Recurrence of primary hyperoxaluria after kidney transplantation: the report of two cases

Abstract

Primary hyperoxaluria (PH) is a rare autosomal recessive disorder of glyoxylate metabolism in which specific hepatic enzyme deficiencies result in overproduction of oxalate. Because oxalate is excreted exclusively by the kidney, hyperoxaluria leads to calcium oxalate nephrolithiasis, nephrocalcinosis, and renal failure.1 PH are considered rare with a prevalence of 0.1-0.2 per 106 population.2 PH was misdiagnosed in some cases initially and unfortunately a case may not be detected until the post-transplant period by allograft biopsy. Positive family history may yield clues for proper diagnosis. Here we reported two cases of primary hyperoxaluria with negative family history, which was diagnosed mainly based on kidney allograft failure and biopsy of the graft. CASE REPORTS Case 1 A 14-year-old girl was admitted to our hospital on February 13, 2008 to undergo kidney transplantation and the donor was her mother. In her past history, she had recurrent kidney stones for seven years. She developed progressive renal failure secondary to nephrolithiasis four years prior to admission. She had been receiving maintenance hemodialysis three times a week through a left arterio-venous fistula since September 2005. The etiology of recurrent kidney stones had never been studied. Her family history was unremarkable. In the immediate postoperative period, her serum creatinine levels gradually fell to the normal. She was discharged from the hospital at the postoperative day 16. The immunosuppressive regimen consisted of tacrolimus, mycophenolate and prednisone. The outcome was not favorable until five months posttransplantation, when a gradual deterioration of renal function was encountered. In July 2008 her serum creatinine was 201 μmol/L. The graft ultrasonography and Doppler scan were normal, while the biopsy was reported to be in acute rejection with a few foci of oxalate deposition within the tubules (Figure 1A) and along the inner surface of the Bowman's capsule (Figure 1B) were shown by light microscopy with a polarized filter. She was pulsed with methyl-prednisolone (320 mg daily for three days) and the dose of tacrolimus was increased. There was no improvement in graft function. In the post-transplant seven months, she had the second allograft biopsy, which showed a serum creatinine level of 279 μmol/L. The biopsy revealed extensive deposits of birefringent calcium oxalate crystals, appearing to involve mainly the lumina of tubules (Figure 2). There was no evidence of chronic or acute rejection. Diagnosis of allograft oxalate nephropathy was made. High diuresis was maintained using furosemide associated with high fluid infusion. The patient also received oral pyridoxine therapy. Unfortunately, therapy was unsuccessful and she was required to start chronic intermittent hemodialysis at the 10th month post-transplantation.Figure 1.: Renal biopsy specimen shows calcium oxalate deposition in the allograft of case 1 at the first-time biopsy. Occasional oxalate crystals deposited (arrows) in dilated tubular lumens (A) and glomerular structure (B) using a polarized filter (HE staining, original magnification ×40).Figure 2.: Renal biopsy specimen shows the calcium oxalate crystals in the allograft of case 1 at the second-time biopsy. Numerous oxalate crystals deposited in dilated tubular lumens using a polarized filter (HE staining, original magnification ×20).We reviewed the patient's X-ray presentation before kidney transplantation. Diffuse bony changes were overlooked. Abdominal plain radiography and no-enhanced CT-scan demonstrated double kidney small and scarred and calculus in the renal parenchyma (Figure 3). A plain radiography of pelvic bones showed a coarse trabecular pattern and cystic radiolucency were represented in the ilium, ischium and femora (Figure 4A) and low density capsular-shaped lucent in the metaphysis of the radius, ulna, and distal phalanges (Figure 4B). Bilateral clavicle and several ribs revealed the same abnormalities on CT-scan (Figure 4C and 4D). The possibility of recurrent PH was considered. The patient then underwent double native nephrectomy. The diagnosis was confirmed by the histological findings of native renal which revealed large oxalate crystals in the specimen (Figure 5).Figure 3.: Radiographic findings show severe nephrolithiasis in patients with PH. Abdominal radiography in patient of case 1 demostrated diffuse nephrolithiasis with small, scarred kidneys (A), and no-enhanced CT scan showing the calculi were in renal parenchyma (B).Figure 4.: Oxalate crystals deposit in the bone (osteolytic lesions, white arrows) of case 1 suffered from PH. Pelvic radiograph of cystic radiolucent was showed in ilium, ischium and femora (A). Hand radiogram of capsular-shaped lucent were revealed in metaphyseal radius, ulna and distal phalanges (B). The decreased radiodensity of bilateral clavicle (C) and ribs (D) were showed on CT-scan films.Figure 5.: Diffuse oxalate crystals deposited within the tubules in the native renal of case 1. There is severe sclerosis glomeruli and interstitial fibrosis (HE staining, original magnification ×10).Case 2 A 38-year-old man underwent cadaveric kidney transplant at our centre on June 20, 2001. He was declared to have end-stage renal disease (ESRD) three months earlier due to bilateral, multiple nephrolithiasis at another hospital, and since then he had been on maintenance hemodialysis three times a week. There was no any family history of renal disease. Examination revealed normal chest X-ray and electro-cardiogram. Blood test revealed hemoglobin of 90 g/L, normal leukocyte and platelet counts, blood urea nitrogen of 18 μmol/L, and serum creatinine of 690 μmol/L. Serum urea acid and alkaline phosphatase levels were within the normal range. Liver function tests were also normal. Without a history of prolonged cold/warm ischemia, the patient had good urine output and his renal functions had immediate improvements after the surgery. He received a triple immunosuppression regimen with prednisone, mycophenolate and cyclosporin A. However, four months after surgery, the renal functions deteriorated. His serum creatinine rose to 310 μmol/L with urine output 2000-2500 ml/d. Ultrasound scan of the abdomen revealed no evidence of renal artery or renal vein thrombosis. The transplanted kidney had increased cortical echogenicity and no hydronephrosis. On abdominal plain films, the native kidneys were small and scarred with diffuse parenchymal nephrocalcinosis (Figure 6). Allograft biopsy revealed numerous crystals in the tubular lumen. The crystals were birefringent under polarized light examination (Figure 7) without inflammatory infiltrate. There was no additional history of supplemental oxalate precursor intake. The findings were compatible with the diagnosis of recurrent primary hyperoxaluria. The following adjustments were made to his treatment protocol: mycophenolate and cyclosporin A were stopped and prednisone was decreased to 7.5 mg/d. The patient restarted the maintenance of hemodialysis three months later.Figure 6.: X-ray plain film of the abdomen demonstrates multiple kidney stones with a staghorn appearance in patient of case 2.Figure 7.: Extensive oxalate crystals were showed along the tubules basement membrane in patient of case 2 (A). It is characterized by birefringent green iridescence, presenting as diamond shaped crystals using polarizing screens (B) (HE staining, original magnification ×40).DISCUSSION The state of hyperoxaluria can be classified as either primary or secondary. PH is a heterogeneous disease with variability in the age of onset and a variable progression to kidney failure. The infantile form is characterized by rapid progression to end-stage renal failure and severe systemic oxalosis at a median age of six months. The juvenile form usually presents with symptoms related to renal calculi. Renal failure commonly develops as a consequence of severe interstitial nephritis secondary to oxalate deposits. The adult form is rare and symptoms are late-onset. Patients are initially diagnosed with renal failure and subsequently have the symptoms and signs of oxalosis. Case 2 is the second reported patient diagnosed late-onset PH type 1 in Chinese.3 Secondary hyperoxaluria can be caused by excessive intake of oxalate or oxalate precursors, bowel disease and decreased excretion. The clinical presentation in the case 1 fits the juvenile type, whereas case 2 fits the adult type. Unfortunately, the cause of kidney stone was overlooked at first. The kidney is invariably involved in PH. The classical presentation is characterized by recurrent calcium oxalate nephrolithiasis and nephrocalcinosis, leading to progressive renal insufficiency. It leads to renal failure due to the deposition of oxalate crystals and the formation of renal stones. Oxalate crystals are also implicated in direct injury to tubular cells. Tubular cell death occurs by oxygen-free radicals-mediated necrosis or by apoptosis.4 It has been demonstrated that the increasing of transcription of activating factors (c-myc, Nur-77, c-jun), mitogen-activated protein kinases, extracellular matrix regulators and growth factors suggested an involvement of oxalate in fibrogenesis of the renal interstitial.5 Oxalate crystals can also occur in extrarenal tissues. Major sites of deposition include bone, heart, blood vessels and nervous system. Pathologic involvement of bone is common. But the bone lesions of oxalosis are less specific and can mimic those of renal osteodystrophy. As case 1 had been treated with haemodialysis for several years, it would be reasonable to suspect a renal osteodystrophy which subsequently might have induced skeletal changes. However, the distribution of skeletal changes in renal osteodystrophy is different from the distribution found in hyperoxaluria. Crystal deposition occurs especially in areas of high vascularity such as metaphyseal segments of tubular bones. The lesions are characteristic in x-rays (radiodense metaphyseal bands, a “bone-within-bone” appearance, and diffuse demineralization with a coarse trabecular pattern).6 The girl in this report showed skeletal changes which are more likely to be concordant with oxalosis. Hyperoxaluria were reported to cause renal failure in both native and transplanted kidneys. Oxalate deposition in renal allograft may develop into four different clinical contexts: group I may be found in allograft biopsies shortly after transplant against the background of acute rejection or acute tubular necrosis; group II, the kidneys typically display chronic allograft nephropathy characterized by tubular atrophy, interstitial fibrosis, interstitial inflammation associated with irreversible loss of renal function; group III is secondary hyperoxaluria due to increased intestinal absorption of oxalate or oxalate-containing drugs. All of them showed few foci of oxalate deposition in specimens that were almost exclusively limited to proximal tubules. If there is extensive oxalate deposition in the renal allograft, recurrent PH (group IV) must be considered.7 It usually develops at various times after kidney transplant because of a heavy burden of oxalate due to specific hepatic enzyme deficiencies. The diagnosis of PH can usually be based on the presentation of recurrent nephrolithiasis, radiographic abnormalities, as well as increased urinary and blood oxalate levels in the absence of a secondary causes. However, diagnosis must be further supported by a biopsy. The sections stained with haematoxylin-eosin were examined using partially crossed polarizing screens. The deposits of oxalate crystals are characterized by birefringent green iridescence, presenting as large plate-like or diamond shaped crystals. The main symptom of diagnosis is the recurrence of kidney stones. In some cases, however, the disease may remain unrecognized either due to the absence of symptoms or to incorrect diagnosis, until it is suspected on pathological examination of postoperative tissue material. There have been instances of similar reports in the literature.8,9 Liver biopsy for enzyme defects is confirmatory of either the deficiency of the enzyme glyoxylate aminotransferase, as in type I, or the enzyme D-glyceric dehydrogenase, as in type II. The optimal therapy for patients with PH is still a matter of intense debate. The primary treatment for hyperoxaluria is large fluid intake, daily doses of pyridoxine, and crystallisation inhibitors (oral citrate and magnesium). Isolated kidney transplantation has yielded very poor results in patients with PH because of recurrent oxalosis of the graft.10 There is a reported graft survival of 15% to 25% at 3 years and a mortality of 26%. Combined hepatorenal transplantation has been successfully applied correcting the metabolic lesion in the liver and replacing the damaged kidneys. It has yielded 80% of 1-year and 60% of 5-year overall graft survivals.11 Sequential liver-kidney transplantation is the best treatment because we have the opportunity to plan extra dialysis before the kidney transplant to avoid oxalate accumulation in the immediate postoperative period, during which the potential for delayed graft function exists. In conclusion, this report provides one example of the absolute need for workup of the causes of stone disease. As oxalate deposition in kidney can recur very soon after renal transplantation, combined liver-kidney transplan-tation is the choice in patients with PH.