2. A 45-year-old Asian lady received a kidney transplant 7 days ago, 000 mismatch, no DSA. Her primary disease reported as “unknown”. No history of passing stones. USS 5 years ago reported bilateral small kidneys with multiple stones (no comment on nephrocalcinosis). A family history of a brother who is on HD in his home country, but the aetiology is also unknown. Kidney biopsy one hour after perfusion was comparable with a picture of ATN. Primary non-function and dialysis dependent. Biopsy one-week post-transplantation was reported as ATN with oxalate crystals in the tubules (see below). CT KUB is shown below:
- What is diagnosis?
- How do you manage this patient post-transplantation?
- What is the commonest cause of death in this condition?
DX : Primary hyperoxalosis type 1 I, t is the most common PH type and also; most severe form with rapid progression to end-stage kidney disease , No available treatment post transplantation ; Just intensify dialysis to keep the plasma oxalate levels less than 50 micromole/l. Later ; Patient can make combined liver and kidney transplants .
Diagnosis: Primary Hyperoxaluria.
Management post renal transplant: the graft has failed, she needs extensive HD, and prepare for liver and Kidney transplantation.
the medical measures like well hydration, B6, diet and Lumasiran, would be not effective in this stage.
cause of death: cardiovascular, heavily calcified vessels
1) The diagnosis is primary hyperoxaluria type1. This type is more severe form of PH. The abdominal CT scan demonstrates nephrocalcinosis and the biopsy sample shows calcium oxalate crystals in tubular lumen.
2) For ESKD patients due to PH combined kidney and liver transplantation is the treatment of choice. For this patient who receives kidney allograft, liver transplantation as soon as possible is the best option. In addition to considering sequential liver transplantation, medical treatment in order to reduce urinary calcium oxalate supersaturation is essential. Medical modalities compose of large daily fluid intake (greater than 3L/day), prescription of phosphate, magnesium and potassium citrate for increasing urinary citrate, phosphate and magnesium level, reduced dietary oxalate intake by restriction of high oxalate content food such as rhubarb and spinach, administration of oxalobacter formigenes, and high dose pyridoxine. Intensive hemodialysis may help to reduce oxalate deposition till preparation for liver transplantation.
3) systemic oxalosis with cardiovascular involvement is the commonest cause of death in this condition.
Ct shows bilateral nephrocalcinosis
Polarize light LM of kidney biospys shows deposition of oxalate crystals ; hyperoxaluria and as there is +ve family history + past history, the most probable diagnosis is recurrent primary hyperoxaluria
– Hemodialysis
– Good hydration guided by UOP
– If renal function improved start CNI
– If remained dialysis dependent so prepare for combined LKT
–
Coronary heart disease
What is diagnosis?
Primary oxalosis or hyperoxaluria.
Clues for Oxalosis in this patient:
How do you manage this patient post-transplantation?
What is the commonest cause of death in this condition?
Oxalate may deposit in the heart tissue causing congestive heart failure, cardio-embolic disease and conduction defects which are behind the cardiac cause of death.
1_ The most diagnosis of the case is primary hyperoxaluria type 1 depending on:
_ past history of renal stones.
_postive family history of ESKD and dialysis in brother.
_ early recurrence post transplant.
_ the native kidneys show calcification in CT abdomen.
_ graft biopsy shows intra-tubular crystal deposition and evidence of ATN (shredded renal tubules and denuded epithelial lining).
_ unfortunately, graft loss is inevitable.
_ hence, exclusion of primary hyperoxaluria is crucial before transplantation in any case with undefined original kidney disease, by simple x ray on abdomen that shows chalky white kidneys or better visualization by CT abdomen.
_ diagnosis by urinary oxalate is difficult in patients with ESKD.However, serum oxalate may help.
_ liver biopsy and enzyme assay is definitive diagnosis
_ genetic study can confirm the diagnosis and is essential before transplantation.
2_ the management plan is:
_ extensive Daily and prolonged homodialysis till reach serum oxalate of 20 mg/ml.
_ continue dialysis till recovery of kidney function and urine output.
_ withhold CNI till recovery of kidney function ( cover this period with steroids), then resume it.
_ pyridoxine therapy.
_ plan for combined or sequential liver_ kidney transplantation with preoperative extensive or intensified hemodialysis.
_ use of larger donor kidney is helpful to eliminate oxalate load easier.
_ lumasiran is a new drug ( targeting mRNA, but not tested in transplantation).
3_ the most common cause of death is cardiac cause from cardiomyopathy and conduction disturbances from oxalate crystal deposition.
1-what is a diagnosis?
based on history is postrenal transplanded lady to unknown cause of ESRD and family history of first degree family member of ESRD also no history suggested secondary oxalosis such as small bowel disease or high oxalate intake.
recurence of disease immediate after transplantion with crystal formation in transplant kidney causing acute tubular injury and CT scan revealed bilateral calcified native kidney and calcification of the aorta ,all these above mention data coping with the diagnosis of primary oxalosis most probably is type 1 as type 2 causing less kidney damage than 1 and type3 does not causes ESRD.
primary hyperoxalurea is autosmal ressive enzymatic defects in the pathway ofglyoxalate metabolism,type1 70% to80% of cases due to AGXT genetic mutation,type2 10% and type 3 5% is due to variants of HOGA1gene.
2- mangment of this pateint
patient is dialysis depended so intensive -dialysis is needed to minimize serum oxalate level and to reduce the body stores of oxalate so, dialy HD are required that last 6 to 8 hours
removal of native kidney at time of transplantion becuse they suspecttible to recurent infection and obstruction.
early liver -kidney transplantion is often required.,
Ditary oxalate restriction are of no substantial benefit in PH.
Several medication included: high -dose pyridoxine,orthophsphate magnesium a,pentosan and increaes urinary volume but all this treatment in dialysis patiet can not be applied.
Lumasiran ia an RNA interference agent that targetHAO1,which reduce the levels of the glycolate oxalate enzyme.in 2020 the FDA approved it to treat primary hyperoxalosis
New and future treatment moddalities under investigation included probiotic supplementaion ,chaperones and hepatocyte cell transplantation and recommbinant gene therapy to replace the enzyme.
3-when kidney function deterorate ,plasma oxalate increase further,leading to oxalate depostion into non-kidney tissue(systemic oxalosis) including the retina,myocardium ,vessel ,skin ,bone and CNS.so most common cause of death is CVS events.
references
uptodate 2022 and Medscape22
The patient in this scenario has a history of ESRD of ‘unknown’ cause, but associated with multiple stones, and a family history of renal failure.
There is primary non-functioning of graft post-transplant, in a setting of 000 mismatch and no DSA.
The kidney biopsy shows ATN with oxalate crystals in tubules
There is no history suggestive of any secondary oxalosis (like small bowel disease or increased oxalate intake)
Considering all these points, the diagnosis seems to be primary hyperoxaluria.
The confirmation of this diagnosis will require genetic testing. Other parameters which can help in diagnosis include:(1)
a) increased urinary oxalate (but not useful in dialysis dependent patients),
b) increased plasma oxalate levels (>30 micromol/L): useful in patietns with eGFR <30
c) liver biopsy: absent of reduced activity of enzymes (AGT: alanine glyoxylate aminotransferase in type 1 and GRHPR: glyoxylate reductase/ hydroxypyruvate reductase in type 2)
A scenario whereby the diagnosis comes to light post-transplant in the unfortunate event, as in this case, intensive hemodialysis can be tried might not be of much use and ultimately graft loss will take place.
The ideal treatment plan in ESRD patients with primary hyperoxaluria includes:(2,3)
1) An early combined liver and kidney transplant (preferably before GFR goes below 15-30 ml/min) with intensive hemodialysis prior to the transplant to decrease systemic oxalate load.
2) Preferably using a large donor kidney to be used for better removal of increased systemic oxalate levels.
3) Intensive hemodialysis post-transplant (if delayed graft function or increased systemic involvement)
4) Immunosuppression to be started in form of MMF and steroids, with addition of calcineurin inhibitors once the serum creatinine decreases to less than 2 mg/dl
5) Use of pyridoxine, neutral phosphate, potassium citrate-citric acid, magnesium oxide and noncalciuric diuretics post-transplant.
6) Increased fluid intake life-long
Newer treatment modalities include RNA interference agents like Lumasiran, which has been used for type I primary hyperoxaluria.(4)
The commonest cause of death in primary hyperoxaluria is due to systemic oxalosis and ESRD, mainly due to cardiac involvement.(5)
References:
1) Harambat J, Fargue S, Bacchetta J, Acquaviva C, Cochat P. Primary hyperoxaluria. Int J Nephrol. 2011;2011:864580. doi: 10.4061/2011/864580. Epub 2011 Jun 16. PMID: 21748001; PMCID: PMC3124893.
2) Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. doi: 10.1056/NEJMra1301564. Erratum in: N Engl J Med. 2013 Nov 28;369(22):2168. PMID: 23944302.
3) Chambers ET, Pearl MH, Ettenger RB (2017). Kidney transplantation in children. In Danowitch GM (Editor), Handbook of kidney transplantation (6th Ed, pp 452-491). Wolters Kluwer.
4) Devresse A, Cochat P, Godefroid N, Kanaan N. Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives. Kidney Int Rep. 2020 Sep 24;5(12):2136-2145. doi: 10.1016/j.ekir.2020.09.022. PMID: 33305106; PMCID: PMC7710835.
5) Cochat P, Groothoff J. Primary hyperoxaluria type 1: practical and ethical issues. Pediatr Nephrol. 2013 Dec;28(12):2273-81. doi: 10.1007/s00467-013-2444-5. Epub 2013 Mar 14. PMID: 23494551.
Given the data above:
· Unknown primary renal etiology
· Positive family history of renal failure
· US showing multiple renal stones
· Primary graft dysfunction with ATN and CT showing small sized kidney with nephrocalcinosis
· Renal biopsy showing Calcium oxalate crystals inducing ATN
· No mention about mal-absorption or intestinal disease that point towards enteric hyperoxaluria
· Accordingly, the most probable diagnosis is primary hyperoxaluria (However, genetic testing is required to confirm diagnosis and subtype in addition to other urinary metabolites like glycolate, glycerate, and HOG) .It is an Autosomal recessive disorder due to deficiency in one of the peroxime enzymes involved in glycine metabolism, There are 3 types ; type is the most common due to AGT deficiency 70-80 %, type 2 due to deficiency of GRHPR 10% and type 3 due to HOGA1 deficiency 10%.
· There is increase in urinary oxalate that combines with CA to form calcium oxalate stones, nephrocalcinosis. As renal function declines systemic oxalosis occur where oxalate deposits in many tissues in the body including heart, skin, eyes, CNS, joints, bones(here estimation of plasma oxalate level is important if >30 micomol/L) .
· Unfortunately, 20-50% of the cases at the time of diagnosis have significant renal impairment
Given the primary graft dysfunction with super saturation with primary oxalate crystals, the usual measures are usually not beneficial c and these include hydration, using pyridoxine the co-factor of AGT in type 1, using crystallization inhibition agents like K citrate, magnesium or orophosphate and aggressive hemodialysis after transplantation until serum oxalate falls to a safe levels to protect the transplanted graft from oxalate deposits (too late as this graft already shows oxalate deposits). siRNA( lumasiran) is a new drug approved in 2020 by FDA for PH1 for the group of patient unable to proceed to liver-kidney transplantation. Combined liver and kidney transplant is the definitive treatment in pyridoxine resistant cases.
Cardiovascular causes are the commonest causes of death due to infiltrative cardiomyopathy and conduction defects
References:
Uptodate 2021
What is the diagnosis?
▪︎Most likely this is:
Primary hyperoxaluria (Heridetary, genetic)
– The biopsy shows acute tubular injury with clear crystals (multiple intratubular calcium oxalate crystals) on H&E stain.
▪︎How do you manage this patient post transplantaction ?
___________________
▪︎ First try to reach a definitive diagnosis of primary hyperoxaluria by genetic studies [1].
▪︎ We can rule out secondary hyperoxaluria by certain diagnostic clues which point towards it and these are: supportive dietary history and tests to detect increased intestinal absorption of oxalate [1].
▪︎The diagnosis can be confirmed by low alanine glyoxylate aminotransferase (AGT) enzyme activity on liver biopsy.
▪︎If found: A retrospective review of the radiologic findings ( to see if there is any increase in the density of vertebral bones).
▪︎After ruling out secondary hyperoxaluria, we can give conservative treatment which include: vigorous hydration and crystallization inhibitors (to decrease calcium oxalate precipitation) [1].
▪︎Pyridoxine and potassium citrate solution along with continuous renal replacement therapy followed by intensive hemodialysis to reduce plasma oxalate concentration [2].
▪︎Dietary restriction of foods high in oxalate
▪︎Minimal invasive methods such as ureteroscopic laser lithotripsy may be recommended.
▪︎Inform the family about the need of screening for Primary hyperoxaluria (1), because it is a hepatic metabolic defect that can lead to end-stage renal failure.
▪︎The posttransplant recurrence of kidney disease c suggest a need for combined liver-kidney transplantation (LKT).
▪︎ Based on her condition, a liver transplantation is highly recommended first, and looking forward for a chance of second kidney transplantation [3].
◇What is the commonest cause of death in this condition?
_______________
▪︎Cardiac failure because of cardiac calcium oxalate crystal deposition, vascular complications or complication from dialysis or transplantation procedures.
______________________________€
Ref:
[1] Bhavna Bhasin, Hatice Melda Ürekli, and Mohamed G Atta. “Primary and secondary hyperoxaluria: Understanding the enigma”
https://doi.org/10.5527/wjn.v4.i2.235
[2] Gholam Hossein Naderi, et al. Primary hyperoxaluria type 1 diagnosed after kidney transplantation: The importance of pre-transplantation metabolic screening in recurrent urolithiasis 2015, Vol: 26, P: 783-785
[3] Zhitao Cai, Mao Ding, et al ” Primary hyperoxaluria diagnosed after kidney transplantation: a case report and literature review” BMC Nephrology . volume 22, Article number: 393 (2021)
Primary hyperoxalurias are congenital abnormalities of glyoxylate metabolism, which is characterized by the overproduction of poorly soluble oxalate. In primary hyperoxaluria , there is increase in urinary excretion leading to deposition in the kidneys with subsequent injury, and in some cases progression to end stage renal disease.
Primary hyperoxaluria (PH) is primarily caused by autosomal recessive variants in three genes that encode enzymes involved in glyoxylate metabolism.
PH type 1: It is the most common PH type and accounts for approximately 70 to 80 percent of PH cases. It is the most severe form of PH with more rapid progression to kidney dysfunction including end-stage kidney disease that develops in one-half of patients by young adulthood.
PH type 2: It accounts for approximately 10 percent of PH cases. Unlike the AGT of PH type 1, this enzyme, although predominantly expressed in the liver, has a wide tissue distribution. Clinical manifestation of PH type is 2 recurrent kidney stones.
PH type 3: PH3 is the mildest form of PH and appears to account for approximately 5 to 10 percent of genetically characterized cases.
The diagnosis of PH is made in a stepwise approach based on:
●Clinical suspicion due to the presence of suggested clinical manifestations
●Metabolic testing demonstrating elevated urinary oxalate excretion
●Confirmation by genetic testing that demonstrates a variant of any of three known causative genes (AGXT, GrHPR and HOGA1)
●If no variant has been found, the diagnosis of PH type 1 and 2 can be made by a liver biopsy demonstrating absent or significantly AGT or GRHPR activity.
Medical management for all forms of PH includes the following modalities:
Large daily fluid intake
Increased urinary phosphate, citrate and magnesium concentration
Reduced dietary oxalate intake
Pyridoxal phosphate and PH type 1 – A trial of high-dose pyridoxine (pyridoxal phosphate), a coenzyme of AGT that promotes the conversion of glyoxylate to glycine, rather than to oxalate, is provided to patients with type 1 disease. Approximately 10 to 30 percent of patients with PH type 1 will respond to pyridoxine therapy with a significant reduction of urinary oxalate excretion.
RNA interference (RNAi) therapeutic agents-Lumasiran and Nedosiran
Liver transplantation is the only curative intervention for PH type 1 as it corrects the underlying enzymatic defect due to mutations of the AGXT gene. Preemptive liver transplant in patients with glomerular filtration rates greater than 40 mL/kg per 1.73 m2 has been proposed as curative treatment in patients with type 1 disease.
Due to systemic oxalosis, fatal cardiac arrythmias may occur due to oxalate deposition in the heart , leading to cardiac arrest.
Primary hyperoxaluria
Possibly PHType I
It occurs due to variants of AGXT encoding the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), involved in the transamination of glyoxylate to glycine ,increasing the glyoxylate pool, which is converted by lactate dehydrogenase to oxalate. It is the most common PH type and it is the most severe form of PH with rapid progression to end-stage kidney disease
1-good hydration with monitoring urinary output
2-Increased urinary phosphate, citrate and magnesium concentration
3-Reduced dietary oxalate intake
4-Oxalobacter formigenes – Enhancing oxalate elimination by the gastrointestinal tract
5-Pyridoxal phosphate where high-dose pyridoxine (pyridoxal phosphate), a coenzyme of AGT that promotes the conversion of glyoxylate to glycine, rather than to oxalate,
6-Lumasiran is an RNA interference (RNAi) therapeutic agent that targets glycolate oxidase resulting in depletion of the substrate for oxalate synthesis, thereby reducing oxalate production
7-Nedosiran a second-generation RNAi agent that targets the mRNA encoding hepatic lactate dehydrogenase A.
8-Intensive dialysis (five-hour daily HD sessions, nocturnal HD, or a combination of HD and PD) is needed to try to match daily oxalate production, but in many patients even intensive dialysis therapy remains inadequate to keep up with their daily oxalate production
9-Combined liver and kidney transplantation
The liver provides the missing enzyme, thereby lowering oxalate production to the normal range. The outcome of simultaneous transplantation is probably best when the procedure is performed as the glomerular filtration rate (GFR) falls below 40 mL/min per 1.73 m2 and prior to marked tissue oxalate deposition
Systemic oxalosis — When the glomerular filtration rate falls below 30 to 40 mL/min per 1.73 m2, the combination of oxalate overproduction and reduced urinary oxalate excretion results in systemic oxalosis with potential calcium oxalate deposition in the heart, blood vessels, joints, bone, and retina
Cardiac conduction defects that may result in cardiac arrest .
Poor peripheral circulation that results in distal gangrene, and difficulties with vascular access for hemodialysis.
Reference
Uptodate 2021
Diagnosis is primary hyperoxaluria.
The way this graft has behaved I think the only way is to remove this kidney and transplant in another recipient.Intensification of dialysis , pyridoxine, lumasiren , K citrate are not going to change much.
Cardiomyopathy and conduction defects are common cause of death
Most likely primary hyperoxalosis type 1with recurrence in the transplanted kidney.
2. Dialy Dialysis
Good hydration
Infection should be treated aggressively
Pyridoxine can help
Diet advise
3. This patient for both liver and kidney transplant
What is diagnosis?
Imaging CT showing Bilateral nephrocalcinosis.
Histopathology slide showing Tubules stained with H&E stain revealed Oxalate crystals deposition in tubules.
And by history there were bilateral kidney stones, with possible positive family history
Diagnosis is most probably Hyperoxaluria.
How do you manage this patient post-transplantation?
Basically Primary hyperoxaluria (PH) is caused by autosomal recessive variants in three genes that encode enzymes involved in glyoxylate metabolism. These result in enhanced oxalate production that leads to excessive oxalate deposition in kidney tissues resulting in nephrocalcinosis and kidney stones.
The better way to have a suspicion and diagnose Hyperoxaluria in pre transplant time
So proper planning for combined liver and kidney transplantation take place as liver transplantation provides the definitive cure for PH type 1 with restoration of the missing enzyme, which lowers oxalate production to the normal range.
Since the patient diagnosed after transplantation with post transplant biopsy of ATN with oxalate deposition and non primary graft function ,dialysis dependent:
-Intensive dialysis daily HD sessions to prevent more tubular injury and to avoid systemic oxalosis, nocturnal HD, or a combination of HD and PD is needed to try to match daily oxalate production(daily oxalate production of 3500 to 7500 micrmol) hemodialysis removing around 1440 micromol/day.
-Hold CNI to avoid CNI toxicity and continue on MMF and prednisolone.
-Genetic testing to define the type of hyperoxaluria
-Since the patient in ATN and expected oliguria or anuria the medical management will not make a great difference.
What is the commonest cause of death in this condition?
Cardiac conduction defects that may result in cardiac arrest
What is diagnosis?
CT Picture- Bilateral nephrocalcinosis
Histology slide- Oxalate deposition in tubules.
There is family history , Primary non functional graft with CT showing calcinosis along with biopsy. This is a case of primary hyperoxaluria ( PH) type 1 and will need enzymatic and genetic testing . Type 1 PH accounts for 80% cases of PH. There is defect in B6 dependent hepatic peroxisomal enzyme -AGT- analnine glyoxalate aminotransferase. It catalyzes transamination of L alanine and glyoxalate to pyruvate and glycine. Its due to defect in AGXT gene on chromosome 2.
How do you manage this patient post-transplantation?
As there is primary non function , patient will need-
Aggressive haemodialysis
Aggressive fluid management
Potassium citrate
Pyridoxine
Neutral phosphate
Avoid high oxalate diet
If confirmed type 1 PH after testing then definite management is combined liver and renal transplant
What is the commonest cause of death in this condition?
Cardiac conduction defects due to oxalate deposition
Bhavna Basin e al. Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol. 2015 May 6; 4(2): 235–244.
Diagnosis
Primary hyperoxaluria by:
History suggestive the presence of small atrophic kidneys with multiple stones, her brother is also ESRD on HDx.
Clinically: early graft dysfunction postoperative and the need of renal replacement therapy by dialysis.
Pathological: renal biopsy demonstrated picture of ATN, and crystal deposition within the renal tubules.
Imaging KUB: Calcium oxalate stones are likely to be visible on the KUB if they are large enough, usually 2 to 3 mm or larger.
Management of this patient post-transplantation:
Renal replacement therapy in the form of dialysis.
Liver transplantation should be the crucial management for such case.
Adequate fluid intake, urinary inhibitors of calcium oxalate crystallization and vitamin B6 may be of little help.
Commonest cause of death in this condition:
Cardiac complication in the form of conduction defects, arrhythmias and cardiomyopathy.
Primary hyperoxaluria type 1.
due to variants of AGXT that encodes the hepatic peroxisomal enzyme
alanine:glyoxylate aminotransferase (AGT).
Hemodialysis.
aggressive medical management (high fluid intake, and the administration of neutral
phosphate, potassium citrate-citric acid) .
pyridoxine in responsive patients.
Combined liver and kidney transplant.
Cardiac conduction defects that may result in cardiac arrest .
When would you commence CNI post-transplant?
I think , Day zero tac is started .
This patient has native kidney stones by US , family history of the same illness, post kidney transplant primary non function & dialysis dependent, kidney biopsy showed oxalate deposition with ATN & CT KUB showed renal calcinosis , all give picture of type 1 hyperoxaluria.( need genetic study & liver enzymes analysis to differentiate it with secondary hyperoxaluria )
This patient has primary non function needs aggressive dialysis to eliminate oxalate load.
If primary hyperoxaluria is approved by investigations, kidney transplant alone is contraindicated, he needs combined liver & kidney transplant or stage operation liver first then kidney transplant.
In case of secondary hyperoxaluria or Type 2 , no need for liver transplant,
the treatment is kidney transplant with preoperative preparations :
1-restrict diet with high oxalate .
2- good Hydration if patient still produce good UOP
3 – using Na , K or Mg citrate to decrease oxalate salts .
4- aggressive dialysis target serum oxalate less than 2 umol/l
the comments cause of death is cardiomyopathy & conduction problem.
Decent reply but when would you commence CNI post-transplant?
1- Diagnosis
A case of primary hyperoxaluria type 1, with early post transplantation ATN due to heavy oxalate deposition in renal tissue.
2- Treatment
– For this graft , no treatment only return on regular hemodialysis
– For preparing to future transplantation : type 1 hyperoxalosis is AR disease due to diffiency of liver specific enzyme so the only curative treatment in this case is combined liver and kidney transplantation that is associated with high morbidity and mortalty complications .
– Other treatment options to decrease oxalate load as
Dietary restiriction of oxalate containg foods
Vigorous hydration to maintan daily UOP (3-4 litre per day), not feasible in ESRD pts
Prevent Ca oxalated crystallizations with oral citrate salts .
Pyridoxine : safew , but variable patients response.
New therapies under investigations
– RNA interference to modify the gene responsible for PH as lumasiran
– LDH type 5 inhibitors
Pretransplantation oxalte load reduction with daily dialysis , nocturnal dialysis or combination of both .
Cause of death
Cardiovascular diseases
good, very nice to mention drugs like lumasiran,nedosiran (RNA interference drugs), diacomit ( LDH type 5 inhibitors
Primary hyperoxaluria, leads to rapid appearance of oxalate deposits in the graft biopsy and nephrocalcinosis
It cause deterioration of kidney functions as oxalate crystals deposition lead to destruction of renal parenchyma.
The patient needs to continue on regular hemodialysis
Should arrange for combined or staged liver and kidney transplantation as the primary defect is in the liver and should have vigorous dialysis to decrease the oxalate load
External calcium oxalate deposition in cardiac muscles leads to cardiomyopathy and conduction disorders leading to early mortality.
Lorenzo-Sellares V, Lorenzo V, Torres-Ramírez A, Torres A, Salido E. Primary hyperoxaluria. Nefrología (English Edition). 2014 May 1;34(3):398-412.
Madiwale C, Murlidharan P, Hase NK. Recurrence of primary hyperoxaluria: an avoidable catastrophe following kidney transplant. Journal of Postgraduate Medicine. 2008 Jul 1;54(3):206.
The answer needs more elaboration. Please also highlight your immunosuppression strategy post transplant
The slide 1 show bilateral nephrocalcinosis in native kid
The slide 2 show oxalate deposition in renal tubules
1-history of renal stone and positive family history of ESRD on hemodialysis and oxalate crystals deposits in renal biopsy
The diagnosis is primary hyperoxalurea recurrent post transplantation
●PH type 1
is due to variants of AGXT that encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5′-phosphate-dependent enzyme, which is involved in the transamination of glyoxylate to glycine
●PH type 2
is due to variants of GRHPR that encodes the cytosolic enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which normally converts glyoxylate to glycolate
●PH type 3
is due to variants of HOGA1 that encodes the liver-specific mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme.
PH type 1 is the most severe form of PH as patients with PH type 1 are more likely to progress to ESKD and at an early age
patients with PH type 2 may also develop ESKD.
Patients with type 3 disease present at an earlier age, typically have a lower urinary oxalate rate and slower progression of kidney disease than those with types 1 and 2. It remains uncertain whether type 3 disease progresses to ESKD.
2-Treatment in this case need renal replacement therapy
Dialysis
The maximal oxalate elimination by conventional hemodialysis (HD) and peritoneal dialysis (PD) is 950 to 1440 micromol/day, which is significantly lower than the daily oxalate production of 3500 to 7500 micromol in patients with PH type 1
plasma oxalate returns to 80 percent of the predialysis value within 24 hours and 95 percent 48 hours after dialysis
Intensive dialysis (eg, five-hour daily HD sessions, nocturnal HD, or a combination of HD and PD) is needed to try to match daily oxalate production, but in many patients even intensive dialysis therapy remains inadequate to keep up with their daily oxalate production
Intensive dialysis therapy may be useful prior to renal transplantation to decrease plasma oxalate as much as possible to reduce subsequent oxalate deposition and injury in the renal allograft.
Liver transplantation is the only curative intervention for PH type 1 as it corrects the underlying enzymatic defect due to mutations of the AGXT gene.
Preemptive liver transplant in patients with glomerular filtration rates greater than 40 mL/kg per 1.73 m2 has been proposed as curative treatment in patients with type 1 disease.
In patients with significant chronic kidney disease, mobilization of oxalate within the tissues is reduced because of the impaired renal function after liver transplantation alone. In these patients, combined liver and kidney transplantation has been advocated over isolated renal transplantation
3-Cardiac – Cardiac conduction defects that may result in cardiac arrest
Reference
Up to date 2022
Good. Needs more reflection on immunosuppression post transplant
Ca-Ox deposits foci appeared polarized under LM.a background of severe ATN
Nephrocalcinosis was seen on both sides of the abdomen on the CT scan.
-The approach for PH1 diagnosis consists of five steps including measurement of urinary Ox, and calculation of urinary Ox over Cr ratio.
– determination of plasma Ox, liver biopsy for enzymatic analysis, and deoxyribonucleic acid (DNA) analysis.
-Plasma Ox level is determined when the values of urinary Ox are falsely low in patients with renal impairment due to Ox retention and systemic deposition as CaOx,
-Liver biopsy for enzymatic analysis is required if liver transplantation is considered and –DNA analysis is used only in populations having a high frequency of a specific mutation. So far, more than 60 mutations have been detected until now(1,2).
How do you manage post-transplant?
If it is primary hyper-oxalosis type 1, it is absolute contraindication to proceed with kidney transplantation only. need combined liver-kidney transplantation. type 2 can proceed for kidney transplantation only.
Ideally, aggressive hemodialysis before transplantation is employed to decrease oxalate load to safe levels and minimize tissue oxalate deposition.
The target plasma oxalate level is less than 50 mg/mL. At transplantation, a large donor kidney is used whenever possible to permit effective excretion of the oxalate burden.
If early renal transplant dysfunction occurs, daily hemodialysis is continued. When good renal function is established, CNI therapy is begun. In addition, posttransplantation treatment includes pyridoxine, neutral phosphate, citrate, magnesium, and non-calciuric diuretics. (3)
What is the most prevalent reason for mortality associated with this condition?
Conduction problems and even cardiac arrest may result from the accumulation of oxalate.
1. Danpure CJ. Primary hyperoxaluria: From gene defects to designer drugs? Nephrol Dial Transplant 2005;20:1525-9.
2. Williams E, Rumsby G. Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1. Clin Chem 2007;53:1216-21.
3- Handbook of kidney transplantation.
Very nice, you are the only one, who has mentioned the large donor kidney and CNI therapy.
H&E staining of a renal allograft biopsy examined by polarized light showing CaOx deposition
The most frequent cause of CaOx crystal deposition within the kidney is hyperoxaluria.
CaOx deposition appears primarily recipient-derived and is frequently observed in for-cause renal allograft biopsies obtained within 3 months post-transplantation.
Secondary hyperoxaluria, for example, due to enteric hyperoxaluria following bariatric surgery, chronic malabsorption from other causes or been exposure to a high dietary load of oxalate or its precursors, e.g. in the setting of unusual and excessive intake of star fruit, rhubarb or ascorbic acid. Ingested ethylene glycol or vitamin C overdose may also cause CaOx deposition in native kidneys. CaOx deposition is a frequent finding in renal transplant biopsy, often as a consequence of acute tubular necrosis and is associated with poorer long-term graft outcomes
The most typical cause of death in these patients is cardiac.
1. Snijders ML, Hesselink DA, Clahsen-van Groningen MC, Roodnat JI. Oxalate deposition in renal allograft biopsies within 3 months after transplantation is associated with allograft dysfunction. Plos one. 2019 Apr 16;14(4):e0214940.
2. Palsson R, Chandraker AK, Curhan GC, Rennke HG, McMahon GM, Waikar SS. The association of calcium oxalate deposition in kidney allografts with graft and patient survival. Nephrology Dialysis Transplantation. 2020 May;35(5):888-94.
3. Geraghty R, Wood K, Sayer JA. Calcium oxalate crystal deposition in the kidney: identification, causes and consequences. Urolithiasis. 2020 Oct;48(5):377-84.
Though the reply is adequate unfortunately you have partially cut/copied and pasted, parts of your answer from https://link.springer.com/article/10.1007/s00240-020-01202-w. I would recommend that you use references as a guide and use your own understanding.
Although oxalosis isn’t a glomerular disease, but should always be kept in mind.
What other cause of oxalate deposition in a graft biopsy with primary non-function or ATN post-transplant?
Enteric hyperoxaluria caused either by malabsorption syndromes or bariatric surgery
Enteric hyperoxaluria, may occur due to
Excess luminal free fatty acids binding to calcium allowing oxalate to be absorbed in large bowel.
Repeated antibiotic use can eliminate oxalobacter formigenes, an anaerobic bowel organism that degrade oxalate.
excess intake of vitamin C or other oxalate precursors.
Rankin AC, Walsh SB, Summers SA, Owen MP, Mansell MA. Acute oxalate nephropathy causing late renal transplant dysfunction due to enteric hyperoxaluria. American Journal of Transplantation. 2008 Aug;8(8):1755-8.
Fakhouri F, Chauveau D, Touam M, Noel LH, Grunfeld JP. Crystals from fat. Acute oxalate nephropathy. Nephrol Dial Transplant 2002;17: 1348–1350
Cuvelier C, Goffin E, Cosyns JP, Wauthier M, de Strihou CY. Enteric hyperoxaluria: A hidden cause of early renal graft failure in two successive transplants: Spontaneous late graft recovery. AmJ Kidney Dis 2002; 40: E3
Secondary oxalosis ; GIT, Pancreatitis, Surgery, Diet , Drugs e.g Vitamin C
Secondary hyperoxaluria due to bowel diseases as IBD, extensive resection and celiac.
Prolonged antibiotics that eliminate oxalobacter that ferment oxalate and metabolize it
References
Arnaud Devresse, Pierre Cochat, Nathalie Godefroid, Nada Kanaan,
Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives,
Kidney International Reports,
Volume 5, Issue 12,
2020,
Well done, thank you
What is the diagnosis?
There is a family history of renal disease of unknown etiology (her brother on hemodialysis) and the biopsy showed oxalate deposition which is suggestive of Primary Hyperoxaluria Type I which results from the deficiency of hepatic peroxisomal alanine glyoxylate aminotransferase (AGT). The deficiency of this enzyme leads to the deposition of oxalate in all body tissues, including the kidneys,
myocardium, and bone. Renal transplantation alone does not correct the enzymatic deficiency, and graft loss is common because of oxalate mobilization from tissue deposits and subsequent deposition in the graft.
How do you manage this patient?
The best treatment is combined liver-and-kidney transplantation has led to higher rates of success. The transplanted liver corrects the enzymatic deficiency and thus prevents further oxalate production.
What is the commonest cause of death in this condition?
Cardiac arrest due to oxalate deposition.
Reference
Danovitch G.M . Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017
What is diagnosis?
This scenario is systemic primary hyperoxalouria type one.
renal biopsy of glomeruli shows oxalate crystals
It’s genetic disorder caused due to deficiency of liver perioxsomal enzyme; lead to overproduction of hepatic oxalate.
It’s severe form associated with renal calculi and systemic oxalate deposition. It’s lead to ESRD
What is the management?
Return patients to hemodialysis
The only cure of hyperoxalouria is kidney and liver transplant together to prevent production of oxalate. but it’s limited data regarding successful liver/ kidney transplant
Other measures to prevent formation of calcium oxalate stone.
What is the main cause of death?
The main cause of death is cardiac arrest due to calcification of conductive system.
References:
Jayasinghe, Kushani1,2; Chadban, Steven1; Wyburn, Kate1; Gracey, David1; Shackel, Nick1; Haber, Anna1: Recurrent Primary Hyperoxalosis Despite Simultaneous Kidney-Liver Transplantation
A Case Report Transplantation: July 2018 – Volume 102 – Issue – p S487
What is diagnosis?
CT : nephrocalcinosis in both native kidneys .
Post ktx biopsy examined by polarized microscopy showing tubules containing crystalline oxalate deposits which are double refractile, showing the full spectrum of colours.
Recurrent primary hyperoxalouria in post kidney transplant recipient.
How do you manage this patient post-transplantation?
Unfortunately there is no specific treatment only to continue on renal replacement therapy.
Prepare for combined LKT.(1)
What is the commonest cause of death in this condition?
Deposition of calcium oxalate crystals in cardiac tissue lead to Cardiomyopathy, valvular diseases and conduction abnormalities which is the most common cause of death.(2)
References:
1-Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives, ArnaudDevresse12PierreCochat34NathalieGodefroid25NadaKanaan12.
https://doi.org/10.1016/j.ekir.2020.09.022.
2-Deposition diseases cardiomyopathy: A review and pooled analysis of pathophysiology, diagnosis and clinical management, Aref Albakri, DOI: 10.15761/TR.1000147.
Excellent
The diagnosis of the current case is recurrence of primary hyperoxaluria (PHO) most probably type 1
PHO is a rare disease, caused by autosomal recessive enzymatic defects in pathways of glyoxylate metabolism that result in ↑ oxalate production with a subsequent increase in urinary excretion of oxalate.
3 types exist :
PH1 is the most aggressive form ( 50 % of patients develop ESRD by young adulthood), followed by PH2 which can present with a milder form of renal dysfunction but can progress to ESRD (25-30 % develop ESRD at the age of 40); lastly, PH3 is the mildest form and very rarely progress to ESRD.
There is variable presentation even between the same family, this means one may present with renal stones and the other may present with ESRD
Presentation
A- Nephrolithiasis / Nephrocalcinosis
B- CKD / ESRD
C- Systemic oxalosis typically occurs when GFR becomes below 30 ml/min leading to retention of oxalate (heart, blood vessels, joints, bone, and retina)
Diagnosis of primary hyperoxaluria
Management of the current case post-transplantation
REFERENCES
Excellent
Primary hyperoxaluria: an inborn error of glyoxylate metabolism characterized by the overproduction of oxalate which is poorly soluble and deposited as calcium oxalate in various organs.
Since the patient is transplanted, there is nothing to do rather supportive treatment including:
Cardiac cause as the deposition of oxalate will lead to conduction defects and cardiac arrest.
Reference:
UpToDate 2022, primary hyperoxaluria. cited at 23-5-2022.
Thank you
How often is the treatment post-transplantation successful?
Treatment post-transplant is not successful and the patient will end with ESRD, prompt diagnosis should be made before transplantation to decide the type of transplantation which is a combined liver and kidney transplantation, in addition, genetic testing need to be done to confirm the type of hyperoxaluria.
Dear all:
Let us agree that post Tx discovered oxalosis is a very ugly surprise.
Treatment attempts whatever enthusiastic are disappointing.
All the mentioned treatment plans are best in suspected cases of early of nephrolithiasis and positive family history who should undergo along side with the lab. work up,enzyme assays and genetic studies to decide the specific therapy.
Combined planned liver and kidney Tx is the treatment of choice in the advanced cases.
# What is diagnosis?
** Primary hyperoxaluria: oxalosis
*Biopsy show Calcium oxalate deposits in the urinary space and in the renal tissue (HE, polarisation microscope, 200X).
* The kidney is the first organ affected, with calcium oxalate aggregates in the urinary space (urolithiasis) and in the renal tissue (nephrocalcinosis) where there is significant development of interstitial fibrosis and renal failure) (1)
# How do you manage this patient
* Treatment may require the coordinated efforts of a team of specialists(surgeons, nephrologists, hepatologists, urologists dieticians, and other healthcare)
* Genetic counseling is recommended to help families understand the natural history of PH and to provide psychosocial support.
* Specific therapeutic procedures may vary, depending upon numerous factors( disease stage, subtype responsiveness to pyridoxine, symptoms,age and general health)
* Adequate fluid intake & avoid dehydration.
* Dietary restriction of foods high in oxalate Vitamin D &C should be avoided in large doses as a precautionary measure.
* Certain medications may be used potassium citrate, thiazides, magnesium, or orthophosphates. ( reduce the risk of calcium and oxalate crystallization but do not prevent stone formation or kidney failure).
* PH type I may respond to dietary supplementation with pyridoxine.
(not all patien respond )
*Minimal invasive methods such as ureteroscopic laser lithotripsy may be recommended.
*Intensive dialysis
* liver transplant, may be considered in individuals without advanced kidney disease (preemptive liver transplantation), but its use controversial because the benefits must be weighed against a relatively high immediate post-operative mortality.
* kidney transplant alone is not an effective, since high oxalate levels excreted into the urine can damage the new transplanted kidney, so
combined( liver & kidney) transplant when the kidneys are already too damaged
* Oxlumo (lumasiran) is the first viable drug alternative to transplantation for PH type I to be approved by the U.S. Food and Drug Administration (FDA).
It is successfully lowers urinary oxalate levels.
It is a type of gene therapy known as RNA interference (2)
# What is the commonest cause of death in this condition?
*Cardiovascular complication due to accumulation of calcium oxalate crystals in the heart
References
1- Cochat P, Rumsby G. Primary Hyperoxaluria. N Engl J Med 2013;369(7):649-58. [Pubmed]
2-JOURNAL ARTICLES
Hu B, Zhong L, Weng Y, et al. Therapeutic siRNA: state of the art. Signal Transduct Target Ther. 2020:5:101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305320/
Well done
What is diagnosis?
Seems to be Primary hyperoxaluria. Her brother seems to have the same problem.
It is an inborn error of metabolism, accumulating calcium oxalate mainly in kidney and heart.
How do you manage this patient post-transplantation?
I don’t believe she’s in a position to save the kidney in question. Hygiene and dietary guidelines are necessary as well as family counseling. High-dose pyridoxine, high fluid intake, urine acidification, and calcium binders may be used.
Theoretically, the first kidney transplant should be performed in conjunction with the liver transplant.
What is the commonest cause of death in this condition?
Cardiac death for calcium deposition
Good you mentioned that the above case is too late to rescue which is the usual case that presents with immediate DGF and biopsy reveals the pathology.
Primary hyperoxaluria type1, rare genetic disease ( inborn-error of glyoxylate metabolism which lead to hepatic overproduction of oxalate led to accumulation of calcium oxalate in different organs including kidney and heart ,primary organ affected is the kidney and lead to nephrocalcinosis and kidney stones with progressive kidney failure and associated with recurrence post transplantation if missed the diagnosis can lead to graft loss, to avoid recurrence post-transplant ideally should go for combined liver and kidney transplant
How do you manage this patient post-transplantation?
I think too late to salvage this kidney and likely she will progress to ESKF meanwhile overhydration and citrate to reduce renal calcium oxalate deposition, pyroxidine to reduce urinary calcium oxalate in some patients usually most of above treatments are ineffective and > 50% progress to ESKD
The best prevention in diagnosed cases to go for dual transplant liver and kidney
Lumasiran is anew RNAI (ILLUMINATE-A Clinical phase 3 trial) it’s promising new therapeutic agent that act by inhibiting the hepatic production of oxalate by blocking glycolate oxidase and reduce the urinary calcium oxalate level after 6 months of use. Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes (2). It’s now FDA approved for PH1 in children and adults since 2020.
What is the commonest cause of death in this condition?
Cardiac death
References:
1-Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O’Riordan WD, Cochat P, Deschênes G, Shasha-Lavsky H, Saland JM, Van’t Hoff WG, Fuster DG, Magen D, Moochhala SH, Schalk G, Simkova E, Groothoff JW, Sas DJ, Meliambro KA, Lu J, Sweetser MT, Garg PP, Vaishnaw AK, Gansner JM, McGregor TL, Lieske JC; ILLUMINATE-A Collaborators. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med. 2021 Apr 1;384(13):1216-1226.
2- Hulton SA, Groothoff JW, Frishberg Y, et al. Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients with Primary Hyperoxaluria Type 1. Kidney Int Rep. 2021;7(3):494-506.
3- up to date medicine 2022.
Excellent( too late to salvage )it takes no time for the liver to generate huge amounts of oxalate.
What is the diagnosis?
The data mentioned above is consistent with the diagnosis of primary hyperoxaluria i.e., ESRD of unknown etiology in a young lady with positive family history of ESRD , CT scan KUB plain showing small kidneys with cortical nephrocalcinosis and allograft biopsy showing calcium oxalate crystals under polarised light leading to ATN like picture, without any obvious features suggestive of secondary hyperoxaluria.
How do you manage this patient post-transplantation?
First of all, diagnosis is to be confirmed with the metabolic testing which showed increase urinary oxalate and urinary glycolate, followed by genetic testing .Liver biopsy to demonstrate absent AGT or GRHPR activity needed in few cases
Treatment:
Medical: Increase fluid intake
Potassium citrate or magnesium oxide for calcium oxalate solubility(Neutral phosphate (orthophosphate not in this patient)
Restrict oxalate in diet glyoxylate to glycine
Oxalobacter formigenes-for increasing oxalate excretion.
High dose pyridoxine (5-20mg/kg)
Trials on drugs –Lumasiran targeting glycolate oxidase resulting in decrease oxalate synthesis, Nedosiran
Hemodialysis helps in reducing oxalate levels 60-80% and theres is rebound after dialysis so intensive hemodialysis i.e.,5 hour daily sessions ,nocturnal or combination of PD and HD can be tried.
Surgical Treatment: Combined or Sequential Liver and kidney Transplantation
What is the commonest cause of death in this condition?
Cardiovascular complicatons because of calcium oxalate deposition in the heart leading to cardiomyopathy and conduction defects causing cardiac failure.
REFERENCE:
1- Bergstralh EJ, Monico CG, Lieske JC, Herges RM, Langman CB, Hoppe B, Milliner DS; IPHR Investigators. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010 Nov;10(11):2493-501.
2- Pierre Cochat, Sally-Anne Hulton, Cécile Acquaviva, et al. Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment, Nephrology Dialysis Transplantation, Volume 27, Issue 5, May 2012, Pages 1729–1736.
Diagnosis :is primary hyperoxaluria with recurrence post kidney transplantation.
Its basically an Autosomal recessive disease caused by deficiency of an Oxalate metabolizing liver enzymes.Its reported to cause allograft oxalate deposition resultant in stone formation , nephrocalcinosis and ATN caused by intratubular deposition of oxalate, due to newly formed and tissue mobilized oxalate after transplantation.Timely diagnosis of hyperoxaluria is the key ,as the early and aggressive medical management can offset the damage related to hyperoxaluria.
Genetic study is important to confirm the diagnosis and stratify the treatment.
Management:
1] large fluid intake :more than 3 L per day.
2]Increased urinary concentration of phosphate, Citrate and magnesium concentration.:
As all are inhibitors of calcium oxalate precipitation:
1}magnesium 500 mg od
2}Neutral phosphate of 40-60 mg od.
3}Potassium Citrate 0.15 g/kg .
3] Pyridoxin administration .10-30 % respond rate.
4}Novel therapies which we need to acknowledge its safety post kidney transplant :
a-Lumasiran RNAi reduce oxalate synthesis.
b-Nedosiran: second generation RNAi ,its safe to treat all types of PH .
Combined liver and kidney transplant is ultimate modality of choice to treat PH.
Only Kidney transplantation can be an option for those PH who are responsive to Pyridoxine or adult patients who got the disease with late onset.
it would be an interesting option to discuss and offer liver transplant for this patient.
The most common cause of death in PH is Cardiac failure due to deposition of calcium oxalate crystal deposition
references:
1]S.M Van Der Hoeven et al . Primary hyperoxaiuria type 1, a too often missed diagnosis and potentially treatable cause of end stage renal disease in adults:result of a Dutch cohort.ndt 27 July 2012.
2]Patrick Niaudet, primary hyperoxauria. http://www.uptodate.com
What is diagnosis?
Primary hyperoxaluria(PH).
PH type I is caused by mutations in the AGXT gene.
PH type II is caused by mutations in the GRHPR gene.
Both are inherited in an autosomal recessive pattern.
Type 2 is less severe than type 1.
The progression to ESRD occurs later in PH type 2 than in PH type1, in which 50% of patients have ESRD by the age of 25.
The CT shows nephrocalcinosis of the atrophied native kidneys.
The polarized light microscopy of the graft biopsy shows oxalate crystal deposition in the tubules.
——————————————————–
How do you manage this patient post-transplantation?
Supportive management, including heamodialysis, followed by combined live-kidney transplantation.
Isolated kidney transplant is usually recommended in PH type 2, but early recurrence leading to graft loss necessitates combined liver-kidney
transplant in this patient.
Type 1 requires combined liver-kidney transplantation.
——————————————————–
What is the commonest cause of death in this condition?
Cardiovascular disease as a complication of ESRD.
Refeerences
1. LETTER TO THE EDITOR Primary hyperoxaluria type 2 successfully treated with combined liver-kidney transplantation after failure of isolated kidney transplantation © 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.
2. John C. Lieske. Primary Hyperoxaluria.NORD@ Rare Disease Database
3. Gill Rumsby and Sally-Anne Hulton. NLM Citation: Rumsby G, Hulton SA. Primary Hyperoxaluria Type 2. 2008 Dec 2 [Updated 2017 Dec 21].
You are right combined kidney and liver Tx
What is the diagnosis?
Given the data
-Unknown etiology for ESRD in a young lady
– positive family history
– early graft compromise with biopsy revealed birefringent calcium oxalate crystals and crystal-induced ATN
– MSCT KUB of small-sized kidneys with nephrocalcinosis
– no history of an increased intake nor enteric pathology i.e. IBD or bypass operation (secondary hyperoxaluria)
This data suggest the diagnosis of primary hyperoxaluria
Which is a rare autosomal recessive disorder that presents in 3 types
Type 1:most common alanine glyoxylate aminotransferase deficiency (AGT) which lead to the transformation of glyoxylate to insoluble oxalate which leads to nephrocalcinosis and renal failure
Type 2: less common, glyoxylate reductase /hydroxy pyruvate reductase deficiency (GRHPR)
Type 3: least common hydroxy oxoglutarate aldolase deficiency (HOGA) deficiency of Alanine glyoxylate
How do you manage this patient post-transplantation?
Confirm diagnosis:
A- Urine studies:
– Urinary glycolic acid: high (305.01 mM/M creatinine with normal range of less than 50 mM/M),
urine oxalate may be normal
serum oxlate may be non specifically high in patients with eGFR <40 ml/min
B- A liver biopsy is particularly necessary for a definite diagnosis prior to hepatic transplantation
C- Further evaluation by genetic testing:
– Sequence for alanine glyoxylate aminotransferase, glyoxylate reductase, and HOGA
· Confirm diagnosis
· Determine the phenotype of the primary oxaluria and hence the prognosis and predict the response to pyridoxin treatment (2 out of known 30 mutations respond to treatment with pyridoxine, Gly170Arg, and Phe152Ile mutations) and the new drug lumasiran only for type I
· The risk for transmission to sibling
Treatment with
a) Medical treatment :
– Hydration 3-4 liters per day
– Pyridoxine 500 mg /day as a coenzyme for AGT conversion of glyoxylate to glycine rather than oxalate
– Probiotic oxalobacter formigenes which metabolize oxalate to formate
– New medication:
– Lumasiran for type 1:target glycolate oxidase..deplete substrate for AGT so decrease oxalate production
– Phase III trial over 39 patients (with progressive CKD not yet on dialysis)
b) Combined liver and kidney transplantation if failed medical treatment
Counsel
the patient about pregnancy and the possibility to have her disease transmitted to her sibling
screening for the other family members by lab investigation
What is the commonest cause of death in this condition?
Cardiovascular complication
Reference:
1- Cochat P and Rumsby Gill. Primary Hyperoxaluria. The new England journal of medicine. 369;7 nejm.org 2013
2- Malakoutian T, Asgari M, Houshmand M, et al. Recurrence of Primary Hyperoxaluria After Kidney Transplantation. Iranian Journal of Kidney Diseases (5) 2011; (429-433)
3- Monico CG, Rossetti S, Olson JB, Milliner DS. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 2005;67:1704-9.
4- Harambat J, Fargue S, Acquaviva C, et al. Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int 2010; 77:443-9
This is an excellent ,best answer as you addressed :
Types and mechanism of causes.
Action of each medication and relation to the type.
Genetic testing for prognosis,
Enzyme assay to choose the relevant drug to be used.
Councelling.
Mentioning of enteric causes for secondary causes as IBD and bypass surgeries.
Diagnosis
Possible diagnosis : Primary hyperoxaluria
Primary hyperoxaluria is a rare genetic disease with excess oxalate production leading to frequent kidney stones, kidney function impairment, and oxalosis.
Histological slide given above :
Calcium oxalate deposits in the urinary space and in the renal tissue. THis is seen under 200X Polarisation microscope, HE.
Management
Commonest cause of death
Death due to cardiac calcium oxalate crystal deposition leading to cardiac failure.
Other causes of death include vascular complications, complications from dialysis.
References :
Thank you Nandita and nice to see your active contribution.
I have not come across a successful treatment either pre or post-transplant unless you do combined kidney and liver transplantation in the first place. 15% of PH is diagnosed post-transplant where they are initially diagnosed as “unknown aetiology”.
Even pyridoxine-sensitive cases are not greatly successful. This index case is a misdiagnosis and highlights the importance of proper history taking and investigation for those cases labelled “unknown aetiology”.
Abdominal CT scan show diffuse cortical nephrocalcinosis, renal biopsy shows deposition of oxalate deposition, in addition to very early graft dysfunction & family history of CKD the diagnosis is primary hyperoxaluria.
It is very rare metabolic disease (AR inheritance ) due to deficiency of enzymes ( AGT in PH1, GRHPR in PH2, & HOGA1 in PH3).
Treatment include:
Oxalate can deposit in renal tissues, BM , blood vessels & myocardium , so the death occur mainly due to cardiac cause ( arrhythmia ) .
References:
Thank you Ban
I have not come across a successful treatment either pre or post-transplant unless you do combined kidney and liver transplantation in the first place. 15% of PH is diagnosed post-transplant where they are initially diagnosed as “unknown aetiology”.
Even pyridoxine-sensitive cases are not greatly successful. This index case is a misdiagnosis and highlights the importance of proper history taking and investigation for those cases labelled “unknown aetiology”.
available data for diagnosis :
primary early non function renal graft , becomes dialysis dependent
positive family history of HD dt unknown etiology
graft bx showed oxalate crystals in the tubules
so we face a case of primary hyper oxalosis
management :
1- hemodialysis
2- prepare for liver transplantation
3- the current graft will not be improved after liver transplantation
4- liver – kidney transplantation can be done combined or sequential
5- some cases of primary hyperoxaluria are sensitive to vitamin B6
6- lumasiran is the only RNAi drug used in such patients with severe kidney dysfunction, including chronic dialysis patients. lumasiran is to be continued lifelong, has impact on a patient’s immunity, and interaction with immunosuppressive drugs.
commonest cause of death in this case is the return to dialysis with its cardiovascular complications with added cardiovascular risk of primary hyperoxaluria
Zhitao Cai, Mao Ding, Rengui Chen, Jiefu Zhu, Lian Li & Xiongfei Wu.Primary hyperoxaluria diagnosed after kidney transplantation: a case report and literature review. BMC Nephrology 2021. volume 22, Article number: 393.
Hillarey K Stone , Katherine VandenHeuvel, Alexander Bondoc , Francisco X Flores , David K Hooper , Charles D Varnell Jr. Primary hyperoxaluria diagnosed after kidney transplant: A review of the literature and case report of aggressive renal replacement therapy and lumasiran to prevent allograft loss.
Am J Transplant. 2021 Dec;21(12):4061-4067
Arnaud Devresse, Pierre Cochat, Nathalie Godefroid, Nada Kanaan.Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives. 2020. Volume 5, Issue 12, Pages 2136-2145.
Jérôme Harambat, Sonia Fargue, Justine Bacchetta, Cécile Acquaviva, and Pierre Cochat. Primary Hyperoxaluria. International Journal of Nephrology / 2011 / Article
Thank you Riham
I have not come across a successful treatment either pre or post-transplant unless you do combined kidney and liver transplantation in the first place. 15% of PH is diagnosed post-transplant where they are initially diagnosed as “unknown aetiology”.
Even pyridoxine-sensitive cases are not greatly successful. This index case is a misdiagnosis and highlights the importance of proper history taking and investigation for those cases labelled “unknown aetiology”.
The early detection of Ca oxalate deposition in the transplanted kidney after a few days of transplantation and the positive family history and the CT scan finding is diagnostic of primary hyperoxaluria.
Primary hyperoxaluria is an autosomal recessive metabolic disorder resulting in excessive oxalate production. The kidney will try to excrete the excessive amount of oxalate, resulting in an oversaturated urine for calcium oxalate, which leads to kidney stones and nephrocalcinosis (1, 2).
The diagnosis can be confirmed by molecular genetic testing or liver biopsy to evaluate the oxalate metabolism’s enzymatic defect (1).
As kidney function deteriorates, plasma oxalate will exceed 30 micromol/L (the plasma supersaturation threshold for calcium oxalate) because of reduced urinary oxalate excretion. This leads to calcium oxalate deposition into non-renal tissues, including the myocardium, vessel walls, the retina, skin, bone, and the central nervous system (systemic oxalosis).
The management for this case scenario post-transplantation is unsatisfactory, and the kidney allograft mostly will be lost due to the burden of accumulated oxalate all over the body. This lady was unlucky as she was diagnosed post-transplantation by an allograft biopsy. Early diagnosis may allow arrangement for combined liver and kidney transplantation which is considered a treatment for both renal failure and the underlying metabolic disorder.
Approaches of management of primary oxalosis include:
– Excessive hydration (will be risky in this case due to the primary non-function of the allograft and anuria).
– Oral phosphate.
– Frequent haemodialysis with high clearance target aims to lower the accumulated oxalate burden.
Cardiac (due to conduction defects that may result in cardiac arrest).
References:
1) Patrick Niaudet. Primary hyperoxaluria. © 2022 UpToDate. (Accessed on 21 May 2022).
2) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Excellent Ahmed as always
Yes, it is too late. This kidney failed, and even we tried intensive dialysis but was not successful.
15% of PH is diagnosed post-transplant, where they are initially diagnosed as “unknown aetiology”.
Even pyridoxine-sensitive cases are not greatly successful.
This index case is a misdiagnosis and highlights the importance of proper history taking and investigation for those cases labelled “unknown aetiology”.
CT shows bilateral nephrocalcinosis.
crystal deposition in tubules with tubular damage.
calcium oxalate crystals are are clear with a refractile quality on routine microscopy and exhibit bright birefringence when viewed under polarised light.
The most frequent cause of CaOx crystal deposition within the kidney is hyperoxaluria.
Secondary hyperoxaluria-
enteric hyperoxaluria following bariatric surgery
ingested ethylene glycol
vitamin C overdose
how do you manage this patient post-transplantation?
intensive high flux hemodialysis
pyridoxine
lumisaran an rnai is approved .
but outcome is loss of allograft function mostly with shift again to maintenance hemodialysis
to prevent in a known case one should go ahead with transplant only when plasma oxalate level is <20.
cardiovascular cause.
about CNI I could not find anything in relation to hyperoxaluria.
further dual liver kidney transplant will be needed