Amelioration of anemia after kidney transplantation in severe secondary oxalosis

INTRODUCTION: In small bowel disease such as M. Crohn, the intestinal absorption of oxalate is increased. Severe calcium oxalate deposition in multiple organs as consequence of enteric hyperoxaluria may lead to severe organ dysfunction and chronic renal failure. The management of hemodialyzed patients with short bowel syndrome may be associated with vascular access problems and oxalate infiltration of the bone marrow leading to pancytopenia. Although the risk of recurrence of the disease is very high after renal transplantation, it may be the ultimate therapeutic alternative in secondary hyperoxaluria. CASE: Here, we report a patient with enteric oxalosis due to Crohn's disease. He developed end-stage renal disease, erythropoietin-resistant anemia, oxalate infiltration of the bone marrow and severe vascular access problems. Following high-urgency kidney transplantation, daily hemodiafiltration of 3 hours was performed for 2 weeks to increase oxalate clearance. Despite tubular and interstitial deposition of oxalate in the renal transplant, the patient did not require further hemodialysis and the hematocrit levels normalized. DISCUSSION: Early treatment of hyperoxaluria due to short bowel syndrome is essential to prevent renal impairment. Declining renal function leads to a further increase in oxalate accumulation and consecutive oxalate deposition in the bone marrow or in the vascular wall. If alternative treatments such as special diet or daily hemodialysis are insufficient, kidney transplantation may be a therapeutic alternative in severe cases of enteric oxalosis despite a possible recurrence of the disease.     

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

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.     

Oxalate kinetics and reversal of the complications after orthotopic liver transplantation in a patient with primary hyperoxalosis type 1 awaiting renal transplantation

We present the case of a young woman with end-stage renal disease secondary to primary hyperoxaluria type 1, who after 3 years and 6 months of maintenance hemodialysis, and despite intensification of the dialytic treatment, developed severe livedo reticularis in her extremities leading to ischemic cutaneous ulcerations, necessitating continuous intravenous infusion of narcotics for pain control. She received a liver transplant after native hepatectomy. However, due to positive crossmatch, she could not receive a kidney from that donor. After transplantation, following serial serum oxalate levels, the hemodialysis regimen was safely reduced from 4 h daily to 3 h three times weekly. Over the course of 6 weeks after liver transplantation, her livedo reticularis resolved, the ischemic ulcers markedly improved, she was weaned off all pain medications, and her erythropoietin-resistant anemia resolved. Our results suggest that in patients with primary hyperoxaluria type 1, who have received a liver transplant and are on maintenance hemodialysis, after serial serum oxalate determinations, some may safely be changed to a thrice-weekly maintenance hemodialysis regimen. Moreover, with this regimen the complications of systemic oxalosis can reverse.     

Reversal of oxalosis cardiomyopathy after combined liver and kidney transplantation

Few data have been published on the course of oxalosis cardiomyopathy after combined liver and kidney transplantation in hyperoxaluria patients with myocardial involvement. We report the case of a primary hyperoxaluria type 1 patient with renal failure who developed end-stage cardiomyopathy. Left venticulography showed severe diffuse hypokinesia and left ventricular ejection fraction was calculated at 12%. Endomyocardial biopsy demonstrated platelike calcium oxalate crystals within the myocardium and the connective tissue, and mild perivascular fibrosis. The patient was first considered for combined liver-heart-kidney transplantation, but as his cardiac function improved slightly with an intensive dialysis program, combined liver and kidney transplantation was performed. Normal cardiac function was demonstrated at 1-year follow-up, and comparative endomyocardial biopsy showed regression of the myocardial oxalate deposits. This case adds stronger clinical, hemodynamic, and histopathological evidence that severe oxalosis cardiomyopathy may be reversed after combined liver and kidney transplantation.     

Regressive course of oxalate deposition in primary hyperoxaluria after kidney transplantation

Primary hyperoxaluria (PH) is a rare autosomal recessive disease caused by the functional defect of alanine-glyoxylate aminotransferase (AGT) enzyme in the liver and it is characterized by the deposition of diffuse calcium oxalate crystals. A 38-year-old male patient presented with history of recurrent nephrolithiasis and has received chronic hemodialysis treatment for 2 years. Cadaveric renal transplantation was applied to the case. The patient was reoperated on postoperative day 13 because of the collection surrounding the urethra. During this operation, kidney biopsy was made due to late decrease in creatinine levels. Deposition of diffuse oxalate crystal was detected in allograft kidney biopsy, whereas in the 0-hour biopsy there were no oxalate crystals. Oxalate level was found to be high in a 24-hour urine specimen (118 mg/L, normal level: 7–44 mg/L). The patient was identified with primary hyperoxaluria and followed up in terms of systemic oxalate deposition as well as allograft kidney. In the kidney biopsy taken after 18 months, we detected that oxalate crystals almost entirely disappeared. In our case, bilateral preretinal, intraretinal, and intravascular diffuse oxalate crystals were detected, and argon laser photocoagulation treatments were needed for choroidal and retinal neovascularization. Repeated ophthalmic examinations showed the regressive nature of oxalate depositions. In the 18th month, fundus examination and fluorescein angiography revealed that oxalate crystals were significantly regressed. To increase the quality of life and slow down the systemic effects of oxalosis, kidney-only transplantation is beneficial.     

Liver-kidney-transplantation in type 1 primary hyperoxaluria: description and comments on a case

BACKGROUND: Primary hyperoxaluria leads to oxalosis, a systemic illness with fatal prognosis in uremic youngsters because of systemic complications. Case report: A 14-year old boy with primary type 1 hyperoxaluria who had a long-lasting history of nephrolithiasis and passed from normal renal function to end-stage renal disease within 7 months. MEASUREMENT of alanine: glyoxylate aminotransferase (AGT) catalytic activity in the liver biopsy disclosed very low activity which was not. responsive to pyridoxin., thus the patient entered onto a priority national waiting list for liver-kidney transplantation and a week later received a combined transplant. In order to increase body clearance of oxalate, the patient underwent medical treatment to increase urine oxalate solubility (sodium and potassium citrate oral therapy, magnesium supplementation and increase of diuresis) and intensive dialysis both before and after transplantation. COMMENT: The medical approach to the treatment of this rare illness is discussed. Since the major risk for the grafted kidney is related to the oxalate burden, i.e. oxalate deposition from the body deposits to the kidney that becomes irreversibly damaged, treatment consists of increasing the body clearance of oxalate both by increasing oxalate solubility in the urine and with intensive dialysis performed both before and after combined transplantation. To the same extent (by limiting body oxalate deposits), a relatively early (native GFR 20-25 ml/minute) transplantation is advisable.     

Identification of a novel AGXT gene mutation in primary hyperoxaluria after kidney transplantation failure

Primary hyperoxaluria is a genetic disorder in glyoxylate metabolism that leads to systemic overproduction of oxalate. Functional deficiency of alanine-glyoxylate aminotransferase in this disease leads to recurrent nephrolithiasis, nephrocalcinosis, systemic oxalosis, and kidney failure. The aim of this study was to determine the molecular etiology of kidney transplant loss in a young Tunisian individual. We present a young man with end-stage renal disease who received a kidney allograft and experienced early graft failure. There were no improvement in kidney function; he required hemodialysis and graft biopsy revealed calcium oxalate crystals, which raised suspicion of primary hyperoxaluria. Genetic study in the AGXT gene by PCR direct sequencing identified three missense changes in heterozygote state: the p. Gly190Arg mutation next to two other novels not previously described. The classification of the deleterious effect of the missense changes was developed using the summered results of four different mutation assessment algorithms, SIFT, PolyPhen, Mutation Taster, and Align-GVGD. This system classified the changes as polymorphism in one and as mutation in other. The patient was compound heterozygous mutations. Structural analysis showed that the novel mutation, p.Pro28Ser mutation, affects near the dimerization interface of AGT and positioned on binding site instead of the inhibitor, amino-oxyacetic acid (AOA).With the novel AGXT mutation, the mutational spectrum of this gene continues to broaden in our population. The diagnosis of PH1 was not recognized until after renal transplant with fatal consequences, which led us to confirm the importance of screening before planning for kidney transplantation in population with a relatively high frequency of AGXT mutation carriers.     

Combined liver-kidney transplantation for primary hyperoxaluria type 1 in young children.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare condition in which deficiency of the liver enzyme alanine:glyoxylate aminotransferase leads to renal failure and systemic oxalosis. Combined liver-kidney transplantation (LKT) is recommended for end-stage renal failure (ESRF) in adults, but management of infants and young children is controversial. We retrospectively reviewed six children who underwent LKT for PH1. METHODS: The median age at diagnosis was 1.8 years (range 3 weeks to 7 years). Two children presented with severe infantile oxalosis at 3 and 9 weeks, five patients had ESRF with nephrocalcinosis and systemic oxalosis, (median duration of dialysis 1.3 years), and one had progressive chronic renal failure. Four children underwent combined LKT, one child staged liver then kidney, and one infant had an isolated liver transplant. The median age at transplantation was 8.9 years (range 1.7-15 years). RESULTS: Overall patient survival was four out of six. The two infants with PH1 and severe systemic oxalosis died (2 and 3 weeks post-transplant) due to cardiovascular oxalosis and sepsis. The other four children are well at median follow-up of 10 months (range 6 months to 7.4 years). No child developed hepatic rejection and all have normal liver function. Renal rejection occurred in three patients. Despite maximal medical management, oxalate deposits recurred in all renal grafts, contributing to graft loss in one (one of the infants who died), and significant dysfunction requiring haemodialysis post-transplant for 6 months. CONCLUSIONS: LKT is effective therapy for primary oxalosis with ESRF but has a high morbidity and mortality rate in children who present in infancy with nephrocalcinosis and systemic oxalosis. We feel that earlier LKT, or pre-emptive liver transplantation, may be a better therapeutic strategy to improve the outlook for these patients.     

Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. The European Study Group on Transplantation in Hyperoxaluria Type 1

The data provided by 14 European centres concerning 22 combined liver-kidney and two isolated liver grafts performed in primary hyperoxaluria type 1 (PH1) were discussed at a workshop which drew the following main conclusions: 1. In end-stage renal failure due to PH1 1-year kidney graft survival rate is far better after combined liver-kidney transplantation than after kidney transplantation alone. This may be due to enhanced renal graft tolerance induced by the simultaneously grafted liver, in addition to the reduced risk of oxalate-induced damage to the kidney graft because the oxalate overproduction has been corrected. 2. Prolonged dialysis using conventional regimes gives rise to extensive systemic oxalosis, especially oxalate osteopathy, which leads to long-lasting excretion of large amounts of oxalate even after oxalate synthesis has been normalised by liver-kidney transplantation, with the risk of jeopardising the success of the kidney graft. In addition, oxalate arteriopathy may endanger the recipient's life. 3. Patients whose GFR is in the range of 25-60 ml/min per 1.73 m2 should be followed up closely, with sequential assessments based on the rate of loss of overall renal function and the plasma and urine oxalate values. An isolated liver transplantation should be considered once the disease has been shown to be following an aggressive course. If this strategy is not followed, planning for an elective liver-kidney graft should begin when GFR decreases to about 25 ml/min per 1.73 m2 and the operation should be as soon as possible. 4. As orthotopic liver transplantation involves the removal of the recipient's biochemically defective but otherwise normal liver, the diagnosis of PH1 should be unequivocally established in every case by the measurement of alanine: glyoxylate aminotransferase enzyme activity in a preoperative liver biopsy.     

Primary hyperoxaluria type 1: still challenging!

Primary hyperoxaluria type 1, the most common form of primary hyperoxaluria, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine: glyoxylate aminotransferase (AGT). This results in increased synthesis and subsequent urinary excretion of the metabolic end product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. As glomerular filtration rate (GFR) decreases due to progressive renal involvement, oxalate accumulates and results in systemic oxalosis. Diagnosis is still often delayed. It may be established on the basis of clinical and sonographic findings, urinary oxalate ± glycolate assessment, DNA analysis and, sometimes, direct AGT activity measurement in liver biopsy tissue. The initiation of conservative measures, based on hydration, citrate and/or phosphate, and pyridoxine, in responsive cases at an early stage to minimize oxalate crystal formation will help to maintain renal function in compliant subjects. Patients with established urolithiasis may benefit from extracorporeal shock-wave lithotripsy and/or JJ stent insertion. Correction of the enzyme defect by liver transplantation should be planned, before systemic oxalosis develops, to optimize outcomes and may be either sequential (biochemical benefit) or simultaneous (immunological benefit) liver–kidney transplantation, depending on facilities and access to cadaveric or living donors. Aggressive dialysis therapies are required to avoid progressive oxalate deposition in established end-stage renal disease (ESRD), and minimization of the time on dialysis will improve both the patient’s quality of life and survival.     

Primary hyperoxaluria type 1: improved outcome with timely liver transplantation: a single-center report of 36 children

BACKGROUND: The appropriate use of liver transplantation in children with type-1 primary hyperoxaluria (PH-1) is not well established. We reviewed our experience with 36 children with PH-1, including 12 who underwent liver transplantation. PATIENTS AND METHODS: From 1989-1998, 36 children from 10 families in northern Israel were diagnosed with PH-1. Eight children presented with renal failure; seven of these eight had the severe infantile form of the disease. One child was treated with kidney transplantation alone. Combined liver-kidney transplantation has been performed in nine children and preemptive liver transplantation in three children. A review of the patients' charts for the following parameters was performed: age, clinical signs, and renal sonographic findings at diagnosis, age at onset of dialysis, and current status. Type of transplant, pre- and posttransplant urine oxalate excretion, current renal function, survival, and complications were recorded in liver recipients. RESULTS: Of the 23 nontransplanted children, 9 died of complications related to severe systemic oxalosis and 14 are alive (mean follow-up, 7.4 years), including 2 who are candidates for transplantation. The child who underwent only kidney transplantation died of unrelated causes. Of the 12 liver recipients, 2 died within the first 3 months posttransplant and another child underwent retransplantation due to hepatic arterial thrombosis. At intervals after transplant ranging from 6-54 months, 10 recipients are alive (7 of the 9 recipients of combined liver-kidney transplants and all 3 recipients of preemptive liver transplants). Mean GFR in the 10 survivors is 77 ml/min/m2. In 9 of these 10, daily urinary oxalate excretion normalized. Renal function has improved (mean GFR 86 vs. 58 ml/min/m2) but renal oxalate deposits remain in the three recipients of isolated liver grafts. CONCLUSIONS: Our decade-long experience with children with PH-1 supports strategies for early diagnosis and timely liver transplantation. Preemptive isolated liver transplantation should be considered in children who develop the disease during infancy or in those with slowly progressive disease when significant symptoms develop. Combined liver-kidney transplantation is suggested for children with end-stage renal disease.     

Renal allograft survival in patients with oxalosis

BACKGROUND: Primary hyperoxaluria is a rare autosomal recessive metabolic disease that often progresses to end-stage renal disease (ESRD). Liver transplantation is curative for patients with the alanine: glyoxylate aminotransferase deficiency. For oxalosis patients with minor enzyme deficiencies, renal transplantation may be the therapy of choice although concern exists about recurrence of oxalosis in the transplanted kidney. To date, previous data has been conflicting with most reports indicating poor renal allograft survival for oxalosis patients who receive a renal transplant alone. To determine whether graft survival in renal transplant recipients with oxalosis is similar to other transplant recipients with other forms of ESRD, we analyzed the United States Renal Data System (USRDS) registry comparing death-censored graft survival for transplant recipients with oxalosis to a reference group with ESRD secondary to glomerulonephritis (GN). METHODS: Using the USRDS and the U.S. Scientific Renal Transplant Registry data, we found 190 adult renal transplant recipients from 1988 to 1998 who had oxalosis as their primary diagnosis for their ESRD. Among the patients with oxalosis, 56 patients had a liver transplant followed by a kidney transplant (LKTx) and 134 patients had a kidney transplant alone (KTA). A Cox proportional hazard model was used to estimate patient survival and death-censored graft survival for patients with oxalosis who received a LKTx or a KTA. Unadjusted death-censored graft survival for oxalosis patients with a cadaveric or living-donor KTA or with a LKTx was obtained from Kaplan-Meier analysis. Recipients of solitary kidney transplants with GN served as the reference group. RESULTS: Oxalosis patients receiving a KTA had a significantly worse adjusted death-censored graft survival (47.9%) compared with patients with GN (61%) at 8 years posttransplantation (P <0.001). In contrast, oxalosis patients who received a LKTx had a significantly higher death-censored graft survival (76%) compared with oxalosis patients who received a KTA (47.9%, P<0.001) and had a trend toward better death-censored graft survival compared with patients with GN (P =0.05). In addition, oxalosis patients who received a living-donor KTA had significantly worse death-censored graft survival compared with oxalosis patients who received a LKTx (22% vs. 64%, P<0.01). Patient survival for oxalosis recipients with a KTA or a LKTx was not significantly different. CONCLUSIONS: Patients with oxalosis who receive a LKTx have superior death-censored graft survival compared with oxalosis patients who receive a cadaveric or living-donor KTA and trended toward better graft survival compared with GN patients.     

Transplantation Outcomes in Primary Hyperoxaluria

Optimal transplantation strategies are uncertain in primary hyperoxaluria (PH) due to potential for recurrent oxalosis. Outcomes of different transplantation approaches were compared using life‐table methods to determine kidney graft survival among 203 patients in the International Primary Hyperoxaluria Registry. From 1976–2009, 84 kidney alone (K) and combined kidney and liver (K + L) transplants were performed in 58 patients. Among 58 first kidney transplants (32 K, 26 K + L), 1‐, 3‐ and 5‐year kidney graft survival was 82%, 68% and 49%. Renal graft loss occurred in 26 first transplants due to oxalosis in ten, chronic allograft nephropathy in six, rejection in five and other causes in five. Delay in PH diagnosis until after transplant favored early graft loss (p = 0.07). K + L had better kidney graft outcomes than K with death‐censored graft survival 95% versus 56% at 3 years (p = 0.011). Among 29 year 2000–09 first transplants (24 K + L), 84% were functioning at 3 years compared to 55% of earlier transplants (p = 0.05). At 6.8 years after transplantation, 46 of 58 patients are living (43 with functioning grafts). Outcomes of transplantation in PH have improved over time, with recent K + L transplantation highly successful. Recurrent oxalosis accounted for a minority of kidney graft losses.     

Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence,risk factors,and effect on renal allograft function

Primary hyperoxaluria (PH) is a metabolic defect that results in oxalate overproduction by the liver and leads to kidney failure due to oxalate nephropathy. As oxalate tissue stores are mobilized after transplantation, the transplanted kidney is at risk of recurrent disease. We evaluated surveillance kidney transplant biopsies for recurrent calcium oxalate (CaOx) deposits in 37 kidney transplants (29 simultaneous kidney and liver [K/L] transplants and eight kidney alone [K]) in 36 PH patients and 62 comparison transplants. Median follow-up posttransplant was 9.2 years (IQR: [5.3, 15.1]). The recurrence of CaOx crystals in surveillance biopsies in PH at any time posttransplant was 46% overall (41% in K/L, 62% in K). Higher CaOx crystal index (which accounted for biopsy sample size) was associated with higher plasma and urine oxalate following transplant (p < .01 and p < .02, respectively). There was a trend toward higher graft failure among PH patients with CaOx crystals on surveillance biopsies compared with those without (HR 4.43 [0.88, 22.35], p = .07). CaOx crystal deposition is frequent in kidney transplants in PH patients. The avoidance of high plasma oxalate and reduction of CaOx crystallization may decrease the risk of recurrent oxalate nephropathy following kidney transplantation in patients with PH. This study was approved by the IRB at Mayo Clinic.     

Combined Liver–Kidney Transplantation for Primary Hyperoxaluria Type 2: A Case Report

Combined liver/kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient liver‐specific AGT enzyme, thus restoring normal metabolic oxalate production. However, primary hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44‐year‐old man with PH2, frequent stone events, and end‐stage renal disease; he received a combined liver/kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate, and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow‐up at 13 months suggests that correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation.     

Primary cultures of renal proximal tubule cells derived from individuals with primary hyperoxaluria

The primary hyperoxalurias, PH1 and PH2, are inherited disorders caused by deficiencies of alanine:glyoxylate aminotransferase and glyoxylate reductase, respectively. Mutations in either of these enzymes leads to endogenous oxalate overproduction primarily in the liver, but most pathological effects are exhibited in the kidney ultimately leading to end-stage renal failure and systemic oxalosis. To provide a non-invasive means of accessing kidney cells from individuals with primary hyperoxaluria, we have derived primary cultures of renal proximal tubule cells from the urine of these patients. The cells stain positively for the epithelial markers pan-cytokeratin and zonula occludens 1 and the proximal tubule marker γ-glutamyl transpeptidase. Mutation analysis confirmed that the cultured cells had the same genotype as the leucocytes of the patients and also expressed glyoxylate reductase at the mRNA level, illustrating their potential value as a source of renal material from these individuals.     

Multiorgan crystal deposition following intravenous oxalate infusion in rat

Deposition of calcium oxalate is responsible for the pathologic manifestations of oxalosis and may contribute to multiorgan dysfunction in uremia and to the progression of renal damage after renal failure is established. We have developed a rat model of oxalosis using a single intravenous injection of sodium oxalate, 0.3 mmol./kg. body weight, in rats. Polarized light microscopy and section freeze-dry autoradiography were used to identify 14C-oxalate within the renal parenchyma and in extrarenal organs. 14C-oxalate crystals under three mu in length were identified within one min. of injection in proximal tubule lumens. Section freeze-dry autoradiography showed occasional minute crystals within glomeruli, heart, lung and liver at one hr. In contrast to concentrative cellular uptake demonstrated in rat renal cortical slices in vitro, intracellular accumulation of 14C-oxalate could not be detected in vivo. Within the first 24 hr., renal oxalate retention reached a maximum of 25 +/- 4 per cent of the injected dose/gm. kidney compared to a maximum of only 7 +/- 3 per cent/gm. kidney after intraperitoneal administration. Although less than one per cent dose/gm. kidney remained after one week, crystal fragments were scattered throughout the cortex and medulla, often surrounded by foci of interstitial nephritis. The retention of crystals in kidney and other body organs following i.v. oxalate provides a model of oxalosis which stimulates pathophysiologic events in a variety of clinical situations characterized by transiently or persistently elevated serum oxalate.     

Bone impairment in oxalosis: An ultrastructural bone analysis

Deposition of calcium oxalate crystals in the kidney and bone is a hallmark of systemic oxalosis. Since the bone compartment can store massive amounts of oxalate, patients present with recurrent low-trauma fractures, bone deformations, severe bone pains and specific oxalate osteopathy on plain X-ray. Bone biopsy from the iliac crest displays specific features such as oxalate crystals surrounded by a granulomatous reaction due to an invasion of bone surface by macrophages. We present data obtained in 10 samples from 8 patients with oxalosis (16–68 years) who underwent iliac crest bone biopsy and bone quality analysis using modern methods (microradiography, microindentation, Fourier Transform InfraRed Microspectroscopy, transmission electron microscopy) in addition to histomorphometry. Disseminated calcium oxalate deposits (whewellite) were found in the bone marrow space (with a granulomatous reaction) but not in the bone matrix. Calcium oxalate deposits were totally surrounded by macrophages and multinucleated giant cells, and a phagocytosis activity was sometimes observed. Very few calcium oxalate crystals were directly in close contact with the mineral substance of the bone. Bone mineralization was not modified by the presence of calcium oxalate even in close vicinity. Bone quality analysis also revealed a harder bone than normal, perhaps in relationship with decreased carbonate content in the mineral. This increase in bone hardness could explain a more “brittle” bone. In patients with oxalosis, the formation and growth of calcium oxalate crystals in the bone appeared independent of apatite. The mechanisms leading to nucleation and growth of oxalate deposits are still unclear and deserve further studies.     

Early liver transplantation for primary hyperoxaluria type 1 in an infant with chronic renal failure

Infantile oxalosis is the most severe form of primary hyperoxaluria type 1, an inborn metabolic disorder caused by a deficiency of the hepatic enzyme alanine: glyoxylate aminotransferase (AGT). Renal insufficiency occurs due to excessive production and renal deposits of oxalate. This report concerns a 22-month-old girl with severe type 1 primary hyperoxaluria and chronic renal failure. Liver transplantation was performed successfully as treatment of AGT deficiency. Endogenous creatinine clearance remained stable at about 10 ml/min per 1.73 m2 at 23 months after transplantation. It is suggested that liver transplantation offers potential cure of an otherwise fatal disease. However, it remains questionable if the procedure influences kidney function in the presence of advanced renal disease.     

Primary hyperoxaluria

Primary hyperoxalurias are rare recessive inherited inborn errors of glyoxylate metabolism. They are responsible for progressive renal involvement, which further lead to systemic oxalate deposition, which can even occur in infants. Primary hyperoxaluria type 1 is the most common form in Europe and is due to alanine-glyoxylate aminostransferase deficiency, a hepatic peroxisomal pyridoxin-dependent enzyme. Therefore primary hyperoxaluria type 1 is responsible for hyperoxaluria leading to aggressive stone formation and nephrocalcinosis. As glomerular filtration rate decreases, systemic oxalate storage occurs throughout all the body, and mainly in the skeleton. The diagnosis is first based on urine oxalate measurement, then on genotyping, which may also allow prenatal diagnosis to be proposed. Conservative measures -?including hydration, crystallization inhibitors and pyridoxine?- are safe and may allow long lasting renal survival, provided it is given as soon as the diagnosis has been even suspected. No dialysis procedure can remove enough oxalate to compensate oxalate overproduction from the sick liver, therefore a combined liver and kidney transplantation should be planned before advanced renal disease has occurred, in order to limit/avoid systemic oxalate deposition. In the future, primary hyperoxaluria type 1 may benefit from hepatocyte transplantation, chaperone molecules, etc.