3. A 24-year-old CKD 5 male presented to you with eGFR 14 mls/min. He is not yet on HD, but he is keen to have kidney transplantation. His sister who is 101 mismatch wants to donate, no DSA. His primary disease is primary oxalosis type 2. Images are shown below:
- How would you manage this case?
- What is the difference between type 1 and type 2?
1.This is a case of Primary hyperoxalosis : management need good hydration , alkalinzation of urine with potassium , magnesium citrate.
Genetic study needed because of his donor is his sister ; Dialysis aggresive in a daily basis needed before kidney transplantation to prevent oxalate deposition and even in the post transplant period , low oxalate diet , check oxalate level regularly.
2.PH type 1 happen due to Alanine glyoxylate transferase (AGT) mutation, more severe form than type 2 result in ESRD. Only treatment is combined LTX and RTX. While ; type 2 is due to GRHPR mutation,increase urinary excretion of glycerate , may need only KTX, not responding to pyridoxin while type 1 can respond in upto 50 %.
Primary hyperoxaluria is an AR disease. the chance that other brothers and sisters don’t have the disease is 75%.
I have a young girl with PH1 got a liver transplant from her brother and kidney transplant from her sister.
This patient needs to managed pre and post transplantation:
Pre-transplant: extensive daily dialysis, rule out any infection because of previous stones and stenting.
Post-transplant: dialysis, daily check of oxalate level keep below 40umol/L, monitor graft function, well hydration, low oxalate diet
Haemodialysis should be initiated for this patient peri-transplantation and intensive hemodialysis after transplantation to avoid oxalosis. Close monitoring for oxalate level and avoidance of high oxalate content foods in addition to high fluid intake more than 3 liters per day are necessary. Potassium and magnesium citrate are useful.
PH type 1 is due to mutation in Alanine glyoxylate transferase and is the most severe form of the disease that results in kidney failure in young age and in some cases responds to high dose pyridoxine treatment. They should receive combined liver and kidney transplantation. PH type 2 is due to GRHPR mutation and is milder
Primary hyperoxaluria 2 is a milder disease than PH1. PH is a disease with autosomal recessive inheritance.
since there is a variable presentation of disease even among the family members and can be different from occasional symptomatic kidney stones to progression to ESKD. Thus, donor genetic testing should be done to demonstrate different variants of PH.
Isolated kidney transplantation is the recommended approach, although the rare cases of oxalate nephropathy relapse has been reported with need to subsequent liver transplantation.
PH1is due to variants of AGXT, and is the most common and most severe type of PH. It leads to increase in the glyoxylate pool. The AGXT maps to chromosome 2. Combined liver and kidney transplantation (either sequential or simultaneously) and high dose pyridoxine are recommended for treatment of PH1.
PH2 is due to variants of GRHPR. It has milder expression compared to PH1, although it can also progress to ESKD. It leads to increase in L-glyceric acid pool. The GRHPR maps on chromosome 9. Isolated kidney transplantation is recommended treatment for PH2.
Genetic testing of PH variants should be done for his sister, because of different penetration of PH gene. If she had not inherited the gene, the patient can proceed with the transplantation.
The treatment of PH type 2 is focused on reducing urinary oxalate by intensive medical management that includes:
●High fluid intake (greater than 3 L/day per 1.73 m2) to decrease tubular fluid oxalate concentration and diminish crystallization and stone formation.
●Urinary pyrophosphate, citrate, and magnesium are inhibitors of calcium oxalate precipitation. Thus, the solubility of calcium oxalate may be increased by the administration of neutral phosphate (orthophosphate, in a dose of 30 to 40 mg/kg), potassium citrate-citric acid (0.15 g/kg) , and/or magnesium oxide (500 mg/day per m2). Orthophosphate should be discontinued if the patient progresses to renal failure to prevent phosphate accumulation and exacerbation of secondary hyperparathyroidism.
– Needs dietician advice for low oxalate food
– Needs to monitor oxalate level
– Daily dialysis few session before transplant if prepared for tx
– Close monitoring after tx
How would you manage this case?
What is the difference between type 1 and type 2?
Primary oxalosis, which is characterized with excessive overproduction of oxalate, is an autosomal recessive condition with three subtypes:
Type 2 has been considered to have a more favorable prognosis than type 1.
1. The case with secondary hyperoxaluria, presence of double J stent on right side, and presence of radiopaque stone on left side.
Management will be by kidney transplantation, but sister as donor can carry risk of occurrence of ESKD in the sister if she has HO type 2, so genetic study for the sister is essential to confirm she is suitable donor.
_ extensive HD prior to transplantation to remove oxalate load and prevent recurrence
_ adequate hydration and limit oxalate intake as in chocolate.
_ native nephrectomy may be needed to eliminate risk of infection or remove double J.
2. Difference between type 1 and 2 in the following table
1- managment
first counselling his sister and evulation icluded all test to daignsis primary hyperoxalurea ,CT scan to diagnosi the donor if have the disease or not.
start HD daily that 6 to 8 hours /day to enhance the oxalate removal and avoid further other organ damage by keeping serum oxalate level to less than 40umol/l.
on the CT scan and KUB x-ray shows RTkidney obstruted with stent? and left one is enlarged with two stone so if the patient has history of recurent UTI bilateral nepherectomy at time of transplantion should be offered.
pyrodoxine no benefit in type2PH.
isolated kidney transplantion .
monitor serum oxalate postrenal transplantaion and keep the level towords the normal and offered dialysis or plasmopharsis postransplat to remove oxalate
vigorous hydration more than 3 L per day
2-type1 PH is more common 70 to 80% of all diagnosis cases of PH while type 2 and 3 are 10% of cases.
type 1PH the missing enzyme is AGT which is normaly found only in hepatic -pre-rexisome .when ATG is lacking oxalate production soars.
pyroxidine (B6) is a cofactor in this chemical pathway which normaly when this pathway is blocked because of adefecincy of AGT so high level of oxalic acid and formation of ca oxalate causing nephrocalcinosis and ESRD.so using vit B6 for life long in type 1PH is required.
Type2 PH missing enzyme GRHPR which can be detected in leucocyte preparation,type2 considred to have favarable prognosis than type1approximsal 25-50% of indivudal with type 2 progress to kidney fauilre and pyrodixine supplement which is benifit in type 1 PH is not effective in patients with type 2PH.
references
Medoscape and Uptodate2022.
Hyperoxaluria type 2 due to hereditary deficiency of the hepatic enzymes glyoxylate reductase and hydroxy pyruvate reductase resulting in impaired metabolism of glyoxylate and hydroxy pyruvate which are metabolized by lactate dehydrogenase to oxalate and L-glycerate ,respectively. Over production of oxalate would lead to massive urinary excretion culminating in hyperoxaluria disease, clinically presenting as recurrent stone formation and nephrocalcinosis that is usually leading to gradual loss of renal function and end stage renal failure. Systemic oxalosis starting when the GFR is dwindling down to below 40 ml/min, as oxalate crystals depositing widely in different organs with variable and particular outcome depending on the organ affected. Main organs affected are heart, eyes, bone, joint, vascular system and skin.
Cardiac involvement features cardiomyopathy and conductive defect with variable heart block. Retinopathy and maculopathy secondary to oxalate crystal deposition presenting as impaired vision. recurrent bone fracture and resistant anemia are another typical presentation of oxalosis.Similarly vascular involvement is usually reported as skin ulcers.
Diagnosis depends on the demonstration of increased urinary excretion in 24 hour urine sample or oxalate creatinine ratio. typically urine oxalate is more than 0.7 Mmol/L(normal is less than 0.4 Mmol/L), similarly plasma oxalate is in excess of 50 mmol/L, to differentiate it from hyperoxalemia of renal failure . Enzymatic defect is is confirmed by assessing enzymatic activity in liver biopsy tissues.
For a patient with hyperoxaluria type 2 who is a candidate for transplantation, ideally he must undergo daily, extended dialysis , to keep the plasma oxalate at its lowest level, PD is not adequate at reducing the plasma oxalate level. Keeping the plasma oxalate at its near normal level would protect the transplant kidney early post transplant.
well hydration of the patient post transplant with more than 2.5 Liters.
is recommended.
reinstitution of oral alkalinizing agents to render oxalate more soluble and prohibit its precipitation must be prompt and right from early post transplant period to protect the kidney. main alkalinizers are K citrate , Na citrate at a dose of 0.15 g/kg on 2 doses. Neutral phosphate 20-30 mg/kg, Magnesium oxide 500 mg /day.
the target of intensified therapy pre and post transplantation is to keep the plasma Oxalate at its lowest nadir,{i.e plasma oxalate below 40 mmol/l which is the saturation level where its damaging effect is paramount and urinary Oxalate below 0.4/l to lessen the injurious effect of allograft by precipitation.
I would recommend sequential liver transplantation after the kidney transplant to correct the genetic defect .
The difference between PO1 and PO2:
1}type 1 is more common, severe and usually presented early, and more likelihood to progress.
2}Type 1 may present with end stage renal at any age. But type 2 PO is usually presenting late.
3}Genetically: type 1 stemmed from mutation of AGXT gene that encode hepatic enzyme alanin glyoxylate aminotransferase . Type 2 related to mutation of GRHPR gene encodes glyoxylate reductase hydroxypyruvate reductase.
◇How would you manage this case?
________________________________
▪︎This is patient has ESRD most likely due to hyperoxaluria type 2.
▪︎Management plan:
– Assess the general condition of the patient
– Consult a urologist because this pt had an atrophied stent in his right kidney and stones in the left kidney.
– Renal replacement therapy should be started.
– Monitor plasma oxalate levels and keep it below the saturation level of ~40 μmol/l.
-Daily hemodialysis
– Counciling and genetic testing for his sister
and select a new donor due
– Plan for transplantation: patients with type 2 may be treated by isolated kidney transplantation, however the success rates are variable and carries the high risk of graft failure due to recurrent oxalosis .
– combined liver-kidney transplantation after failure of isolated kidney transplant.
◇What is the difference between type 1 and type 2?
________
Primary hyperoxaluria is a rare disease and consists of 3 types (1, 2 and 3)
▪︎Regarding the difference between type 1 and 2:
☆Inherentance:
_____________
▪︎Both are rare diseases and inherited as autosomal recessive disorder which leads to excess oxalate in the body.The excess oxalate then binds with calcium to form calcium oxalate stones.
▪︎Each type is caused by a different gene. PH1 is caused by mutations (changes) in the alanine glyoxylate aminotransferase (AGXT) gene,
▪︎Primary hyperoxaluria type 2 is caused by the shortage (deficiency) of an enzyme called glyoxylate reductase/ hydroxypyruvate reductase (GRHPR) that normally prevents the buildup of oxalate. This enzyme shortage is caused by genetic changes in the GRHPR gene.
☆Development of kidney stons and renal failure:
_____________
Type 1: the kidney stones typically begin to appear anytime from childhood to early adulthood, and ESRD can develop at any age. Primary hyperoxaype 2 is similar to type 1, but ESRD develops later in life [1].
☆Frequency:
______________
▪︎Primary hyperoxaluria is estimated to affect 1 in 58,000 individuals worldwide. ▪︎Type 1 is the most common form, accounting for approximately 80 percent of cases [2]. Types 2 and 3 each account for about 10 percent of cases.
☆Severity:
____________
▪︎PH2 is a less aggressive form of PH with better preservation of renal function and lower incidence of end stage renal disease and less severe nephrocalcinosis compared to PH1. The differences are accounted for by the higher oxalate excretion in PH1 and altered urine composition with reduced urinary levels of citrate and magnesium in PH1 compared to PH2[3].
☆Management:
__________________
▪︎Role of pyridoxine
Pyridoxine supplementation has been shown to be beneficial in patients with PH1
▪︎Transplantation
Transplantation must be planned when GFR falls between 15-30 mL/min per 1.73 m2. As the defective enzyme is liver specific in PH1, these patients require preemptive liver, sequential liver- kidney, or combined liver-kidney transplantation.
▪︎In PH1 combined liver-kidney transplant is best suited for patients who are on chronic renal replacement therapy and not responsive to pyridoxine. Isolated kidney transplantation may be the procedure of choice for adult patients who are sensitive to pyridoxine.
▪︎For patients with PH2, isolated kidney transplantation is the preferred treatment of choice – which has variable success- as the defective enzyme is found in various body tissues.
_____________________
Ref
[1] https://medlineplus.gov/
[2] Neveen A. Soliman, Marwa M. Nabhan, […], and Alaa Fayez. Clinical spectrum of primary hyperoxaluria type 1: Experience of a tertiary center.
https://doi.org/10.1016/j.nephro.2016.08.002
[3] Milliner DS, Wilson DM, Smith LH. Phenotypic expression of primary hyperoxaluria: comparative features of types I and II. Kidney Int. 2001;59:31–36.
This is a patient with ESRD, basic diagnosis being primary hyperoxaluria type 2.
Issues involved include:
1) Pre-operative preparation:
a. Increased fluid intake: But restrict fluid if oliguric/ anuric
b. Intensive hemodialysis to keep plasma oxalate levels low (<40 micromol/l)
2) Donor selection:
a. Considering the donor available is a related donor (sister), genetic testing of the sister should be done prior to taking her up as a donor to rule out her being either afflicted by primary hyperoxaluria or an asymptomatic carrier, in which case she should not be taken up as donor.
3) Post-operative management: In PH-2, kidney transplant alone can be done.(1,2)
a. Intensive dialysis: 6-8 hours daily (to keep plasma oxalate levels low) in initial post-operative period
b. Immunosuppression: MMF and steroids initially, add CNI once creatinine is less than 2 mg/dl
c. Increased fluid intake life-long
d. Use of magnesium oxide, neutral phosphate, potassium citrate-citric acid post-transplant.
The differences between primary hyperoxaluria type 1 (PH-1) and 2 (PH-2) are as follows:(1,2,3)
1) Clinical features:
a. PH-1: onset at all ages, but mostly in childhood. Presents with calcium oxalate kidney stones, nephrocalcinosis and ESRD (in 50%).
b. PH-2: onset in all ages, in childhood but later than in PH-1. Presents with calcium oxalate kidney stones. Severity of the disease is milder with slower rate of progression and lower risk of ESRD (25-33%). Median age of ESRD is 40 years
2) Cause:
a. PH-1: AGXT variant gene on chromosome 2q, encoding liver peroxisomal enzyme AGT (Alanine glyoxylate aminotransferase).
b. PH-2: GRHPR variant gene on chromosome 9p, encoding enzyme GRHPR (glyoxylate reductase/ hydroxypyruvate reductase)
3) Treatment:
a. PH-1: Supportive (hydration, pyridoxine, magnesium oxide, potassium citrate- citric acid), RNA interference therapeutic agents (Lumasiran, Nedosiran), Transplant (combined liver and kidney transplant)
b. PH-2: Supportive (hydration, magnesium oxide, potassium citrate- citric acid), RNA interference therapeutic agent (Nedosiran), Transplant (kidney transplant alone)
References:
1) 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.
2) 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.
3) Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int. 2009 Jun;75(12):1264-1271. doi: 10.1038/ki.2009.32. Epub 2009 Feb 18. PMID: 19225556; PMCID: PMC4577278.
The provided CT scan of abdomen shows small right kidney probably due chronic obstruction, and few tiny stones in the left kidney.
Right j-j catheter is inserted in the right collecting system.
From immunological point of view, this is an ideal donation, with minimal HLA mismatches and no sensitization.
In the other hand, the patient has established hyperoxaluria type 2 which is characterized by frequent renal stone formation and nephrocalcinosis. 1/4 to 1/3 cases progress to end stage renal disease.
While the patient is candidate for preemptive kidney transplantatin from his sister, it is crucial to screen for PH in his sister. if his sister does not have genetic mutation compatible with PH, then i will proceed with transplantation.
Differences between PH 1 and PH2
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. It is more aggressive than PH2.
Surgical treatment for type 1 is combined liver-kidney transplantation.
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. Treatment for ESRD in type 2 is kidney transplantation with preventive measures.
-How would you manage this case?
As a diagnosed case of PH type 2; his sister as a donor need to undergo targeted mutation genetic analysis screening for the most common variants, variants of GRHPR, c.103delG (40 percent) in exon 2 and c.403_405+2 del AAGT (16 percent) in exon 4 .
The patient will need reduction of urinary calcium oxalate through adequate daily fluid intake and treatment with inhibitors of calcium oxalate crystallization (orthophosphate, potassium citrate, and magnesium); temporary intensive dialysis for ESRD, followed by transplantation.
Isolated kidney transplantation has been the recommended approach immediate recurrence and subsequent graft loss has been reported .
Case reports of combined liver/kidney transplant in adults have shown normalization of plasma oxalate, urine oxalate, and urine glycerate levels .
The case needs close monitoring of disease recurrence post transplant
-What is the difference between type 1 and type 2?
In PH type I, the decreased or absent activity of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), which normally converts glyoxylate to glycine, leads to an overproduction of oxalate and glycolate.
PH type 1 is the most severe form of PH as patients are more likely to progress to ESKD and at an early age
The median age range at diagnosis ranges is approximately 5 to 5.5 years of age but ranges from less than one year of age to over 50 years of age
Presentations
Renal manifestations
· Infantile oxalosis (26 percent)
· Childhood with recurrent kidney stones and rapid decline in kidney function (30 percent)
· Adult with occasional stone formation (30 percent).
· Recurrent disease after renal transplantation (10 percent).
· those identified after family screening were younger and had fewer number of stones at the time of diagnosis
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
In PH type II, the decreased or absent activity of glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which normally converts glyoxylate to glycolate, leads to an overproduction of oxalate and L-glycerate.
The reported median ages of first-noted symptom vary from 3.2 to 7.4 years. But the age of presentation ranges from 0.1 to 41 years of age.
Presenations
Renal manifestations
•Kidney stones
· Kidney function impairment and ESKD
· Systemic oxalosis .
· Patients who progress to ESKD were also at risk for systemic oxalosis (eg, retinal deposits and cardiomyopathy and conduction abnormalities).
Reference
Uptodate 2021
He can go for a transplant however his sister should go for genetic testing before considering her a suitable donor.As inheritance is autosomal recessive there is 25% chance that she might turn out to be a suitable donor.
He should be adequately hydrated 1.5 to 3 liter intake daily if feasible
Intensified hemodialysis to keep plasma oxalate level below supersaturation threshold of 30umol/l
Type 1 PH is most common form comprising 80% of cases , presents early and mostly leads to ESKD
However it can present as late as 50 years of age. Primary defect is in variants of AGXT that encodes the hepatic peroxisomal enzyme alanine glyoxylate aminotransferase.
Primary hyperoxaluria type 2 — Primary hyperoxaluria (PH) type 2 is generally a milder disease than PH type 1 as the risk for ESKD is lower and kidney function deterioration is slower,
age of presentation ranges from 0.1 to 41 years of age. the defect is in Glyoxylate-Reductase HydroxyPyruvate-Reductase(GRHPR) which has a wide tissue distribution but primarily hepatic cytosol and to some extent mitochondria.
How would you manage this case?
Basically, the Information on the management of PH is primarily derived from treating patients with PH type 1, the most common form of the disease and early diagnosis of course is better for early management.
Since this disease is genetic disease, Primary hyperoxaluria (PH) is caused by autosomal recessive variants involved three genes that encode enzymes involved in glyoxylate metabolism. These lead to enhanced oxalate production and oxalate deposition in kidneys causing nephrocalcinosis and ESRD.
-I will not accept the offer from his sister and need genetic screening.
-Since the patient is CKD stage 5 not on RRT as a preparation for renal transplantation
will do the following:
1-Initiate him on HD sessions with intensified dialysis sessions is needed to try to match the daily oxalate production(daily oxalate production of 3500 to 7500 micrmol) hemodialysis removing around 1440 micromol/day ,as well as minimizes nonrenal complications.
2-Medical treatment focused on reduction of urinary calcium oxalate saturation and oxalate production and depends mainly on residual renal function:
–Large daily fluid intake : resulting in a high urinary output (greater than 3 L/day per 1.73 m2)
–Reduced dietary oxalate intake :foods with high oxalate content as tea, chocolate, spinach should be restricted from their diet, has a little role.
–Oxalobacter formigenes – Enhancing oxalate elimination by the gastrointestinal tract.
-A trial of high-dose pyridoxine, a coenzyme of AGT that promotes the conversion of glyoxylate to glycine, rather than to oxalate, is provided to patients with type 1 disease mainly.pyridoxine is continued indefinitely or until liver transplantation is performed.
-Urological treatment :Intervention is required when stones obstruct the urinary tract.
-Regarding transplantation: In PH type 2 isolated kidney transplantation has been the recommended approach. In the other side ,there is a Case reports of combined liver/kidney transplant in adults have shown normalization of plasma oxalate, urine oxalate, and urine glycerate levels.
3- Monitor of plasma oxalate and keep below the saturation level (the plasma supersaturation threshold around 40 umol/L to avoid calcium oxalate deposition into nonrenal tissues including the retina, myocardium, vessel walls, skin, bone, and the central nervous system (systemic oxalosis).
What is the difference between type 1 and type 2?
PH type 1 :
-Most common cause is due to variants of AGXT that encodes the hepatic peroxisomal enzyme alanine: glyoxylate aminotransferase.
-Affected infants and children present at a median age of 5 years (range from < 1 year to over 50 years of age) with symptoms related to nephrocalcinosis, kidney stones, and/or chronic kidney disease.
-Combined liver and renal transplantation in patients with ESKD is the preferred option.
PH type 2 :Present 10 percent of cases is due to variants of GRHPR that encodes glyoxylate reductase/hydroxypyruvate reductase.
Patients with PH type 2 present with recurrent kidney stones and progress to ESKD, typically at an older age.
In patients with PH type 2 disease and ESKD, data are insufficient on determining the optimal choice of transplantation but isolated renal transplantation is recommended.
How would you manage
This is the case of primary hyperoxaluria type 2. There is excessive oxalate load which will need aggressive management.
Patient will need hydration with at least 2.5-3 litres of fluids .
Daily dialysis with target to achieve oxalate levels below 40 Micromol /L.
Avoid Vitamin C and D
Avoid diets rich in oxalates.
Use of K citrate, Orthophosphate and Mg citrate
Pyridoxine use
As regards kidney donation her sister cannot be accepted and their family also requires full screening. A suitable and compatible donor will be needed
Difference between type 1 & Type 2
PH Type 1
This accounts for 80% cases and is more severe. 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.
Isolated renal transplant is not recommended and best management will be combined liver and renal transplant
PH Type 2
This accounts for 10% cases of PH while type 111 also accounts for 10 % cases. In type 2 PH there is dysfunction of enzyme glyoxalate/hyroxypyruvate reductase- GRHPR due to mutation in GRHPR gene located oon chromoosome 10- So there in high urinary excretion of L-glyceric acid and Oxalate.
Diagnosis is based on clinical, biochemical, radiological , enzymatic and genetic studies.
Milder forms of PH type may require only conservative measures while severe forms will need isolated renal transplant.
Management:
Adequate fluid intake urinary inhibitors of calcium oxalate crystallization and vitamin B6
Routine dialysis(daily basis)
Related donation is not recommended for such cases.
Difference between type 1 and type 2:
Type 1 (recessive autosomal disease) caused by a deficiency of the liver peroxisomal enzyme alanine-glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine.
24-h urine oxalate, urinary oxalate-to-creatinine molar ratio, plasma oxalate and hepatic AGT activity are of help.
In cases of hyperoxaluria type 1, although the renal graft is able to function, excessive oxalate production occurs in the liver, which continues to deposit calcium oxalate in the renal parenchyma and tubules. Sequential liver and kidney transplantation with the benefit of haemodialysis in the time between liver and renal transplant.
Since the metabolic defect is in the liver, isolated kidney Tx cannot correct the primary metabolic defect but only the damaged target organ. Indeed, the risk of recurrence in the absence of liver Tx is 90–100%. A combined liver and kidney Tx is therefore required for most patients.
Type 2 is caused by a GPHPR deficiency, which catalyzes the conversion of hydroxypyruvate to d-glycerate.
A small number of patients with the Gly170Arg AGXT mutation may present with evidence of pyridoxine responsiveness, sometimes allowing isolated kidney Tx with lifelong pyridoxine intake.
Dear All
Plasma oxalate levels need to be monitored and should be kept below the saturation level of ~40 μmol/l. It is important to add to the other measures you mention daily dialysis.
Management of this case:
Adequate daily fluid intake 2.5L/day
Use of potassium citrate or Mg citrate to prevent calcium oxalate formation 0.1 to 0.15g/kg
Orthophosphate 20-30mg/kg
Avoid vit C&D which enhances calcium absorption
Low salt diet
Avoid diet rich with oxalate like chocolate coca cola rhubarb and star fruit
Early initiation of haemodialysis
Kidney transplant alone
What is difference between hyperoxalouria type one and two
Type one// It’s a rare autosomal recessive
Gene defect chromosome 2
It’s account majority of cases
It’s Caused by deficiency of liver specific peroximal alanine oxyoylate aminotransferase
it’s associated with nephrocalcinosis
It’s severe form lead to ESRD
It’s treated by liver- kidney transplant
Type 2// It’s rare autosomal recessive
Gene defect chromosome 9 (9p11)
It’s caused by deficiency of enzyme glyoxylate reductase / hydroxypyruvate reductase which normally prevent accumulation of oxalate
It’s mild form
It’s asymptomatic clinical course for many years
It’s associated with unilateral nephrolithiasis and less frequently nephrocalcinosis
It’s treated by kidney transplant alone
How can you prepare the index case:
Would you accept his sister
What are the precautions.
Frequency of HD
Amount of fluid for hydration
Which drugs are used in HO 2
I will not accept his sister because it’s a genetic disease better to shift another compatible donor.
family need genetic screening
Daily dialysis to keep level of calcium oxalate under normal level
Amount of hydration 2.5L/day
Drug used// Calcium-oxalate crystallization inhibitors (i.e., potassium or sodium citrate, orthophosphate, and magnesium)
Thank You
Plasma oxalate levels need to be monitored and should be kept below the saturation level of ~40 μmol/l. It is important to add to the other measures you mention daily dialysis.
Yes daily dialysis
Thank doctor
Management
Difference between type 1 and type 2
Thank You, this is an excellent conclusion.
Plasma oxalate levels need to be monitored and should be kept below the saturation level of ~40 μmol/l. It is important to add to the other measures you mention daily dialysis.
The KUB is showing a stent at the right ureter.
Primary hyperoxaluria (PH) constitutes a group of rare inherited disorders of the liver characterized by the overproduction of oxalate. Primary hyperoxaluria (PH) is primarily caused by autosomal recessive variants in three genes that encode enzymes involved in glyoxylate metabolism.
There are 3 types of PH: type 1 (PH1), type 2 (PH2), and type 3 (PH3). PH1 is the most common and the most severe form, accounting for 70% to 80% of all cases.
PH1 is an ultra-rare, inherited disease in which excessive amounts of oxalate are produced by the liver. PH1 affects approximately 4 individuals per million in the United States and Europe, with an estimated 1,300 to 2,100 diagnosed cases. In some regions, such as the Middle East and North Africa, the genetic prevalence of PH1 is higher. Currently, the only curative treatment for PH1 is a liver transplant. If the patient has already progressed to kidney failure, then a dual liver/kidney transplant is required.
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. It accounts for approximately 10 percent of PH cases. Pathologic variants of GRHPR result in increased amounts of glyoxylate and hydroxypyruvate, which are converted by lactate dehydrogenase to oxalate and L-glycerate. These metabolites are excreted in excessive amounts in the urine, which in the case of oxalate, leads to recurrent kidney stones.
Genotype/phenotype correlation — 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. However, 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.
Management:
The management of PH is primarily derived from treating patients with PH type 1, the most common form of the disease.
For patients with PH type 1, the initiation of medical management (reduction of urinary calcium oxalate excretion) as soon as possible prolongs renal function, which delays end-stage kidney disease (ESKD) and potentially minimizes non-renal sequelae.
Currently, with the introduction of new RNA interference (RNAi) drugs, it is unclear whether liver transplantation will be necessary in the future as it is hoped that these new interventions will significantly alter oxalate production, thereby slowing the progression of kidney injury and the risk of ESKD.
Medical management —
•Large daily fluid intake – Large fluid intake resulting in a high urinary output (greater than 3 L/day per 1.73 m2) is the most effective therapy to decrease tubular fluid oxalate concentration and diminish intratubular oxalate deposition.
•Increased urinary phosphate, citrate and magnesium concentration. Thus, the solubility of calcium oxalate may be increased by the administration of neutral phosphate (orthophosphate, in a dose of 30 to 40 mg/kg with a maximum dose 60 mg/kg per day), potassium citrate-citric acid (0.15 g/kg), and/or magnesium oxide (500 mg/day per m2). Orthophosphate should be discontinued in patients with impaired renal function to prevent phosphate accumulation and exacerbation of secondary hyperparathyroidism.
•Reduced dietary oxalate intake – Although intestinal oxalate absorption is lower in patients with PH compared with healthy subjects, foods with high oxalate content (such as tea, chocolate, spinach, and rhubarb) should be restricted from their diet. However, as most of the oxalate is of an endogenous source, these dietary measures are of little help.
●Additional measures:
•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. As a result, a trial of pyridoxine that lasts at least three months is warranted in all patients with type 1 PH.
•RNA interference (RNAi) therapeutic agents
-Lumasiran and PH type 1 – Lumasiran is RNA interference (RNAi) therapeutic agent that targets glycolate oxidase resulting in depletion of the substrate for oxalate synthesis, thereby reducing oxalate production. Long-term follow-up regarding the efficacy of lumasiran in reducing the risk of ESKD is needed. In animal models, administration of lumasiran resulted in an increase of glycolate and reduced urinary oxalate concentration up to 50 percent after a single dose in the genetic mouse model of PH1 and up to 98 percent after multiple doses in a rat model of hyperoxaluria.
-Nedosiran and all PH types – Data from a phase I clinical trial for nedosiran, a second-generation RNAi agent that targets the mRNA encoding hepatic lactate dehydrogenase A, suggest that nedosiran may be a safe therapeutic option for the treatment of all types of PH.
• Unproven agents for medical treatment — ongoing efforts to develop new strategies for medical therapy include:
●Oxalobacter formigenes-derived bioactive factors – Although the administration of Oxalobacter formigenes has not been shown to improve outcome, data from in vitro human cell cultures and a mouse model using O. formigenes culture-conditioned medium have suggested a potential role for O. formigenes-derived bioactive factors as a novel therapeutic agent for prevention and/or treatment of hyperoxaluria.
●Dequalinium chloride (DECA) may be beneficial as it may restore normal peroxisomal trafficking of AGT, thereby inhibiting the misdirected AGT transport into the mitochondria.
●Stiripentol, an antiseizure medication that decreases hepatic oxalate production, is a potentially promising agent, as it reduced urinary oxalate excretion and renal oxalate deposition in rat model studies and decreased urinary oxalate excretion in a 17-year-old patient with severe type 1 hyperoxaluria.
• Urological treatment — Intervention is required when stones obstruct the urinary tract. Nephrostomy, ureteroscopy, and ureteral JJ stent are preferred interventions for stone removal.
• Dialysis — the maximal oxalate elimination via 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. 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.
• Transplantation: PH type 1 – The optimal transplantation strategy for patients with PH type 1 remains uncertain. Three different transplant options are available.
•Combined liver and kidney transplantation
•Isolated liver transplantation
•Isolated renal transplantation
Reference: up-to-date, https://www.uptodate.com/contents/primary-hyperoxaluria?search=primary%20hyperoxaluria&source=search_result&selectedTitle=1~21&usage_type=default&display_rank=1
Very good
What would be your plan for the index patient:
Would you accept his sister?
How do you prepare him.
Primary hyperoxaluria type 2
-Primary hyperoxaluria (PH) type 2 is generally a milder disease than PH type 1 as the risk for ESKD is lower and kidney function deterioration is slower
-Age at presentation and diagnosis – The reported median ages of first-noted symptom vary from 3.2 to 7.4 years. But the age of presentation ranges from 0.1 to 41 years of age.
-Kidney function impairment and ESKD
Approximately one-quarter to one-third of patients with PH type 2 will progress to ESKD. The median age for reaching ESKD was 40 years (range 34 to 48 years of age), which is older than what is typical for PH type 1 disease.
-Approximately one-third of patients maintained normal kidney function and the remainder had had evidence of kidney dysfunction.
-Systemic oxalosis – Patients who progress to ESKD were also at risk for systemic oxalosis (eg, retinal deposits and cardiomyopathy and conduction abnormalities).
diagnosis of PH is made in a stepwise approach based on:-
1-Clinical suspicion due to the presence of suggested clinical manifestations
2-Metabolic testing demonstrating elevated urinary oxalate excretion
type 1 and 2 disease have higher urinary excretion of oxalate with levels as high as 1.5 to 3 mmol/1.73 m2 per day (135 to 270 mg/1.73 m2 per day).
***Differentiating amongst the PH types
Since all three types of PH have elevated urinary oxalate excretion, they can be distinguished from one another by assessing urinary excretion of metabolites associated with a specific underlying genetic cause of PH.
●Glycolate and PH type 1 – In general, hyperoxaluria plus increased urinary excretion of glycolate is strongly suggestive, but not absolutely diagnostic of PH type 1
●L-glyceric acid and PH type 2 – Patients with type 2 PH typically have elevated levels of L-glyceric acid (>28 mmol/mol creatinine), which is not observed in patients with type 1 or type 3 disease
3-Genetic testing — Definitive diagnosis is possible by molecular testing
PH type 1(AGXT)
PH type 2 (GrHPR)
4-Liver biopsy
liver biopsy that demonstrated AGT deficiency for patients with PH type 1 disease and decreased GRHPR activity for those with type 2 disease.
Medical management
1-Large daily fluid intake ((greater than 3 L/day per 1.73 m2))
2-Increased urinary citrate concentration by potassium citrate-citric acid
3-Reduced dietary oxalate intake
4-Oxalobacter formigenes
5-Pyridoxal phosphate just in PH type 1
6-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 and useful prior to renal transplantation to decrease plasma oxalate as much as possible to reduce subsequent oxalate deposition and injury in the renal allograft.
7-Transplantation
PH type 2 – For patients with PH type 2 who progress to ESKD, data are insufficient on determining the optimal choice of transplantation. Although isolated kidney transplantation has been the recommended approach but immediate recurrence and subsequent graft loss has been reported in a pediatric patient with PH type 2 who underwent isolated kidney transplantation so combined liver/kidney transplant
Before accepting his sister as a donor we should do genetic screen for the donor and other family members to exclude hyperoxalurea
Reference
Up to date 2022
Very good clinical and lab. differences
Well done
Thank You, this is an excellent conclusion.
Plasma oxalate levels need to be monitored and should be kept below the saturation level of ~40 μmol/l. It is important to add to the other measures you mention daily dialysis.
· How would you manage this case?
This patient has preemptive CKD stage 5, due to oxalosis type 2 , in the images, there were stones in the right kidney with a DJ stent, so the treatment is kidney transplant alone without liver transplant( kidney transplant alone is an absolute contraindication ) .
pre-transplant preparations include the following
avoid the diet containing high oxalate.
good hydration( patient is preemptive).
aggressive dialysis
Genetic study & enzymatic deficiency of the donor is crucial to exclude oxalosis
.
· What is the difference between type 1 and type 2?
Type one is the most common and more severe & its` cause is enzymatic deficiency in the liver so the treatment is combined liver & kidney transplant.
Type 2 oxalosis is less common and less aggressive & its cause is the defect in (GR/HPR) which is not related to the liver so a kidney transplant alone is enough.
There is contradiction between your first and third paragraph!,
the first paragraph was about type 2 oxalosis
How would you manage this case?
Medical management for all forms of PH :
Large daily fluid intake.
neutral phosphate (orthophosphate, in a dose of 30 to 40 mg/kg.
Potassium citrate (0.15gm/kg). Magnesium oxide (500 mg/day per m2).
Reduced dietary oxalate intake .
Pyridoxal phosphate.
Type 1
Glycolate high in type 1.
more severe disease.
Type 2
L- glyceric acid higher in type 2
milder disease .
His sister need to investigate for oxaluria and gene testing GRHPR before donation.
– In type 1 primary hyperoxalosis : there is a defect in specific liver enzyme and it’s a severe form and only cured with liver transplantation , while type 2 is aa milder form due to mutation of GRHPR enzyme that is expressed by many tissue other than the liver so liver transplantation is not needed .
– How to manage this case
– 1- Diet : restrict diet with high oxalate content
– Hydration : plenty fluid intake ( only if the patient still has good UOP
– Pyridoxine
– Decrease crystalliazation of oxalate salts using Na , K or Mg citrate
– Pretransplanation :
Measure serum oxalate level : if still high , consider daily HD or nocturnal HDt till achieve serum oxalate level < 2 u mol /l
For the donor : PH type 2 is AR disorder , so gentic testing for mutation in GRHPR is needed . If she did not have this mutation , she can donate safely.
And daily dialysis to prepare this patient for transplantation
How would you manage this case?
What is the difference between type 1 and type 2?
1- it is the most common type of primary oxalosis.
2- it is caused by mutations in alanine glyoxylate aminotransferase (AGXT)
3- it is more severe than type 2 and most patients develop the disease at earlier ages.
4- for patients with ESRD, combined liver and kidney transplantation should be done as kidney transplantation alone is not sufficient.
1- less common and less severe.
2- most patients develop mild/moderate disease and at later ages.
3- caused by glyoxylate reductase/hydroxypyruvate reductase.
4- for ESRD patients, renal transplantation alone is sufficient.
Good
Can state how to medically prepare this patient meaning:
Where does each drug act
Newer drugs and there indication
– renal replacement therapy should be started early (GFR 30–40 mL/min/ 1.73 m2), before systemic oxalosis occurs.
Plasma oxalate levels need to be monitored and should be kept below the saturation level of ~40 μmol/l.
-Unfortunately, oxalate is cleared poorly by dialysis. Hemodialysis with high flux membranes has the highest oxalate clearance, but even daily sessions are often not sufficient to maintain plasma oxalate levels in the desired range.
Isolated renal transplantation improves oxalate clearance, but carries the high risk of graft failure due to recurrent oxalosis. (2)
-Pharmacologic doses of pyridoxine are used as a treatment in individuals with PH1 because of its role as a cofactor for the defective enzyme. There is no supportive evidence for the use of pyridoxine in individuals with PH2. neutral phosphate, citrate, and magnesium can be used.
–In autosomal recessive (AR) disease, unless there is a family history of consanguinity, only siblings have a significant risk of developing the disease (25%). Parents will be obligate gene carriers and second-degree relatives will be at 50% risk of also being gene carriers. For most AR diseases, carrier status will have no important clinical sequelae and individuals may be considered as potential donors. (1)
-The approach for PH 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.
-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.
-PH type 1: defect in alanine-glyoxylate transferase (AGXT).
Most commonly presents in childhood with:
• recurrent nephrolithiasis or nephrocalcinosis;
• associated symptoms (polyuria, dysuria, hematuria). Rarely, is diagnosed in late adulthood based on the occasional stone passage.
In the most severe form, PH1 presents in infancy with rapidly progressive kidney failure and strikingly echoes bright kidneys (on USS), and extrarenal oxalosis, especially in bones, leading to pain and erythropoietin-resistant anaemia. Other organs may be affected including:
• heart: arrhythmias, heart block;
• nerves: neuropathy;
• retina: flecked retinopathy.
PH type 2: defect in glycoxylate reductase/hydroxypyru- vate reductase (GR/HPR).
Typically presents during adolescence with recurrent oxalate stones. Progressive CKD occurs in ~10% of patients. (2)
–Prognosis
Prognosis depends on the severity of symptoms. Because of poor genotype-phenotype correlation, genetic analysis is not particularly helpful in determining prognosis, except that patients with PH2 seem to fare better than those with PH1, where roughly half progress to ESRD before the age of 25 years. Obviously, the earlier the presentation, the more severe the disease and the more likely progression will occur.
1-BTS LDKT Guidelines 4th edition consultation draft, December 2017.
2-Oxford desk reference nephrology.
Excellent
Thank You
Plasma oxalate levels need to be monitored and should be kept below the saturation level of ~40 μmol/l.
How would you manage this case?
Primary hyperoxaluria is a group of rare disorders due exclusively to genetic defects that cause a loss of specific enzymatic activity, so I will not accept his sister as a donor and she needs genetic screening, better to search for another compatible donor.
Reduction of hyperoxaluria :
1.Magnesium
Supplementation with magnesium in the form of magnesium hydroxide and magnesium oxide has been used. Magnesium can complex with oxalate in the intestinal tract, reducing the level of available free oxalate and urinary calcium oxalate supersaturation.
When used in combination with pyridoxine, significant reductions in urinary oxalate levels have been noted.
2.Increased urinary volume
Increasing urinary volume is essential. Optimal 24-hour urinary volumes of 3-4 L/d may be needed to ameliorate the effects of severe hyperoxaluria.
3.Glycosaminoglycans (pentosan polysulfate)
Supplementation with glycosaminoglycans may help to reduce calcium oxalate crystallization and stone formation by reducing crystal aggregation. It also may decrease intestinal oxalate transport and urinary oxalate excretion.
4.Lumasiran
Lumasiran (Oxlumo) is an RNA interference (RNAi) agent that targets hydroxyacid oxidase (HAO1), which then reduces levels of the glycolate oxidase (GO) enzyme. Decreased GO levels reduce the amount of available glyoxylate, a substrate of oxalate production.
5.Intensive dialysis
Daily hemodialysis sessions are required that last 6-8 hours per day, which is considerably more dialysis than the typical patient with end-stage kidney disease needs.
6. Early liver-kidney transplantation is often required for definitive cure.
-Removal of the native kidneys often is recommended at the time of kidney transplantation because the native kidneys often have significant damage and residual stones, which makes them particularly susceptible to recurrent infections and obstruction.
–New and future treatment modalities under investigation include probiotic supplementation, chaperones and hepatocyte cell transplantation, and recombinant gene therapy to replace the enzyme.
What is the difference between type 1 and type 2?
–Type 1 has been estimated to occur in 1 per 120,000 live births and to account for 70-80% of all diagnosed cases of primary hyperoxaluria, while types 2 and 3 are each estimated to account for approximately 10% of cases.
–In type 1 primary hyperoxaluria, the missing enzyme is alanine-glyoxylate aminotransferase (AGT), which is normally found only in the hepatic peroxisomes. This enzyme is necessary to detoxify glyoxylate. When AGT is lacking, oxalate production increase.
-Pyridoxine (vitamin B6) is a cofactor in this chemical pathway, which normally converts glyoxylic acid (C2 H2 O3) to glycine. When the pathway is blocked because of a deficiency or absence of AGT, the result is high levels of glycolic and oxalic acid, which readily convert to oxalate. Oxalate, which is soluble, complexes with calcium to form calcium oxalate, which is insoluble. Calcium oxalate crystallizes and causes nephrocalcinosis and eventually the development of end-stage renal failure, usually in childhood.
–In type 2 primary hyperoxaluria the missing enzyme is glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which can be detected in leukocyte preparations. This deficiency promotes the conversion of glyoxylate to oxalate.
– Type 2 has been considered to have a more favorable prognosis than type 1, The majority of patients (82.8%) presented with urolithiasis. Approximately 25-50% of individuals with type 2 progress to kidney failure.
– Pyridoxine supplementation, which may benefit some patients with type 1 primary hyperoxaluria, is generally not effective in patients with type 2 primary hyperoxaluria.
Reference:
Bijan Shekarriz. Hyperoxaluria.Medscape. Jan 21, 2022
Excellent review and explanation lam sure you can specify a medical and surgical plan for each type.
His sister even if she is asymptomatic should go for urine analysis with 24 urine oxalate excretion and if indicated should go for genetic counselling prior to decide about her as a donor. PH2 is inherited in an autosomal recessive manner. Each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and another 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known. So, the sister should go for testing by urine analysis for fractional excretion of oxalate and genetic counselling as might she is asymptomatic carrier and better to avoid her as donor
What is the difference between type 1 and type 2?
Type1 hyperoxaluria(PH1) is more common type 80% of PH cases , aggressive and lead to ESRD in about 50% of cases , IF the diagnosis missed and underwent isolated kidney transplant the disease will reoccurred and lead to graft loss within 3 years and the best treatment for PH1 will be combined liver and kidney transplantation.
Specific variant of AGXT (c.508G>A and c.454T>A) of HA 1 responsive to pyridoxine, Pyridoxine is a cofactor for alanine-glyoxylate transaminase (AGT), a pyridoxal phosphate-dependent enzyme. Pyridoxine increases the activity of mistargeted AGT and decreases oxalate production BY 30% and in some cases even normalize the oxalate level. The dose 5mg/kg / day with max daily dose reach up to 20mg/ KG /DAY
And only 30% OF PH1 are responsive to pyridoxine therapy.
Lumasirin is a new therapeutic agent, RNAi therapy FDA approved for PH1 since 2020, given as Sc injection monthly for first 4 months then another two doses every 3 months very promising agent with acceptable safety profile but may not be appropriate for some cases, such as those with pyridoxine responsiveness.
Probioteca agents like oxalo-bacter formigenes (Oxabact), an anaerobic gut bacterium with the ability to increase oxalate metabolism, phase 11 trial
Intense daily dialysis to avoid systemic oxalosis effect (heart, bone, eye, skin) which is worsening with the Advanced kidney disease due to decrease UO excretion
the intensive dialysis use as a bridge before get access to combined liver and kidney transplantation
Primary hyperoxaluria type 2 occurs in 10% of PH, usually less aggressive than PH1 ,and lower risk of ESKD and slow progression, caused by deficiency of the enzyme glyoxylate reductase/hydroxy pyruvate reductase (GR/HPR), is a rare autosomal recessive disease caused by mutations in the GRHPR gene, leading to an accumulation of oxalate and L-glycerate with recurrent kidney stone formation and nephrocalcinosis, gross hematuria , UTI , Renal colic and urinary tract obstruction which can progress to renal failure and systemic oxalosis.
Primary hyperoxaluria type 2 should be considered in patients with history of nephrolithiasis since childhood, especially in those with consanguineous parents. Biochemical analysis and genetic mutation identification should be the way to achieve the final diagnosis of primary hyperoxaluria type 2.
For the patient himself with PH2 still can go for single kidney transplantation with intensive HD prior to transplant
Overhydration, low salt diet and avoid oxalate rich food, avoid ascorbic VIT c supplement
Use of potassium citrate to prevent the calcium oxalate crystallization
Increase the frequency and intensity of HD sessions followed by single kidney transplantation.
References:
1-David J. Sas, Felicity T. Enders, Ramila A. Mehta, Xiaojing Tang, Fang Zhao, Barbara M. Seide, Dawn S. Milliner, John C. Lieske, Clinical features of genetically confirmed patients with primary hyperoxaluria identified by clinical indication versus familial screening, Kidney International, Volume 97, Issue 4,2020, Pages 786-792, ISSN 0085-2538,
2-Rumsby G, Hulton SA. Primary Hyperoxaluria Type 2. 2008 Dec 2 [updated 2017 Dec 21]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. PMID: 20301742.
3-evin-Iaina N, Dinour D, Romero L, Ron R, Brady RL, Cramer SD, Holtzman EJ. Late diagnosis of primary hyperoxaluria type 2 in the adult: effect of a novel mutation in GRHPR gene on enzymatic activity and molecular modeling. J Urol. 2009 May;181(5):2146-51. doi: 10.1016/j.juro.2009.01.045.
4-Metry EL, van Dijk LMM, Peters-Sengers H, Oosterveld MJS, Groothoff JW, Ploeg RJ, Stel VS, Garrelfs SF. Transplantation outcomes in patients with primary hyperoxaluria: a systematic review. Pediatr Nephrol. 2021 Aug;36(8):2217-2226.
5-Gupta A, Somers MJG, Baum MA. Treatment of primary hyperoxaluria type 1. Clin Kidney J. 2022;15(Suppl 1):i9-i13. Published 2022 May 17
Excellent
What about Pyridoxine therapy?
Any utility of pyridoxine after transplant?
Will genetic testing dictate your decision to add pyridoxine to medical treatment post transplant?
Thanks Dear Prof Ala for your question
Yes molecular genetic testing very important to decide about the type of transplant and the response to pyridoxine therapy alone in specific PH1 candidates with confirmed a homozygous for the G170R mutation as they can develop normal urine oxalate levels with pyridoxine therapy and they are candidates forsingle kidney transplantation (1).
References:
1-Lorenz, E C et al. “Sustained pyridoxine response in primary hyperoxaluria type 1 recipients of kidney alone transplant.” American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons vol. 14,6 (2014): 1433-8.
How would you manage this case?
This a case of primary oxalosis type 2 with history of nephrolithiasis with JJ in right kidney and GFR less than 15 ml/min.
No role for medical treatment specially with low GFR and so the patient should be prepared for isolated kidney transplant .
Some cases of primary oxalosis type 2 with history of extensive stone formation treated with combined LKT (1).
Better to avoid donation from his sister specially if she had history of nephrolithiasis.
What is the difference between type 1 and type 2?
Primary hyperoxaluria type 1 (PH1) :
-The most common and severe form of PH.
-It accounts for approximately 80% of the cases of PH. (2).
-Caused by defect in the Vitamin B6 dependent hepatic peroxisomal enzyme, Alanine Glyoxalate Aminotransferase (AGT).
-Majority of the patients reach ESRD during 3rd-5th decade of life.
-ESRD cases treated by combined KLT.
Primary hyperoxaluria type 2 (PH2):
-Represent 10% of the patients with PH.
-Dysfunction of the enzyme glyoxalate/hydroxypyruvate reductase (GRHPR) occurs secondary to a mutation in the GRHPR gene located on chromosome 10.
– 25-30 % develop ESRD at the age of 40.
-ESRD cases treated mainly by isolated kidney transplantation.
References:
1- Dhondup T, Lorenz EC, Milliner DS, Lieske JC. Combined Liver-Kidney Transplantation for Primary Hyperoxaluria Type 2: A Case Report. Am J Transplant. 2018;18(1):253-257. doi:10.1111/ajt.14418.
2- Bhasin B, Ürekli HM, Atta MG. Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol. 2015;4(2):235-244. doi:10.5527/wjn.v4.i2.235.
Very good
How would you manage this case?
Her sister should not be accepted for donation as it is a familial disease and family people can have this disease so she might have similar disease in future which may lead to nephrolithiasis and cortical and medullary nephrocalcinosis , ultimately causing ESRD.
What is the difference between type 1 and type 2?
Type 1 is a severe form with early progression to ESRD, and affects people with median age of presentation i.e., <1year to >50 years and have varied presentations in different age groups. One half patients become dialysis dependent by young adulthood without a diagnosis. Hyperoxaluria and increased urinary excretion of glycolate is seen in type 1. .High dose of pyridoxine will help in conversion of glyoxylate to glycine. Lumasiran which targets glycolate oxidase reducing oxalate synthesis has been tried in clinical trials. Three options for type 1-Combined liver and kidney transplantation, isolated liver transplantation and renal transplantation.
PH2 is milder disease and risk for ESRD is lower and age of presentation varies from 01- 41 years of age. One-third patients progress to ESRD. Increased levels of L-glyceric acid is seen in type 2 .Isolated renal transplantation is the treatment option but results are uncertain.
REFERENCE:
1-Bergstralh EJ, Monico CG, Lieske JC, et al. Transplantation outcomes in primary hyperoxaluria. Am J Transplant. 2010 Nov;10(11):2493-501.
2-Garrelfs SF, Rumsby G, Peters-Sengers H, et al. Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up. Kidney Int. 2019 Dec;96(6):1389-1399.
Very good
What is the difference between type 1 and type 2?
PH type 1
PH type 2
How would you manage this case?
REFERENCES
Very good
What would you suggest as medical treatment apart from the surgery in type 2 as the index case.
I will not accept the sister as a donor, as she may have the disease and at risk of nephrocalcinosis, renal stones, and ESRD. This is a genetic disease, all family members should be screened.
Type 1 is the most common form and accounts for 70-80% of the cases. it is a more severe form and more rapid progression to ESRD ( more than one-half of patients develop ESRD in adulthood). So the age of presentation is earlier than other types of hyperoxaluria.
The presentation varies with age and clinical findings because of marked heterogeneity of disease expression. Age range of diagnosis is from less than 1 year to over 50 years.
There are 5 clinical presentations of this type:
Type 2 is generally milder disease than type 1 as the risk of ESRD is lower and kidney function deterioration is lower.
Median age of presentation is from one month to 41 years of age.
information on clinical findings is limited due to the rarity of the disease.
Renal manifestation ( based on information from 2 large case series):
Regarding transplantation as a form of RRT fo these patients:
Reference:
UpToDate 2022, primary hyperoxaluria by Niaudet P. cited at 23rd May,2022.
Well done Hoda
Can you suggest the proposed preparation for a particular patient. meaning for example:
Lumarisan is used in type 1
Pyridoxin as a coenzyme for AGT
Probiotic oxalobactor acts on the final step to transform oxalate to fumarate so useful in both types.
Plus all the general methods. hydration very frequent HD.
Primary hyperoxaluria type 2 is a rare disease with a less severe course than primary hyperoxaluria type 1. In patients with PH2 having ESRD, isolated kidney transplantation is recommended. However, there are few case reports in this setting, and the expert recommendations are based on low-level evidence.
Regarding therapeutic options pre-transplant:
References:
How would you manage this case?
We would not accept the sister’s kidney.
She may have the same underlying disease and should undergo genetic counseling and investigation of possible disease. The sister needs to know the risks of her own need for a transplant in the future.
What is the difference between type 1 and type 2?
In type 1 the ideal treatment would be a combined liver and kidney transplant, controlling the underlying disease and decreasing the chances of recurrence of kidney disease. Type 2 you can undergo only with a kidney transplant, but with varying results.
Type 2 is less severe than type 1.
Excellent Filipe
How would you prepare him for transplantation? I have transplanted this patient and the graft is still functioning well.
Interesting!!!! do you publish the case? can we have a copy of it?
How would you manage this case?
The patient has DJ stent in the right kidney which is
atrophied. There is a radio-opaque stone in the left
kidney.
I will talk with the urologist about the appropriate course
& timing of DJS removal.
Assess for the presence of sepsis & treat accordingly.
Although patients with type 2 may be treated by isolated kidney transplantation, however the success rates are variable.
Most reported cases are from deceased donors.
Some type 2 patients were successfully treated with
combined liver-kidney transplantation after failure of isolated kidney transplantation.
Also there is the possibility of his sister being positive for the genetic disorder; I will consider genetic testing after counseling her.
================================
What is the difference between type 1 and type 2?
Both are rare inherited disorders (autosomal recessive pattern).
Causes:
Type 1 is caused by mutations in the alanine-glyoxylate aminotransferase (AGXT) gene.
Type 2 is caused by mutations in the glyoxylate reductase-hydroxypyruvate reductase (GRHPR) gene.
Epidemiology:
Type 1 is the most common type (accounts for 70-80% of all cases).
The prevalence of type 1 is 1-3/1,000,000 people in the general population.
The incidence is 1 case/120,000 live births/ year in Europe.
Type 2 accounts for about 10% of cases.
Age of onset:
Type 1 has 2 forms
– Severe infantile form which present with failure to thrive.
– Childhood or adolescence onset which presents with urinary tract stones.
Type 2 presents during childhood.
Severity:
Type 2 is less severe than type 1.
Progression to ESRD:
Occurs later in type 2 than in type 1.
Almost 50% of patients with type 1 have ESRD by the age of 25.
Treatments:
Type 1 patients usually need combined liver & kidney transplantation.
Type 2 may be treated by isolated kidney transplantation, which has variable success.
References
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].
Excellent Mohamed
How would you prepare him for transplantation? I have transplanted this patient, and the graft is still functioning well.
In addition to the conventional medical, psychosocial, immunological, & counseling for risks of surgery, the following are more or less unique for cases of PH:
Usually when patients with PH reach ESRD stage, dialysis is started.
Frequent & short HD sessions (2–3 h/day) using high flux filters are better than the standard HD regimens.
The addition of nocturnal PD can further increase oxalate removal.
However all theses modalities will not eliminate systemic build up of oxalate, so the dialysis is only temporary therapy until definite therapy.
The following may play a role in some patients:
1. Avoidance of large doses of vitamin C.
2. Avoidance of foods high in oxalate (e.g. chocolate).
3. Potassium citrate, sodium citrate, & orthophosphates (neutral phosphates) reduce crystallization & further stone formation.
4. Pyridoxine (FDA-approved) can decrease oxalate in the urine.
5. Aggressive hydration, though indicated in all patients with PH, however it will not be practical in CKD5.
Novel therapies that have been clinically tested, however in PH type 1, include:
– Lumasiran (FDA-approved)
– Probiotics(Oxabact), Phase III
Reference
Kevin Shee and Marshall L. Stoller.Perspectives in primary hyperoxaluria— historical, current and future clinical interventions.NaTure Reviews | UROlOgy volume 19 | March 2022 | 137
management of this case
the patient should not receive the kidney from his sister because she has primary oxalosis type 2
he should be investigated for primary oxalosis , then combined liver-kidney transplantation should be done
primary oxalosis has 3 types based on different enzyme deficiency and onset of presentation
type 1 missing alanine-glyoxylate aminotransferase (AGT) enzyme , and present early in childhood, and is the most common type
type 2 missing enzyme is glyoxylate reductase/hydroxypyruvate reductase (GRHPR), present late than type 1 and has more favorable outcome than type 1
type 3 has mutations in the HOGA1 (formerly DHDPSL) gene, onset of presentation earlier than type 1 and 2 but kidney function decline slowly than type 1 and 2
Bijan Shekarriz. Hyperoxaluria. Medscape 2022
Thank you Riham
I disagree with your decision. How would you prepare him for transplantation? I have transplanted this patient, and the graft is still functioning well.
why you transplant this case, and accept his sister as a donor?