rejection with de novo DSA. Patients with higher risk of graft loss should be treated with augmentation of IS and use of steroids & IVIG. Without poor prognostic factors, management should include ATG ;if cellular component is present, plasmapheresis, rituximab, bortezomib & eculizumab if refractory to treatment. FSGS recurrence to be managed with high dose steroids, IVIG & PE. IgA N recurrence needs ACEI or ARBs with oral steroids. Membranous nephropathy needs rituximab In case of graft loss, second transplantation with a live donor avoidance of HLA mismatch as the preferred option.
Causes of CAN
previously was the first 1 CNI Toxicity
Now multiple other causes e.g Non compliance (up to 40%) , Rejection , Infections , medical causes and CNI toxicity
1. Immunological causes of allograft rejection:
Probability of graft failure was significantly higher in patients with DSA, C4d staining or both, and the severity ​of clinical injury directly correlated with the intensity of the antibody ​response .
5 years post-transplant in unsensitized recipients and develop​ment of de novo DSA is associated with significant worse 10-year graft ​survival 57% compared to 96% in patients without de novo DSA
The mechanism of chronic injury frequently involves primarily ​an antibody-mediated injury to the endothelium of multiple vascular ​beds including glomeruli,peritubular capillaries and small-medium ​sized vessels , This endothelium injury leads to cellular hypertro​phy, expansion and duplication of the basement membrane and some ​podocyte injury, with the pathologic appearance of transplant glomeru​lopathy on kidney biopsy .
2. Recurrence of Original GN e.g FSGS (early with bad prognosis) , IgA nephropathy (better prognosis with ACE-I)
3. Infections
BK
is a ubiquitous ​virus that is tropic to the kidney tubules and may proliferate out of ​control in the setting of immunosuppression. Donor and recipient BK ​serologies do not predict the risk of infection and the intensity of immu​nosuppression seems to be the predominant risk factor .
30%– ​65% of patients that develop BK-associated nephropathy lose their kid​ney allograft withi 1 year of diagnosis . BK infection does ​not have any systemic symptoms, which significantly delays the diag​nosis.
surveillance of ​BK with serum PCR has become routine in most transplant centers
biopsy is important to confirm the diagnosis with SV40 staining for ​the BK virus and exclusion of any other etiology of graft dysfunction.
CMV
infections such as urinary tract ​infections may also lead to chronic injury either due to direct injury to ​the allograft in the setting of an infection affecting the kidney or ​indirectly, through triggering a rejection process due to the activation ​of innate immune system with increased
expression of costimulatory ​molecules and lowering of the threshold for T cell activation ​and proliferation.
CNI exposure:
current protocols ​using lower dosage and exposure to CNI in kidney transplant recipients ​do not seem to be the primary
culprit of many of the graft deteriorations ​that occur and avoidance of CNI
without any substitute agent will lead ​to poor outcomes.
low to
moderate-dose tacrolimus (target 3–7 ng/mL, ​median 7 ng/mL achieved, range
4.3–10.0 ng/mL) in combination with ​mycophenolate and steroids was associated with the best outcomes in​cluding lower rejection rate, lowerfibrosis and improved renal function ​at one year of follow-up .Extension of follow-up to 3 years failed to ​confirm that improvement
Poor quality donors :
the expansion of the donor pool to include kidneys from do​nors after cardiac death, elderly donors or those with comorbidities ​(e.g. diabetes and hypertension) may
significantly affect the allograft ​survival due to presence of preexisting injury, lower nephron mass ​and greater susceptibility of new insults
Renal artery stenosis may lead to graft ischemia and injury ,Gold-standard imaging
for diagnosis is arteriography ​though a Doppler ultrasound is frequently used as a screening method ​in suspected cases.
ureteral obstruction due to anastomotic ​stenosis or ureter ischemia (fragile vasculature of ureter) may lead to ​significant hydronephrosis and graft injury
based on the heterogene​ity of causes of late graft dysfunction, a kidney biopsy should be ​performed in the majority of
patients with dysfunction and no clear re​versible factor present or if other
worrisome features such as significant ​proteinuria or cellular casts are
present.
the distinction among the ​different DSA IgG isotypes seems to be relevant, with IgG3 showing ​worse outcomes .
Best way to avoid CAN is to prevent ABMR and early treat ABMR if occurred .
· Summarize this article
INTRODUTION
The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors. In the largest longitudinal surveillance biopsy study available, El-Zoghby et al, they observed that death with a functioning graft was the most common cause of graft loss.
IMMUNOLOGICAL CAUSES
The persistent presence of allo-MHC molecules in the donor kidney leads to a life-long low-grade exposure to foreign antigens that may lead to chronic immunologically mediated injury. This process may take the form of cellular, antibody-mediated or a mix rejection. Diagnosis of chronic ABMR requires a kidney biopsy to exclude other potential causes.
Risk of subsequent graft failure was significantly higher in patients with DSA, C4d staining or both, and the severity of clinical injury directly correlated with the intensity of the antibody response. The recognition of alloantibodies as a major cause of chronic rejection has also been driven by the development of novel techniques that allowed better identification and quantification of anti-HLA DAS, histologic assessment of injury through C4d staining, electron microscopy and gene profiling of kidney biopsies.
The mechanism of chronic injury frequently involves primarily an antibody-mediated injury to the endothelium of multiple vascular beds including glomeruli, peritubular capillaries and small-medium sized vessels. This endothelium injury leads to cellular hypertrophy, expansion and duplication of the basement membrane and some podocyte injury, with the pathologic appearance of transplant glomerulopathy on kidney biopsy.
GLOMERULAR DISEASE RECURRENCE
No clear risk factors were identified that predicted recurrence risk and other trials failed to demonstrate a direct association of type of immunosuppression. The importance of recurrence of native kidney disease in the allograft has changed with recent longitudinal protocol biopsy studies demonstrating their significant impact on graft injury.
While some forms of primary kidney disease are associated with high-risk of recurrence and graft loss early after transplant, others may be associated with a delayed presentation and slowly progressive course: (A) – focal segmental glomerulosclerosis (FSGS); (B) – Atypical hemolytic-uremic syndrome; (C) – IgA nephropathy.
Many patients do not have a established etiology of their primary kidney disease (e.g. presumed hypertension) and recurrence of disease could be a significant unexpected complication.
Infections (viral/bacterial)
Both viral and bacterial infections may lead to kidney allograft injury. BK nephropathy has become a major cause of both acute and chronic allograft dysfunction. Donor and recipient BK serologies do not predict the risk of infection and the intensity of immunosuppression seems to be the predominant risk fator. The greatest challenge in regards to BK is that 30%– 65% of patients that develop BK-associated nephropathy lose their kidney allograft within 1 year of diagnosis. Therefore, surveillance of BK with serum PCR has become routine in most transplant centers since early detection of a rise in BK viral load may drive reduction of immunosuppression. This is particularly important since BK infection does not have any systemic symptoms, which significantly delays the diagnosis.
CMV infection is one of the most common opportunistic infections after kidney transplantation and may lead to a range of clinical presentations, from CMV syndrome (fever, weakness, myalgia) to end-organ disease (colitis, pneumonitis, hepatitis). In addition, CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility for infection and rejection. Indeed, kidney recipients that developed CMV post-transplant have significantly worse graft and patient survival.
Non-immunological causes
CNI nephrotoxicity
CNI is known to have significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy. the Symphony study that compared tacrolimus-based regimens (high-dose vs. low dose) with either cyclosporine or CNI-free, sirolimus-based therapy. Their results revealed that low to moderate-dose tacrolimus (target 3–7 ng/mL, median 7 ng/mL achieved, range 4.3–10.0 ng/mL) in combination with mycophenolate and steroids was associated with the best outcomes including lower rejection rate, lower fibrosis and improved renal function at one year of follow-up. Despiste this, one of the major limitations of the hypothesis of CNI nephrotoxicity is that the CNI-related histologic lesions in the kidney are relatively nonspecific.
Poor quality donor grafts
The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities (e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults.
Renal artery stenosis and urinary tract obstruction
Renal artery stenosis may lead to graft ischemia and injury. This condition occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation. Underlying etiology includes stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant artery. Gold-standard imaging for diagnosis is arteriography though a Doppler ultrasound is frequently used as a screening method in suspected cases
DIAGNOSTIC STRATEGIES
The management of patients with chronic allograft injury depends primarily in the underlying cause of injury. Therefore obtaining a careful history in regards to the primary renal disease, the early posttransplant course (e.g. severe delayed graft function might indicate significant irreversible early allograft damage), episodes of acute rejection (if any), degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important. The likelihood of different causes of graft injury is strongly influenced by the timing after transplantation.
Some tests can be used as screening to differentiate the etiologies: Urinalysis, kidney ultrasound and kidney biopse.
Noninvasive biomarkers
Noninvasive biomarkers have the potential to earlier identify ongoing graft injury as well as predict response to treatment, helping the clinician to individualize immunosuppression and provide earlier intervention prior to clinically evident dysfunction. For examples, levels of : CXCL9, CD3E, CXCL10 and 18S ribosomal RNA. Although, none of the above biomarkers are currently in clinical use outside of the research setting.
Protocol biopsies
The justification to perform those protocol biopsies includes the detection of specific, often unsuspected, graft injury with consequent change in management.
PREVENTIVE STRATEGIES
Alternatives to CNI
The research for alternatives to CNI to minimize nephrotoxicity has led to the development of the costimulatory blockade agent belatacept. Your regimen suggest a significant better graft function and survival in patients on belatacept when compared to cyclosporine, which may result in significant changes in practice . Belatacept is contraindicated in patients with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder and is associated high rate of acute cellular rejection in the first year after transplantation has limited the wide use of this agente.
Other CNI-sparing agents such as mTOR inhibitors have not shown a benefit in improving long-term graft survival with specific concerning side.
Better controlling blood pressure post-transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant. Furthermore, each 20-mmHg increase in systolic blood pressure in kidney transplant recipients is associated with a 32% increased risk of cardiovascular disease and 13% increased risk of death.
Techniques to better preserve the donor kidney after retrieval have been explored. In particular, the use of a machine perfusion has demonstrated a greater benefit in 3-year graft survival in particular in expanded-criteria donor kidneys when compared to cold static storage.
Preventing non-compliance
Risk factors and clues for noncomplicance include poor social support, missed appointments, fluctuating drug levels, differences between drug prescribed and dispensed, unexpected late rejection, psychiatric disorder, substance abuse, adolescence, increased time since transplant and financial crisis.
TREATMENT STRATEGIES
Management of chronic rejection
The most significant risk factor for chronic ABMR is acute ABMR, so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients. Potential alternatives to rituximab to reduce antibody production include bortezomib. In severe cases of ABMR, eculizumab that inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be considered as an adjuvant therapy.
While various approaches have been used to treat acute ABMR, few have been tested in chronic ABMR . The allografts treated with IVIG and rituximab or rituximab alone or Thymoglobulin® to steroids/IVIG did not improve graft survival significantly.
Management of recurrent primary glomerulonephritis
FSGS probably has podocyte dysregulation and circulating humoral involved, so therapeutic strategies may include high dose steroids and cyclosporine aiming podocyte stabilization, in combination with plasma exchanges to remove circulating humoral factors.
Recurrent IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor blockers.
Recurrent membranous nephropathy may be managed with rituximab, and some patients respond to therapy up to one year after treatment
CONCLUSION
Chronic allograft injury can significantly affect long-term graft survival. Therefore, prevention of injury should be a major focus of caring of transplant recipients. Based on the heterogeneity of causes of injury, strategies may include CNI minimization, better preservation of the allograft after retrieval, use of protocol biopsies, active noncompliance screening, measurement of DSA post-transplant and other potential novel biomarkers of graft injury, BK surveillance and aggressive treatment of hypertension, hyperglycemia and hyperlipidemia.
Summarize this article :
1- Better preservation of allografts after retrieval.
2- CNI minimization.
3- DSA monitoring.
4- Other potential novel biomarkers of CAI.
5- Protocol biopsies.
6- BK surveillance.
7- Aggressive ttt of traditional vascular risk factors.
8- Active non-compliance screening.
Chronic allograft injury: Mechanisms and potential treatment targets

KTX has good short-term outcomes, but the long-term outcomes are still haven’t achieve a good outcome. 10-year graft loss of more than half, resulting from both immunological and non-immunological causes. Interstitial fibrosis and tubular atrophy on biopsy may be due to rejection (both cellular and antibody mediated), BK virus nephropathy, recurrent pyelonephritis, non-standard donor kidney, ureteral stenosis and CNI nephrotoxicity.
Immunological causes:
Chronic injury can occur by antibodies acting on foreign antigens in the donor kidney (DSA), leading to chronic rejection leads to presenting with proteinuria or impaired sr creatinine.
Late acute rejection – increase the risk of chronic graft dysfunction
Risk of graft failure is high in patients with increased DSA levels and/or C4d positivity on kidney biopsy.
Recurrence of glomerular disease
Infections
Non-immunological causes:
Calcineurin inhibitor (CNI) nephrotoxicity
if high levels are maintained for longer duration although the changes seen in biopsy are non-specific and it has been seen that CNI elimination has worse graft outcomes.
Poor quality of donor graft – extended criteria donors, increased cold ischemia time and significant donor/recipient size mismatch (>2.3g/kg)
Renal artery stenosis leading to graft injury
ureteral obstruction due to ureteral stenosis or ischemia may responsible for chronic graft injury.
Diagnostic strategies
Thorough history
-primary disease
comorbidities – diabetes and hypertension, previous rejection episodes
underimmunosuppression due to non-adherence or physician advised
CNI drug levels.
Investigations
Protocol biopsies – subclinical AMR have worse outcomes than those without rejection or with subclinical cellular rejection.
Preventive strategies
Treatment strategies
Recurrence of the primary glomerular disease must be treated.
## Summarize this article
* There are many causes of chronic allograft loss , including both immunological and non-immunological factors .
*El-Zoghby et al. evaluated 1317 kidney transplant recipients with protocol biopsies at time 0, 4 months, 1, 2 and 5 years post-transplant, with a mean follow up of 50 months, they conducted that:
*Most common cause of graft loss was death with a functioning graft .
*Patient with 5 years graft survival protocol biopsies showed glomerular disease in the form of recurrent glomerular disease and transplant glomerulopathy (37%).
*(IFTA; 30.7%) and acute rejection (12% of cases
# Immunological causes
*Allo MHC molecules leads to chronic immunologically mediated injury( cellular, ABMR or a mix rejection).
*Acute rejection is less common after the first year, but the rate of late acute rejection is about 5% per year.
*It result from prolonged cellular and/or antibody mediated immune response directed to the transplanted organ
*The patient presented with rise in creatinine and/or proteinuria.
*The (DSA) as a major cause of graft dysfunction late after transplant.
*The risk factors are, non compliance affecting more than 40% of kidney recipients and more than half of cases with late rejection & graft loss .
*Diagnosis of chronic ABMR by biopsy exclusion.
*DeKAF conducted that the risk of graft failure was higher in patients with DSA, C4d staining or both & the severity of injury correlated with intensity of the antibody
response.
*Both pretransplant and de novo DSA are associated with significant graft loss.
* The mechanism of chronic injury due to antibody mediated injury to the endothelium of multiple vascular beds( glomeruli, peritubular capillaries and small-medium sized vessels ), this injury leads to cellular hypertrophy, Expansion, duplication of the basement membrane, podocyte injury and finally transplant glomerulopathy.
# Glomerular disease recurrence
*Some types of primary kidney disease (FSGS) has early recurrence and graft loss after transplant (50%–80% ) , while others with a delayed presentation and slowly progression, IgA nephropathy has a high recurrence rate ( 40%), but rarely causes early graft loss and exacerbate with reduction of immunosuppression late after transplantation
* Atypical hemolytic-uremic syndrome rate of recurrence (30%–90%).
# Infections (viral/bacterial)
* lead to kidney allograft injury, associated with the increased use of potent immunosuppressive
* BK nephropathy is a major cause of acute and chronic allograft dysfunction.
* 30%– 65% of patients with BK nephropathy lose their kidney allograft within 1 year of diagnosis.
* Early detection BKV load with serum PCR is mandatory with reduction of immunosuppression.
*CMV may cause injury through an immunomodulatory mechanism leading to
higher susceptibility for infection and rejection.
*CMV post-transplant have significantly worse graft and patient survival.
*UTI lead to chronic inj ury either due to direct injury to the allograft in the setting of an infection affecting the kidney or indirectly, through triggering a rejection process by activation of innate immune system.
# Non-immunological causes
CNI have nephrotoxicity (ranging from vasoconstriction, to tubular, vascular injury and TMA.
# Poor quality donor grafts
*The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors, those with comorbidities, genetic susceptibility in kidney donors and mismatch between donor and recipient size all these affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults .
# Renal artery stenosis and urinary tract obstruction
* lead to graft ischemia and injury.
*It occurs in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after
transplantation.
*The etiology includes stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant artery.
*Diagnosis by arteriography though a doppler ultrasound
*Ureteral obstruction due to anastomotic stenosis or ureter ischemia
# Diagnostic strategies
*The management of patients with chronic allograft injury depends in the underlying cause of injury careful history, degree of hypertension/blood sugar , CNI levels and noncompliance is important.
*Urinalysis with sediment visualizationmay
*kidney ultrasound to exclude mechanical complications ( ureteric obstruction and vascular stenosis).
*Kidney biopsy the justification to perform protocol biopsies includes the detection of specific, unsuspected, graft injury with consequent change in management.
# Noninvasive biomarkers
*It identify earlier ongoing graft injury, predict response to treatment, helping
to individualize immunosuppression and provide earlier intervention prior to clinically evident dysfunction.
# Preventive strategies
* Alternatives to CNI
Researches was done for alternatives to CNI to reduce nephrotoxicity :
-Belatacept( co stimulatory blockade agent )
-mTOR inhibitors have not shown a benefit in improving long-term graft survival
-Everolimus with CNI minimization
-Controlling blood pressure post transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant
-ACEI inhibitors/ARBs no randomized trial has yet demonstrated a benefit in renal transplantation
# Preventing non-compliance
Risk factors include( poor social support, missed appointments, fluctuating drug levels, differences between drug prescribed and dispensed, unexpected late rejection, psychiatric disorder, substance abuse, adolescence, increased time since transplant and financial crisis) so screening at every clinic visit is important
# Treatment strategies
Management of chronic rejection
*Prevention by combined therapies including plasmapheresis, rituximab and (IVIG) in sensitized patients alternatives to rituximab is bortezomib.
*Eculizumab In severe cases of ABMR, eculizumab, inhibits one of the predominant effector functions of the anti-HLA antibody, the complement activation, can be
considered as an adjuvant therapy.
*Adequate treatment of acute ABMR.
* Management of recurrent primary glomerulonephritis, FSGS with high dose steroids, cyclosporine andplasma exchanges to remove circulating humoral factors. *IgA nephropathy may be treated with ACE inhibitors or angiotensin receptor blockers, but specific protocols for recurrence management are lacking.
for native IgA nephropathy, oral prednisone may be advisable.
*Recurrent membranous nephropathy managed with rituximab.
*The treatment of recurrent (MPGN) according to under lying etiological factors.
Despite the improved short-term outcomes of kidney transplantation, more than 50% of kidney allografts are lost by 10 years after transplant. This paper has explored the mechanisms leading to graft injury and what could be its remedy.
Immunological causes
The persistent presence of allo-MHC molecules in the donor kidney leads to a life-long low-grade exposure to foreign antigens that may lead to chronic immunologically mediated injury.
Both pretransplant and de novo DSA are associated with significant graft loss . The rate of de novo DSA ranges between 15% and 20% at 5 years post-transplant in unsensitized recipients and develop- ment of de novo DSA is associated with significant worse 10-year graft survival (57% compared to 96% in patients without de novo DSA)
Glomerular disease recurrence
Non-immunological causes
CNI nephrotoxicity
Poor quality donor grafts
Renal artery stenosis and urinary tract obstruction
Infections( viral/ bacterial)
BKV
CMV
UTI
All can lead to graft failure
Diagnostic strategies
The management of patients with chronic allograft injury depends primarily in the underlying cause of injury .
Noninvasive biomarkers
Can help to identify injury early
Protocol biopsies
Can be considered once strongly indicated
Preventive strategies
Alternatives to CNI
Preventing non-compliance
Treatment strategies
Management of chronic rejection
Management of recurrent primary glomerulonephritis
Chronic allograft injury can significantly affect long-term graft survival. Therefore, prevention of injury should be a major focus of caring of transplant recipients. Based on the heterogeneity of causes of injury , strategies may include
CNI minimization,
better preservation of the allograft after retrieval, use of protocol biopsies,
active noncompliance screening,
measurement of DSA post-transplant and other potential novel biomarkers of graft injury,
BK surveillance
aggressive treatment of hypertension, hyperglycemia and hyperlipidemia.
This paper describes potential mechanisms and treatments for chronic graft injury, after all, 50% of transplants do not exceed ten years for various reasons, including immunological or non-immunological factors.
Immunologic causes tend to be cellular, antibody or mixed mediated. The presence of increased creatinine or proteinuria suggests rejection. DSA and/or C4d deposits are also risk factors. The increase in DSA promotes glomerulitis, capillaritis, and other endothelial lesions.
Recurrent glomerular disease, viral (mainly BK and CMV), bacterial, fungal infections are non-immunological causes that can lead to graft loss. Calcineurin inhibitor-induced nephrotoxicity, graft quality, clinical conditions, ischemia time, and veno-occlusive obstruction are other forms of chronic graft injury.
Diagnostic strategies are highly variable and depend heavily on the availability and standardization of each service. Histopathological tends to follow the pattern established by the BAANF.
The main risk factors are poor social support, frequent absences, fluctuating drug levels, psychiatric illness, adolescence, illicit drug use, and long transplant times. Chronicity, DSA MFI > 2500, and elevated proteinuria are laboratory markers that complement the clinical findings.
Introduction
The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors. Death with a functioning graft was the most common cause of graft loss. For those patients that survived up to 5 years after transplant, the predominant findings on protocol biopsies were glomerular disease (37%), tubular atrophy/tubular atrophy (IFTA; 30.7%) and acute rejection (12% of cases).
Cellular and/or antibody-mediated rejection (ABMR) was the leading culprit of IFTA followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity.
Immunological causes
The most common type of rejection after the first year of transplant is chronic rejection, defined as a prolonged cellular and/or antibody mediated immune response against the graft that may present with either a rise in creatinine and/or proteinuria.
The role of donor-specific antibodies (DSA) as a major cause of graft dysfunction late after transplant in being increasingly determined.
Noncompliance may be a major culprit, affecting up to 40% of kidney recipients and associated with more than half of cases of late rejection leading to graft loss.
Diagnosis of chronic ABMR requires a kidney biopsy to exclude other potential causes.
Risk of subsequent graft failure was significantly higher in patients with DSA, C4d staining or both, and the severity of clinical injury directly correlated with the intensity of the antibody response.
Both pretransplant and de novo DSA are associated with significant graft loss. The rate of de novo DSA ranges between 15% and 20% at 5 years post-transplant in unsensitized recipients and development of de novo DSA is associated with significant worse 10-year graft survival (57% compared to 96% in patients without de novo DSA).
Transplant glomerulopathy is one of the predominant findings on chronic ABMR,but it is not specific to rejection as other causes of chronic endothelial injury may lead to similar pattern of injury including thrombotic microangiopathy, recurrent autoimmune glomerulonephritis and hepatitis C-related glomerulonephritis.
Glomerular disease recurrence
Recurrence was the third leading cause of graft loss.
Focal segmental glomerulosclerosis (FSGS) tends to recur early after transplant with massive proteinuria and is associated with graft loss in 50%–80% of cases. Atypical hemolytic-uremic syndrome has also a high rate of recurrence (30%–90%).IgA nephropathy has a high recurrence rate (up to 40%) but rarely causes early graft loss and commonly may exacerbate with reduction of immunosuppression late after transplantation.
Early recognition and intervention of recurrence may potentially improve long-term graft survival.
Infections (viral/bacterial)
With the increased use of more potent immunosuppressive drugs in the past 15 years, BK nephropathy has become a major cause of both acute and chronic allograft dysfunction. Donor and recipient BK serologies do not predict the risk of infection and the intensity of immunosuppression seems to be the predominant risk factor. The challenge in regards to BK is that 30%–65% of patients that develop BK-associated nephropathy lose their kidney allograft within 1 year of diagnosis, so surveillance of BK with serum PCR has become routine in most transplant centers since early detection of a rise in BK viral load may drive reduction of immunosuppression.
Patients with greater than 10,000 copies of BK and allograft dysfunction are likely to have BK nephropathy, biopsy is important to confirm the diagnosis with SV40 staining for the BK virus.
CMV infection is one of the most common opportunistic infections after kidney transplantation. CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility for infection and rejection. Direct involvement of CMV infection on the kidney is demonstrated by necrotizing crescentic glomerulonephritis with viral inclusions.
General infections such as urinary tract infections may also lead to chronic injury either due to direct injury to the allograft or indirectly, through triggering a rejection process due to the activation of innate immune system with increased expression of costimulatory molecules and lowering of the threshold for T cell activation and proliferation.
Non-immunological causes
CNI nephrotoxicity
It has significant nephrotoxicity ranging from vasoconstriction to tubular and vascular injury, and in rare cases thrombotic microangiopathy. Long-term allograft fibrosis was related to chronic CNI toxicity that led to IFTA, glomerulosclerosis and arteriolar hyalinosis.
Poor quality donor grafts
The expansion of the donor pool to include kidneys from donors after cardiac death, elderly donors or those with comorbidities(e.g. diabetes and hypertension) may significantly affect the allograft survival due to presence of preexisting injury, lower nephron mass and greater susceptibility of new insults.
Subsequent graft insults may come on the form of ischemic injury such as during prolonged cold ischemic time after kidney retrieval, poor blood pressure or blood sugar control post-transplant, infections and/or superimposed alloimmune injury.
Renal artery stenosis and urinary tract obstruction
It occurs in up to 5% of kidney recipients and is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in blood pressure within the first few years after transplantation.
Gold-standard imaging for diagnosis is arteriography though a Doppler ultrasound is frequently used as a screening method.
Ureteral obstruction due to anastomotic stenosis or ureter ischemia may lead to significant hydronephrosis and graft injury.
Diagnostic strategies
Urinalysis with sediment visualization may help in the identification of potential etiologies as cellular casts, granular casts or significant proteinuria indicative of an active glomerulonephritis, acute tubular necrosis or transplant glomerulopathy.
Ultrasound may exclude mechanical complications such as ureteric obstruction and vascular stenosis.
Biopsy should be performed in the majority of patients with dysfunction and no clear reversible factor present or if other worrisome features such as significant proteinuria or cellular casts are present.
Noninvasive biomarkers: protein and mRNA levels of CXCL9 was shown to be a great predictor of rejection. A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection. NK cell immunophenotyping
The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA for the prediction of antibody-mediated rejection. The distinction among the different DSA IgG isotypes seems to be relevant, with IgG3 showing worse outcomes.
Protocol biopsies
Treatment strategies
Preventative measures (controlling blood pressure, Techniques to better preserve the donor kidney after retrieval, preventing non-compliance to medications).
Preventive combined therapies including plasmapheresis, rituximab and intravenous immunoglobulin (IVIG) are used in sensitized patients.
Management of recurrent primary glomerulonephritis.
Conclusion
Chronic allograft injury can significantly affect long-term graft survival.
Strategies may include CNI minimization, better preservation of the allograft after retrieval, use of protocol biopsies, active noncompliance screening, measurement of DSA post-transplant and other potential novel biomarkers of graft injury, BK surveillance and aggressive treatment of hypertension, hyperglycemia and hyperlipidemia.
Summarize this article
Abstract:
Despite improvement of the short term graft survival after kidney transplant still long term graft survival hampered by many immunological and non-immunological factors that lead to progressive allograft injury and loss , this review study focus on identification of the pathogenesis of the different factors and treatment options.
According to the evidence from reviewing the protocol biopsies over different follow up time from day 0,1month, 4month 1,2 years and up to 5 years mean fu 50 months mainly from registry studies and the finding as follows.
Death with functioning graft is the most common cause of graft loss
5 years post-transplant protocol biopsies findings:
Acute rejection in 12% only while late acute rejection after 1 year reported in 5%.
After 1 year most common type of rejection is chronic ABMR which typically characterized by graft dysfunction and proteinuria and positive DSAs
Recurrence or denovo glomerulonephritis in 37%
IFTA found in 30.7%, which is nonspecific sign of chronic graft injury is just replaced the previous term of chronic allograft nephropathy as per the Banff classification since 2005 and IFTA could be part of chronic TCMR and CAMR, or chronic CNI toxicity, BKV Nephropathy, pyelonephritis, ureteral obstruction and part of ECD with poor quality of the donor kidney.
The DeKAF study reported the histological finding after 7 years FU for chronic graft injury includes Rejection CABMR ,which significantly correlated with C4D staining , clinical proteinuria, and the level of DSA and main risk factor for chronic rejection is the nonadherence to immunotherapy which was reported in 40% of cases either intentional immunosuppressive reduction in case of serious infection or malignancy or due other personal strain like mental stress ,cost, its more in young recipients .
Immunological factors:
Poor HLA match,Prior sensitization, new alloantibodies, non-compliance ,rejection episode both performed and denovo DSA associated with chronic rejections, denovo DSA associated with poor 10 years graft survival.
Transplant glomerulopathy nonspecific to chronic graft rejection and can be seen in chronic TMA, chronic HCV glomerulopathy or autoimmune glomerulopathy which characterized by chronic endothelial injury .
Non immunological factors :
Infections like BKV, CMV, pyelonephritis, sepsis
Recipients related factors associated with chronic allograft injury includes
Cni toxicity, Ischemic heart disease, Hypertension, renal artery stenosis, Diabetes Dyslipidemia Drug induced interstitial nephritis
Glomerular or denovo recurrence of glomerular diseases is the 3rd leading cause of chronic graft injury as per Australian registry data some of glomerular disease relapse early post-transplant like FSGS, ahus, IgA nephropathy and some they have lower rate and slower progression like MGN early recognition and intervention is the key to prevent graft loss.
Many donors related risk factors of chronic allograft injury:
ECD from old patients with comorbid disease, DCD, small nephron mass, long cold ischemia, DGF, IRP, and size mismatch.
Management of chronic graft injury :
No specific protocol or guideline for management of chronic allo graft injury and the best strategy is to focus on prevention by identification of the risk factors and work on minimization or avoidance improved compliance with medication and diagnostic tools like using DSA monitoring, protocol biopsies and adopt new novel molecular biomarkers that would help in early diagnosis , better selection of the donors and avoid repeat mismatches, treatment of non-immunological medical conditions like control of DM , heart disease ,HTN , proteinuria ,dyslipidemia, infections , drug toxicity .
Chronic allograft injury: Mechanisms and potential treatment targetsintroduction
after 10 years of transplant >50% of kidney allograft have been lost.
immunological factors is leading cause of graft loss.
causes of IFTA:
1)cellular and or antibody -mediated rejection.
2)BK virus.
3) recurrent pyelonephritis.
4)poor quality donor kidney.
5)ureteral stenosis.
6)CNI nephrotoxicity.
Banff 2005 classification system renamed CAN to IFTA.
this article will highlight details the pathogenesis and treatment strategies of chronic allograft injury.
immunological causes
chronic immunological induced injury is result from lifelong low grate exposure to foreign antigens.
it is unclear if subclinical inflammation is related to cellular -mediated rejection or other process.
chronic rejection is common after one year of transplant and mainly result from DSA.
chronic ABMR diagnosis by kidney biopsy.
10 year graft survival has worse outcome in the patient has develop of de novo DSA.
late allograft failure result from alloimmune response which is mainly caused by DSA.
glommular disease recurrence:
at 10 years after transplant recurrence disease was the third leading cause of graft loss
FSGS recurrence and associated with graft loss in 50 to 80 % of cases..
Atypical HUS 30 to 90% rate of recurrence
overall recurrence disease posttransplant is heterogenous process with variable consequence.
early recognize and intervention may improve long term graft survival.
Infection(viral /bacterial)
allograft injury maybe caused by bacterial or viral infection.
BK virus major cause of graft and chronic allograft dysfunction.
risk factor for BK virus is the intensity of immunosuppression.
30 to 65% of patients develop BK -associated nephropathy loose their kidney allograft within 1 years of diagnosis.
surveillance of BK PCR to detect early the risk of BK viral load may drive reduction of immunosuppression.
BK virus >10000 copies of BK virus and allograft dysfunction are likely to have BK nephropathy.
so renal biopsy is important to confirm diagnosis with SV40 stanning for the BK virus.
CMV infection is one of the most common opportunistic infection after kidney transplant.
recipient whom develop CMV posttransplant have worse graft and patient survival.
NON Immunological
CNI nephrotoxicity
mechanism of CNI nephropathy
1)vasoconstriction
2)acute tubular injury.
3)vascular injury.
4)TMA is rare.
CNI regimen still the best over others and this supported by:
1)combination of CNI with other standard immunosuppression regimen is out come after 3 years follow up is lower rate of rejection ,lower fibrosis and improved renal function..
2)premature randomized trial CNI withdrawal there is high rate of development of dnDSA.
Poor quality donor graft
factors associated with worse graft outcome:
1)deceased donor from cardiac death
2)elderly donors.
3)comorbidities DM, HTN.
4)Genetic susceptibility in kidney donor (two high risk alleles for APOL1).:
5)significant mismatching between donor and recipient size (kidney weight /recipient weight <2.3g/kg) .
6)prolong cold ischemia
Renal artery stenosis and urinary tract obstruction.
RAS result in graft ischemia and injury
present by :
1)persistent uncontrolled HTN.
2)Flash pulmonary oedema.
3)acute elevation of Bp with few years after transplant.
ureteric obstruction
due to:
1)anastomotic stenosis.
2)ureteric ischemia.
lead to hydronephrosis and graft injury.
diagnostic strategies:
management of chronic allograft injury depend on primary underlying cause of injury .
Non invasive biomarker
non-invasive biomarker is detected ongoing graft injury and response to treatment
make timely decision to clinician to avoid clinical evident of graft dysfunction e.g protein and mRNA level of CXCL9 is predictor of rejection detected 30 days before biopsy proven rejection.
anti HLA DSA is best non-invasive biomarker clinically available. although not all patients with DSA carry worse prognosis .
DSA IgG3 showing worse outcome.
Protocol biopsies
protocol biopsy used to detected specific ,unsuspected graft injury with consequent change in management.
subclinical rejection need to specific the cause of subclinical inflammation to select appropriate effective therapy .
Preventive strategies alternative to CNI
Research for alternative to CNI to minimize nephrotoxicity has led to development of costimulatory blocker agent(beltacept).
beltacept first given every 2 week then monthly as an infusion in place of CNI
despite approval of FDA but its use is limited as associated with high rate of acute cellular rejection in the first year of transplant.
Bp controlled posttransplant is associated with an improvement in graft survival in 1 and 3 years posttransplant
preventing non compliance:
detect the risk of non compliance is crucial such as :
1)poor social support
2)psychiatric illness
3)substance abuse and others.
management of chronic rejection
most common cause of chronic ABMR is acute ABMR.
prevention is use plasmapheresis ,rituximab or bortezomib and IVIG in sensitized patient
eculizumab in sever ABMR can be adjuvant therapy
FDA has no approval therapy for chronic ABMR.
clinical trials are needed to address the safety and efficacy of B cell and DSA depleting strategies in chronic rejection
poor prognostic marker of CABMR:
1)serum creatinine >3mg/dl
2)protein /creatinine ratio>1g/day
3)Banff>8
4)DSA>2500MFI
increase immunosuppression and consider steroid and IVIG.
if no poor prognostic marker in cABMR treatment as follow:
Step1
1)increase immunosuppression baseline
2)steroid /IVIG
3)Thymoglobulin .
Step2
1)Adjuvant therapy with pp/rituximab( low grate evidence)
2)protease inhibitor or eculizumab(very low grate evidence)
prepare patient for next transplant:
1)do not stop all immunosuppression after graft fail
2)avoid repeat HLA mismatch if possible
management of recurrent Primary GN
recurrent FSGS treatment with steroid ,cyclosporin and PLEX has better result comparing group without plasma exchange.
recurrent IgA treated with ACE but no specific treatment for recurrent I
recurrent MN treated with Rituximab.
MPGN treatment:
secondary MPGN treat the cause
primary MPGN no consensuses exists
some of type 1MPGN recurrent
cases successfully treated with rituximab.
recurrent c3 glomerulopathy and dense deposit disease treated by eculizumab with variable response
Conclusion
chronic allograft injury affect long term graft survival
strategies to prevent Chronic allograft injury:
1)CNI minimization
2)prevention of the allograft after retvieral
3)use of protocol biopsy.
4)active non compliance screening.
5)measurement of DSA posttransplant
6)protentional novel biomarker of graft injury
7)BK virus surveillance and aggressive treatment of HTN ,DM and hyperlipemia.
.
Thank You, try to make it shorter Dr Manal
Summarize this article
Kidney transplantation is the best treatment for end stage renal disease. Short term outcomes of graft and patient survival, are successfully achieved. However, long-term outcomes are suboptimal.
The graft survival on the long term is affected by several factors including immunological and immunological causes.
Interstitial fibrosis and tubular atrophy in chronic allograft nephropathy are the cornerstone of diagnosis. This could be due to:
– Rejection (both cellular and antibody mediated)
– Viral infection namely BK virus nephropathy
– Recurrent pyelonephritis
– EDK criteria
– Ureteral stenosis
– CNI nephrotoxicity
Immunological vs non-immunological
Immunological causes: activation of immune response due to the presence of foreign antigen resulting in the formation of de novo DSA, which manifest clinically in proteinuria and slowly progressive renal failure.
Risk of graft failure:
– High DSA level
– C4d positivity on kidney biopsy
Another major immunological cause is recurrence of glomerular disease which requires early diagnosis and management.
– FSGS has recurrence of 20-80% with 50-80% graft loss.
– IgA nephropathy has 20-40% recurrence rates with 5-15% graft loss.
– Infections like BK virus causes chronic graft injury in 30-65% patients.
– CMV infection, due to immunomodulatory mechanism, leads to increased rejection with poorer graft survival.
– Urinary tract infections can also trigger a rejection process by activating innate immune system.
Non-immunological causes:
– CNI nephrotoxicity when exposure to high levels for prolonged periods.
– Poor quality of donor graft due to extended criteria donor
– Increased cold ischemia time
– Donor/recipient size mismatch
– Renal artery stenosis
– Ureteral obstruction
Early diagnosis of chronic allograft injury is required as early interventions may be helpful. Diagnostic strategies for chronic graft injury include:
– Comorbidities as diabetes, hypertension and ASCVD
– Adequate history about the primary disease
– Previous rejection episodes including biopsy results
– Non-adherence
– CNI levels.
Required investigations
– Urinalysis
– Renal imaging with graft ultrasound
– Kidney biopsy
Preventive strategies
– Maintaining therapeutic CNI levels
– Blood pressure control
– Early identification of rejection episodes (including subclinical rejections in protocol biopsies for previously sensitized patients)
– Early identification and treatment of infectious complications
Thank You
Chronic Allograft Nephropathy was defined as dysfunctional kidney grafts without clear cause, which was later replaced by IFTA in the revised Banff 2005 classification. There are multiple causative factors of chronic graft loss and one of the study showed the commonest cause of graft loss is the death with a functioning graft and almost 50% of allografts failed within 10years post transplant.
Immunological Causes of IFTA
Lifelong low grade exposure to foreign antigens resulting in antibody-mediated, cellular or mixed rejection.
Late onset acute Rejection
Infections
Non Immunological causes
CNI toxicity
Poor donor selection
Renal artery stenosis
TMA
Post renal urinary obstruction
Diagnosis ; Careful detailed history including the primary disease, comorbidities like diabetes and hypertension, previous rejection episodes, under immunosuppression due to non-adherence or asking about the CNI drug levels should be taken. Investigations like urinalysis to check for cast and proteinuria , Doppler ultrasound of the grafted kidney as well as allograft biopsy including the protocol biopsies should be part of the center protocol. Non-invasive biomarkers like anti-HLA DSA with IgG isotyping (IgG3 showing worse outcomes), mRNA levels of CXCL9, urinary mRNA signatures of CD3E,CXCL10, 18S ribosomal RNA and NK cell immuno-phenotyping e.g NKG2A(45,46, 47)have shown increased correlation with chronic graft injury.
Treatment of chronic ABMR
Treatment of chronic active ABMR is difficult since it is associated with irreversible tissue damage and no proper FDA approved treatment mentioned in the literature for chronic active ABMR, Current treatment is directed against the following:
Main therapy
High dose Methylprednisolone -Decreasing inflammation produced by rejection
IVIG -Decreasing production of antibodies
Intensify baseline immunosuppression
ATG if associated with cellular rejection
Second line agents in case of refractory chronic ABMR (poor evidence)
Rituximab- Depleting B cells only if there is biopsy evidence of active microvascular inflammation and given 1 week after completion of IVIG
Plasmapharesis- Removing DSA play no rule in chronic active ABMR
Third-line agents (very poor evidence)
Bortezomib and eculizumab showed no benefit in treatment of chronic active ABMR
In case of graft failure, it is recommended not to stop immunosuppression in order to prepare the patient to the next transplant to avoid rebound of DSA
Thank You
III. Chronic allograft injury: Mechanisms and potential treatment targetsï‚· Summarize this article
Chronic allograft injury can result from both immunological & non-immunological factors.
1. Immunological causes:
Chronic immunologically mediated injury results from life-long exposure to foreign allo-HLA molecules in the donor kidney.
This injury could be cellular, antibody-mediated or a mix rejection.
The rate of late acute rejection is about 5%/year.
It is the most common type of rejection after the 1st year of transplant; it presents with either a rise in creatinine &/or proteinuria.
The role of DSA as a major cause of graft dysfunction late after transplant is being increasingly recognized.
Risk factors include noncompliance, affecting up to 40% of recipients & associated with more than half of cases of late rejection leading to graft loss.
Diagnosis of CABMR requires a biopsy to exclude other potential causes.
In DeKAF, the risk of graft failure was significantly higher in patients with DSA, C4d or both, & the severity of clinical injury directly correlated with the intensity of the antibody response.
Both preformed & dnDSA are associated with significant
graft loss.
The mechanism of injury involves an antibody-mediated injury to the endothelium of glomeruli, PTCs & small-medium sized vessels. The endothelial injury leads to cellular hypertrophy, expansion & duplication of the BM & some podocyte injury, with the pathologic appearance of TG on biopsy.
TG is, however, not specific; it can be seen in TMA, recurrent autoimmune GN & HCV-related GN.
—————————————————————–
2. Glomerular disease recurrence:
At 10 years after transplant, recurrence was the 3rd leading cause of graft loss (Australia/New Zealand registry).
No clear risk factors were identified that predicted
recurrence risk.
FSGS recurs early after transplant with massive proteinuria & is associated with graft loss in 50%–80% of cases.
Atypical HUS has also a high recurrence rate (30%–90%) depending on the underlying complement abnormality.
IgA nephropathy has a high recurrence rate (up to 40%)
but rarely causes early graft loss & commonly may exacerbate with reduction of IS late after transplantation.
Early recognition & intervention potentially improve long-term graft survival.
————————————————————
3. Infections (viral/bacterial)
BK nephropathy:
A major cause of both acute & chronic graft dysfunction.
The intensity of IS is the main risk factor.
Viruria is followed by viremia & then nephropathy.
A 30%–65% of patients lose their graft within 1 year of BK nephropathy.
Surveillance with serum PCR is important(early detection mandate reduction of IS).
Biopsy is needed to confirm the diagnosis & to exclude any other etiology of graft dysfunction.
CMV infection:
A common post-transplant infection.
Presentations include:
– CMV syndrome (fever, weakness, myalgia)
– Colitis
– Pneumonitis
– Hepatitis
– Higher susceptibility for infection & rejection through immunomodulatory mechanisms.
Recipients who developed CMV post-transplant have significantly worse graft & patient survival.
General infections such as UTIs may lead to chronic injury either due to direct injury to the allograft or indirectly, through triggering a rejection process due to the immunological activation.
================================
4. Non-immunological causes
CNI nephrotoxicity
Ranges from vasoconstriction to tubular & vascular injury, & rarely TMA.
Multiple trials tested the hypothesis that CNI minimization or avoidance could reduce graft injury & improve long-term graft survival.
However, studies failed to confirm this benefit on long term follow up.
CNI cause significant nephrotoxicity,particularly with high maintenance levels.
Current protocols of lower CNI exposure do not seem to be the primary cause of many of the graft deteriorations that occur & avoidance of CNI without any substitute agent will lead to poor outcomes.
Poor quality donor grafts
– DCD, elderly donors or those with comorbidities(e.g. DM & hypertension)
affect graft survival due to presence of preexisting injury & lower nephron
mass.
– Presence of genetic susceptibility in kidney donors (e.g. 2 high-risk alleles
for APOL1) is associated with worse graft survival.
– Significant mm between donor & recipient size is associated with a higher
rate of hypertension, proteinuria & lower graft survival.
Renal artery stenosis
RAS may lead to graft ischemia & injury.
It occurs in up to 5% of kidney recipients & is suspected in patients with persistent uncontrolled hypertension, flash pulmonary edema, or an acute elevation in BP within the 1st few years after transplantation.
It is caused by stenosis in the anastomotic site or the development of an atherosclerotic plaque in the transplant artery.
Diagnosis by arteriography; Doppler ultrasound is an screening test.
Urinary tract obstruction
Is due to anastomotic stenosis or ureter ischemia & may cause significant hydronephrosis & graft injury. Ultrasound would identify an obstruction & fluoroscopy would identify the exact obstructed site.
Diagnostic strategies
H/O the primary renal disease, the early post-transplant course & events e.g. severe DGF, episodes of acute rejection, degree of hypertension/blood sugar control, CNI levels over time & noncompliance is important.
Urinalysis: cellular casts, granular casts or significant proteinuria may indicate an active GN, ATN or TG, respectively.
Ultrasound may exclude ureteric obstruction & vascular stenosis.
A kidney biopsy should be performed in the majority of patients with dysfunction and no clear reversible
factor present; it is also indicated if there is significant proteinuria or cellular casts.
Noninvasive biomarkers
Mostly restricted to research setting.
Measurement of anti-HLA DSA for the prediction of AMR is the best noninvasive biomarker clinically available.
Testing for DSA C1q fixation properties are of limited value in predicting future chronic injury.
Differential DSA IgG isotypes is helpful, with IgG3 showing worse outcomes.
Protocol biopsies
May detect specific, often unsuspected, graft injury with consequent change in management.
25% of biopsies may lead to change in management (Henderson et al).
Preventive strategies
Alternatives to CNI
1. Belatacept (co-stimulatory blockade):
It is a CTLA4Ig fusion protein that blocks the CD80/CD86 interaction with CD28 preventing T cell activation.
Contraindicated in EBV-ve status(higher risk of PTLD)
High rates of ACR in the 1st post-transplant year has limited its use.
Data of 7-year follow-up with belatacept regimen suggest a significant better graft function & survival when compared to cyclosporine; not compared to the most commonly used tacrolimus.
2. mTOR inhibitors:
Do not improve long-term graft survival.
The potential role of everolimus with CNI minimization is promising.
TRANSFORM is an ongoing randomized trial comparing minimized CNI plus everolimus vs. standard CNI plus MMF.
3. ACEI inhibitors/ARBs:
No randomized trial has yet shown a benefit in renal transplant.
Significant S/E (e.g. anemia, hyperkalemia & GFR reduction) has limited its broad use.
Preventing non-compliance
– Screening at every clinic visit is important
– More frequent monitoring of drug levels & kidney function in high-risk
patients.
– Address complexity of the drug regimen & financial issues
Treatment strategies
Management of chronic rejection:
Focused on avoiding acute ABMR as it is the most significant risk factor for chronic ABMR.
PP, rituximab & IVIG are used in sensitized patients.
Bortezomib is a potential alternative to rituximab
to reduce antibody production.
Eculizumab used as adjunctive in severe cases of ABMR.
Treating acute ABMR avoids CABMR, however, >40% of cases do not resolve after standard treatment with rituximab.
Only few treatments have been tested in CABMR.
In the largest study of CABMR published to date(123 patients with BP-CABMR followed for a median of 9.5 years pos-transplant & 4.3 years after CABMR), the addition of rituximab or ATG to steroids/IVIG did not improve graft survival significantly.
Management of recurrent primary GN
Recurrent FSGS:
High dose steroids & cyclosporine aiming podocyte stabilization, combined with PP to remove circulating humoral factors. Better results seen with this regimen compared to historical control group without PP.
Recurrent IgA nephropathy:
May be treated with ACE i or ARBs; specific protocols for management are lacking.
Oral prednisone may be advisable.
Recurrent membranous nephropathy:
May be managed with rituximab; some patients respond to therapy up to 1 year after treatment.
Recurrent MPGN:
No consensus exists for the idiopathic cases related to immune complexes, & steroids, cyclophosphamide &/or PP have been unsuccessful.
Rituximab was successful in some recurrent type I or idiopathic disease.
MPGN due to dysregulation of alternative complement pathway, C3 glomerulopathy & DDD have been recently managed with eculizumab, with variable responses.
Thank You, this is massive. Try to make your summary shorter Dr Mohamed
Summary:
Despite the improvement in short term outcomes of kidney transplantation, many grafts are lost 10 years post-transplantation.
The causes of chronic allograft loss are multifactorial including both immunological and non-immunological causes.
Five years post-transplantation, the predominant feature in graft biopsy are IFTA, glomerular disease, and acute rejection.
Chronic Allograft Nephropathy was used to describe dysfunctional kidney grafts of unclear cause, then it was replaced by the term IFTA by the revised Banff 2005 classification.
Immunological causes:
The presence of allo-MHC molecules in the donor’s kidney leads to chronic immunologically mediated injury ( chronic rejection).
Chronic injury presented usually with either rise in serum creatinine or proteinuria.
The role of DSA and non-compliance are increasingly recognized.
The importance of recurrence of native kidney disease in the allograft has changed by the protocol biopsy studies as they demonstrate their significant impact on graft injury. While some forms of primary kidney disease are associated with a high risk of recurrence and graft loss early after transplant, others may be associated with a delayed presentation and slowly progressive course such as FSGS may recur early after transplantation and is associated with early graft loss while IgA nephropathy has a high recurrence rate (up to 40%) but rarely causes early graft loss.
Both viral and bacterial infections may lead to kidney allograft injury such as BK virus infection, as 30-65% of patients that develop BK nephropathy lose their allograft within 1 year of diagnosis.In addition, CMV may also exert injury through an immunomodulatory mechanism leading to higher susceptibility to infection and rejection. General infections such as urinary tract infections may also lead to chronic injury either due to direct injury to the allograft or indirectly, through triggering a rejection process.
Non-immunological causes:
Diagnostic strategies:
Noninvasive biomarkers:
Noninvasive biomarkers have the potential to earlier identify ongoing graft injury as well as predict response to treatment.
Protein and mRNA levels of CXCL9 were shown to be a great predictor of rejection with an elevation in levels detected 30 days before a biopsy-proven rejection. A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was also associated with rejection. All these biomarkers are used only in research settings.
The best noninvasive biomarker clinically available is the measurement of anti-HLA DSA for the prediction of antibody-mediated rejection with C1q binding and IgG3 subclass shown to be associated with worse allograft survival.
Preventive strategies:
Treatment strategies:
Management of chronic rejection:
Avoiding Acute ABMR as it is a significant risk factor for chronic ABMR, using combined PP, IVIG and rituximab in sensitized patients, an alternative to rituximab is bortezomib, and in severe cases, eculizumab may be used.
Management of recurrent glomerular disease:
recurrent FSGS: PP+ steroids (high dose)+ cyclosporin
recurrent IgA: ACEi or ARB, oral prednisolone for 1-2 months may be advisable. no specific protocol for treatment.
recurrent MN: rituximab
recurrent MPGN: according to the aetiology
Thank You
According to Elzoghby et al (n =1317 transplanted patients) , death with a functioning graft was the most common cause of graft loss among transplanted recipients with protocol biopsies at different times up to 5 years post-transplant.
Other main risk factors and causes of chronic allograft injury include:
vAlloimmune :
1- Poor HLA match
2- Prior sensitization
3- New alloantibodies
4- Non compliance
5- Rejection episode:
Chronic rejection in form of prolonged cellular and/or antibody mediated immune response against transplanted organ leading to increased creatinine and/or proteinuria.
vRecurrence of de novo glomerular disease:
1- FSGS: has 20 to 50 % of recurrence and 50 to 80% risk of graft loss.
2- Atypical HUS
3- Dense Deposit Disease
4- C3 glomerulopathy
5- IgA nephropathy
6- Membranous GN
Also systemic diseases like oxalosis, scleroderma, SLE, ANCA vasculitis, diabetic nephropathy …etc
vRecipient related causes:
1- CNI nephrotoxicity
2- Diabetes
3- Hypertension
4- Renal artery stenosis
5- Ureteral obstruction
6- Heart failure
7- Drug induced acute interstitial nephritis
vDonor related:
1- Poor quality donor kidney: kidneys from donors after cardiac death, elderly donors or with comorbidities.
2- Prolonged ischemia
3- Delayed graft function
4- Significant size mismatch
vInfections :
1- BK nephropathy:
It is a major cause of both acute and chronic allograft dysfunction. It found in renal tubule and with the use of strong immunosuppressant it will replicate largely causing viruria, viremia and then nephropathy.
30 to 65% of patients with BK nephropathy lose their kidney allograft within 1 year of diagnosis.
2- CMV infection:
It can lead to end organ disease (pneumonitis, colitis, hepatitis) and may cause injury through immunomodulatory mechanism leading to high risk of infection and rejection.
Direct kidney affection is rare causing necrotizing crescentic glomerulonephritis.
3- Recurrent pyelonephritis
4- Sepsis
Diagnostic strategies:
Careful history taking of the primary cause.
Control of diabetes and hypertension
Urine analysis
Kidney ultrasound with Doppler
Kidney biopsy
Investigations for BK and CMV infection
Anti-HLA DSA and its isotype
Protocol biopsies
Preventive strategies:
1- Alternatives to CNI: use of Belatacept which blocks the CD80/CD86 interaction with CD28 preventing T cell activation.
2- Preventing non-compliance: with social, psychological and financial support.
Continuous education and warning in each follow up visit.
Treatment strategies:
1- Proper management of chronic rejection
2- Management of recurrent primary cause
3- Aggressive management of infection
4- Modulation and reduction of immunosuppression drugs for the most common viral infections.
Thank You Naglaa
Nice to see your active contributions
Thank You Mohamed
Mechanisms of chronic allograft injury:
1- Chronic glomerular injury proved by mesangial sclerosis and basement membrane duplication and it is cause by the following diseases: a- DM, HTN
b- recurrent GN like FSGS, immune complex deposition
disease
c- AMR
d-TMA
2- Chronic endothelial/vascular injury proved by basement membrane duplication, arterial wall thickening and hyalinosis…this caused by AMR, cellular rejection, TMA, CNI toxicity
3- Chronic tubulointerstitial injury proved by IF/TA interstitial fibrosis and tubular atrophy and caused by CNI toxicity, BK nephropathy, rejection and recurrent UTI and obstruction.
Treatment target of chronic graft injury is based on
1- Prevention kidney protection from the start of process old age kidney, DCD,ECD, also try to minimize cold and warm ischemia so try to protect kidney, also identification of high risk patients, intensify immunosuppression, desensitization program.
2- Early detection and diagnosis of high bl.p and bl.glucose so optimization of the treatment is important, detection of CNI toxicity and recurrent GN , BK nephropathy and UT obstruction and infection
3- Early diagnosis and management of chronic AMR
4- Prepare for next transplant before going to dialysis
Thank You
. -50% of kidney allografts are lost by 10 years after transplant.
-The causes of chronic allograft loss are multifactorial, including both immunological and non-immunological factors.
-Death with a functioning graft was the most common cause of graft loss.
– For those patients that survived up to 5 years after transplant, the predominant findings on protocol biopsies were glomerular disease (37%), tubular atrophy/
tubular atrophy (IFTA; 30.7%) and acute rejection (12% of cases).
-Glomerular diseases can be recurrent glomerular disease or transplant
glomerulopathy.
– Causes of IFTA: Cellular and/or antibody-mediated rejection (ABMR) followed by BK nephropathy, recurrent pyelonephritis, poor quality donor kidney, ureteral stenosis, and calcineurin inhibitor (CNI) nephrotoxicity.
-The persistent presence of allo-MHC molecules in the donor’s kidney leads to chronic immunologically mediated injury that may take the form of cellular, antibody-mediated, or a mix rejection.
-The kidney graft inflammation detected early on surveillance biopsies that do not fit the criteria of rejection has been associated with the development of tubular atrophy and/or graft loss.
-The most common type of rejection after the first year of transplant is chronic
rejection, which is defined as a prolonged cellular and/or antibody-mediated
immune response against the transplanted organ that may present with either a rise in creatinine and/or proteinuria.
– Noncompliance may be a major cause, affecting up to 40% of kidney recipients and associated with more than half of cases of late rejection leading to graft loss.
-Risk of subsequent graft failure was significantly higher in patients with DSA, C4d staining, or both, and the severity of clinical injury directly correlated with the intensity of the antibody response.
-Both pretransplant and de novo DSA are associated with significant
graft loss.
– Transplant glomerulopathy is one of the predominant findings on chronic ABMR, it is not specific to rejection since other causes of chronic endothelial injury may lead to a similar pattern of injury including thrombotic microangiopathy,
recurrent autoimmune glomerulonephritis and hepatitis C-related
glomerulonephritis
-Some forms of primary kidney disease are associated with a high risk of recurrence and graft loss early after transplant, and others are associated with a delayed presentation and slowly progressive course.
-Both viral and bacterial infections may lead to kidney allograft
injury.
-With the increased use of more potent immunosuppressive
drugs in the past 15 years, BK nephropathy has become a major cause
of both acute and chronic allograft dysfunction.
-30%–65% of patients that develop BK-associated nephropathy lose their kidney
allograft within 1 year of diagnosis
-CMV infection is one of the most common opportunistic infections
after kidney transplantation and may lead to a range of clinical presentations,
from CMV syndrome (fever, weakness, myalgia) to end-organ
disease (colitis, pneumonitis, hepatitis).
-kidney recipients that developed CMV post-transplant have significantly worse
graft and patient survival .
-General infections such as urinary tract infections may also lead to chronic injury either due to direct injury to the allograft in the setting of an infection affecting the kidney or indirectly, through triggering a rejection process due to the activation of innate immune system with increased expression of costimulatory
molecules and lowering of the threshold for T cell activation and proliferation.
-One study suggests that some of the allograft changes presumed to be
related to CNI are actually from other etiologies.
– CNI canbe associated with significant nephrotoxicity, in particular if high levels
of CNI are maintained post-transplant.
-The expansion of the donor pool to include kidneys from donors
after cardiac death, elderly donors or those with comorbidities
(e.g. diabetes and hypertension) may significantly affect the allograft
survival due to presence of preexisting injury, lower nephron mass
and greater susceptibility of new insults.
-A significant mismatch between donor and recipient size (kidney weight/recipient weight b2.3 g/kg) is associated with a higher rate of hypertension, proteinuria and lower graft survival .
-Renal artery stenosis occurs in up to 5% of kidney recipients and is suspected in patientswith persistent uncontrolled hypertension, flash pulmonary edema, or
an acute elevation in blood pressure within the first few years after
transplantation.
-Ureteral obstruction due to anastomotic stenosis or ureter ischemia (fragile vasculature of ureter) may lead to significant hydronephrosis and graft injury.
–The management of patients with chronic allograft injury :
1.careful history in regards to the primary renal disease
2.The early posttransplant course (e.g. severe delayed graft functionmight indicate significant irreversible early allograft damage).
3.episodes of acute rejection(if any) .
4.degree of hypertension/blood sugar control.
5. CNI levels over time and noncompliance are important.
6. Urinalysis with sediment visualization may help in the identification
of potential etiologies as cellular casts, granular casts, or significant
proteinuria indicative of active glomerulonephritis, acute
tubular necrosis or transplant glomerulopathy, respectively.
7. A kidney ultrasound: exclude mechanical complications such as ureteric obstruction and vascular stenosis.
8. kidney biopsy: should be performed in the majority of patients with dysfunction and no clear reversible factor present or if other worrisome features such as significant proteinuria or cellular casts are present.
-Protein and mRNA levels of CXCL9 were shown to be a great predictor of rejection
(AUC 0.88) with an elevation in levels detected 30 days before a
-A urinary mRNA signature that includes CD3E, CXCL10, and 18S ribosomal RNA
was associated with rejection (AUC 0.85).
-NK cell immunophenotyping correlated with the presence of DSA, cABMR, and worse graft function.
-The distinction among the different DSA IgG isotypes seems to be relevant, with IgG3 showing worse outcomes.
-Protocol biopsies can detect specific, often unsuspected, graft injury with the consequent change in management.
-The research for alternatives to CNI tominimize nephrotoxicity has led to the development of the costimulatory blockade agent belatacept .
-Belatacept is contraindicated in patients with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder.
-Belatacept-associated high rate of acute cellular rejection in the first year after transplantation has limited the widespread use of this agent.
-The data of 7-year follow-up with a belatacept regimen suggest a significant
better graft function and survival in patients on belatacept when
compared to cyclosporine.
-mTOR inhibitors have not shown a benefit in improving
long-term graft survival with specific concerning sides.
-Better controlling blood pressure post-transplant is associated with an improvement in graft survival at 1 and 3 years post-transplant.
-Risk factors and clues for noncompliance include poor social support,
missed appointments, fluctuating drug levels, differences between
drug prescribed and dispensed, unexpected late rejection, psychiatric
disorder, substance abuse, adolescence, increased time since transplant
and financial crisis.
–Management of chronic rejection
-The most significant risk factor for chronic ABMR is acute ABMR so prevention strategies have been focused on avoiding it. Preventive combined therapies including plasmapheresis, rituximab, and intravenous immunoglobulin (IVIG) are
used in sensitized patients.
-Potential alternatives to rituximab to reduce antibody production include bortezomib.
-In severe cases of ABMR, eculizumab can be considered an adjuvant therapy
Thank You, Reem; this is massive. You need to shorten your summary
Kidney transplants have achieved good short-term outcomes, but the long-term outcomes are still unsatisfactory with 10 year graft loss of more than 50%, resulting from both immunological as well as non-immunological causes. Interstitial fibrosis and tubular atrophy on biopsy may be due to rejection (both cellular and antibody mediated), BK virus nephropathy, recurrent pyelonephritis, non-standard donor kidney, ureteral stenosis and calcineurin inhibitor (CNI) nephrotoxicity.
Immunological causes: Chronic injury can occur by antibodies acting on foreign antigens in the donor kidney (DSA), leading to chronic rejection presenting with proteinuria or elevated serum creatinine. Late acute rejection episodes also increase the risk of chronic graft dysfunction. Risk of graft failure is high in patients with increased DSA levels and/or C4d positivity on kidney biopsy. Recurrence of glomerular disease is another major immunological cause of chronic graft injury which requires early identification and treatment. FSGS has recurrence of 20-80% with 50-80% graft loss. IgA nephropathy has 20-40% recurrence rates with 5-15% graft loss. Infections like BK virus also lead to chronic graft injury with 30-65% patients having BK virus nephropathy losing graft within 1 year of diagnosis. CMV infection, due to immunomodulatory mechanism, leads to increased rejection with poorer graft survival. Urinary tract infections can also trigger a rejection process by activating innate immune system.
Non-immunological causes: Calcineurin inhibitor (CNI) nephrotoxicity has been seen if high levels are maintained for prolonged periods although the changes seen in biopsy are non-specific and it has been seen that CNO elimination has worse graft outcomes. Poor quality of donor graft due to extended criteria donors, increased cold ischemia time and significant donor/recipient size mismatch is another cause of chronic graft injury. Renal artery stenosis leading to graft injury and ureteral obstruction due to ureteral stenosis or ischemia is also responsible for chronic graft injury.
Diagnostic strategies for chronic graft injury include detailed history including the primary disease, comorbidities like diabetes and hypertension, previous rejection episodes, underimmunosuppression due to non-adherence or physician advised and the CNI drug levels. Investigations like urine examination, ultrasound graft kidney as well as kidney biopsy give important clues. Non-invasive biomarkers like anti-HLA DSA with IgG isotyping (IgG3 showing worse outcomes), DSA c1q fixation properties, protein and mRNA levels of CXCL9, urinary CD3E, CXCL10 and 18S ribosomal RNA, NK cell immunophenotyping with increased NKG2A+ cells have shown increased correlation with chronic graft injury. Protocol biopsies have shown that grafts with subclinical AMR have worse outcomes than those without rejection or with subclinical cellular rejection.
Preventive strategies include emphasis on maintaining drug compliance and CNI alternatives including belatacept, a co-stimulatory blockade agent which is associated with increased acute cellular rejection in first year, but better long-term graft and patient survival. mTOR inhibitors have not shown benefit in long-term outcomes. Blood pressure control also has a role in preventing chronic graft.
Treatment strategies include prevention and adequate treatment of acute AMR. Subclinical rejection should be treated in presence of de novo DSA. Patients with chronicity score >8, DSA MFI >2500, serum creatinine >3mg/dl and urinary protein creatinine ratio >1g/g have higher risk of graft loss. Such patients should be managed with augmentation of immunosuppression as well as use of steroids and IVIG. In the absence of the poor prognostic markers, patients should be additionally treated with ATG (if cellular component is present), plasmapheresis, rituximab, bortezomib and eculizumab if refractory to initial treatment. Recurrence of the primary glomerular disease must be treated. FSGS recurrence can be managed with high dose steroids, IVIG and plasma exchange. IgA nephropathy recurrence may need ACE inhibitors or ARBs with oral steroids. Recurrent membranous nephropathy may need rituximab for treatment. In the unfortunate event of graft loss, re-transplantation with a live donor avoiding repeat HLA mismatch as the preferred choice should be planned.
Perfect Amit
Chronic allograft injury: Mechanisms and potential treatment targets
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
▪︎Chronic allograft nephropathy (CAN) was
used to define dysfunctional kidney grafts of unclear cause and renamed by Banff 2005 classification system  to tubular atrophy (IFTA), without evidence of any specific etiology. Â
☆Immunological causes:
__________________________
▪︎ Chronic rejection is the most common type of rejection after the first year of transplant.
▪︎ DSA is  as a major cause of  late graft dysfunction
☆Mechanism of chronic injury:
__________________
▪︎ There is an antibody-mediated injury to the endothelium of multiple vascular beds which cause cellular hypertrophy,
☆Glomerular disease recurrence after transplant
___________
(A) Primary renal diseases:
1) FSGS: tends to recur early
2)Â Atypical hemolytic-uremic syndrome.
3) IgA nephropathy 4)Dense deposit disease
5) C3 GN 6) MPGN (C3+ Ig+) 7) IgA nephropathy 8)Â Membranous GN
9)Â Anti GBM disease( Rare)
(B) Systemic disease:
Oxalosis ,Scleroderma, Immunoglobulin deposition, Amyloidosis, ANCA vasculitis, SLE (2%–7%) and Fabry disease.
☆Infections (viral/bacterial):
_____________________________
â—‡BK infection:
▪︎ BK nephropathy is a major cause of acute and chronic allograft dysfunction.
▪︎BK is tropic to the kidney tubules.
▪︎ It follows a predictable pattern (viruria →viremia →nephropathy).
▪︎ Does not have any systemic symptoms, which significantly delays the diagnosis.
▪︎ Biopsy is imp. to confirm the diagnosis.
â—‡CMV infection:
▪︎ One of the most common opportunistic infections after kidney transplantation.
▪︎Cause a range of clinical presentations
▪︎Direct involvement of CMV infection on the kidney is rare. But, it exert injury through an immunomodulatory mechanism
â—‡UTI:
▪︎ Can cause  direct or indirect injury (by activation of innate immune system).
☆Non-immunological causes:
_______________________________
â—‡CNI nephrotoxicity
▪︎ Range from vasoconstriction to tubular and vascular injury, and in rare cases TMA.
▪︎ CNI-related histologic lesions in the kidney are relatively nonspecific.
☆Poor quality donor grafts:
______________________________
Graft survival may be affected by:
1) Kidneys from donors after cardiac death, elderly or those with comorbidities
2) Presence of genetic susceptibility in kidney donors.
3) A significant mismatch between donor and recipient size.
4) A graft insults.
☆Renal artery stenosis(RAS) and urinary tract obstruction:
___________
▪︎RAS may lead to graft ischemia & injury.
▪︎ Gold-standard imaging for diagnosis is arteriography though a Doppler ultrasound
▪︎ Ureteral obstruction may lead to significant hydronephrosis and graft injury.
☆Diagnostic strategies of Chronic allograft injury: by:
________
1. Careful history in regards to the primary renal disease, the early posttransplant course, episodes of acute rejection (if any), degree of hypertension/blood sugar control, CNI levels over time and noncompliance is important.
2.The time of transplantation
3. Urinalysis with sediment visualization.
4. US may to mechanical complications
5. A kidney biopsy
6. Noninvasive biomarkers: predict ongoing graft injury and response to treatment
7. Protocol biopsies: have emerged in few centers as a critical monitoring tool.
☆Preventive strategies:
_________________________
1. Alternatives to CNI:
▪︎Belatacept.
▪︎mTOR inhibitors
▪︎ everolimus with CNI minimization.
2. Better controlling blood pressure
3. Limit the use of ACEI inhibitors/ARBs.
4. Use of techniques to better preserve the donor kidney after retrieval ( eg: a machine perfusion)
5. Â Preventing non-compliance.
☆Treatment strategies
1. Management of chronic rejection
▪︎Preventive combined therapies including plasmapheresis, rituximab (Bortezomib is an alternative), IVIG are used in sensitized patients.
▪︎ In severe cases of ABMR, eculizumab.
▪︎ Adequate treatment of acute ABMR.
2. Management of recurrent GN:
▪︎FSGS: high dose steroids, cyclosporine and plasma exchanges
▪︎No specific treatment of recurrent IgA nephropathy.
▪︎ Recurrent membranous nephropathy may be treated with rituximab.
▪︎Recurrent MPGN: Treatment is based in underlying cause.
Thank You Tahani
introduction;
Recent developments in transplantation have contributed to better graft outcomes in the short term. However, there was still a significant problem with long-term graft survival owing to the fact that more than fifty per cent of allografts fail within ten years after the transplantation due to chronic allograft damage. This article sheds light on the genesis of chronic allograft nephropathy as well as the therapeutic strategy for this condition.
Immunological factors include a high HLA mismatch, TCMR, AMR or mixed rejection, and non-compliance (40 per cent of cases).
-Recurrent or de novo glomerular disease; diseases with a high recurrence rate include FSGS (with rates ranging from 20 to 30 per cent), atypical HUS (with rates ranging from 15 to 80 per cent), MPGN (with rates ranging from 80 to 100 per cent), and IgA nephropathy (with rates ranging from 20 to 40 per cent).
-Risk factors and causes of chronic allograft injury. • Alloimmune Poor HLA match Prior sensitization New alloantibodies Non-compliance Rejection episode • Recurrent or de novo glomerular disease • Recipient-related: CNI nephrotoxicity Diabetes Hypertension Renal artery stenosis Ureteral obstruction Heart failure Drug-induced acute interstitial nephritis • Donor-related Poor quality donor kidney Prolonged ischemia Delayed graft function Significant size mismatch • Infections BK nephropathy CMV infection Recurrent pyelonephritis Sepsis.
-Diagnosis:
Consequently, it is essential to collect a comprehensive history regarding the primary renal disease, the early posttransplant course (for example, severely delayed graft function could indicate significant irreversible early allograft damage), CNI levels over time, and noncompliance.
. Urinalysis with sediment visualization has the potential to assist in the identification of potential causes, such as cellular casts, granular casts, or significant proteinuria, each of which is indicative of active glomerulonephritis, acute tubular necrosis, or transplant glomerulopathy, respectively. Ultrasonography of the kidney might potentially rule out the presence of mechanical problems including ureteric blockage and vascular stenosis.
. Additionally, a kidney biopsy should be performed if other concerning characteristics, such as significant proteinuria or cellular casts, are present.
-Preventive strategies:
Different Options for CNI
A CTLA4Ig fusion protein called belatacept is responsible for blocking the CD80/CD86 interaction with CD28, which in turn prevents T cell activation.
Because of the increased likelihood of a post-transplant lymphoproliferative disease, it is not administered to patients with a negative EBV status.
There is insufficient evidence to determine if belatacept improves graft survival over the long term.
mTOR inhibitors did not result in an increase in graft survival over the long run.
The results of research evaluating the effect of everolimus on CNI reduction are encouraging.
Avoidance of noncompliance with regulations
-The management of persistent instances of rejection:
Taking into account that chronic ABMR is a significant contributor to late graft loss, it is reasonable to make treating this disease a high priority for developing preventative and therapeutic measures. Acute ABMR is the most important risk factor for developing chronic ABMR, and as a result, preventative methods have concentrated on avoiding getting acute ABMR.
Patients who have been sensitized to the virus are candidates for preventative combination therapy. These therapies include plasmapheresis, rituximab, and intravenous immunoglobulin (IVIG).
Bortezomib is one of the potential alternatives to rituximab that may be used to decrease antibody production. Eculizumab, which blocks one of the primary effector activities of the anti-HLA antibody, the complement activation, might be regarded as an adjuvant treatment for severe instances of ABMR. This is because complement activation is one of the most important functions of the anti-HLA antibody.
Thank You Weam
The long term outcome of kidney transplantation is still unsatisfactory as 50% of allografts are lost within 10 years post transplant.
Chronic allograft loss is multifactorial and a study showed that death with a functioning graft is the commonest cause.
Immunological causes of chronic allograft nephropathy (CAN):
Chronic rejection:
The most common type of rejection one year post transplant, non compliance is considered a major risk factor for late rejection and graft loss.
DSA has a significant role in late allograft failure, pre transplant and de novo DSA are associated with significantly higher risk of graft loss.
Glomerular disease recurrence:
The risk of recurrence of primary kidney disease or systemic disease is variable with different consequences
Some glomerular disease are associated with high risk of recurrence while others are associated with delayed presentation
Infections:
BK nephropathy:
A major cause of acute and chronic graft dysfunction and leads to graft loss in 30-65% of patients within one year.
It has no systemic symptoms so surveillance of BK with serum PCR allows early detection, however, a biopsy is still needed to confirm the diagnosis and to exclude other causes.
CMV infection:
The most common opportunistic infection post transplant, varies from CMV syndrome to end-organ disease and has an immunomodulatory effect.
Patients with CMV post transplant have worse patient and graft survival.
General infection as UTI may also lead to chronic injury.
Non immunological causes of CAN:
CNI nephrotoxicity:
CNIs are known to cause vasoconstriction, tubular and vascular injury.
High levels of CNI post transplant are associated with significant nephrotoxicity, however, avoidance of CNI without any substitute resulted in poor outcome.
Poor quality donor graft:
Kidneys from donors after cardiac death, elderly donors or those with comorbidities.
Donors with genetic susceptibility
Significant mismatch between donor and recipient size.
Renal artery stenosis and urinary tract obstruction:
Renal artery stenosis leads to graft ischemia, suspected in patients with uncontrolled HTN or with flash pulmonary edema.
Ureteral obstruction may lead to significant hydronephrosis and graft injury.
Diagnostic strategies:
Careful history, urinalysis, kidney ultrasound and graft biopsy are needed to determine the cause of graft injury.
Non invasive biomarkers:
Are still under investigation, may help in early identification of graft injury before being clinically evident.
The clinically used biomarker is anti-HLA DSA, used for prediction of AMR and the results should be carefully interpreted.
Protocol biopsies:
Longitudinal surveillance biopsies are used to detect unsuspected graft injury allowing early intervention.
Preventive strategies:
Alternatives to CNI:
Belatacept, A co-stimulatory blockade agent, used as CNI sparing drug, associated with high rate of acute cellular rejection in the first year post transplant, long term trials are needed to determine its beneficial effect compared to tacrolimus.
mTORi, didn’t show significant benefit, however, everolimus is promising and is still under investigation.
Better control of HTN is associated with better graft survival.
Using machine perfusion was also associated with better graft survival in expanded criteria donor kidneys compared to cold static storage.
Preventing noncompliance through screening at clinic visits and monitoring of drug levels with explanation of potential consequences of non adherence.
Treatment strategies:
Management of chronic rejection
Prevention of acute AMR as it is a major risk factor through combine plasmapheresis, rituximab and IVIG.
There is no approved therapy for chronic AMR and interventional clinical trials are needed to determine safety and efficacy of B cell and DSA depleting strategies.
Management of recurrent primary GN:
FSGS, High dose steroid, cyclosporine and plasma exchange showed better results compared to same regimen without plasma exchange
IgA nephropathy, No specific protocols are available, ACE inhibitors or ARBs with oral steroids may be used.
MPGN, treatment varies according to the etiology.
good effort
Thank You Heba
The chronic allograft loss causes are multiple, including both immunological and non-immunological factors.
El-Zoghby et al. concluded that death with a functioning graft was the most common cause of graft loss.
Immunological causes
chronic rejection is the most common rejection type after the first year of transplantation in the forum of prolonged cellular and/or antibody mediated immune response against the transplanted organ that may present with either a rise in creatinine and/or proteinuria.
DSA is a major risk factor in graft dysfunction.
Chronic ABMR requires a kidney biopsy to be diagnosed in order to exclude other potential causes.
Transplant glomerulopathy is a predominant feature of chronic ABMR,but it is not specific to rejection as it can be associated with thrombotic microangiopathy, recurrent autoimmune glomerulonephritis and hepatitis C-related glomerulonephritis.
Glomerular disease recurrence
Some primary kidney diseases are associated with high-risk of recurrence and graft loss early after transplant, others can present later with slowly progressive course.
focal segmental glomerulosclerosis (FSGS) and atypical HUS can recur early after transplantation .IgA nephropathy has a high recurrence rate and commonly may exacerbate with reduction of immunosuppression late after transplantation.
Infections
BK nephropathy has become a major cause of both acute and chronic allograft dysfunction due to the potent immunosuppressive drugs use causing graft loss within 1year of detection.
Biopsy with SV40 staining is needed for diagnosis.
CMV infection is frequent post transplantation ranging from CMV syndrome to end organ disease
Non immunological causes
CNI nephrotoxicity
Long-term allograft fibrosis was related to chronic CNI toxicity that led to IFTA, glomerulosclerosis and arteriolar hyalinosis.
A study concluded that low to moderate-dose tacrolimus with mycophenolate and steroids was associated with lower rate of rejection and better graft survival for 1 year follow up.
Poor graft quality
A graft taken from a cadaver ,elderly donors or those with comorbidities ,mismatched kidney size affect the allograft survival
RAS and urinary tract obstruction
RAS is suspected by persistent elvation of bp and flash pulmonary oedema , the diagnostic imaging is arteriography though a Doppler ultrasound.
A bedside ultrasound usually identifies obstruction and flouoroscopy detect exact site.
Diagnostic strategies
Non invasive biomarkers
Detection of DSA IgG isotypes seems to be relevant, with IgG3 giving the worst outcome.
A urinary mRNA signature that includes CD3E, CXCL10 and 18S ribosomal RNA was associated with rejection
NKG2A+ cells in high levels after kidney transplantation correlate with the presence of DSA, cABMR
Protocol biopsies
To detect specific graft injuries with individualisation of management accordingly.
Preventive strategies
Alternatives to CNI
Belatacept is a CTLA4Ig fusion protein that blocks the CD80/CD86 interaction with CD28 preventing T cell activation.
It is not given with negative EBV status due to the higher risk of post-transplant lymphoproliferative disorder.
Betalacept effect on long term graft survival is not definite
mTOR inhibitors didnot improve long-term graft survival
A study testing everolimus with CNI minimization is promising .
Avoidence of non compliance
Treatment protocols
Management of chronic rejection
Preventive mixed therapies including plasmapheresis, rituximab and IVIG are used in sensitized patients
Bortezomib and Eculizumab are other alternatives
Treatment of acute ABMR.
There is no approved therapy for chronic ABMR.
Management of recurrent primary glomerulonephritis
For recurrent FSGS plasma exchange , high dose steroids and cyclosprorine
For recurrent Ig A nephropathy ACEI ,orARBS and oral steroids
Recurrent membranous can be treated with rituximab
Recurrent MPGN varies according to the cause
C3 glomerulopathy and dense deposit disease was treated with eculizumab.
Conclusion
Prevention of allograft injury need to be the main target
good efffort.
More than 50% of graft are lost by 10 years and death censored attritition rates have unchanged over the last 25years. TG is the most common finding on biopsy in chronic allograft injury in patients with glomerular diseases. IFTA is a non specific finding and causes of this can be Acute antibody mediated or cellular rejection, Infections. poor donor selection, BK nephropathy, immunosuppressive agents toxicity or surgical factors.
Immunological Causes of IFTA
Lifelong low grade exposure to foreign antigens resulting in antibody mediated, cellular or mixed rejection.
Late onset acute Rejection
Infections
Non Immunological causes
CNI toxicity
Poor donor selection
Renal artery stenosis
TMA
Post renal urinary obstruction
Diagnostic strategies
Biomarkers- in research settings
Protocol biopsies
Prevention Strategies
Alternatives to CNI-Betacept, god control of hypertension
Prevent non adherence -provide social support to avoid missed appointment, better communication, Financial support, monitor drug levels
Management Strategies
Management of chronic rejection
Prevent acute ABMR, and treatment in the form of IVIG PP, Rituximab. In severe cases Ecluzimab.
Control medical conditions
Monitor DSA
Management of recurrent primary glomerulonephritis.
The summary is OK but you need to add most discussion to the diagnostic and prevention strategies. The discussion is thin on words.
Introduction ;
Transplantation advances helped to improved short term graft outcomes. However long-term graft survival remained a huge challenge because > 50% of the allogarft are failed by 10 years after transplantation due chronic allograft injury(2). This article gives an insight about etiology and management approach for chronic allograft nephropathy
Immunological causes ; High HLA mismatch,TCMR, AMR or mixed rejection, non-compliance(40% of cases)
Recurrent or de novo glomerular disease ; Diseases with high recurrence rate are FSGS(20 -30%), atypical HUS(15-80%), MPGN(80%-100%)IgA nephropathy20-40%).(25).
It is wroth mentioned that recurrence disease is generally less aggressive with low rates of graft loss except in cases of FSGS(26,27%)
Infections ;
Non-immunological causes ;
Diagnosis ; Careful & detailed clinical history is essential
Prevention ;
1.Alternative to CNIs ; this was not successful up to date(55,57)
2.Prevent non-compliance ; early screening and frequent monitoring for those at high risks e.g poor social conditions, adolescence, mental problems, substance abuse and financial issues.
3.Blood pressure control ; trial of ACE-i/ ARBs
4.Better techniques for organ preservation after retrieval ; Machine perfusion
Treatment strategies ;
Chronic rejection
Recurrent primary Disease ; Mostly treated in the way as the native disease
Conclusion ;
Chronic allograft injury is associated with poor graft outcomes and it is essential to the identify the causes for better management outcomes. Since the diagnosis and treatment of chronic allograft injury can be very difficult, prevention of this condition is of paramount importance.
Thank you
Wlcm prof
Nearly half of kidney transplant recipients loose there graft after 10 years
The most common cause of graft failure is death with functioning graft
Causes of chronic allograft dysfunction can be classified into
Tubulointerstitial (IFTA) causes :
Glomerular causes:
Vascular causes
Post renal causes:
Diagnosis of chronic graft dysfunction
Prevention of chronic graft dysfunction
Treatment of chronic ABMR
Treatment of chronic active ABMR is difficult since there it is associated with irreversible tissue damage
No optimal FDA approved treatment is set for chronic active ABMR, Current treatment is directed against the following:
Main therapy
Second line agents in case of refractory chronic ABMR (poor evidence)
Third-line agents (very poor evidence)
In case of graft failure, it is recommended not to stop immunosuppression in order to prepare the patient to the next transplant to avoid rebound of DSA
Thank you
Review article. level 4
Summery:
50% of renal graft lost by 10 years post transplant. Chronic graft loss can result from immune or non immune cause. TG is the most common finding of protocol biopsy ( in glomerular disease). IFTA can a sequel of :
Immunological causes:
Chronic injury commonly involve Ab-mediated endothelial injury ( glomeruli, PTC, small & medium size vessels), persistent endothelial injury lead to duplication of peritubular basement membrane to give TG.
TG is non specific finding can occur in ABMR, TMA, recurrent autoimmune GN, & hepatitis-C related GN.
Recurrence of glomerular disease is a frequent cause of graft loss 10 years after transplantation. FSGS can recur in early post transplant period with graft loss in 50-80% of cases, aHUS recurrence differ according to complement abnormality( 15% in MCP mutation, & 80% in circulatory protein mutation), but IgA nephropathy can recur in 40% of cases nut graft loss is uncommon early. So through protocol biopsy & early diagnosis & proper treatment can improve long term graft survival.
Non immune causes:
Diagnosis:
Prevention:
Management:
Thank you
[Continuation of summary]
Diagnostic strategies
Management depends on underlying cause of allograft injury.
Preventive care
Alternatives to CNI such as co-stimulators blockade agent belatacept, initially given every 2 weeks and then monthly. It is contraindicated in negative EBV patients because of risk of PTLD.
Preventing non-compliance
Treatment strategies
Thank you
Summary
This article winds around identifying sources of threats to long term graft surival in renal transplant recipients. CNIs which have been long villainized in the transplant community as the cause of graft damage in the long term have been mentioned, and replaced with other factors as the major cause of graft damage or reduced graft survival. These factors include non-adherence to medication, BK nephropathy, disease recurrence, and antibody mediated injury.
Furthermore, the pathogenesis of chronic allograft nephropathy and associated treatment methods have been discussed,
Contents of this article can be subdivided as follows :
Causes
Immunological causes
Alloimmune response due to DSA is a major cause of chronic allograft injury.
Mechanism of chronic injury involves antibody mediated injury to endothelium of various different vessels of glomeruli, peritubular capillaries and small to medium size vessels. The endothelium injury results in cellular hypertrophy, basement membrane duplication, podocyte injury. This can appear similar to transplant glomerulopathy on biopsy.
Recurrence of glomerular disease
Recurrence of disease is the third leading cause of loss of graft at 10 years post transplant. The time of graft loss after kidney transplant depends on the specific disease that is recurring. Some primary kidney disease that recur cause graft loss early after transplant, while others can be slow and cause graft loss late after transplant, more than 10 years post surgery.
For instance, FSGS recurs early after transplant with significant proteinuria and causes graft loss in 50% patients. On the other hand, IgA nephropathy recurs late after renal transplant and causes graft loss.
The mechanism of graft loss caused by recurrence of glomerular disease is unclear, however suspicion is toward circulating factors that result in podocyte injury.
Viral and bacterial infections can also cause damage to renal allograft. The major infections affecting the renal graft outcome post transplant include
BK nephropathy occurs due to infection by BK virus. This virus colonizes the tubules of the kidney. The patient remains without any symptoms and hence serum PCR has to be done as part of routine check to ensure absence of infection. Aggressive immunosuppression is the major risk factor for BK virus. Early detection is key since most patients lose graft within one year of BK diagnosis.
CMV infection can cause graft loss. CMV syndrome involving fever, weakness and myalgia, as well as end organ disease including but not limited to colitis, pneumonia and hepatitis.
Urinary tract infection is another chronic cause of graft damage. It can affect the graft directly through infection of kidney or indirectly by activating the innate immune system.
Non-immunological causes
CNI nephrotoxicity ranges from tubular to vascular injury. CNI regimen has been associated with fibrosis leading to IFTA in the long term. CNI minimization or elimination was attempted to find out if there is better outcome. However, protocol biopsies show that chronic CNI nephrotoxicity is not the main culprit for graft loss in long term in most patients. Hence, avoiding CNI may not lead to better outcome, but, in fact, may lead to a worse outcome. However, maintenance of high doses of CNIs post transplant for long periods of time causes significant nephrotoxicity.
Poor quality of donor pool can lead to graft insult and injury resulting in poor outcome. There are different factors that can lead to poor graft quality, such as :
Renal artery stenosis and urinary tract obstruction can lead to graft ischemia and injury. It is more seen in patients with
Thank you