Background
Primary hyperoxaluria is a rare disease with a prevalence of 1-3 per million in the Western population, but a higher rifeness (1 per 58,000) is reported worldwide [1-3]. It is caused by an inborn enzymatic defect leading to impaired glycol-oxalate metabolism, resulting in enhanced oxalate production and disseminated systemic and visceral deposition of the insoluble calcium oxalate crystals. The disease presentation is extremely variable because of the marked heterogeneity of disease expression. We present an interesting case of a 36-year-old gentleman with renal transplant failure secondary to hyperoxalosis. His 8-year-old daughter also had primary hyperoxalosis with typical medullary calcification.
Case Presentation
A 36-year-old gentleman, known to have chronic renal failure, presented to the hospital with exacerbation of symptoms and oliguria. His previous imaging, performed a few years before the current admission, showed enlarged echogenic kidneys. No etiologic diagnosis was made and he was placed on chronic renal failure treatment. On admission, his creatine and BUN (blood urea nitrogen) were 5.8 and 108 mg/dl. He underwent a renal biopsy which was of very low yield, having few hyalinized glomeruli and mostly fibrosed tissue with a small focus of necrotizing glomerulonephritis. This was interpreted as tubulointerstitial nephritis with focal necrotizing glomerulonephritis. He was labeled as end-stage renal failure and was started on hemodialysis awaiting renal transplantation. Autoimmune work-up was not performed because of biopsy showing mostly fibrosed tissue. Subsequently, he underwent a living-related renal transplant with a good postoperative graft function and was discharged on cyclosporine, cellcept, and prednisone after initial graft care. During the second year of transplant, he started to show graft dysfunction with elevated serum creatinine of around 1.5-2. Ultrasound at that point showed mild-to-moderate hydronephrosis of the graft. No luminal obstructive lesions were noted. The patient underwent a ureteric reimplantation. Biopsy of the ureter showed nonspecific chronic inflammation, fibrosis, and occasional crystals. The patient’s renal function continued to decline, despite excellent compliance with immunosuppression.
CT scan showed heavy calcification in the native kidneys (nephrocalcinosis) and severe hydronephrotic transplanted kidney with cortical thinning and few calcifications (Figure 1a and b). Renal osteodystrophy was also noted.
Graft core biopsy was performed which primarily showed transmural hyalinization, hyaline deposits in the adventitia, interstitial fibrosis, and tubular atrophy (Figure 2). Additionally, there were crystals in the tubules, the significance of which was not further elaborated. The interstitial inflammation was interpreted as chronic cell-mediated rejection. His immunosuppression was readjusted, but the patient continued to have worsened renal failure; he was started back on dialysis because of poor graft clearance functions. He developed ascites and the graft had to be excised.
Biopsy of the excised graft showed “almost complete necrosis of the graft with scanty atrophic and degenerate glomeruli with interstitial scarring” (Figure 3). Crystalline material was scattered throughout, but this was not commented upon in the final report. After about a year of graft excision, with the patient on hemodialysis, a Doppler of the right thigh was ordered for follow-up of a known iatrogenic femoral artery thrombosis. The Doppler scan showed recanalized thrombus in the right superficial femoral artery, but there were also multiple areas of focal calcification in the thigh muscles on both sides (Figure 4). The exam was extended to the abdomen and heavily calcified native kidneys were seen (Figure 5). The liver and thyroid showed punctate echogenicity, but no areas of macrocalcification could be seen. There was no ultrasound evidence of intrathyroidal parathyroid adenomas. A CT scan showed heavily calcified kidneys and multiple foci of calcification in the tongue and skeletal muscles (Figure 6). A 99mTc MDP (Methylene Diphosphonate) bone scan showed a “superscan” with low background and well-visualized appendageal skeleton (Figure 7). The patient’s calcium, phosphorus, and vitamin D levels were within normal limits. Liver biopsy for alanine glyoxylate aminotransferase (AGT) deficiency (hyperoxalosis) was considered, but nationally immunoblotting to analyze the protein was not available. Interestingly, the patient’s 8-year-old daughter had a diagnosis of primary oxalosis based on the 24-hour urinary oxalate levels and typical ultrasound features of medullary nephrocalcinosis on ultrasound and CT (Figures 8 and 9).
(A) Coronal CT of native kidneys showing extensive calcification. (B) Coronal CT through the transplant in the left lower quadrant. The graft is severely hydronephrotic and a few calcifications are seen in the kidney, but no significant calcium deposits are noted in the skeletal muscles.
Core biopsy of the failed transplant showing interstitial inflammation and vascular hyalinization. Tubular atrophy periglomular fibrosis, but no oxalate crystal deposition.
Biopsy of the resected graft showing “almost complete necrosis of the graft with scanty atrophic and degenerate glomeruli with interstitial scarring.” Crystalline material was found scattered throughout, but this was not commented upon in the final report.
Discussion
Primary hyperoxaluria is a rare genetic disorder which is secondary to AGT deficiency, mostly inherited in the autosomal recessive pattern. Three types are described: type 1, present in 80% of the patients, results from a defect in vitamin B6-dependent hepatic peroxisomal enzyme, AGT; type 2 occurs in about 10% and is due to dysfunction of the enzyme glyoxalate/hydroxypyruvate reductase; and type 3, recently described, is seen in 10% of the cases and is due to error of mitochondrial 4-hydroxy 2-oxoglutarate aldolase [4].
CT scan with coronal reconstruction showing heavy cortical calcification of the kidneys (open arrow) and innumerable small calcifications in the skeletal muscles seen as punctate white spots (arrows).
Presentation can be variable, with 50% of the cases manifesting in infancy and early childhood [5,6]. Most patients present with chronic renal failure, but can also present as an acute renal failure too [7]. Many patients are diagnosed after transplant failure [8-10].
The error of metabolism is in the liver, secondarily affecting the kidneys. The treatment of choice is a combined liver-kidney transplant for type 1 hyperoxalosis that makes up for most cases. This is associated with a 5-year survival of 80%. A kidney-only transplant is recommended for those with pyridoxine-responsive type I disease, as well as for cases of type II disease. In this case, with a kidney-only transplant, the recurrence of renal oxalosis is probable due to mobilization of oxalates in tissues [11]. This led to graft failure in our patient. The earliest reported case of graft failure after transplant for oxalosis occurred within a few hours of surgery [12], but typically it takes some time for graft failure to occur. In our case, the graft failed after 1 year and had to be excised after 18 months of the transplant.
Tc99m-MDP bone scan showing a superscan with faintly visualized kidneys, but very clearly visualized skeleton; vertebrae are clearly seen as is the appendageal skeleton.
Our case is unusual in that repeated imaging with ultrasound and CT and biopsies of the native kidneys and the excised failed transplant did not diagnose hyperoxalosis. Oxalate crystals were seen in the failed and excised graft, but given that oxalate crystals can be seen in graft failure without hyperoxalosis [13,14], the diagnosis was not made.
The condition progressed to extensive heterotopic skeletal muscle calcification, almost 1 year after graft excision, which led to the diagnosis retrospectively, strengthened by the fact that the daughter has typical medullary nephrocalcinosis and hyperoxaluria.
Nephrocalcinosis is a relatively easy diagnosis to make on ultrasound and CT, but most cases are of the medullary type, and cortical nephrocalcinosis is relatively rare. Oxalosis is differential in both medullary and cortical types of nephrocalcinosis. In this case, the father’s disease progressed to complete calcification of the kidneys, while the daughter’s kidneys showed medullary nephrocalcinosis.
Conclusion
We hope to alert the physician to consider primary hyperoxalosis as a differential diagnosis in renal failure patients with recurrent calcium oxalate renal stones and/ or nephrocalcinosis.
What is new?
A renal transplant was performed due to end-stage renal disease, but graft failure occurred and had to be excised. The diagnosis of oxalosis was missed, despite imaging and graft biopsy. It was only when muscle calcification was noted for an unrelated indication that a diagnosis was made. The case highlights the importance of excluding all causes of nephrocalcinosis, including rare ones like oxalosis, in the management of chronic renal disease.