Successful transplantation in a child with rapid progression of autosomal recessive polycystic kidney disease associated with a novel mutation

Autosomal recessive polycystic kidney disease (ARPKD) is the most common pediatric renal cystic disease with liver involvement. The vast majority of patients with ARPKD carry mutations in the recently characterized PKHD1 gene on chromosome 6p12. A Turkish female demonstrated rapid growth of both kidneys after delivery. Accelerated growth of both kidneys and increasing respiratory distress necessitated right-sided nephrectomy at the age of three months. Because of persistent dyspnea and ongoing growth of the remaining kidney, the second kidney also had to be removed one month later. Biopsies taken from the kidney and the liver confirmed the diagnosis of ARPKD histologically. Renal ultrasound of the patient's consanguineous parents and her older brother showed normal results. PKHD1 mutation analysis yielded a novel homozygous missense mutation (c.1116C >G, F372L) in exon 14, coding for an Ig-like domain (TIG), possibly involved in the increased growth of the kidneys. Peritoneal dialysis was performed for 12 months. The patient had successful transplantation at the age of 15 months and is doing well with actual immunosuppression with cyclosporine, mycophenolate mofetil, and prednisolone. In conclusion, the present case clearly demonstrates the favorable outcome of a child with severe ARPKD after bilateral nephrectomy, pre-emptive dialysis, and successful transplantation.     

Polycystic kidney disease and other genetic kidney disorders

Cystic kidney diseases encompass a range of genetic disorders in which the primary cilia of the cells are affected and thereby cysts form as a result. There are an increasing range of cystic renal diseases recognized due to the advances in genomics. The most common genetic kidney condition is autosomal dominant polycystic kidney disease (ADPKD). ADPKD leads to renal failure in adulthood. In children, hypertension is common and if treated, may slow down renal decline. The most common cystic kidney disease causing renal failure in children is autosomal recessive polycystic kidney disease (ARPKD). ARPKD also affects the liver. These conditions often have extra-renal features which also need to be addressed. Until recently, treatments were mainly supportive but now it is possible to slow down development of cyst formation and renal decline in ADPKD. This raises hope for treatment for other cystic renal conditions as more genes are identified and underlying mechanisms defined.     

Renal function outcome in pediatric liver transplant recipients

The orthotopic liver transplantation (OLT) allows survival of children followed for severe hepatic injury, provided that the immunosuppressive treatment is prolonged. The nephrotoxicity of cyclosporine predicts the long-term outcome of the adult patients receiving a liver transplant. The aim of this study was to determine the long-term outcome of renal function in children receiving OLT. This study included 12 children, with a median for age of 7.1 yr (2-15 yr) at the time of OLT. The duration of follow-up was at least 4 yr, being 7 yr in 10 patients and more than 10 yr in seven. Renal function was evaluated with the serum level of creatinine, calculated glomerular filtration rate (cGFR), and measurement of glomerular filtration rate using chrome 51 ethylenediaminetetraacetate ((51)Cr EDTA) clearance performed at least once during follow-up. The doses and the serum concentrations (C(0)) of cyclosporine were reported at each study time. The cGFR decreased significantly 2 yr after the OLT [median (range): 106 mL/min/1.73 m(2) (71-150) at the time of OLT vs. 85 mL/min/1.73 m(2) (57-128) 2 yr after the OLT, p = 0.03], and decreased again between 7 and 10 yr after OLT [median (range): 99 mL/min/1.73 m(2) (76-125) 7 yr after OLT vs. 81 mL/min/1.73 m(2) (66-140) 10 yr after OLT, p = 0.04]. Six patients developed chronic renal failure (cGFR from 57 to 80 mL/min/1.73 m(2)) 2 yr after OLT associated with high doses of cyclosporine [median (range): 8.8 mg/kg/day (3.5-13)]. The cGFR overestimated renal function by 16% compared with the isotopic measurement of GFR (p = 0.03). Using the (51)Cr EDTA measurement, six of seven patients followed up more than 10 yr after OLT presented mild (n = 3) or moderate (n = 3) chronic renal failure. In our study, the majority of OLT recipients developed a chronic renal failure 10 yr after transplantation. Cyclosporine seems to be the most important factor responsible for the impairment of renal function. The use of the mycophenolate mofetil, a new immunosuppressive agent, allowing a reduction in the dose of cyclosporine, could minimize renal dysfunction. While awaiting the results of a prospective long-term study, close drug monitoring is advised.     

Liver disease in autosomal recessive polycystic kidney disease

Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD). PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation. Portal hypertension and biliary disease are the major liver problems seen in ARPKD. Complete blood counting, physical examination, ultrasonography and magnetic resonance (MR) cholangiography are indicated as screening procedures for hepatic disease in ARPKD. Medical and surgical interventions are potentially indicated for children with portal hypertension and/or biliary disease. A high index of suspicion for the diagnosis of cholangitis needs to be maintained in children with biliary disease. The implications of hepatic disease need to be considered in the decision-making regarding renal transplantation in ARPKD.     

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

Renal failure in children with hepatic failure undergoing liver transplantation

Over a 3 1/2 year period, 133 children with hepatic failure underwent orthotopic liver transplantation (OLT) at our center. Renal failure (creatinine clearance less than 20 ml/min/1.73 m2) was present in 19 (14.3%) of these children. In seven of the 19 children, renal failure was present before OLT, and in the other 12 after OLT. The causes of renal failure included hepatorenal syndrome in seven, postischemic acute tubular necrosis in five, severe prerenal azotemia in five, and cyclosporine nephrotoxicity in two. Eight other patients died of renal failure while awaiting emergency transplantation. Of the total of 31 deaths among 133 children who underwent OLT, nine occurred in the 19 patients with renal failure. Thus patients with OLT and renal failure had a significantly higher mortality than other patients with transplants (P less than 0.025). Dialysis was not associated with improved survival. The majority of deaths in patients with renal failure were related to severe hemorrhage, thromboembolic events, and systemic fungal infections. Our experience suggests that renal failure is common in children with hepatic failure and is associated with reduced patient survival after OLT.     

Individualized concept for the treatment of autosomal recessive polycystic kidney disease with end‐stage renal disease

Management of children with autosomal recessive polycystic kidney disease (ARPKD) who develop end‐stage renal disease (ESRD) remains challenging because of concomitant liver disease. Patients with recurrent cholangitis are candidates for liver‐kidney transplantation, while the treatment for patients with splenomegaly and pancytopenia due to portal hypertension is controversial. Herein, we report 7 children who were treated using an individualized treatment strategy stratified by liver disease. Two patients with recurrent cholangitis underwent sequential liver‐kidney transplantation, while 4 patients with splenomegaly and pancytopenia but without recurrent cholangitis underwent splenectomy followed by isolated kidney transplantation. The remaining patient, who did not have cholangitis and pancytopenia, underwent isolated kidney transplantation. Blood cell counts were normalized after splenectomy was performed at the median age of 8.7 (range, 7.4‐11.7) years. Kidney transplantation was performed at the median age of 8.8 (range, 1.9‐14.7) years in all patients. Overwhelming post‐splenectomy infections and cholangitis did not occur during the median follow‐up period of 6.3 (range, 1.0‐13.2) years. The estimated glomerular filtration rate at the last follow‐up was 53 (range, 35‐107) mL/min/1.73 m². No graft loss occurred. Our individualized treatment strategy stratified by recurrent cholangitis and pancytopenia can be a feasible strategy for children with ARPKD who develop ESRD and warrants further evaluation.     

Association of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease

The association of autosomal recessive polycystic kidney disease (ARPKD) with congential hepatic fibrosis (CHF) is well known; a rare occurrence is that of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease (ADPKD). We report a family with ADPKD in which congenital hepatic fibrosis with severe portal hypertension (PHT) presented in a 4-year-old girl; the kidneys were initially normal. Typical changes of autosomal dominant polycystic kidney disease developed in the next decade and were also found in the mother and sister (neither of whom had any evidence of portal hypertension). Severe variceal bleeding was treated by sclerotherapy and beta receptor blocade.     

Polycystic kidney disease in children

Polycystic renal diseases in children include 2 pathologically and genetically distinct diseases: autosomal recessive polycystic kidney disease (ARPKD), incorrectly called the "infantile form", characterized by a constant hepato-renal involvement, and autosomal dominant polycystic kidney disease, often termed the "adult form", which is more and more frequently detected in children as a result of advances in renal imaging techniques. The differential diagnosis is not based on age at discovery, clinical symptoms or renal imaging, which may all be similar in the 2 diseases, but on the presence, detected by either pathology or ultrasonography, of the biliary dysgenesis specific to ARPKD, and mainly on the mode of inheritance, confirmed by the results of ultrasonography in parents and grandparents.     

Congenital hypothyroidism in association with Caroli's disease and autosomal recessive polycystic kidney disease: patient report

Autosomal recessive polycystic kidney disease (ARPKD) is an important renal disease of childhood. Congenital hypothyroidism has been associated with glomerulocystic kidney disease, but to date no association has been made with ARPKD. To our knowledge this is the first reported case of congenital hypothyroidism in an infant with ARPKD.     

Body growth in children with polycystic kidney disease

We analysed the body growth of 121 prepubertal children with polycystic kidney disease participating in a longitudinal multicentre study. The patients were followed from an age of 1 to 9 years in girls and 1 to 10 years in boys over a mean period of 3.6 years. Children with end-stage renal disease were excluded. Fifty-four patients had the autosomal dominant form of the disease and 67 the autosomal recessive form. At last observation, 2% of patients with the dominant form and 28% of those with the recessive form had an estimated glomerular filtration rate of < 60 ml/(min 1.73 m²). At first observation, the mean height SD score (SDS) in patients with the dominant form was almost the same as in controls, whilst in those with the recessive form it was significantly decreased (girls –0.82 SDS, boys -0.68 SDS, p < 0.001). During the follow-up the height SDS decreased slightly in both groups (NS). In patients with autosomal recessive kidney disease the degree of growth retardation appeared to be related to renal function: at last observation the height of girls with an estimated glomerular filtration rate of < 60ml/(min 1.73 m²) was more retarded than that of boys (mean -2.1 SDS versus -1.5 SDS, NS). The height SDS and renal function at last observation correlated in girls ( r = 0.83, p < 0.001) but not in boys ( r = 0.55) with the recessive form. No correlation was found between the height SDS and hypertension. The weight-for-height SDS at onset was significantly reduced in patients with the recessive form with decreased renal function. Our data suggest that the autosomal recessive, but not the dominant, form of polycystic kidney disease is associated with early growth retardation, which seems to be more severe in girls, probably due to the more rapid deterioration of renal function.     

Pediatric liver transplantation for fibropolycystic liver disease

Fibropolycystic liver disease includes CHF, Caroli's syndrome, and Caroli's disease. Patients with Caroli's disease and Caroli's syndrome have an increased risk of recurrent cholangitis, intrahepatic calculi, biliary cirrhosis, and cholangiocarcinoma. The aim of this study was to examine the post-transplantation outcomes of children with fibropolycystic liver disease. Of the 158 children transplanted at Seoul National University Hospital, there were four patients with Caroli's syndrome, two patients with CHF, and one patient with Caroli's disease. One patient underwent combined liver/kidney transplantation. Associated renal manifestations included ARPKD in three children and nephronophthisis in one child. The indications for LT were recurrent cholangitis, decompensated cirrhosis, and refractory complications of portal hypertension. Both graft and patient survival rates were 100% at a median follow-up period of two yr after LT. Three children with growth failure achieved catch-up growth after LT. In three patients with ARPKD, mean serum creatinine levels increased from 0.53 mg/dL at the time of LT to 0.91 mg/dL at the last follow-up (p = 0.01). LT is an excellent option for children with complications from fibropolycystic liver disease. Renal function should be monitored cautiously after LT in the patients with ARPKD.     

Congenital hepatic fibrosis: a very uncommon cause of pancytopenia in children

The disease presentation of autosomal recessive polycystic kidney disease (OMIM #263200, ARPKD) is highly variable and includes polycystic kidneys, pulmonary hypoplasia, and congenital hepatic fibrosis. The authors report an unusual case of ARPKD presenting with hepatosplenomegaly and cytopenia mimicking acute leukemia.     

Glomerular and tubular function following orthotopic liver transplantation in children

Since its advent, cyclosporine nephrotoxicity has been a major concern to pediatricians attending to liver transplant recipients. The aims of this study were to examine glomerular and tubular function after orthotopic liver transplantation (OLT) in children, their correlation to CsA, and how they differed according to the underlying disease. Patients and methods: Glomerular and tubular function was examined in 28 patients aged 7 months to 14 yr at the time of transplantation (mean 4.0 +/- 3.6), retrospectively examining creatinine clearance, tubular phosphate reabsorption (TRP), calcium/creatinine ratio, sodium excretion fraction, and protein/creatinine ratio. The group with metabolic disease and an underlying tubulopathy was compared with the group with liver disease only. The effect of CsA trough levels and cumulated dose on these indices was examined, as was the effect of antihypertensives on creatinine clearance. Both glomerular and tubular functions improved significantly following liver transplantation. In patients on CsA (n = 21), CrCl decreased significantly at 1 month post-OLT (42.6 +/- 26.6 mL/min/1.73 m(2)) when compared with pretransplantation, and 3, 12 and 60 months post-OLT (p < 0.05). It improved between 12 and 60 months post-OLT (p < 0.05). It was correlated with cyclosporine trough levels (p < 0.03), and with total dose of CsA at 12 months. This was not true for patients on tacrolimus (n = 7). Overall pretransplant TRP was below normal (73.7% +/- 19.6), which was significantly lower than the values at years 2, 3, and 5 post-OLT (p < 0.05), owing mainly to the metabolic group which recovered normal proximal tubular function by the end of the second week post-OLT. Calcium/creatinine ratio was significantly worse in the group with liver disease only (p < 0.01). Protein/creatinine ratio normalized rapidly in both groups. Urinary sodium excretion fraction (FENa) was very abnormal in the early postoperative phase, normalizing thereafter in both groups. Kidney function improved after liver transplantation in patients with and without pre-existing kidney dysfunction. Overall, creatinine clearance was correlated to CsA trough levels suggesting CsA did not have an irreversible 'sclerosing' effect in the medium term. Combined antihypertensive therapy using nifedipine and enalapril may be the optimal choice for patients requiring medical management of their hypertension, although the observed effect on creatinine clearance did not reach statistical significance in this study. Tubular dysfunction is frequent in both groups of patients, pre- and post-transplant, and may contribute to bone mineral density as well as to metabolic disturbances in this population.     

Successful liver transplantation in a child with Caroli's disease

Abstract:  CD is a rare autosomal recessive disease, characterized by multifocal cystic dilatation of intrahepatic bile ducts. The course of the disease is characterized by intrahepatic cholelithiasis, recurrent episodes of cholangitis, because of cholelithiasis, hepatic abscesses often ending in death caused by uncontrolled infection. Other conditions such as choledochal cyst and renal cystic disease are frequently associated, and patients have a higher risk for the development of cholangiocarcinoma. Endoscopic drainage of the bile duct is palliative and ineffective. OLT appears to be the treatment of choice. In monolobar cases partial liver resection has been shown to be a curative therapeutic option. We report on the course of disease in a Turkish girl who was diagnosed with CD in the neonatal period. At the age of 8.2 yr, she received OLT and is in good health 57 months post-transplantation.     

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF)

ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.     

Survival of childhood polycystic kidney disease following renal transplantation: the impact of advanced hepatobiliary disease

Childhood PKD encompasses the diagnoses of AR and ADPKD, glomerulocystic disease, and syndromes such as tuberous sclerosis or Jeune's syndrome. Given the fact that a majority of PKD children with ESRD carry the diagnosis of ARPKD, natural history studies assessing the long-term prognosis of PKD patients following renal transplantation must focus on morbidity and mortality issues related to complications from congenital hepatic fibrosis. Using the NAPRTCS registry, we analyzed the patient and graft survival rates of 203 PKD patients and 7044 non-PKD patients undergoing renal transplantation between 1987 and 2001. Deceased PKD patients, all with a diagnosis of ARPKD, were further identified and characterized using a special questionnaire submitted to the principal investigators. Overall graft and patient survival rates were not significantly different between PKD and non-PKD patients. No differences in rates of acute rejection or time to first rejection were noted between PKD and non-PKD patients. The relative risk of living longer than 3 yr in the PKD patients was not significantly different from non-PKD patients (RR = 0.70, p = 0.28). Sepsis was identified as a likely factor in the cause of death in nine (64%) ARPKD patients and was comfirmed with a positive blood culture in four patients. Despite similar graft and patient survival rates among PKD and non-PKD children following renal transplantation, our results suggest that ARPKD transplant recipients appear to be at increased risk for sepsis that may be related to hepatic fibrosis and ascending cholangitis. The utility of early liver transplantation in ARPKD patients with significant hepatobiliary disease is discussed.     

MR cholangiography in children with autosomal recessive polycystic kidney disease

Background. Magnetic resonance cholangiography (MRC) is a relatively new, non-invasive imaging technique of the biliary tree that has shown good correlation with endoscopic retrograde cholangiopancreatography. The liver manifestation of autosomal recessive polycystic kidney disease (ARPKD) is congenital hepatic fibrosis (CHF). CHF may be accompanied by Caroli's disease, which is characterised by a non-obstructive dilation of the intrahepatic bile ducts. Objective. A prospective study was conducted to determine the presence and extent of Caroli's disease in children with ARPKD. Materials and methods. Seven children with ARPKD aged from 3.0 to 10.1 years were examined. CHF was confirmed in all biopsied cases (5 of 7). All children had been followed by repeated abdominal US examinations for many years. The MR examination included a morphological imaging study using a T2-weighted turbo spin-echo sequence and a heavily T2-weighted inversion-recovery turbo spin-echo sequence with three-dimensional maximum intensity projection (MIP) reconstructions for MRC. Results. The diagnosis of Caroli's disease could be made in one case by US; in two other children Caroli's disease was suspected, but the differentiation from hepatic cysts was not possible. By MRC, Caroli's disease could be diagnosed in three of seven children. Furthermore, MRC with MIP reconstructions demonstrated the extent of the disease by showing the entire biliary tree from different angles. Conclusions. MRC is a valuable method to establish the diagnosis and demonstrate the extent of Caroli's disease. Received: 5 January 1998 Accepted: 9 December 1998     

Spectrum of pediatric developmental and genetic renal lesions and associated congenital malformations--an autopsy study from north India

Pediatric developmental and genetic renal lesions are a known cause of mortality in the perinatal/neonatal period. These lesions are associated with a wide range of extrarenal congenital malformations that influence the outcome of the patients. In this autopsy study, we have analyzed the spectrum of pediatric developmental and genetic renal lesions and their associated congenital malformations. A total of 4,099 autopsies (20 weeks of gestation to 1 year of life) were reviewed, of which 158 cases (3.85%) of pediatric developmental (143 cases) and genetic renal lesions (15 cases) were found. Autosomal recessive polycystic kidney disease was the commonest genetic lesion. Primitive ducts with cuffing of immature mesenchyme—the sine qua non of renal dysplasia—was found in all cases of dysplasia. Associated congenital malformations were seen in all cases and thus a thorough search for them is mandatory. Ductal plate malformation was found in all cases of autosomal recessive polycystic kidney disease and in 1 case of bilateral multicystic dysplasia.     

Transjugular intrahepatic portosystemic shunt prior to renal transplantation in a child with autosomal-recessive polycystic kidney disease and portal hypertension: A case report

Autosomal-recessive polycystic kidney disease (ARPKD) can cause renal failure and portal hypertension in children. Portal hypertension may complicate the course of renal transplantation (Tx). We report the successful outcome of a patient with end-stage renal disease (ESRD) and portal hypertension treated with transjugular intrahepatic portosystemic shunt (TIPS), a minimally invasive endovascular technique of portosystemic shunt, prior to renal Tx.