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

Abstract

Primary hyperoxaluria type 1 is a rare inherited disorder caused by abnormal liver glyoxalate metabolism leading to overproduction of oxalate, progressive kidney disease, and systemic oxalosis. While the disorder typically presents with nephrocalcinosis, recurrent nephrolithiasis, and/or early chronic kidney disease, the diagnosis is occasionally missed until it recurs after kidney transplant. Allograft outcomes in these cases are typically very poor, often with early graft loss. Here we present the case of a child diagnosed with primary hyperoxaluria type 1 after kidney transplant who was able to maintain kidney function, thanks to aggressive renal replacement therapy as well as initiation of a new targeted therapy for this disease. This case highlights the importance of having a high index of suspicion for primary hyperoxaluria in patients with chronic kidney disease and nephrocalcinosis/nephrolithiasis or with end stage kidney disease of uncertain etiology, as initiating therapies early on may prevent poor outcomes.

Introduction

Primary hyperoxaluria type 1 (PH1) is a rare cause of end stage kidney disease (ESKD) in children. This inherited disorder of glyoxylate metabolism leads to overproduction of oxalate, crystalluria and nephrolithiasis, progressive kidney injury, and ultimately systemic oxalosis ¹. Clinical presentation is variable, ranging from nephrocalcinosis and progressive kidney disease during infancy to recurrent nephrolithiasis presenting in adulthood ¹. Occasionally, this diagnosis is made after a patient progresses to ESKD or even after the disease recurs following kidney transplantation ².

Here we present a case of PH1 diagnosed following kidney transplantation in a young child without prior history of nephrolithiasis or nephrocalcinosis at presentation. We share this case to bring attention to this uncommon presentation of a rare disorder, to suggest that the use of broad diagnostic testing prior to transplantation in patients presenting with ESKD of unclear etiology may help prevent similar situations, and to highlight the availability of a new drug to treat this disorder which makes early detection of this disease even more crucial.

Case

The patient presented at age 5, after referral to the emergency department for pallor and fatigue. Laboratory studies at that time revealed hemoglobin 7.1 g/dL, BUN 129 mg/dL, creatinine 8.68 mg/dL. Urinalysis was negative for blood or protein. Complement levels were within normal limits. Renal ultrasound revealed small kidneys bilaterally (6.4 cm and 6 cm, both at or below the second standard deviation for age) with markedly increased echogenicity and poor corticomedullary differentiation. One 4 mm cyst was noted in the left upper pole.

The patient’s prior medical history included anemia that was detected at 12 months of age on routine screening. After evaluation by hematology, he was diagnosed with idiopathic normocytic anemia, though kidney function was not evaluated as part of this workup. His history was negative for hematuria, kidney stones, urinary tract infections, or hypertension. The patient’s mother had a history of polycystic kidney disease, presumed autosomal dominant though no genetic testing had been performed. There was no other family history of kidney disease, hypertension, or kidney stones. The patient was diagnosed with end stage kidney disease and began hemodialysis. Given his unclear presentation and positive family history, a hereditary cystic kidney disease genetic panel was ordered. No pathogenic or likely pathogenic variants were identified, so the patient was presumed to have renal dysplasia as the etiology of his kidney disease.

At age 7 years, the patient received a living-unrelated donor kidney transplant with an unremarkable perioperative course. He received induction with basiliximab and methylprednisolone, followed by maintenance immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone on post-operative day 1. His immediate post-operative course was as expected with decreasing creatinine; however, his creatinine started to rise on post-operative day 2. Renal ultrasound was obtained, revealing adequate perfusion and mild pelvocaliectasis. On post-operative day 3, the patient underwent cystoscopy and placement of an allograft ureteral stent due to concern for possible obstruction as the cause of his transplant dysfunction. The patient’s creatinine continued to rise, and urine output decreased despite this intervention. A biopsy was performed on post-operative day 5 which showed mild acute tubular necrosis and occasional intratubular crystals (Figure 1).

Figure 1.

H&E stain from biopsy on post-operative day 5, showing mild acute tubular necrosis and occasional intratubular crystals (green arrows).

Over the next several days, the patient’s creatinine continued to rise, and oliguria worsened. Hemodialysis was started on post-operative day 8 for fluid overload. On post-operative day 15, the patient returned to the OR for cystogram, externalization of the allograft nephro-ureteral stent to differentiate between native and transplant urine output and repeat transplant kidney biopsy. Histology again showed evidence of mild acute tubular necrosis, as well as numerous scattered intratubular crystals demonstrating birefringence under polarized light and negative Von Kossa staining, consistent with oxalate crystals (Figures 2 and 3). Plasma oxalate level was ordered, given new concern for systemic oxalosis as the cause of his transplant dysfunction. Given high clinical suspicion for hyperoxaluria, high dose renal replacement therapy was initiated while awaiting this lab result. This was initially achieved using continuous veno-venous hemodialysis (CVVHD) at a rate of 8,000 mL/1.73m²/hr in addition to daily hemodialysis. The patient’s plasma oxalate level resulted as 58.8 mcmol/L (reference range <1.9 mcmol/L). He was subsequently transitioned to CVVHD with a dose of 8,000 mL/1.73m²/hr for 8 hours per day, followed by 4,000 mL/1.73m²/hr for 16 hours per day with the goal to reduce plasma oxalate levels below the supersaturation point of approximately 30 mcmol/L ³. Genetic testing was sent and resulted with two pathogenic variants in AGXT: c. 33dup (p.Lys12Glnfs*156) and c.454T>A (p.Phe152Ile), confirming his diagnosis of primary hyperoxaluria type 1. After the diagnosis was clear, retrospective review of pre-transplant chest x-rays obtained for confirmation of correct dialysis catheter placement revealed visible kidneys, raising concern for nephrocalcinosis. He was evaluated for other signs of systemic oxalosis. Echocardiogram was normal, and an eye exam showed retinal findings consistent with maculopathy of hyperoxaluria.

Figure 2.

H&E stain from kidney biopsy on post-operative day 12, showing acute tubular injury and numerous intratubular crystals (green arrows).

Figure 3.

Examination of the crystals under polarized light reveals refractility, a typical feature of oxalate crystals.

Urine output improved significantly, and plasma oxalate levels decreased to below the accepted threshold of supersaturation with continuous renal replacement therapy (Figure 4), so the patient was transitioned to daily outpatient hemodialysis (5-6 hours per day) on post-operative day 30. Lumasiran, a recently approved drug to treat PH1, was initiated on post-operative day 34. The patient continued to gain kidney function and his plasma oxalate levels remained below the supersaturation threshold (Figure 5). His hemodialysis regimen was slowly weaned while closely following oxalate levels and discontinued at approximately 4 months post-transplant. The patient’s kidney function at that time was 38 mL/min/1.73m² by nuclear medicine GFR. Urine oxalate levels continued to decline since discontinuing hemodialysis, though they remain above the upper limit of normal (Figure 6). Overall, in the first five months after starting lumasiran therapy, urine oxalate levels decreased by 65.9%; this is similar to the reductions observed in clinical trials ⁴. In addition to lumasiran, the patient was prescribed high fluid intake, pyridoxine, and potassium citrate.

Figure 4.

Laboratory findings and urine output in the first month following kidney transplant. Dashed green line represents the accepted plasma oxalate supersaturation threshold of 30 mcmol/L. Abbreviations: CRRT, continuous renal replacement therapy; HD, hemodialysis.

Figure 5.

Plasma oxalate and major management changes. Pre- and post- dialysis levels displayed when available. Dashed green line represents the accepted plasma oxalate supersaturation threshold of 30 mcmol/L. Abbreviations: CRRT, continuous renal replacement therapy; HD, hemodialysis.

Figure 6.

Spot urine oxalate to creatinine ratios over time. (Reference range: 16.0-48.0 mg/g). Abbreviations: creat, creatinine; HD, hemodialysis

The patient was monitored closely for adverse effects associated with lumasiran therapy, especially given his low GFR. He did not experience injection site reactions, which is the most commonly reported side effect ⁴. Liver function tests were followed closely; AST and ALT remained within normal limits, while alkaline phosphatase and GGT were just slightly above the upper limit of normal. One concern with the use of glycolate oxidate (GO) inhibition by drugs such as lumasiran in patients with a low GFR is the possibility of metabolic acidosis from accumulation of glycolate (an oxalate precursor). This patient did develop a non-anion gap metabolic acidosis after discontinuing renal replacement therapy, with serum bicarbonate level as low as 14 mmol/L and anion gap 8 mmol/L. Given this patient’s kidney function, it was thought that this acidosis was consistent with his degree of chronic kidney disease; therefore, sodium bicarbonate therapy was initiated, and the metabolic acidosis resolved. Overall, lumasiran was well tolerated and seemingly efficacious in this post-transplant patient.

Discussion

The primary hyperoxalurias are a rare group of inherited disorders caused by deficiency of liver specific enzymes. Primary hyperoxaluria type 1 is the most severe type, owing to a deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). PH1 is inherited in an autosomal recessive manner and is caused by biallelic pathogenic variants in the AGXT gene, which encodes AGT - an enzyme that catalyzes the conversion of glyoxylate to glycine ⁵. When deficient, glyoxalate accumulates and is converted to oxalate. While normally cleared by the kidneys, overproduction of oxalate leads to crystalluria and kidney stones. This eventually results in progressive kidney injury and chronic kidney disease. Once glomerular filtration rate declines to less than 30 mL/minute, oxalate is no longer cleared effectively by the kidneys, and systemic oxalosis occurs ^1,5.

Primary hyperoxaluria (PH) can present during infancy or early childhood with nephrocalcinosis and chronic kidney disease, or later in life with recurrent nephrolithiasis ¹. Urolithiasis and nephrocalcinosis are present in 90% and 48% of patients at diagnosis, respectively ⁶. Twenty percent of patients with PH are diagnosed after reaching ESKD, and 7% after the disease recurs following kidney transplant ⁶. A number of cases of primary hyperoxaluria diagnosed post-transplant have been described in the literature; unfortunately, most have resulted in early graft failure ^2,7-16.

To date, treatment of PH has consisted of supportive care with hyperhydration, urine alkalinization, and inhibition of calcium oxalate crystallization with phosphate and magnesium supplementation ¹⁷. Pyridoxine, which is an AGT cofactor, successfully decreases oxalate levels in a small subset of patients. Patients who progress to ESKD require intensive renal replacement therapy and ultimately combined liver and kidney transplantation ¹⁷. Lumasiran is the most recent treatment for PH1 and is now available for use in the United States. This small interfering RNA targets the gene encoding glycolate oxidase, leading to depletion of glycolate oxidase and subsequent reduction in oxalate production ¹⁸. In a recent phase 3 trial, subcutaneous injections of this medication were given monthly for three months and then quarterly to patients age 6 years and older with PH1 and estimated GFR of at least 30 mL/min/1.73 m². The results showed decreased urinary oxalate excretion and plasma oxalate level during the six-month study period in patients treated with lumasiran compared to those receiving placebo ⁴. We do not yet have data in patients with a GFR less than 30 or in those who have received a kidney transplant, though trials are underway¹⁹ and these data are greatly needed to assess for both efficacy and safety for these patient populations. Additionally, it is not known how lumasiran will change the management of patients with PH1 long-term and whether this treatment can replace or delay the need for organ transplantation.

To date, 14 other cases of PH1 diagnosed after post-transplant recurrence have been reported in the literature ^2,7-16, as summarized in Table 1. The majority of these patients developed early graft failure requiring re-initiation of chronic dialysis, and several died of complications. Of the three grafts reported to survive beyond 6 months ^7,13,16, only one had a definitive diagnosis of PH1 by genetic testing or liver biopsy ⁷. We present the case of a child diagnosed with PH1 following kidney transplant, a diagnosis that was unsuspected given his lack of the usual signs and symptoms of nephrocalcinosis or nephrolithiasis noted on renal ultrasound at time of presentation with ESKD. Thanks to a relatively early diagnosis and initiation of aggressive renal replacement therapy, as well as the availability of a novel medication to treat PH1, we were able to prevent early graft loss, reduce plasma oxalate levels, and maintain our patient’s kidney function off renal replacement therapy with most recent estimated GFR of 30 ml/min by cystatin c and 29 ml/min using the bedside Schwartz formula at 6 months post-transplant.

Table 1.

Reported cases of primary hyperoxaluria type 1 (confirmed or presumed) in the literature. Abbreviations: IV, intravenous; HD, hemodialysis; PJP, Pneumocystis jirovecii pneumonia; RRT, renal replacement therapy

Reference	History of nephrolithiasis/ nephrocalcinosis?	Age at transplant (years)	Time from transplant to diagnosis of PH	Genetic testing?	Other definitive testing?	Management	Outcome
Bilgin et al. 14	Yes	27	18 days	No	No	IV methylprednisolone, intensive HD	Graft nephrectomy and reinitiation of chronic HD
Kim et al. 15	No	43	15 days	No	Liver biopsy with low AGT activity, negative AGT immunoreactivity	Methylprednisolone	Graft failure and reinitiation of hemodialysis several months after transplant
Madiwale et al. 12	Yes	25	8 weeks	No	No	Pyridoxine	Developed invasive zygomycosis, multi organ infarcts, shock, died 10 weeks post transplant
Celik et al. 16	No	38	13 days	No	No	Pyridoxine, magnesium, phosphorus, HCTZ, hyperhydration	Graft still functioning 60 months post transplant
Spasovski et al. 9	Yes	48	4 months	Yes, AGXT c.33_34InsC and c.508G>A	No	Pyridoxine	Graft failure and reinitiation of HD at 6 months post transplant
Malakoutian et al. 8	Yes	22	2 months	Yes, AGXT c.584T>G	No		Graft failure and initiation of HD at 3 months post transplant
Naderi et al. 10	Yes	20	10 days	No	Liver biopsy with low AGT activity	Pyridoxine, potassium citrate, "vigorous serum therapy", daily HD	Graft failure and nephrectomy on POD 98
Taheri et al. 13	Yes	26	3 days	No	No	Pyridoxine	Died one year post transplant
Taheri et al. 13	Yes	15	43 days	No	No	Plasmapheresis	Graft nephrectomy, initiation of HD and PD
Taheri et al. 13	Yes	15	5 days	No	No		Graft failure and nephrectomy at 9 months post transplant
M'dimegh et al. 11	Yes	23	2 months	Yes, AGXT c.568G>A and c.82C>T	No		Graft failure and death from cardiomyopathy and arrhythmias attributed to systemic oxalosis
Rios et al. 7	Yes	33	1 year	Yes, AGXT c.731T>C and c.307G>A	No		Slow progression of graft nephropathy over six years
Cai et al. 2	No	26	38 days	Yes, AGXT c.33dupC and c.215A>T	No	Pyridoxine, intensive hemodialysis	Graft failure and reinitiation of hemodialysis
Cai et al. 2	Yes	34	75 days	No	No	Hemodialysis	Died of PJP pneumonia at 5 months post transplant
Current report	No	7	15 days	Yes, AGXT c.33dup and c.454T>A	No	Intensive RRT, pyridoxine, hyperhydration, potassium citrate, phosphorus, magnesium, lumasiran	Off hemodialysis with functioning graft at 6 months post transplant

Primary hyperoxaluria can present without classic features of nephrolithiasis and nephrocalcinosis, and therefore a high index of suspicion may be required in order to make a timely diagnosis. We present this case as a reminder of this rare disorder and its atypical presentations. Especially given new therapies available to treat this disorder, we propose that screening for PH1 should be considered in any patient with ESKD of uncertain etiology. Kidney ultrasound and/or abdominal radiographs may be useful in detecting nephrolithiasis or nephrocalcinosis in patients with advanced disease; however, these tests may be non-diagnostic. As genetic testing for PH is now widely available at a relatively low cost and with short turnaround time, this may be the best option to screen for this disorder. In response to this case, our transplant program plans to pursue genetic testing for any transplant candidate with a history of nephrocalcinosis/nephrolithiasis as well as all patients with ESKD of uncertain etiology.

Abbreviations

AGT

alanine-glyoxylate aminotransferase

ALT

alanine aminotransferase

AST

aspartate aminotransferase

BUN

blood urea nitrogen

cm

centimeter

CKD

chronic kidney disease

CRRT

continuous renal replacement therapy

CVVHD

continuous veno-venous hemodialysis

dL

deciliter

ESKD

end stage kidney disease

GGT

gamma glutamyl transferase

GFR

glomerular filtration rate

GO

glycolate oxidase

g

gram

HD

hemodialysis

hr

hour

IV

intravenous

L

liter

m

meter

Mcmol

micromole

mg

milligram

mm

millimeter

PJP

Pneumocystis jirovecii pneumonia

PH

primary hyperoxaluria

PH1

primary hyperoxaluria type 1

RRT

renal replacement therapy

RNA

ribonucleic acid

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.