Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

Fatal outcome of autosomal recessive polycystic kidney disease in neonates with recessive PKHD1 mutations.

Autosomal recessive polycystic kidney disease (ARPKD) is the most common inherited childhood-onset renal disease, with underlying ciliopathy, and varies widely in clinical severity. The aim of this study was to describe the most severe form of ARPKD, with a fatal clinical course, and its association with mutations in polycystic kidney and hepatic disease 1 (fibrocystin) (PKHD1). Clinical, imaging, pathological, and molecular genetic findings were reviewed in patients prenatally affected with ARPKD and their families.Five unrelated Korean families, including 9 patients, were analyzed. Among the 9 patients, 2 fetuses died in utero, 6 patients did not survive longer than a few days, and 1 patient survived for 5 months with ventilator support and renal replacement therapy. A total of 6 truncating mutations (all nonsense) and 4 missense mutations were detected in a compound heterozygous state, including 4 novel mutations. The most severe phenotypes were shared among all affected patients in each family, irrespective of mutation types.Our data suggest a strong genotype-phenotype relationship in ARPKD, with minimal intra-familial heterogeneity. These findings are important for informing future reproductive planning in affected families.

[PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD): Genotype-phenotype correlations from a series of 308 cases to improve prenatal counselling]. / Mutations PKHD1 dans la polykystose autosomique récessive : corrélations génotype­phénotype dans une série de 308 cas pour guider le diagnostic anténatal.

OBJECTIVES: ARPKD is a recessive rare disease due to PKHD1 mutation. The main objective of the study was to characterize the phenotypic variability according to the different types of PKHD1 mutations. METHODS: This study was performed in 308 ARPKD patients with a genetic diagnosis from our genetic center. Related physicians provided minimal clinical and biological data. RESULTS: Patients were divided into three genotypic groups: the first group (G1; n=65) consisted of patients with two truncating mutations, the second group (G2; n=117) of patients with one truncating and one non-truncating mutation, and the third group (G3; n=126) of patients with two non-truncating mutations. In the entire cohort, the outcomes consisted of 31% of pregnancy termination, 18% of neonatal deaths and 51% of patient survival after the neonatal period. The proportion of severe ARPKD (pregnancy termination or neonatal death) was significantly greater in G1: 94% versus 47% in G2 and 27% in G3 (P<0.001). CONCLUSION: The presence of two truncating mutations in PKHD1 is associated with the most severe perinatal phenotype. However, the phenotypic variability observed in the other genotypic groups requires caution for prenatal counseling.

[Early bilateral nephrectomy in neonatal autosomal recessive polycystic kidney disease : Improved prognosis or unnecessary effort?] / Frühe beidseitige Nephrektomie bei Säuglingen mit pränataler ARPKD : Prognoseverbesserung oder unnötiger Aufwand?

BACKGROUND: Neonatal autosomal recessive polycystic kidney disease (ARPKD) is associated with giant kidneys, lung hypoplasia, pulmonal hypertension, and end-stage renal failure. Depending on the study, mortality is reported to range between 20 and 80%. OBJECTIVES: Does bilateral nephrectomy improve survival? PATIENTS AND METHODS: Between 2010 and 2016, we treated 7 children with prenatally diagnosed ARPKD. All had a planned delivery by cesarean section. After birth, oscillated ventilation with nitrogen enrichment was initiated to achieve maximum oxygenation and to decrease pumonary hypertension. All children had bilateral massive kidney hyperplasia (length 13-16 cm). RESULTS: Nephrectomy on one side was performed within 72 h together with placement of a peritoneal dialysis catheter in the intensive care unit. Contralateral nephrectomy was performed after 1-2 weeks when the child was stabilized by dialysis. In 2 children, kidney transplantation has already been performed and they are doing fine. One child died after 10 months due to infection. The other children are stable on home peritoneal dialysis awaiting transplantation. CONCLUSIONS: Early bilateral nephrectomy in neonatal ARPKD is feasible, but requires distinctive care at a pediatric intensive care unit and a high amount of organizational efforts to treat these children adequately in the first few days. In our experience, the procedure is a promising approach to improve ventilation and enable dialysis. However, kidney transplantation, best from a living donor, is required within the first years of life.

Kidney Versus Combined Kidney and Liver Transplantation in Young People With Autosomal Recessive Polycystic Kidney Disease: Data From the European Society for Pediatric Nephrology/European Renal Association-European Dialysis and Transplant (ESPN/ERA-EDTA) Registry.

BACKGROUND: The choice for either kidney or combined liver-kidney transplantation in young people with kidney failure and liver fibrosis due to autosomal recessive polycystic kidney disease (ARPKD) can be challenging. We aimed to analyze the characteristics and outcomes of transplantation type in these children, adolescents, and young adults. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: We derived data for children, adolescents, and young adults with ARPKD with either kidney or combined liver-kidney transplants for 1995 to 2012 from the ESPN/ERA-EDTA Registry, a European pediatric renal registry collecting data from 36 European countries. FACTOR: Liver transplantation. OUTCOMES & MEASUREMENTS: Transplantation and patient survival. RESULTS: 202 patients with ARPKD aged 19 years or younger underwent transplantation after a median of 0.4 (IQR, 0.0-1.4) years on dialysis therapy at a median age of 9.0 (IQR, 4.1-13.7) years. 32 (15.8%) underwent combined liver-kidney transplantation, 163 (80.7%) underwent kidney transplantation, and 7 (3.5%) were excluded because transplantation type was unknown. Age- and sex-adjusted 5-year patient survival posttransplantation was 95.5% (95% CI, 92.4%-98.8%) overall: 97.4% (95% CI, 94.9%-100.0%) for patients with kidney transplantation in contrast to 87.0% (95% CI, 75.8%-99.8%) with combined liver-kidney transplantation. The age- and sex-adjusted risk for death after combined liver-kidney transplantation was 6.7-fold (95% CI, 1.8- to 25.4-fold) greater than after kidney transplantation (P=0.005). Five-year death-censored kidney transplant survival following combined liver-kidney and kidney transplantation was similar (92.1% vs 85.9%; P=0.4). LIMITATIONS: No data for liver disease of kidney therapy recipients. CONCLUSIONS: Combined liver-kidney transplantation in ARPKD is associated with increased mortality compared to kidney transplantation in our large observational study and was not associated with improved 5-year kidney transplant survival. Long-term follow-up of both kidney and liver involvement are needed to better delineate the optimal transplantation strategy.

Long-Term Follow-Up of Kidney Transplant Recipients With Polycystic Kidney Disease.

OBJECTIVES: Patients with polycystic kidney disease are candidates for kidney transplant. We report the results of our single center study of 250 first transplant recipients with polycystic kidney disease (autosomal dominant [64%], medullary cystic [16%], autosomal recessive [6%], and nonspecified [14%]). MATERIALS AND METHODS: Patient groups were divided and analyzed according to the origin of the graft (deceased donor or living donor). We also analyzed demographic data of donors and recipients, waiting time, duration of dialysis, transfusion, nephrectomy, hospitalization, morbidities, and graft and patient survival. The study was approved by the Ethical Review Committee of the Institute. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. RESULTS: The deceased-donor group comprised 79% and the living-donor group comprised 21% of the cases. Nephrectomy was performed on 21% of the recipients. The deceased-donor group showed significantly higher values than the living-donor group regarding rate of hemodialysis (82% vs 68%), duration of dialysis (1571 vs 1002 days), waiting time (1129 vs 33 days), and blood transfusions (45% vs 27%). In deceased-donor versus living-donor transplant recipients, surgical complications included arterial stenosis (1% vs 0%), venous thrombosis (1% vs 0%), urine leakage (0.5% vs 1.9%), ureteral stenosis (0.5% vs 0%), reflux (0% vs 1.9%), lymphocele (11.7% vs 8.1%), and hernia (5.2% vs 8.1%), with no statistically significant differences shown between the groups. The living-donor group had graft and patient survival rates as high as the deceased-donor group. CONCLUSIONS: The low rate of morbidity and excellent survival rates make kidney transplant an excellent option for patients with polycystic kidney disease. Although fear of future appearance of polycystic kidney disease may reduce the rate of related living donors, our study showed that graft and patient survival rates in the living-donor group were as high as in the deceased-donor group.

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.

Clinical and genetic characterization of a founder PKHD1 mutation in Afrikaners with ARPKD.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) occurs in 1:20,000 live births. Disease expression is widely variable, with approximately 30 % of affected neonates dying perinatally, while others survive to adulthood. Mutations at the PKHD1 locus are responsible for all typical presentations. The objectives of this study were to define the clinical and genetic characteristics in a cohort of South African patients of Afrikaner origin, a population with a high prevalence of ARPKD. METHODS: DNA from the cohort was analyzed for background haplotypes and the p.M627K mutation previously identified in two unrelated Afrikaner patients. The clinical phenotype of the homozygous group was characterized. RESULTS: Analysis of 36 Afrikaner families revealed that 27 patients, from 24 (67 %) families, were homozygous for the p.M627K substitution, occurring on a common haplotype. The clinical phenotype of the homozygous individuals was variable. CONCLUSIONS: Our data provide strong evidence that the p.M627K substitution is a founder mutation in the Afrikaner population and can be used for streamlined diagnostic testing for at-risk pregnancies. The observed clinical variability suggests that disease expression is modulated by other genetic loci or by gene-environment interactions.

[Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case].

Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance.

Kidney and liver transplantation in patients with autosomal recessive polycystic kidney disease: a multicentric study.

BACKGROUND AND OBJECTIVES: In contrast to the improvement in our understanding of the pathogenesis and presentation of autosomal recessive polycystic kidney disease (ARPKD), data regarding the issue of kidney and liver transplantation in patients with ARPKD remain particularly scarce. Here, we report the results and outcome of renal and/or liver transplantation in a series of patients with ARPKD. METHODS: Fourteen ARPKD patients (age: 3-25 years) who underwent renal transplantation with or without liver transplantation were retrospectively identified in five French nephrology departments. The patients' medical charts were reviewed and relevant data were collected. RESULTS: The clinical and radiological presentation of the 14 patients was highly variable illustrating the heterogeneity of ARPKD. Six patients underwent kidney and/or liver transplantation in adulthood. First renal graft survival was 92, 78 and 14% at 1, 5 and 10 years after renal transplantation, respectively. Mortality rate was relatively high (3/14; 21%) in these young patients and was directly related to infectious complications (recurrent angiocholitis) of severe Caroli's disease (dilatation of intra- and/or extra-hepatic bile ducts), a typical feature of ARPKD. CONCLUSIONS: Our data suggest that ARPKD patients evaluated for renal transplantation should be carefully screened for severe Caroli's disease. Even though the limited number of patients included in our study precludes any definite recommendation, pre-emptive liver transplantation may be a therapeutic option in ARPKD patients with severe Caroli's disease evaluated for renal transplantation.

Pattern of liver diseases in Oman.

UNLABELLED: Arab Gulf countries including Oman have a high rate of consanguineous marriage with an associated increased frequency of a variety of genetic disorders including liver diseases. AIM: To describe the pattern of chronic liver diseases at The Royal Hospital, Muscat during the period January 2005 to January 2007. METHODS: A retrospective study of all children with chronic liver diseases seen at the Royal Hospital, which is a tertiary referral centre for gastro-enterology and hepatology for the whole of Oman. RESULTS: Seventy-nine patients with chronic liver disease were identified. The consanguinity rate amongst parents was 78%. The mean (SD) age of patients at the time of final diagnosis was 5 years (4). The two most common liver disorders were progressive familial intrahepatic cholestasis (30%) and fibrocystic disease of liver and kidney (21%). One-third of the patients came from the Sharqiya region. Complications included growth retardation (75%), cirrhosis (26%) and portal hypertension (39%). Three children died and three others received living related liver transplant. CONCLUSION: About half of the chronic liver disorders in Oman are hereditary in origin. At least three children per year will require liver transplant.

Management of polycystic liver disease.

The adult forms of polycystic liver disease are characterized by autosomal dominant inheritance and numerous hepatic cysts, with or without renal involvement. Mutations in two distinct genes predispose to renal and liver cysts (PKD1 and PKD2), and mutations in two different genes yield isolated liver cysts (PRKCSH and SEC63). Mutations at certain loci of PKD1 may predispose to more severe renal cystic disease or cerebral aneurysms. Risk factors for severe hepatic cystic disease include aging, female sex, pregnancy, use of exogenous female steroid hormones, degree of renal cystic disease, or severity of renal dysfunction (in patients with mutations in PKD1 or PKD2). Although liver failure or complications of advanced liver disease is rare, some patients develop massive hepatic cystic disease and become clinically symptomatic. There is no effective medical therapy. Treatment options include cyst aspiration and sclerosis, open or laparoscopic cyst fenestration, hepatic resection, and liver transplantation.

Autosomal recessive polycystic kidney disease: outcomes from a single-center experience.

Autosomal recessive polycystic kidney disease (ARPKD) is a relatively common form of pediatric polycystic kidney disease with an incidence of 1:20,000 live births. Previous reports, primarily from populations of European origin, indicate that the clinical presentation and disease course are quite variable. Using a retrospective study design, we sought to determine whether the clinical course and outcome of our multi-ethnic patient cohort differs from the published literature. A 10-year (1990-2000) retrospective study was conducted in which we reviewed the clinical, histopathological, and imaging records of our 31 ARPKD patients. Patients were diagnosed between 0 and 14 years of age, with 17 (55%) presenting within the 1st month of life. The mean follow-up was 67 months and age at last follow-up ranged from 0.5 to 16 years. Of the 17 patients diagnosed as neonates, 11 (65%) had respiratory insufficiency complicated by pneumothoraces. Two died shortly after birth and 2 died within the 1st year of life due to respiratory failure. Among the 13 neonatal survivors, 7 (54%) developed progressive renal insufficiency, whereas 6 of 14 (43%) of those children who presented beyond 1 month of age developed renal insufficiency. Hypertension was present in 55% of our patients, with nearly all neonatal survivors requiring antihypertensive management. Evidence of portal hypertension was found in 10 (37%) of the 27 patients who survived the 1st year of life. In our multi-ethnic ARPKD cohort, the 1-year survival rate (87%) and the clinical variability are comparable to those previously reported. With the recent identification of the PKHD1 gene, characterization of disease-causing mutations should provide new insights into the molecular basis for this phenotypic variability.

Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group.

BACKGROUND: Although autosomal dominant polycystic kidney disease type 2 (PKD2) is known to have a milder clinical phenotype than PKD1, neither disorder has been compared with an unaffected control population in terms of survival. We report the findings of a multicentre survey that aimed to define more precisely the survival and clinical expression of PKD1 and PKD2. METHODS: Clinical data from 333 people with PKD1 (31 families) were compared with data from 291 people with PKD2 (31 families) and 398 geographically matched controls. Survival analysis was used to compare age-at-event data. Differences in the prevalence of complications were assessed by logistic regression. FINDINGS: Median age at death or onset of end-stage renal disease was 53.0 years (95% CI 51.2-54.8) in individuals with PKD1, 69.1 years (66.9-71.3) in those with PKD2, and 78.0 years (73.8-82.2) in controls. Women with PKD2 had a significantly longer median survival than men (71.0 [67.4-74.8] vs 67.3 [64.9-69.7] years), but no sex influence was apparent in PKD1. Age at presentation with kidney failure was later in PKD2 than in PKD1 (median age 74.0 [67.2-80.8] vs 54.3 [52.7-55.9] years). PKD2 patients were less likely to have hypertension (odds ratio 0.25 [95% CI 0.15-0.42]), a history of urinary-tract infection (0.50 [0.31-0.83]), or haematuria (0.59 [0.35-0.98]). INTERPRETATION: Although PKD2 is clinically milder than PKD1, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder.

Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors.

Autosomal recessive polycystic kidney disease causes renal and hepatic dysfunction in childhood. We describe the clinical outcome of 52 children with this diagnosis born between 1950 and 1993. Currently 23 are alive, 24 dead and 5 have been lost to follow-up; 1 has been dialysed and 7 transplanted. Life-table analysis of the patients surviving the 1st month of life revealed an actuarial renal survival of 86% at 1 year and 67% at 15 years. The probability of requiring anti-hypertensive treatment was 39% at 1 year and 60% at 15 years of age. Bleeding from gastro-oesophageal varices occurred in 8 patients at a mean age of 12.5 years, and was preceded by haematological evidence of hypersplenism in 6 of them. The study indicates a relatively good prognosis for patients with this condition who survive the neonatal period and emphasises the importance of early detection and appropriate management of systemic and portal hypertension.

Autosomal recessive polycystic kidney disease in 115 children: clinical presentation, course and influence of gender. Arbeitsgemeinschaft für Pädiatrische, Nephrologie.

The clinical course of 66 boys and 49 girls with autosomal recessive polycystic kidney disease recruited from departments of paediatric nephrology was investigated over a mean observation period of 4.92 years. This is a selected study group of children from departments of paediatric nephrology who in most cases survived the neonatal period, since birth clinics did not participate. The median age at diagnosis was 29 days (prenatal to 14.5 years). We observed decreased glomerular filtration rates (GFRs) in 72% (median age at onset of decrease of GFR < 2 SD, 0.6 years; range, 0-18.7 years), and 11 patients developed end-stage renal disease. Hypertension requiring drug treatment was found in 70% (median age at start of medication, 0.5 years; range, 0-16.7 years). Kidney length was above the 97th centile in 68% of patients, and kidney length did not increase with age or deterioration of renal function. Urinary tract infections occurred in 30%, growth retardation in 25%, and clinical signs of hepatic fibrosis were detected in 46%. Thirteen patients (11%) died during the observation period, 10 of them in the first year of life. There was a statistically significant sex difference in terms of a more pronounced progression in girls. The survival probability at 1 year was 94% for male patients and 82% for female patients (p < 0.05) in this study. Urinary tract infections occurred more frequently in girls (p < 0.025) and were observed earlier. In addition, more girls had impaired renal function, developed end-stage renal disease and showed growth retardation; these differences, however, were not significant. For the children in this study, however, our results indicate that the long-term prognosis in the majority of cases is better throughout childhood and youth than often stated.

New autosomal recessive lethal disorder with polycystic kidneys type Potter I, characteristic face, microcephaly, brachymelia, and congenital heart defects.

We report on 3 pairs of sibs from unrelated families, who present with polycystic kidneys Potter type I claimed to be specific for the ARPKD, and with microbrachycephaly, hypertelorism with telecanthus, large posteriorly angulated fleshy ears and various congenital malformations including congenital heart defects. We suggest that they represent a previously unrecognized autosomal recessive lethal developmental disorder within the group of infantile polycystic kidney disease and Potter sequence.