Cholestasis After Pediatric Liver Transplantation-Recurrence of a Progressive Familial Intrahepatic Cholestasis Phenotype as a Rare Differential Diagnosis: A Case Report.

INTRODUCTION: Nonobstructive cholestasis after pediatric liver transplantation is a common diagnostic and therapeutic dilemma. We describe a girl with neonatal cholestasis because of progressive familial intrahepatic cholestasis 2 (PFIC-2) and presence of a homozygous splice site mutation in the ABCB11 gene. Liver transplantation was performed because of end-stage liver disease at the age of 6. Cholestasis with normal gamma-glutamyl transferase (GGT) developed 8 years after liver transplantation. A liver biopsy showed canalicular cholestasis and giant cell hepatitis without evidence of rejection, mimicking PFIC-2. Immunofluorescence staining of normal human liver sections with patient's serum revealed reactivity toward a canalicular epitope, which could be identified as bile salt export pump (BSEP) using BSEP-yellow fluorescent protein (YFP) transfected cells. Our patient developed a recurrence of a PFIC-2 phenotype due to production of antibodies against BSEP (alloimmune BSEP disease [AIBD]). Intensification of immunosuppressive therapy as well as antibody treatment with plasmapheresis and Rituximab were initiated, leading to stabilization of the clinical condition and depletion of anti-BSEP antibodies in serum. However, after 1 year liver transplantation was necessary again because of end-stage liver insufficiency. Afterward, immunomodulatory treatment consisted of tacrolimus, mycophenolate mofetil, prednisone, immunoadsorption, and high-dose immunoglobulin therapy (1 g/kg/d). CONCLUSION: Cholestasis after liver transplantation may indicate an AIBD with a PFIC-2 phenotype. Besides enhancement of immunosuppressive therapy, an antibody depletion with plasmapheresis, immunoadsorption, immunoglobulins, and B-cell depletion represents a therapeutic option.

Immigrating progenitor cells contribute to human podocyte turnover.

Podocyte depletion is a critical event in glomerular diseases in general and in the development of focal segmental glomerulosclerosis in particular. Progenitor cell immigration is a possible mechanism of podocyte replacement for the preservation of nephron function since, with rare exception, mature podocytes are thought to be incapable of replication. We examined eight paraffin-embedded renal biopsies from six male recipients of female transplant kidneys for receiver-derived podocytes. Fluorescent in situ hybridization for the Y chromosome was combined with immunofluorescence for the podocyte marker, Wilms tumor-1 antigen. Recipient-derived podocytes were found in 4 of 8 biopsies representing 3 of the 6 patients. Overall, 5 of the 740 podocytes examined in the female-donated kidneys were male derived. Our study suggests that immigrating progenitor cells are able to replace podocytes in humans; however, the importance of this process in physiologic and pathologic conditions is unknown.

Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations.

Management of idiopathic glomerular disease associated with nephrotic syndrome (INS) remains controversial and one of the most complex areas relates to utilization of the drug cyclosporin. This is despite its demonstrated effectiveness in several histologic types of the INS in randomized controlled trials. Cyclosporin is effective in inducing remission of proteinuria in approximately 80% of steroid-sensitive cases of minimal change disease (MCD). Cyclosporin is also effective in both the induction of remission and long-term preservation of renal function in steroid-dependent/-resistant MCD and steroid-resistant focal segmental glomerulosclerosis (FSGS). The overall response rate in FSGS is lower than in MCD, and long-term therapy (>12 months) may be required to both achieve remission and sustain it. Cyclosporin therapy is also of benefit in reducing proteinuria in 70-80% of patients with steroid-resistant membranous nephropathy (MGN). In MGN, the maximum benefit is often delayed compared to MCD (>12 weeks). Cyclosporin is generally well tolerated and safe. The major concern remains the nephrotoxicity, but with careful monitoring of the patient's renal function; minimizing the maintenance dose and utilizing repeat renal biopsy in those receiving long-term therapy, this risk can be minimized. The algorithms have been developed derived from the best evidence in the literature in each of the histologic types to help provide a guide to the integration of cyclosporin into the management of INS for the practicing nephrologist.

[Obstructive nephropathy]. / Obstruktive Nephropathie.

Congenital anomalies of the kidney and urinary tract (CAKUT) are regarded as a single entity. The degree of obstruction may have an additional influence on the parenchymal malfunction. Congenital dilatation of the upper urinary tract associated with symptomatic urinary tract infection must be treated early with intensive antibiotic therapy. In some cases temporary urinary diversion is also required. Further diagnostic procedures are then postponed in such cases. In all other cases of dilatation of the upper urinary tract diagnosed prenatally or early in the postnatal period, diuresis renography is still the cornerstone of diagnosis, even though it has definite limitations in young infants and in babies with poor kidney function. Functional gadolinum MR-urography will become the method of choice in the near future, since it combines good functional and excellent morphological presentation. When an obstruction hampering function is definitely present surgical correction is indicated: open and endoscopic surgery yield similarly good results. Molecular markers in CAKUT may soon be used as prognostic indicators. Examination of the molecular alterations that occur in renal and urinary tract anomalies may also lead to medicamentous protection of renal function.

Unusual manifestation of posttransplant lymphoproliferative disorder in the esophagus.

Early manifestations of posttransplant lymphoproliferative disorders (PTLD) are mainly associated with a primary Epstein-Barr virus (EBV) infection. Rapid increases in peripheral blood EBV DNA load are supposed to reliably predict PTLD. We report a boy who 6 months after living-related kidney transplantation presented with an extranodal esophageal manifestation of PTLD. Despite a primary EBV infection with tonsillitis, the peripheral blood EBV DNA remained low, hiding the progression to PTLD.

[Occurrence, diagnostics and therapeutic management of hydronephrosis in pediatric patients in Germany]. / Schwerwiegende kindliche Anomalien des Harntrakts. Vorkommen, Diagnostik und Therapie in Deutschland.

As urinary tract obstruction in children may impair renal function, the early detection and evaluation of the degree of obstruction using adequate diagnostic tools is necessary for the choice of the optimal therapeutic procedure. This study describes diagnostic and therapeutic standards in relation to the quality of management of pediatric hydronephrosis in Germany in the first 6 months of the year 2000. In our study 407 of 711 (57.2%) children with a hydronephrotic condition were detected by routine ultrasound. This, and the fact that 25% of the patients, who were prenatally detected, had a diagnosis of vesicoureteral reflux, underlines the importance of this routine procedure. Our study illustrates the panel of diagnostic and therapeutic procedures used in the management of pediatric hydronephrosis in Germany.

Efficacy and tolerability of interleukin-2 receptor blockade with basiliximab in pediatric renal transplant recipients.

Rejection remains a major threat in pediatric renal transplantation (Tx), causing graft failure and increased exposure to drugs. The new chimeric antibody, basiliximab, directed against the alpha-chain of the interleukin-2 receptor (IL-2R), has been shown to be effective in preventing rejection episodes in adult renal transplant recipients. In our single-center experience from Essen, Germany, we evaluated prospectively the efficacy and tolerability of basiliximab, in combination with cyclosporin A (CsA) and prednisone, in 38 unselected pediatric patients. Mean patient age at Tx was 10.1 yr. Twenty-eight children received a cadaveric organ and 10 children received living-related donor grafts. The 1-yr patient survival rate was 100% and the 1-yr graft survival rate was 95% (36/38 patients). No graft was lost as a result of immunological factors, and single rejection episodes were observed in eight patients (21%). Two of these rejections were steroid-resistant and responded to tacrolimus rescue therapy. The rate of infections was not enhanced; overt cytomegalovirus (CMV) disease was observed in two patients only. Malignancies have not been seen to date. The blockade of the alpha-chain of the IL-2R lasted for up to 6 weeks. We conclude that the addition of basiliximab to standard immunosuppression in pediatric renal transplant recipients is well tolerated and results in a low incidence of rejection. The simple mode of application and the lack of side-effects make basiliximab an especially useful adjunct in pediatric patients.

Kidney transplanted children come of age.

BACKGROUND: The aim of renal replacement therapy in children is to restore their potential for normal growth and development in order to reach mature adulthood. Because pediatric kidney transplantation started in the late 1960s, it is now possible to document the progress and outcome of these patients from transplantation in childhood to survival into adulthood. METHODS: In this single-center study, all 150 children born before December 1977 and having received a kidney transplant between 1970 and 1993 were selected for long-term follow-up. The mean age at transplantation was 12.1 years (range 3.2 to 16.7), and the mean follow-up was 13.1 years (range 2.0 to 25.0). In December 1995, 124 grown-up patients with a mean age of 25.4 years (range 18.4 to 40.3) were alive, 89 with a functioning graft. Fifty had the first graft functioning longer than 10 years. The fate of all patients was traced, and those living were analyzed in regard to their somatic and socioeconomic states. RESULTS: The actuarial 25-year survival rate for the patients was 81%, and for the first graft it was 31%. The best graft survival rates were observed after living related donation, preemptive transplantation, and immunosuppression with cyclosporine. The latter benefit, however, vanished after eight years. The mean creatinine clearance declined over the years from 76 to 45 ml/min/1.73 m2, and the incidence of hypertension increased to more than 80% of the patients. Malignancies occurred in 2.6%. Final height was stunted in 44% of noncystinotic patients, whereas all patients with cystinosis were extremely growth retarded. Twenty-seven percent suffered from additional disabilities. A majority of adult patients were rehabilitated in regard to education and socioeconomic status, and 14% were unemployed. CONCLUSIONS: The results indicate that renal transplantation in children leads to a high degree of rehabilitation in adulthood. The life of a kidney transplant, however, is limited, which points out the need for more specific immunosuppression with fewer side-effects in order to reach the goal of lifelong graft function.

End-stage renal failure in children younger than 6 years: renal transplantation is the therapy of choice.

UNLABELLED: Between 1975 and 1994, 46 children under 6 years of age received a total of 52 renal transplants. Obstructive uropathy and dysplasia accounted for most causes of terminal renal failure (17 and 12 cases respectively). Four patients required a second, 1 patient a third transplantation. Cadaveric organs were used on 33 occasions; 19 patients received a living-related donor kidney. Immunosuppression was performed with azathioprine in 5, with cyclosporine A in 21 and combined azathioprine/cyclosporine therapy in 20 cases. After 1 year, graft survival was 81%, and after 5 years 78%. Creatinine clearance declined slightly between 1 and 5 years from 69 to 56 ml/min per 1.73 m2. Main causes of graft failure were thrombotic complications in 6 cases and death with functioning graft in 5 cases. Graft thrombosis occurred only in grafts from young donors under the age of 7 years and after vascular anastomosis to the iliac vessels. Only two transplants were lost in rejection episodes. Patient survival was 94% after 1 and 90% after 5 years. Two patients died due to septiacemia, 1 died of a ruptured aortic aneurysm, 1 of cerebral ischaemia and 1 suddenly of unknown cause. Patient and graft survival was not different compared with 204 patients aged 6-16 years who received a renal transplantation during the same time period at our institution. After transplantation the patients receiving cyclosporine A showed a marked catch-up growth in the 1st year. The median standard deviation score (SDS) of body length improved from -2.63 to -1.39 standard deviations. CONCLUSION: Renal transplantation is the treatment of choice in end-stage renal failure in children under 6 years.

Ectopic neural tissue as an unusual cause of a retroperitoneal tumor.

In a 3-year-old boy an abdominal mass was palpated by chance, which consisted of cystic and solid structures and was shown on ultrasound scan and computed tomography to be located retroperitoneally. Intraoperatively, the cystic tumor contained clear, yellowish fluid and had a stalk leading to the interspinal space between L2 and L3. However, no signs of dysraphism, were found. Neuropathologic examination surprisingly showed non-neoplastic ectopic neural tissue, which has never been recorded at this extraspinal site before.

Steroid resistant nephrotic syndrome associated with spondyloepiphyseal dysplasia, transient ischemic attacks and lymphopenia.

Focal segmental glomerulosclerosis, nephrotic syndrome and chronic renal failure were associated with spondyloepiphyseal dysplasia, growth failure, lymphopenia and transient ischemic attacks leading to severe neurological symptoms in three children. Two boys and one girl developed the full syndrome at the age of 5, 6 and 10 years. Positron emission tomography revealed perfusion defects of both cerebral and cerebellar arteries. A variant of the disease was found in two other children who had a nephrotic syndrome and terminal renal failure with only mild spondyloepiphyseal dysplasia, impaired growth and a normal cerebral function. It is concluded that there may be a close association between focal segmental glomerulosclerosis and spondyloepiphyseal dysplasias.

Cerebral ultrasonography before and after cardiac surgery in infants.

Cerebral ultrasonography was performed in 66 infants before and after open heart surgery in order to study the incidence of cerebral complications. The underlying cardiac malformations were ventricular septal defect (n = 28), transposition of the great arteries (n = 11), tetralogy of Fallot (n = 8), complete atrioventricular septal defect (n = 5), total anomalous pulmonary venous drainage (n = 3), truncus arteriosus communis (n = 2), and complex cardiac malformations (n = 9). In 60 of the 66 infants ultrasonography of the brain preoperatively was normal, 3 had minor structural abnormalities, and 3 had ventriculomegaly of various degrees. Postoperatively, 46 infants had a normal brain ultrasound scan; 6 had slight structural abnormalities; and 5 had slight symmetric or asymmetric widening of the ventricles. Five infants showed severe ventriculomegaly with cerebral atrophy, and in 4 patients there was intracerebral hemorrhage, associated in 2 cases with severe ventriculomegaly. On repeat examinations it was found that up to 4 weeks after the operation an initially normal cerebral ultrasound scan could convert to a pathologic one. Most of those children who showed significant deterioration on the cerebral ultrasound scan suffered from complex cardiac malformations or had severe problems during the postoperative period.

[Spontaneous regression of neonatal ovarian cysts. A prospective study]. / Spontane Regression von neonatalen Ovarialzysten. Eine prospektive Studie.

With routine use of ultrasonography in pregnancy and newborns neonatal ovarian cysts are discovered more often. In view of the risk of possible complications they still pose a therapeutic problem. Frequent observations of their spontaneous regression suggest a conservative treatment. From 1988 to 1991 we investigated 21 newborns with the sonographic diagnosis of an ovarian cyst. In three children the cysts were resected primarily because of clinical symptoms or uncertain diagnosis. 18 children were controlled regularly by ultrasound. One of these had a mesenteric cyst, which had to be removed at the age of four months. In the others a complete resolution of all 19 ovarian cysts could be documented after intervals of up to 16 months. In these patients a clinically relevant complication did not occur. Therefore a conservative strategy with regular ultrasound controls is justified in all children with uncomplicated neonatal ovarian cysts. A surgical intervention is indicated only in case of complications or uncertain diagnosis.

Paediatric aspects of renal transplantation: experience of a single centre.

From 1970 to 1991 a total of 244 renal transplantations were performed in 203 children at the Medical School in Hannover. The mean patient age was 10.4 years with a range between 11 months and 16.9 years. Fifty-nine children received a living donor graft from one parent and 144 received cadaveric grafts. Forty-two children were transplanted without prior dialysis treatment. After 20 years the overall survival rates were 86% for the patients and 39% for the first grafts. Grafts from donors below 5 years of age had a less favourable survival (44% after 5 years). Pre-emptive transplantation yielded comparable results with the benefit of a shorter period of uraemia. Hypertension developed in 80% of transplanted patients. Only children with living related donor grafts had significantly less hypertensive problems independent of the immunosuppressive regimen. Post-transplantational growth improved under cyclosporin. Children with nephropathic cystinosis also showed catch up growth after transplantation under cyclosporin. The long-term outcome and rehabilitation of grown-up recipients were encouraging.

Renal transplantation in 22 children with nephropathic cystinosis.

In 1989, 22 children (11 boys, 11 girls aged 8-23 years) with nephropathic cystinosis, who had received a total of 28 renal allografts over the previous 14 years, were reviewed. Nineteen were alive, of whom 17 had functioning grafts 5 months to 13 years after transplantation. The mean serum creatinine level in these 17 was 135 mumol/l. Patient and graft survival did not differ from non-cystinotic children. Persistent hypothyroidism was found in 3 patients, transient diabetes mellitus in 1, severely disturbed vision in 1 and brain atrophy in 11. Arterial hypertension was present in 16 patients. Growth retardation was universal, although in 4 patients on cyclosporin A post-transplant catch-up growth occurred. Five patients over 15 years completed puberty. Readjustment in terms of school performance was good but was less good for psychosocial development. None of the patients had ever been treated with cystine-depleting agents; the data will therefore provide a historical control group with which to compare the results from a group treated with these agents.

[Multicystic kidney dysplasia]. / Die multizystische Nierendysplasie.

The clinical course of 48 children (27 boys and 21 girls) with multicystic kidney dysplasia was analysed retrospectively. The patients were seen and treated at the Children's Hospital of Medical School Hannover between 1976 to 1989. There was no familial occurrence of the disease, yet in eight families various other renal diseases could be observed. In 20 patients the diagnosis of multicystic renal dysplasia was presumed by prenatal sonographic examination, in the other patients the diagnosis was established at the age between 1 day to 12 years. The first manifestations were palpable abdominal mass (n = 16), urinary tract infection (n = 4), casually because of a sonographic evaluation for other reasons (n = 4) and vomiting (n = 2). Associated malformations were found in 18 patients: cardiac malformations (n = 6), dysplasia of the other kidney (n = 5), ureter obstruction of the other kidney (n = 3), horseshoe kidney (n = 1) and others (n = 3). There was no hypertension and serum creatinine levels were normal in those children, who did not suffer from associated malformations of the other kidney. The multicystic kidney was removed operatively in 42 patients at the age of 3 days to 9.5 years (median 4 weeks). The prognosis of multicystic kidney dysplasia depends on associated renal and other malformations.

Association of spondylo-epiphyseal dysplasia with nephrotic syndrome.

The association of a spondylo-epiphyseal dysplasia and growth failure with the nephrotic syndrome was found in three boys. Renal biopsy performed on two revealed focal and segmental glomerulosclerosis. The nephrotic syndrome occurred at the age of 3-7 years, leading to end-stage renal failure in all patients. Growth failure persisted after successful renal transplantation. This association may represent a distinct disease entity.

[Cystic kidneys in children]. / Zystennieren im Kindesalter.

From 1976-1987 a total of 26 infants and children with polycystic kidney disease were treated at the Children's Hospital of the Medical School Hannover. 13 of them suffered from infantile recessive polycystic kidney disease (IRPKD), and 13 from adult dominant polycystic kidney disease (ADPKD). IRPKD was diagnosed at a median age of 0.33 years (range 1 day-13 years), ADPKD at 6.0 years (3 days-14 years). Of those with IRPKD two infants died from bacterial infection and two others developed terminal renal insufficiency at the age of 8 years, while the others are living and 1-20 years old. All those suffer from severe arterial hypertension and have reduced renal function, but only 5 developed signs of liver fibrosis. Of those with ADPKD one infant died from sepsis and renal insufficiency, while the others are well and now 2-17 years old. Only one child needs an antihypertensive treatment. The most important criteria to differentiate IRKPD and ADKPD in children are the genetic transmission, age of first manifestation, hypertension and renal function. The prognosis is much more severe in IRPKD than in ADPKD, but is not as infaust in IRPKD as often assumed.