Recurrent Renal Diseases
It’s the third leading cause (following rejection and infection) of allograft dysfunction and failure, particularly glomerular diseases, which constitute the primary cause of native kidney failure around the world.it is responsible for a significant proportion of cases ranging from 18–50% Despite proper donor selection and effective immunosuppressive therapies. This paper deals with the pathologic features and the significant role of EM, mainly in the diagnosis of recurrent glomerular diseases.
Critical Role of EM and When to Use It in Diagnosing Recurrent Glomerular Diseases
EM in the setting of transplant kidney biopsies plays a crucial role in the diagnosis and confirmation of both subclinical and overt clinical
·       recurrent diseases (almost all the glomerular lesions require EM, providing further ultrastructural details for a specific diagnosis)
·       early and late features of the transplant rejection process.
While most of the recurrent tubulointerstitial and vascular lesions are recognized by LM.
EM enables the detection of
·       early immune deposits
·       subtle findings of extra- and intraglomerular cellular changes,
·       basement membrane alterations
·       intracellular and extracellular inclusion bodies
·       nature and location of immune complex (IC) deposits
Most immune complex-mediated diseases show some difference in their recurrence in the renal allograft caused by immunosuppressive medications. These differences include milder lesions, lack of abundant or “full-house” deposits, slower progression, or evidence of resolving changes.
EM for an accurate and complete diagnosis including
1.     recurrent focal segmental glomerulosclerosis (FSGS) to detect the extent of foot process effacement in its initial phase
2.     IC diseases to confirm deposits and location of deposits (MGN, IgA nephropathy, lupus nephritis [LN], membranoproliferative glomerulonephritis [MPGN], and C3 glomerulonephritis [C3GN]/dense deposit disease [DDD])
3.     early basement membrane and mesangial alterations (DKD and thrombotic microangiopathy [TMA]), or to confirm the absence of deposits (crescentic glomerulonephritis [GN] and TMA).
Morphology of Common Recurrent Lesions in Renal Transplantation
Focal Segmental Glomerulosclerosis in Children and Adults (All Variants)
Recurrence of FSGS, an established primary form of podocytopathy, is defined clinically by rapid onset of proteinuria, often nephrotic range, usually in the early posttransplant period within a few weeks to a year. This is characterized by mainly extensive effacement of foot processes by EM with the eventual development of segmental collapse and sclerosing lesions by LM in a few weeks to months.
·       Clinical Features
The hallmark of recurrent FSGS is nephrotic syndrome, with a rate of recurrence that ranges from 25 to 55%. The risk factors for this condition include young age of onset, progression to end-stage within 3 years of onset, living-related donors, previous recurrence in an allograft, and mesangial hypercellularity in the original disease. In adults, older age groups, white race, and higher BMI are risk factors. Although graft failure can occur in 13–20% of cases in children and maybe as high as 39% in adults, a substantial proportion of them exhibit partial or complete remission following plasmapheresis and antiCD20 therapy (rituximab) therapy. Idiopathic collapsing glomerulopathy as a variant of a severe form of primary FSGS also manifests marked proteinuria frequently associated with rising renal insufficiency. Inherited or familial forms of FSGS rarely recur, but certain polymorphisms in podocin or nephrin encountered in some of these patients are regarded as potential risk factors (some heterozygous NPHS2 variants), although still with a low frequency. Serum permeability factors may be mediators of FSGS; the biochemical nature of a few is identified as soluble urokinase receptor (SuPAR), cardiotrophin-like 1, and an autoantibody to CD40. Secondary forms of FSGS generally do not recur. Sometimes, the challenge will be to differentiate from the de novo form of FSGS, since the distinction may be somewhat difficult based on the posttransplant interval, degree of proteinuria, and morphologic findings including the extent of foot process effacement. A thorough clinical evaluation and consideration of underlying pathophysiologic mechanisms may be useful.
·       Light Microscopy
in the early stage of recurrence (a few hours to several weeks post-transplantation) relatively normal glomerular architecture, despite significant proteinuria, is often termed the “minimal change phase of recurrent FSGS.”.
The latter lesions are the segmental collapse of glomerular capillaries and sclerosis, visceral epithelial hyperplasia, and luminal foam cells. The following variants of FSGS can occur as a recurrent disease: (1) glomerular tip, (2) cellular, (3) segmental/global collapsing, and (4) peripheral or not otherwise specified as seen in LM. The perihilar variant which is a secondary form of FSGS does not recur. The collapsing variant of FSGS also shows a high tendency to recur, the pathologic findings are segmental and/or global collapse of the glomerular capillary tufts with occlusion of the lumina
This lesion needs to be differentiated from the de novo form of collapsing glomerulopathy, which generally occurs later in the posttransplant period due to certain infections and microvascular obliterative changes in the setting of vascular arteriolar rejection, hyalinosis in DKD, and calcineurin inhibitor therapies.
·       Electron Microscopy
The earliest ultrastructural change “minimal change phase,” is widespread glomerular epithelial foot process effacement with condensation of actin filaments adjacent to the basement membrane but these findings may be modified by immunosuppression, and foot processes may show patchy or focal effacement with irregular distortion making its differentiation from 2ry FSGS more difficult.No IC deposits are identified. The EM findings of collapsing glomerulopathy disclose extreme collapse of the glomerular capillaries, which express evidence of severe podocyte injury and focal detachment with no hyaline deposits.
Membranous Glomerulonephritis
Definition: Recurrence of primary MGN is defined by the reappearance of subepithelial deposits in the glomerular capillary basement membranes composed of polyclonal IgG and C3 deposits by IF, confirmed by the presence of M type phospholipase A2 receptor (PLA2R) staining or other less common antigens that have been recently identified and EM localization of deposits. This may be accompanied by severe nephrotic syndrome early in the posttransplant period or more often begin as subnephrotic proteinuria in cases of later onset.
·       Clinical Features
On average, 15–40% of cases of primary MGN recur in transplants during the life of the allograft. While most recur within 2 years, a small proportion of them is seen in a few weeks manifesting a rapidly progressive course to end-stage with the reappearance of high titers of PLA2R antibodies. Since antibodies to PLA2R are documented in only about 70% of primary MGN, additional putative autoantigens have emerged as targets, such as the N-terminal region of thrombospondin 7A, exostosin 1/exostosin 2, neural epidermal growth factor-like 1 protein. As serologic testing and immunohistochemical stains become available, these could be identified definitively and differentiate them from the PLA2R-negative cases. The risk factors identified for a potential recurrence include shorter clinical course to chronic renal failure in the native kidney, older recipient age, previous recurrence in the allograft, steroid-free immunosuppressive protocols, and living related donor with more compatible donor-recipient HLA molecular haplotypes and risk alleles (HLA-A3, HLA DRB1/DQA1 loci). Graft failure ranges from 20 to 50% in over 5–10 years.
·       Light Microscopy
there is a progressive irregular thickening of the capillary walls, forming basement membrane spikes, best seen by PAS and silver stains (in the later stages). Silver staining can also uncover small subepithelial/intramembranous lucencies or “pinholes” early in the disease.
·       IF Microscopy
IF is the best diagnostic modality that can detect the earliest recurrence of MGN, even before LM or EM features of deposits become apparent, and is termed stage 0 MGN. A faint-to-low intensity of finely granular staining is seen for polyclonal IgG and C3 and C4d, which increases in strength with the progression of the lesion. Although these IF findings are similar to those of de novo MGN, the presence of mainly IgG4 subtype (20% of primary MGN may be negative for IgG4 and +ve for IgG 1,3) and localization of PLA2R within the deposits along with detectable serum PLA2R antibodies are suggestive of recurrent primary MGN.
·       Electron Microscopy
EM is helpful in recognizing extensive early foot process effacement, even if only scant deposits without spikes or no visible deposits may be apparent, and is termed “stage 0”. The lamina densa thickening with increasing subepithelial deposits with no mesangial or subendothelial deposits is evident in this setting. However, when they are present, the possibility of a secondary form of MGN should be entertained and investigated further clinically.
IgA Nephropathy
Definition: Recurrent IgA nephropathy is the most common primary glomerular disease in the renal transplant, where glomerular mesangial deposits of IgA are found and remains an important cause of graft dysfunction and failure in the long term
·       Clinical Features
The clinical presentation of recurrent IgA nephropathy is fairly heterogeneous, and although it is a hematuric disease, the presence of mesangial IgA deposits only by IF in pathology. In addition to isolated hematuria or proteinuria, mild to moderate elevation of creatinine may be observed with or without abnormal urinary findings. The incidence of recurrence ranges around 30. The usual risk factors for recurrence and of prognostic significance for the course of disease in the graft and outcome are young age of the patient at transplantation, IL-10 genotype, living-related donors with close to 0 HLA mismatch, and more aggressive proliferative glomerular disease in the native kidney with increased crescents with rapid progression. The ongoing immunosuppression or induction protocols in these patients have not shown to be effective in preventing of recurrence or slowing the progression of the disease to graft loss. Nevertheless, the overall 10-years graft survival is over 60%.
·       Light Microscopy:
renal biopsy evaluation remains the mainstay of a definitive diagnosis of IgA nephropathy. The recurrence in asymptomatic cases can be purely a “histological,” found in nearly one-third of protocol biopsies in the first 2 years posttransplant or an incidental finding in “for cause” biopsies.
·       IF Microscopy
The localization of dominant polyclonal IgA deposits with a lesser intensity of IgM and C3, restricted to the mesangial areas is a standard feature.
·       Electron Microscopy
variable finely granular electron-dense deposits in the paramesangial areas in the earlier stages, involving the mesangial areas. No capillary basement membrane deposits are noted.
Membranoproliferative Glomerulonephritis
this pattern of glomerular injury has shown that the pathophysiologic categorization of MPGN is appropriately done based on the glomerular deposits by IF or immunohistochemistry, where the 2 main categories are IC-mediated MPGN (primary and secondary forms to infections, autoimmune diseases, and paraproteinemia) and MPGN with predominantly C3 deposits (also known as C3 glomerulopathies).
IC-Mediated MPGN (Formerly MPGN Type 1)
Definition: IC-mediated MPGN (formerly known as MPGN type 1) in which the glomerular shows global proliferative GN with thickening of the peripheral capillary walls by cellular interposition giving rise to double contours, and subendothelial and mesangial, polyclonal immunoglobulin deposits. As some secondary forms have no specific treatment, but instead are treated with generic immunosuppressive agents, complete treatment may not always be possible.
·       Clinical Features
The clinical renal presentation is relatively nonspecific, with nephritic features of hematuria, and subnephrotic to nephrotic range proteinuria. Serologic workup shows mainly persistent hypocomplementemia with positive parameters in the secondary forms related to infections and autoimmune diseases. 2% of all patients with IC-mediated MPGN related to 1ry cause related to complement protein abnormalities and underlying mutation. Its a rare disease with a high rate of recurrence 30–70% with 25–30% graft loss. Some of the known risk factors are younger age at diagnosis, living-related donors, persistent hypocomplementemia, severe glomerular lesions with crescents, and an aggressive course in the native kidney.
·       Light Microscopy
active segmental/global endocapillary hypercellularity with occasional crescents, mesangial hypercellularity, and advancing subendothelial cellular interposition giving rise to “double contours,” resulting in a more irreversible pattern of glomerular injury termed MPGN. These are best visualized by PAS and silver stains.
·       IF Microscopy
IF plays a major role in the diagnosis of primary and secondary forms of the disease, namely primary IC-mediated MPGN with predominantly polyclonal IgG and C3 staining, including positive C4d within the deposits because of the classical pathway of complement involvement.
·       for hepatitis C-related MPGN
a different panels of immune reactants are positive with strong IgM kappa, C1q with weaker IgG and lambda, for hematological malignancies appropriate monoclonal proteins are positive.
·       Electron Microscopy
The unique glomerular pattern of IC-mediated MPGN is best visualized by EM, the immune deposits of fine to coarsely granular are accumulating in the subendothelial and mesangial areas, Mesangial expansion into the loose zone of lamina rara interna causes endothelial separation with new layers of basement membrane formation corresponding to “double contours” by LM and irreversible basement membrane remodeling. The clinical renal findings are relatively nonspecific, the MPGN pattern of glomerular injury should be differentiated from transplant glomerulopathy and healed forms of TMA (all causes).
C3 Glomerulopathies
Definition the glomerular lesions are mediated by almost exclusively C3 deposits, and the 2 common entities that are familiar to renal pathologists are C3GN and DDD and EM are required for a definite diagnosis. Both result from hyperactivation of the alternate pathway of complement due to genetic mutations or development of autoantibodies to complement-related proteins or regulatory factors so as expected the genetic one will be resistant to immunosuppressive therapies and it will persist in the posttransplant period, setting up a relatively early and high rate of recurrence.
·       Clinical Features
range from asymptomatic microhematuria or proteinuria initially, or an acute nephritic or nephrotic syndrome. While persistent hypocomplementemia is a common feature in almost all the cases of pretransplantation, nearly 35% of them may have normal C3 levels posttransplantation. C3GN has been seen to recur in 30–50% of the cases within the first 2 years, having a higher rate of graft loss, while DDD is known to recur in 80–100% of cases as early as 2 weeks posttransplant and progresses in an indolent manner with about 15–25% graft loss in 5–10 years.
·       Light Microscopy 
mesangial proliferative, endocapillary proliferative with or without exudative features, MPGN, and crescentic GN with segmental or global sclerosing lesions. IF Microscopy The dominant or the only parameter that is localized in C3GN and DDD is C3, varying in intensity depending on the number of deposits. There is a granular pattern of staining along the glomerular capillary walls and mesangial areas in C3GN, while mesangial and capillary wall stretches of granular or ribbon-like pseudo linear staining is noted in DDD. No significant amounts of immunoglobulins are noted in the glomerular deposits. Staining for C4d is negative within the deposits as the alternate pathway of complement pathway is involved.
·       Electron Microscopy
EM is critical for distinguishing C3GN from DDD and therefore is required for the diagnosis of recurrence of either entity in the allograft. Even with EM, there are instances that show significant overlap having features of both entities, In C3GN, the deposits may be more widespread involving the mesangium, subendothelial, focal intramembranous, and occasional subepithelial areas, a few resembling “hump-like” deposits or finely granular to waxy, and amorphous in character. In DDD, extremely dense homogeneous osmiophilic deposits within the glomerular basement membranes (GBMs) and smaller aggregates replace the mesangial matrix.
Lupus Nephritis
Definition Recurrence of LN in the renal allograft generally represents milder forms.
·       Clinical Features
Based on the nature of the recurrent LN lesions. The overall recurrence rate reported in some series is as high as 30–50% based on histologic diagnoses from protocol biopsies, though only around 10% show symptomatic clinical renal disease with low complement levels, contributing to relatively low graft loss. The risk factors for recurrence are younger age; living related donors, especially those having closer to 0 antigen mismatch; and patients of African descent, with a graft loss of 5–15% in 10 years.
·       Renal Pathology
The most common pattern that is noted in recurrent disease is mesangial LN, with a few focal LN and membranous LN cases and very rarely diffuse LN.
·       IF in most cases reveals positive staining for polyclonal IgG, IgM, C3, and C1q in the glomerular mesangial and/or capillary wall locations in various stages of resolution, depending on the type and class of LN.
·       EM exhibits the following: mesangial deposits observed in all classes; subendothelial and/or subepithelial deposits, depending on the class of LN; and endothelial tubuloreticular inclusions may or may not be readily visible. In cases of membranous LN, the subepithelial deposits may be small, frequently intramembranous, and in various stages of resolution with variable foot process effacement.
Fibrillary Glomerulonephritis
FGN is a primary form of glomerular disease, accounting for about 1% with predominantly organized fibrillar polyclonal IC deposits in the capillary walls and the mesangial areas
·       Clinical presentation:
asymptomatic proteinuria, nephrotic or a nephritic syndrome, hypertension, and varying renal insufficiency depending on the pathological lesions. FGN presented mainly in adult patients with a slight predilection for females. Although no specific serological marker is known, a proportion of these patients have underlying malignancies or autoimmune diseases, and most (>85%) reach end-stage disease in 4 years. Transplant recurrence of FGN is not uncommon, and over one-third of cases may recur within 1–10 years presenting with subnephrotic or nephrotic range proteinuria, causing graft loss in<50% in a study. Another larger outcome study reported that the renal allograft survival was comparable to other causes of ESKD.
·       Light Microscopy
The glomerular lesions of FGN range from a mild form of mesangial GN to proliferative/exudative GN with or without crescents to an MPGN pattern.
·       IF microscopy
there is polyclonal dominant IgG with strong C3 staining of the immune deposits with lesser intensities of IgA and IgM and sometimes trace to 1 + C1q, demonstrating a smudgy, rather homogeneous/semilinear staining pattern, in the mesangial areas and capillary walls. Recently, DNAJB9 has been exclusively localized within the fibrillary deposits by immunohistochemistry. Although most cases are negative for Congo red stain, a small number of cases with congophilic fibrillar deposits are reported.
·       The diagnosis of FGN is essentially made by EM
 where the deposits typically appear mostly fibrillar, infiltrating the extracellular matrix in the mesangial areas and subepithelial and intramembranous locations. The fibrils are of variable length, randomly arranged and straight, with a solid cross-section, often displaying an irregular or a stellate shape, ranging from 15 to 25 nm in thickness.
Paraprotein-Related Renal Lesions
Monoclonal Immunoglobulin Deposition Disease
Monoclonal immunoglobulin deposition disease (MIDD) is a systemic disease as a result of deposition of abnormal, monoclonal light and/or heavy chains originating from an overt or subclinical form of plasma cell dyscrasia or sometimes B-cell malignancies or monoclonal gammopathy of renal significance (MGRS), mostly affecting adults. The kidney is a major target of the monoclonal proteins and MIDD, producing a spectrum of glomerular lesions and tubulointerstitial and vascular disease due to a unique pattern of monoclonal deposits, with a tendency to progress to end-stage within 24–36 months. Due to the advances in the treatment of myeloma and other monoclonal disorders leading to longer survival of patients, the renal transplant has been used as replacement therapy but the level of hematological remission to be achieved and when to transplant in such patients still no clear answers with very limited data regarding the posttransplant course of the disease but MIDD tends to recur at a high rate and rapidly in renal transplants, within the first 6 months to 3 years and this can affect the allograft almost immediately following transplantation, producing pathological lesions akin to the original disease in the native kidney.
·       Clinical Features
initial low level of proteinuria and progressive rise in creatinine up to nephritic picture may develop. monoclonal serum markers are available for detection and Complement levels in these cases are normal. The detection of serum or urine monoclonal protein is less predictable in cases of MIDD, due to the absence of significant bone marrow disease, and low levels of monoclonal protein produced by smaller clones, as described in MGRS. The course of posttransplant MIDD and graft survival following recurrence, spans 7–25 years, depending on the hematological response to treatment.
·       Light Microscopy
minimal focal mesangial prominence and capillary wall thickening that is PAS-positive. The other lesions are mesangial proliferative GN and some progression to sclerosing changes or nodular sclerosis resembling diabetic glomerulopathy.
·       IF Microscopy
 there is diffuse linear staining along the glomerular capillary basement membranes in the mesangial areas and all tubular basement membranes for monoclonal kappa or lambda light chains, or with IgG heavy chains. No localization of other immunoglobulins or complement components is noted.
·       Electron Microscopy (deposits everywhere)
The fine particulate electron-dense deposits localized as a narrow band-like pattern mainly along the inner aspect of the lamina rara interna of the GBMs in an attenuated or global diffuse manner. This is a typical or unique feature of MIDD, not seen in other forms of paraproteinemia-associated renal lesions. There may be focal involvement of the lamina densa. Similar deposits may be seen in the mesangial matrix. The tubular basement membranes display these coarsely granular to “peppery” deposits on the outer aspect or partly incorporated into the superficial layers of the matrix with time.
Proliferative Glomerulonephritis with Monoclonal IgG Deposits
deposition of an intact monoclonal IgG with light chain restriction and a single subtype, commonly IgG3, found in the glomerular subendothelial zones of the capillary basement membrane and mesangial areas, giving rise to endocapillary proliferative or MPGN.
·       Clinical Features
This is a disease commonly occurring in older age, mostly Caucasian. The initial recurrent within a few days to weeks following transplantation, characterized by sub nephrotic or nephrotic range proteinuria and progressive renal insufficiency. Cases of proliferative GN with monoclonal IgG deposits have shown a high potential for rapid recurrence in >90% of patients, as seen in protocol biopsies. No established serum markers sensitive to detecting monoclonal protein are currently available in the majority of the cases, and some fall under the category of MGRS. Another important feature is the presence of hypocomplementemia and detectable monoclonal protein in the serum in a small proportion of patients.
·       Light Microscopy
mesangial proliferative or focal proliferative GN with minimal or moderate hypercellularity and without the significant tubulointerstitial disease. These lesions can progress to develop global proliferative changes with exudative features of infiltrating neutrophils or MPGN patterns revealing segmental to circumferential capillary wall interposition resulting in double contours by PAS or silver stains with infiltrating capillary mononuclear leucocytes, particularly macrophages, following which segmental to global glomerulosclerosis
·       IF Microscopy
IgG deposits with a kappa or lambda light chain restriction primarily involve glomeruli, along the capillary walls and mesangial areas in global distribution with a mainly granular pattern of staining. These deposits also almost always stain strongly for C3 and to some extent for C1q.
·       Electron Microscopy
EM generally demonstrates granular subendothelial and mesangial deposits with segmental capillary wall interposition, without the involvement of the extraglomerular structures, such as the Bowman capsule, tubular basement membranes, arterial vessels, and adjacent microvasculature, a feature of this entity. On occasion, small clusters of organized fibrils may be present amid mostly granular deposits, as a few short bundles measuring 20–25 nm in thickness in the subendothelial and mesangial zones.
Amyloidosis
Most forms of amyloidosis (systemic light chain AL type, systemic amyloid A-AA type that are secondary to familial Mediterranean fever, other chronic inflammatory states, and certain hereditary types) have been found to recur with various frequencies.
·       Clinical Features
Subnephrotic proteinuria on routine testing without significant renal dysfunction. Alternately, they may present with new-onset nephrotic syndrome. The overall long-term (5–10 years) graft survival following a recurrence of amyloidosis of most types has been documented as >50% or higher.
·       Renal Pathology
minimal glomerular changes may be pale staining amorphous deposits accumulating progressively in the glomeruli, tubulointerstitial compartment, or vascular walls in the later stages, confirmed by routine Congo red staining.
·       IF, immunohistochemistry
amyloid protein deposits, correlating with the original type of amyloid deposits.
·       EM
the classic morphology and size of fibrillar deposits are identified within the various locations of the glomeruli, tubule-interstitium, and microvasculature, depending on the predilection and type of amyloid involved. The fibrils are randomly arranged, rigid with a solid cross-section, ranging from 8 to 12 nm in diameter.
Diabetic Kidney Disease
Recurrence of renal histological features of diabetes in a nondiabetic allograft at 2–3 years post-transplantation, with or without initial overt clinical renal disease or mild proteinuria, indicates the onset of diabetic glomerular disease and generally, it may require at least 5 years or more to fully develop the typical glomerular, tubulointerstitial, and vascular lesions. Risk factors of recurrence are suggested as inadequate posttransplant glycemic control. The recurrence rate may be as high as 25–40% with graft loss in 5–10 years, comparable to those with other diseases.
·       Light Microscopy
The subtle glomerular alterations may begin to appear within 6 months, as arteriolar hyalinosis and moderate glomerulomegaly with minimal or no mesangial expansion by matrix followed by progressive thickening of glomerular and tubular basement membranes and a mild to moderate increase in the mesangial matrix, spanning 2–3 years. Late changes, in addition to the above, include a marked increase in the mesangial matrix, with or without nodular configuration after 5–10 years, without significant hypercellularity (average 8 years).
·       IF Microscopy
Linear positive staining of IgG and albumin is seen in all glomerular and tubular basement membranes in a diffuse distribution. No IC-type electron-dense deposits are detected.
·       Electron Microscopy
The ultrastructural examination is most useful in the early diagnosis of evolving DKD, mild to moderate mesangial expansion with increasing nodular matrix in all the glomeruli. The foot processes are preserved early, with mild partial effacement, as the diabetic lesion advances, thickening of the basement membranes occurs. Although IC-type deposits are not present, focal capillary and mesangial finely granular insulative protein/hyaline deposits may be seen.
Differential Diagnosis
Some of the earliest features by EM of the recurrent diabetic glomerular disease may be nonspecific, such as GBM thickening and mild mesangial expansion with the matrix. Similar findings may be seen in hyperfiltration-related GBM injuries such as from metabolic disease, obesity, hypertension, prolonged smoking history, or long-standing solitary kidney, as in a renal allograft. Patients with HIV, autoimmune disease, or a donor with an underlying genetic disease such as APOL1 high-risk alleles may also manifest thickening of the GBM. It is useful to obtain clinical information for a relevant clinicopathologic correlation in these cases.
Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Crescentic GN
Renal involvement is known to occur in antineutrophil cytoplasmic antibody (ANCA)-associated systemic SVV that includes microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatous with polyangiitis. These may develop ESKD despite adequate immunosuppressive therapy in nearly 25% of cases in a few years. Recurrence of ANCA-mediated SVV in nearly 20% of renal allografts.
·       Clinical Features
The recurrence can occur as early as within the first week of transplantation or several years later. It may not always be dependent on serological evidence of ANCA (although it is detected in most cases), the specificity of the ANCA (MPO vs. PR3), or the type of donor used (living-related vs. unrelated vs. deceased). The onset is relatively rapid with hematuria, active urine sediment, rise in creatinine, and minimal proteinuria. As the response to the conventional immunosuppression therapy is generally favorable, graft loss is relatively low, at 2–3% in 10 years.
·       Renal Pathology
The morphological findings of crescentic GN. No immune deposits are localized by IF. EM findings are usually nonspecific with no alterations of the glomerular capillary basement membranes thickness or epithelial foot processes and the absence of electron-dense deposits.
complement-mediated TMA/Also Known as Atypical Hemolytic Uremic Syndrome
the presence of glomerular and microvascular endothelial injury and noninflammatory intracapillary or microvascular thrombosis presenting with hypertension and acute renal failure. This can be renal limited or manifest clinically with thrombocytopenia and microangiopathic hemolytic anemia. TMA involving the renal allograft may have a wide range of etiologies, and it is important to perform a clinicopathologic correlation considering an evaluation for antibody-mediated rejection, and immunosuppressive medication (calcineurin inhibitor)-induced TMA, or de novo infections, as well. This is in addition to entities that could be recurrent such as genetic susceptibility causing complement dysregulation, autoimmune diseases, monoclonal gammopathy associated autoantibodies, or continuation of endothelial toxic medications, or a combination of more than one of these factors.
·       Clinical Features
Recurrence of complement-mediated TMA, a non-diarrhea-associated TMA, depending on the frequency and the quality of the detectable genetic abnormalities of complement factors or complement regulatory protein activation/dysregulation (e.g., complement factor H [CFH], complement factor I, membrane cofactor protein, C3 gene variant, CFH receptor 3-1, and complement factor B) can develop both in children and adults, ranging from 30 to 80.
The clinical features vary from relatively asymptomatic expressing minimal hematologic changes to rapid renal graft dysfunction, with peripheral smear schistocytes, thrombocytopenia and microangiopathic hemolytic anemia, the elevation of LDH, and low haptoglobin, as well as moderate to severe hypertension. The triggers/risks proposed for the initiation of endothelial injury in complement-mediated TMA are therapeutic interventions such as transplant surgery, ischemia-reperfusion injury, immunosuppressive medications (tacrolimus and mTOR inhibitors), rejection, or infections. The 1-year graft loss is significantly high, with over 90% in 5 years. We should consider de novo TMA should also be considered in the posttransplant period secondary to rejection, immunosuppressive medications, and infections. The poor outcome of renal transplantation is observed in those patients who have developed ESKD with CFH and complement factor I mutations within 2 years than those with membrane cofactor protein mutation. Several management strategies are used to either prevent or treat recurrent complement-mediated TMA.
·       LM and IF Microscopy
The LM findings can appear focal, mild to severe, ranging from ischemic collapse to prominent microthrombi obstructing the capillaries and focal margination of neutrophils. Endothelial separation, trapping of fragmented RBCs, and mesangiolysis can also be seen by H&E, PAS, and silver stains. The more glomerular chronic changes with peripheral double contours can resemble those features seen in transplant glomerulopathy. IF is generally noncontributory, except for strong staining for fibrin deposits in the early and active stages. In the absence of antibody-mediated rejection, C4d is usually negative.
·       Electron Microscopy
Although in overt cases of TMA, the diagnosis is made by LM in the healing phases reorganization of the matrix with new layers of basement membrane material and subendothelial cellular interposition, mimicking MPGN pattern of chronic transplant glomerulopathy and differentiation is done by EM.