Impact of liver transplantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease

Congenital hepatic fibrosis (CHF) is an uncommon autosomal recessive malformation. It may be associated with extrahepatic manifestations such as polycystic kidney disease. The main consequence is portal hypertension and bleeding from varices. Despite liver transplantation as a therapeutic option for this patient, long-term impact of liver transplantation on renal functions of patients with autosomal recessive polycystic kidney disease with associated liver disease is not well known. In this study, we aimed to analyze the patient's renal function after liver transplantation by creatinine clearance, glomerular filtration rate, and renal resistive indexes. Between March 1997 and September 2002, three of 50 orthotopic liver transplantation (OLT) were performed because of CHF associated with ARPKD at Ege University Organ Transplantation and Research Center. Baseline immunosuppression consisted of prednisone and cyclosporine A (CSA). The mean follow-up of the patients was 2.1 yr. Blood urea and creatinine levels were decreased after operation in all patients and remained within the normal range at the sixth and 12th month, whereas the level of the third patient were increased at the 18th month. RRI values of patients were not found different at the sixth month whereas, RRI values of patients were decreased at the 12th month and remained unchanged at the 18th month of follow-up. During the study period hypertension developed in one patient at the 16th month and resolved with antihypertensive treatment and decreasing dosage of CSA. Kidney function has remained satisfactory in all of the patients despite the use of cyclosporine. OLT can provide good survival in patients with CHF associated with ARPKD.     

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.     

Kidney and liver transplantation in children with fibrocystic liver–kidney disease: Data from the US Scientific Registry of Transplant Recipients: 1990–2010

The natural history and survival of children with fibrocystic liver–kidney disease undergoing solid organ transplantation have infrequently been described. We report outcomes in a cohort of US children with fibrocystic liver–kidney disease receiving solid organ transplants over 20 yr. Retrospective cohort study of pediatric transplant recipients with diagnoses of fibrocystic liver–kidney disease from 1/1990 to 3/2010, using data from the SRTR. Subjects were categorized by the first transplanted organ: LT, KT, or SLK. Primary outcomes were death, re‐transplant, transplant of the alternate organ, or initiation of dialysis. Seven hundred and sixteen subjects were transplanted in this period. Median age at first transplant was 9.7 yr. Of the LT, 14 (19%) required a second liver transplant at median of 0.2 yr, and five (7%) required kidney transplant or dialysis at a median of 9.0 yr. Of the KT, 188 (31%) required a second kidney transplant or dialysis at a median of 5.9 yr. Twenty‐nine (5%) subsequently received liver transplant at a median of 6.0 yr. Among patients in this registry, far more children underwent kidney than liver transplants. The risk of subsequently needing transplantation of an alternate organ was low.     

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.     

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.     

Four pediatric patients with autosomal recessive polycystic kidney disease developed new‐onset diabetes after renal transplantation

NODAT is increasingly prevalent. Compared with adult recipients, NODAT is less prevalent in pediatric renal transplant recipients; however, some risk factors for its development in young patients have been defined. We report four pediatric renal transplant recipients with ARPKD who developed NODAT. We review the current pediatric NODAT literature and hypothesize that ARPKD may be an additional risk factor for NODAT.     

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.     

Comparison of parameters of chronic kidney disease following paediatric preemptive versus non‐preemptive renal transplantation

Sinha R, Marks SD. Comparison of parameters of chronic kidney disease following paediatric preemptive versus non‐preemptive renal transplantation.
Pediatr Transplantation 2010: 14:583–588. © 2010 John Wiley & Sons A/S. Abstract: PRT is the preferred modality for renal replacement therapy in children. Despite this, there are no studies CKD parameters as per K/DOQI criteria between PRT and NPRT in children. This was a single‐centre cross‐sectional study of RTR with at least one yr of post‐transplant follow‐up. CKD parameters as per K/DOQI were compared between PRT and NPRT. Thirty percent (39/129) of our study population was PRT. Despite similar baseline characteristics at the time of transplantation and similar post‐transplantation follow‐up period, a significantly lower proportion of PRT (1, 2%) were in Stage 4 CKD in contrast to NPRT (14, 16%); p = 0.03. This was also reflected in better CKD parameters among PRT with significantly lower incidences of hypertension and acidosis (p = 0.02). CKD medications were also more commonly prescribed in NPRT (p = 0.002). We demonstrated improved CKD parameters and lower use of CKD medications among PRT when compared with NPRT. This finding should act as an added impetus for PRT programmes.     

Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of ectatic renal collecting ducts, intrahepatic biliary dysgenesis, and portal fibrosis. Portal hypertension and recurrent bacterial cholangitis can dominate the clinical picture in long-term survivors. Predominant extrahepatic bile duct disease was revealed in four patients who underwent magnetic resonance cholangiopancreatography. All four patients had portal hypertension, although liver biochemistries did not suggest biliary disease. In two of the patients, cholangitis was clinically ascribed to the bile duct disease. Western blot analysis of plasma membranes from normal rat extrahepatic bile duct and kidney revealed the presence of polyductin as a single approximately 440 kDa protein. Although the exact function of polyductin in the extrahepatic duct is unknown, it may have a role in the development and control of lumenal size. Clinical management of patients with ARPKD should include consideration of potential problems related to extrahepatic bile duct disease.     

常染色体隐性遗传性多囊肾病的研究进展

常染色体隐性遗传性多囊肾病(ARPKD),发病率较低,多发于新生儿期和婴儿期,其致病基因为多囊肾/多囊肝病变1基因(PKHD1)。ARPKD的发病机制目前尚不十分清楚,治疗原则主要是控制并发症,延缓疾病的进展。文章综述近年来国内外ARPKD发病机制和治疗的新进展。     

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.     

Chronic kidney disease in children following lung and heart–lung transplantation

Abstract:  CKD is a major co-morbidity in pediatric lung transplant recipients. We report the prevalence of renal impairment post-lung transplant at a single center, using a modified, age-adjusted eGFR for the best approximation of true GFR, and investigated associations and possible predictors of decline in renal function post-transplant. Renal function was assessed by eGFR pre-transplant, three and 12 months post-transplant, and at last follow-up. Decline in renal function was analyzed as percentage fall in eGFR in two phases (0–3 and 3–12). Furthermore, we investigated impact of gender, age, pre-transplant diagnosis and renal function, transplant type, early post-transplant dialysis, and tacrolimus trough levels on decline in eGFR using multivariate analysis. Over a five-yr period, 30 transplants were performed. Mean eGFR pretransplant was 117 mL/min/1.73 m² (s.d. 35) with mean decline in eGFR during the first three months post-transplant of 33% (s.d. 31, p < 0.001). Thereafter, mean decline in eGFR was 8% (s.d. 18, p = 0.02). None of the factors assessed were significantly associated with decline in eGFR post-transplant. In conclusion, many children have decline in renal function following lung transplantation, particularly early post-transplant. Unlike in adults, we were unable to detect any predictors of renal impairment in pediatric lung transplant recipients.     

Cardiac magnetic resonance imaging in children with chronic kidney disease and renal transplantation

CV disease is the major cause of death in patients with CKD. Recently, CMR imaging emerges as a complementary method providing advantages in cardiac assessment; however, data on CMR in pediatric CKD are scarce. We performed CMR in 15 children: two with CKD, six on peritoneal dialysis, seven on hemodialysis, and in 18 children 5.1 (0.4-15.4) yr after kidney Tx. Eight children underwent CMR six months before and after Tx. Results are presented as mean z score ± SD. LV EF was higher and in the normal range in Tx patients compared with CKD (-0.3 ± 1 vs. -2.1 ± 1.6, respectively, p < 0.05), whereas RV EF was similar (-0.9 ± 1.4 vs. -0.9 ± 1.8, p = n.s.). End-diastolic and end-systolic LV volume index (0 ± 1.7 vs. 2.1 ± 3.1; 0.2 ± 1.2 vs. 3.1 ± 3.7, both p < 0.05) and LV mass index (1.4 ± 1.5 vs. 3.4 ± 2.9, p < 0.05) were lower in Tx children. All parameters improved in the eight children after Tx. In conclusion, our CMR analysis suggests marked improvement of cardiac function and morphology in children after kidney Tx. CMR might be an appropriate complementary method for measuring detailed cardiac status in children with CKD.     

Combination therapy for severe portopulmonary hypertension in a child allows for liver transplantation

Severe PPHTN is a contraindication to liver transplantation and predicts an abysmal 5‐year outcome. It is defined as a resting mPAP >45 mm Hg with a mean pulmonary artery wedge pressure of <15 mm Hg and pulmonary vascular resistance of >3 wood units in the setting of portal hypertension. There have been limited reports of successful treatment of PPHTN leading to successful liver transplantation in adults, and one reported use of monotherapy as a bridge to successful liver transplant in pediatrics. To our knowledge, we describe the first use of combination therapy as a successful bridge to liver transplantation in a pediatric patient with severe PPHTN. This report adds to the paucity of data in pediatrics on the use of pulmonary vasodilator therapy in patients with severe PPHTN as a bridge to successful liver transplantation. Early diagnosis in order to mitigate or avoid the development of irreversible pulmonary vasculopathy that would preclude candidacy for liver transplantation is crucial, but our report demonstrates that combination therapy can be administered safely, quickly, and may allow for successful liver transplantation in patients with severe PPHTN.     

Pediatric kidney transplantation

Since first performed in 1954, kidney transplantation has evolved as the preferred long-term treatment of children with end stage renal disease (ESRD). The etiology of chronic kidney disease (CKD) and ESRD in children is broad and can be quite complicated, necessitating a multidisciplinary team to adequately care for these patients and their myriad needs. Precise surgical techniques and modern protocols for immunosuppression provide excellent long-term patient and graft survival. This article reviews the many etiologies of renal failure in the pediatric population focusing on those most commonly leading to the need for kidney transplantation. The processes of evaluation, kidney transplantation, short-term and long-term complications, as well as long-term outcomes are also reviewed.     

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.     

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.     

Autosomal recessive polycystic kidney disease in 115 children: clinical presentation, course and influence of gender

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 < 2SD, 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.     

Hemihypertrophy in a boy with renal polycystic disease: Varied patterns of presentation of renal polycystic disease in his family

Hemihypertrophy is a condition that has been described in association with a variety of other malformations and diseases; quite often these have had a renal origin. — It is the purpose of this paper to record and discuss the occurrence of polycystic disease in a family, to note that the disease was manifest as either the adult or the infantile form, and detail the fact that one member of the family who had infantile type polycystic disease also had hemihypertrophy. —The pattern of inheritance of renal polycystic disease, its age at presentation and the variation in the boy of its manifestation with the passage of time are discussed. The need for caution in offering a prognosis and genetic counselling is stressed.     

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.