Primary hyperoxaluria type 1 in children: Clinical classification, renal replacement therapy, and outcome in a single centre experience.

Primary hyperoxaluria type 1 (PH1) is a rare disease that is challenged by the overproduced oxalate and commonly presented with radiopaque renal stones or obstructive uropathy. This study aimed to report clinical presentations, renal replacement therapy (RRT), and outcome of PH1 in end stage kidney disease (ESKD) children. This is an observational cohort study. Data of 22 patients with ESKD due to PH1 were analyzed at Pediatric Nephrology Unit, Faculty of Medicine Cairo University. Infantile onset patients (n = 10) had worst renal outcome (80% with ESRD at presentation, p = 0.019) and worse patient outcome (mortality 40%, p = 0.016) than juvenile (n = 9) and late onset (PH1 n = 3) patients. RRT modalities include peritoneal dialysis (PD) in 7 (31.8%), hemodialysis (HD) in 11 (50%), and combined liver kidney transplantation (CLKT) in 4 (18.2%) patients. Infectious complications were encountered in 42.8% of PD patients. Better HD adequacy was observed with frequent HD (n = 6) and/or HD via arteriovenous fistula (AVF) than with infrequent dialysis (n = 5) and/or via central venous line (CVL) (p = 0.0001 and 0.0047, respectively). Morbidity and mortality (infection related) rates of the whole cohort were 63.6% and 31.8%, respectively. Clinical presentation of PH1 varies according to the age of onset (infantile onset being the most aggressive form). Aggressive HD (better through AVF) is needed to achieve acceptable HD adequacy, PD was challenged by infection. Infection found to be the main cause of mortality even after successful CLKT.

[Clinical analysis of seven cases with primary hyperoxaluria type 1 in children].

Objective: To investigate the clinical, imaging and molecular characteristics of primary hyperoxaluria type 1 (PH1) in children and to sum up existing evidence for further understanding the phenotype-genotype correlation of infantile PH1. Methods: This retrospective analysis was based on the medical records of children with PH1 diagnosed by gene test in the Department of Nephrology, Guangzhou Women and Children's Medical Center from June 2016 to May 2019. Targeted exome sequencing was performed on tubular disease-related genes of the probands and Sanger sequencing was conducted to validate suspected pathogenic variants of family members. Logistic regression analysis of NC and CCr was adopted to show the relation between NC and renal function. The literature review was conducted, and the clinical, imaging and molecular biogenetic characteristics of the disease were analyzed and summarized. Results: A total of 7 children from 6 families were enrolled. The median age of onset was 5 months. The median age of diagnosis was 8 months. Five cases had progressed to end-stage renal disease (ESRD), one case had chronic kidney disease (CKD) stage 1, and the other one had CKD stage 2. Four cases died, one case maintained on hemodialysis, and the other two non-dialysis cases were followed up. Among the 7 cases, 4 patients had infantile PH1, 1 patient had child and adolescent type, 1 patient had family type and the other one had unknown classification. There were two siblings (the younger brother had uremia and the sister had normal renal function) who had the delayed diagnosis for 5 and 3 years respectively. All patients in this cohort had proteinuria and microscopic hematuria, but no patients had gross hematuria. Three cases had hypercalciuria. Comprehensive diagnostic imaging evaluation include CT scan, MR scan, radiography and ultrasound led to the diagnosis of nephrocalcinosis (NC) in 5 cases, including 4 cases of simple NL and 1 case of NC with nephrolithiasis (NL), 1 case of multiple NL and 1 case of microcrystal deposition in renal medulla. However, only one case of NC was identified by ultrasound, the other 4 cases of NC were identified by radiograph examination. In the logistic regression analysis involving NC and creatinine clearnce rate (CCr), the results showed that NC was an independent risk factor for renal dysfunction (OR 2.5, 95%CI 0.7-1.2, P<0.05). All the 7 cases had AGXT gene variant, including homozygous variant in 4 cases and compound heterozygous variant in 3 cases. A total of 9 variant genotypes were found, and exon 6 variants were found in 4 children. Among them, there were 3 cases with c.679_680delAA. To our knowledge, both c.679_680delAA and c.190A>T in the cohort have not been reported previously. Conclusions: Infantile PH1 is the most common type of PH1 in children, which progresses rapidly or even begins with renal failure, with poor prognosis. It is also highly heterogeneous in phenotype and genotype. NC is an independent risk factor leading to renal failure. Radiograph examination showed high specificity for the diagnosis of NC. At present, the misdiagnosis and delayed diagnosis of PH1 are still common in China. It is of great significance to carry out quantitative determination of uric oxalate in order to reduce the misdiagnosis rate and enhance follow-up technologies for evaluating the therapeutic effect.

Combined liver-kidney transplantation for primary hyperoxaluria type I in children: Single Center Experience.

Primary hyperoxalurias are rare inborn errors of metabolism with deficiency of hepatic enzymes that lead to excessive urinary oxalate excretion and overproduction of oxalate which is deposited in various organs. Hyperoxaluria results in serious morbid-ity, end stage kidney disease (ESKD), and mortality if left untreated. Combined liver kidney transplantation (CLKT) is recognized as a management of ESKD for children with hyperoxaluria type 1 (PH1). This study aimed to report outcome of CLKT in a pediatric cohort of PH1 patients, through retrospective analysis of data of 8 children (2 girls and 6 boys) who presented by PH1 to Wadi El Nil Pediatric Living Related Liver Transplant Unit during 2001-2017. Mean age at transplant was 8.2 ± 4 years. Only three of the children underwent confirmatory genotyping. Three patients died prior to surgery on waiting list. The first attempt at CLKT was consecutive, and despite initial successful liver transplant, the girl died of biliary peritonitis prior to scheduled renal transplant. Of the four who underwent simultaneous CLKT, only two survived and are well, one with insignificant complications, and other suffered from abdominal Burkitt lymphoma managed by excision and resection anastomosis, four cycles of rituximab, cyclophosphamide, vincristine, and prednisone. The other two died, one due to uncontrollable bleeding within 36 hours of procedure, while the other died awaiting renal transplant after loss of renal graft to recurrent renal oxalosis 6 months post-transplant. PH1 with ESKD is a rare disease; simultaneous CLKT offers good quality of life for afflicted children. Graft shortage and renal graft loss to oxalosis challenge the outcome.

Clinical spectrum of primary hyperoxaluria type 1: Experience of a tertiary center.

BACKGROUND AND AIM: Primary hyperoxalurias are rare inborn errors of metabolism resulting in increased endogenous production of oxalate that leads to excessive urinary oxalate excretion. Diagnosis of primary hyperoxaluria type 1 (PH1) is a challenging issue and depends on diverse diagnostic tools including biochemical analysis of urine, stone analysis, renal biopsy, genetic studies and in some cases liver biopsy for enzyme assay. We characterized the clinical presentation as well as renal and extrarenal phenotypes in PH1 patients. METHODS: This descriptive cohort study included patients with presumable PH1 presenting with nephrolithiasis and/or nephrocalcinosis (NC). Precise clinical characterization of renal phenotype as well as systemic involvement is reported. AGXT mutational analysis was performed to confirm the diagnosis of PH1. RESULTS: The study cohort included 26 patients with presumable PH1 with male to female ratio of 1.4:1. The median age at time of diagnosis was 6 years, nevertheless the median age at initial symptoms was 3 years. Thirteen patients (50%) were diagnosed before the age of 5 years. Two patients had no symptoms and were diagnosed while screening siblings of index patients. Seventeen patients (65.4%) had reached end-stage renal disease (ESRD): 6/17 (35.3%) during infancy, 4/17 (23.5%) in early childhood and 7/17 (41.29%) in late childhood. Two patients (7.7%) had clinically manifest extra renal (retina, heart, bone, soft tissue) involvement. Mutational analysis of AGXT gene confirmed the diagnosis of PH1 in 15 out of 19 patients (79%) where analysis had been performed. Fifty percent of patients with maintained renal functions had projected 10 years renal survival. CONCLUSION: PH1 is a heterogeneous disease with wide spectrum of clinical, imaging and functional presentation. More than two-thirds of patients presented prior to the age of 5 years; half of them with the stormy course of infantile PH1. ESRD was the commonest presenting manifestation in two-thirds of our cohort.

Combined liver and kidney transplantation and kidney after liver transplantation in children: Indication, postoperative outcome, and long-term results.

CLKT and sequential KALT are decided on a case-by-case basis in children for special indications such as ARPKD or PH1. We report on 21 children who underwent CLKT or KALT at our hospital between 1998 and 2013. Eleven children were diagnosed with PH1 and six with ARPKD. Other diagnosis were Joubert syndrome (n = 1), nephronophthisis (n = 1), CF (n = 1), and hepatocellular carcinoma (n = 1). Children (12 males, nine females) were aged 7.8 ± 6.2 yr (range, 10 months to 18 yr) at time of transplantation. Average wait time was 1.9 ± 0.9 yr (range, four months to 2.3 yr). Fifteen patients received dialysis prior to transplantation. In PH1 patients, four children received CLKT, five received KALT, and two infants have received only an LTx, whereas all six patients with ARPKD received CLKT. In patients with other indications, CLKT was performed in three cases and KALT in one girl. Cumulative 10-yr survival of all 21 patients was 78.4%. At the time of transfer into adult care, 13 patients retained stable liver and kidney function. Regardless the underlying diagnosis, CLKT and KALT can be performed in children with good surgical outcomes and long-term survival.

Long-term results of combined liver-kidney transplantation for primary hyperoxaluria type 1: the French experience.

Primary hyperoxaluria type 1 (PH1) is a hepatic metabolic defect leading to end-stage renal failure. The posttransplant recurrence of kidney disease can suggest a need for combined liver-kidney transplantation (LKT). However, the risk of LKT is theoretically far higher than the risk of kidney-alone transplantation (KAT). An unselected consecutive series of 54 patients with PH1 was analyzed according to the type of transplantation initially performed between May 1979 and June 2010 at 10 French centers. The duration of dialysis, extrarenal lesions, age, and follow-up were similar between the groups. Postoperative morbidity and mortality did not differ between the groups, and 10-year patient survival rates were similar for the LKT (n = 33) and KAT groups (n = 21; 78% versus 70%). Kidney graft survival at 10 years was better after LKT (87% versus 13%, P < .001) . Four patients (12.1%) lost their first kidney graft in the LKT group, whereas 19 (90%) did in the KAT group (P < .001). The recurrence of oxalosis occurred in 11 renal grafts (52%) in the KAT group but in none in the LKT group (P < .001). End-stage renal failure resulting from rejection was also higher in the KAT group (19% versus 9%, P < 0.0001). A second kidney transplant was performed for 15 patients (71%) in the KAT group versus 4 patients (12%) in the LKT group (P < 0.001). In conclusion, LKT for PH1 provides better kidney graft survival, less rejection, and similar long-term patient survival and is not associated with an increased short-term mortality risk. LKT must be the first-line treatment for PH1 patients with end-stage renal disease.

Liver transplantation for primary hyperoxaluria type 1: a single-center experience during two decades in Japan.

BACKGROUND: Primary hyperoxaluria type-1 (PH1) is an autosomal recessive disorder caused by impaired activity of hepatic peroxisomal alanine-glyoxylate aminotransferase that leads to end-stage renal disease (ESRD). A definitive diagnosis is often delayed until ESRD appears. Based on the etiology, liver transplantation (LT) seems to be the definitive treatment. PATIENTS AND METHODS: Three PH1 patients underwent LT at our institution during two decades. RESULTS: Two of the patients had family histories of cryptogenic ESRD. All three showed disease onset in childhood, but the definitive diagnosis was delayed in two cases (17 and 37 years of age). These delayed cases resulted in ESRD, and hemodialysis (HD) had been introduced before LT. One patient received domino LT, and the other two underwent living-donor LT (LDLT). One patient finally died of sepsis, and was unable to receive a kidney transplantation (KT) after the domino LT. One patient did not show ESRD, and did not have to undergo KT after LDLT, although extracorporeal shock wave lithotripsy was required for residual ureterolithiasis (8 years after LDLT). The third patient had an uneventful course after LDLT and received living-donor KT from the same donor 8 months after LDLT. Subsequently, HD was successfully withdrawn. CONCLUSIONS: Establishment of a definitive diagnosis of PH1 is essential. If a methodology for early diagnosis and an intensive care strategy for neonates and infants during the waiting time become well-established, a timely and preemptive LT alone can provide a good chance of cure for PH1 patients.

Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy.

BACKGROUND AND OBJECTIVES: Primary hyperoxaluria (PH) as a cause of ESRD in children is believed to have poor outcomes. Data on management and outcomes of these children remain scarce. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included patients aged <19 years who started renal replacement therapy (RRT) between 1979 and 2009 from 31 countries providing data to a large European registry. RESULTS: Of 9247 incident patients receiving RRT, 100 patients had PH. PH children were significantly younger than non-PH children at the start of RRT. The median age at RRT of PH children decreased from 9.8 years in 1979-1989 to 1.5 years in 2000-2009. Survival was 86%, 79%, and 76% among PH patients at 1, 3, and 5 years after the start of RRT, compared with 97%, 94%, and 92% in non-PH patients, resulting in a three-fold increased risk of death over non-PH patients. PH and non-PH patient survival improved over time. Sixty-eight PH children received a first kidney (n=13) or liver-kidney transplantation (n=55). Although the comparison was hampered by the lower number of kidney transplantations primarily derived from the earlier era of RRT, kidney graft survival in PH patients was 82%, 79%, and 76% at 1, 3, and 5 years for liver-kidney transplantation and 46%, 28%, and 14% at 1, 3, and 5 years for kidney transplantation alone, compared with 95%, 90%, and 85% in non-PH patients. CONCLUSIONS: The outcomes of PH children with ESRD are still poorer than in non-PH children but have substantially improved over time.

[Combined liver-kidney and kidney after liver transplantation: indications and experiences from a nephrological perspective at a single center]. / Die kombinierte und sequentielle Leber-Nieren-Transplantation: Indikationen und Zentrumserfahrungen aus Sicht des Nephrologen.

Combined liver-kidney transplantations (CLKT) and kidney after liver transplantations (KALT) are established treatments for patients with end-stage hepatic and renal disease and the number of transplantations has continuously increased over the past few years. The most frequent indications for CLKT in adults are polycystic kidney disease with severe liver involvement and liver cirrhosis of different origins with concomitant chronic kidney failure due to chronic glomerulonephritis or diabetic nephropathy. In children, CLKT is most frequently required due to primary oxalosis type I. At present the main indication for KALT still is calcineurin inhibitor-induced chronic nephrotoxicity, emphasizing the need for a nephron-sparing long-term immunosuppression in liver transplant recipients. Compared to KALT, the indications for CLKT are not as well defined and the decision must therefore be made on a case-by-case basis by a multidisciplinary team of experienced clinicians to avoid unnecessary transplantations of both organs in patients with reversible kidney failure, given the scarcity of organs for transplantation worldwide. In hepatorenal syndrome CLKT should only be considered if the GFR is lower than 20 ml/min for more than three months or if the patient has been on renal replacement treatment for more than one month. In CLKT, there appears to be a certain immunological protection for the kidney transplant by the liver transplant.

Liver transplantation in oxalosis prior to advanced chronic kidney disease.

While curative of the disease, combined kidney and liver transplantation (K/LTx) for primary hyperoxaluria type 1 (PH1) continues to carry with it a risk for patient death of 15-25%, which over time may not differ from that of kidney transplantation alone (KTx). In this editorial, survival data are reviewed as well as the limited data available for kidney graft function, which may favor K/LTx in the short term but is more uncertain in the longer term. The window of opportunity that favors preemptive K/LTx is relatively narrow and is likely even narrower for preemptive isolated LTx. Capability and experience in the medical management of such patients, and the opportunities available, as well as likely patient compliance, so far without supporting data, may be the most important determination of the best strategy for management.

Is there a genotype-phenotype correlation in primary hyperoxaluria type 1?

There is ongoing debate about a genotype-phenotype correlation in patients with primary hyperoxaluria type 1 and specific AGXT mutations. However, other determinants like environmental factors or modifer genes may play a pivotal role in the heterogeneity of the disease. The report of Lorenzo and co-workers highlights this situation, presenting data of a whole population with just one specific AGXT mutation.

Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT mutation: Single-center experience.

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by allelic and clinical heterogeneity. We aim to describe the presentation and full single-center experience of the management of PH1 patients bearing the mutation described in our community (I244T mutation+polymorphism P11L). Since 1983, 12 patients with recurrent renal lithiasis have been diagnosed with PH1 and renal failure in the Canary Islands, Spain. Diagnostic confirmation was based on the presence of oxalosis in undecalcified bone or kidney allograft biopsy, reduced alanine:glyoxylate aminotransferase activity in liver biopsy, and blood DNA analysis. Patients underwent different treatment modalities depending on individual clinical circumstances and therapeutic possibilities at the time of diagnosis: hemodialysis, isolated kidney, simultaneous liver-kidney, or pre-emptive liver transplantation. In all cases, the presentation of advanced renal disease was relatively late (>13 years) and no cases were reported during lactancy or childhood. The eight patients treated with hemodialysis or isolated kidney transplantation showed unfavorable evolution leading to death over a variable period of time. In contrast, the four patients undergoing liver transplantation (three liver+kidney and one pre-emptive liver alone) showed favorable long-term allograft and patient survival (up to 12 years follow-up). In conclusion, in this PH1 population, all bearing the I244T mutation, the development of end-stage renal disease was distinctive during late adolescence or adulthood. Our long-term results support pre-emptive liver transplantation at early stages of renal failure, and kidney-liver transplantation for those with advanced renal disease.

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.

Combined liver-kidney transplantation in primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder characterised by an increased urinary excretion of calcium oxalate, leading to recurrent urolithiasis, nephrocalcinosis and accumulation of insoluble oxalate throughout the body (oxalosis) when the glomerular filtration rate falls to below 40-20 mL/min per 1.73 m(2). The disease is due to a functional defect of the liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT), the gene of which is located on chromosome 2q37.3. The diagnosis is based on increased urinary oxalate and glycollate, increased plasma oxalate and AGT measurement in a liver biopsy. AGT mistargeting may be investigated by immuno-electron microscopy and DNA analysis. End-stage renal failure is reached by the age of 15 years in 50% of PH1 patients and the overall death rate approximates 30%. The conservative treatment includes high fluid intake, pyridoxine and crystallisation inhibitors. Since the kidney is the main target of the disease, isolated kidney transplantation (Tx) has been proposed in association with vigorous peri-operative haemodialysis in an attempt to clear plasma oxalate at the time of Tx. However, because of a 100% recurrence rate, the average 3-year graft survival is 15%-25% in Europe, with a 5-10-year patient survival rate ranging from 10% to 50%. Since the liver is the only organ responsible for the detoxification of glyoxylate by AGT, deficient host liver removal is the first rationale for enzyme replacement therapy. Subsequent orthotopic liver Tx aims to supply the missing enzyme in its normal cellular and subcellular location and thus can be regarded as a form of gene therapy. Because of the usual spectrum of the disease, isolated liver Tx is limited to selected patients prior to having reached an advanced stage of chronic renal failure. Combined liver-kidney Tx has therefore become a conventional treatment for most PH1 patients: according to the European experience, patient survival approximates 80% at 5 years and 70% at 10 years. In addition, the renal function of survivors remains stable over time, between 40 and 60 mL/min per 1.73 m(2) after 5 to 10 years. In addition, liver Tx may allow the reversal of systemic storage disease (i.e. bone, heart, vessels, nerves) and provide valuable quality of life. Whatever the transplant strategy, the outcome is improved when patients are transplanted early in order to limit systemic oxalosis. According to the European experience, it appears that combined liver-kidney Tx is performed in PH1 patients with encouraging results, renal Tx alone has little role in the treatment of this disease, and liver Tx reverses the underlying metabolic defect and its clinical consequences.

Transplantation for primary hyperoxaluria in the United States.

BACKGROUND: Transplantation (TX) has become an acceptable treatment for renal failure in primary hyperoxaluria (PH). We have analyzed data from three U.S. sources to estimate the success or failure of different modes of management in PH patients. METHODS: The United States Renal Data System (USRDS) tapes provided coded medical record data, with PH assigned to 235 patients from 1974 to 1996. Another 45 patients were found from USRDS hospitalization records. We limited patients to those developing end-stage renal disease at <55 years of age after 1984 (95 PH patients). The North American Pediatric Renal Transplantation Cooperative Study (NAPRTCS) identified 34 (11 new) PH patients, and the United Network for Organ Sharing (UNOS) database identified PH in 34 (16 new, 5 more in both UNOS and NAPRTCS) patients. These secondary sources were used to correct some data from the USRDS and to add 32 more patients, with a total of 128 PH patients. Considering kidney TX (KTX) prior to combined kidney/liver TX (K/LTX) as a separate record for some calculations, the total "cases" were 138. RESULTS: By life table analysis, the 94 total TX patient survival was better than for the 34 NoTX patients (P<0.001). The 52 KTX patients' survival was better than either the 32 primary K/LTX (P<0.001) or the 10 K/LTX that following KTX (P<0.001). The 62 KTX cases' survival was better than the 42 K/LTX cases (P<0.005), which did not differ from the 34 NoTX (P<0.67). The overall survival of these 62 KTX patients was 76%. The survival of 42 K/LTX was 69%, and the survival of 34 NoTX patients was 44%. Kidney graft life table projected survival curves for TX patients did not differ between K/LTX (56% at 6 years) and isolated KTX (51% at 6 years, 35% at 10 years, P<0.91). CONCLUSION: KTX offers better patient survival in the United States then either K/LTX or NoTX. Graft survival does not differ between KTX and K/LTX. Because K/LTX can still follow a failed KTX, isolated living related donor KTX is still a reasonable first option for PH type 1 if a strictly managed protocol is followed.