Anne-Margret Wingen

Immunosuppression and Renal Outcome in Congenital and Pediatric Steroid-Resistant Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA. RESULTS Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%). CONCLUSIONS The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA.

Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism

BACKGROUND Newborns with inborn errors of metabolism often present with hyperammonaemic coma, requiring prompt diagnosis and specific medical therapy, nutritional support and efficient toxin removal. Little information regarding the efficacy and safety of continuous venovenous haemodialysis (CVVHD) as an option for extracorporal ammonia detoxification in children is available. METHODS Twenty-one patients with hyperammonaemia [19 neonates (mean age 4.1 +/- 2.4 days) and two children 1 and 7 years of age, respectively] were admitted to our hospital for dialysis between 1996 and 2008. Seventeen children (15 neonates), received CVVHD. Four neonates received continuous peritoneal dialysis (CPD). All started medical treatment with sodium benzoate, l-arginine hydrochloride and carnitine as well as protein-restricted parenteral diets with high caloric intake before dialysis. RESULTS Plasma ammonia levels (range 464-7267 microg/dl before dialysis and 27-3317 microg/dl after dialysis) were significantly reduced by 50% within 4.7 +/- 2.5 h with CVVHD compared with 13.5 +/- 6.2 h with CPD (P < 0.0001). Plasma ammonia levels <200 microg/dl critical range were achieved within 22.4 +/- 18.1 h in CVVHD patients compared with 35.0 +/- 24.1 h with CPD. Depending on the weight and blood pressure stability of the patients, mean blood flow velocities of 9.8 +/- 3.4 ml/kg/min and mean dialysate flow rates of 3925 +/- 2398 ml/min/1.73 m(2) were employed. Blood and dialysate flows significantly correlated with ammonia clearance and decay of ammonia in vivo. Because of the severe underlying disease, 18% of CVVHD patients died compared with 50% undergoing CPD. In total, 82% of CVVHD patients survived the first 6 months after dialysis. Among these, 43% were without sequelae, 43% developed moderate mental retardation, and two (14%) developed severe mental retardation. CONCLUSION CVVHD effectively and quickly eliminates plasma ammonia. To optimize long-term mental outcome, rapid identification and appropriate treatment of the underlying disease as well as starting dialysis early are of enormous therapeutic value.

Nutrition in children with preterminal chronic renal failure. Myth or important therapeutic aid

Abstract Nutrition has been believed to be an important therapeutic instrument in children with chronic renal failure (i) for improving growth, and (ii) for slowing down the deterioration of renal function. The therapeutic strategies for both targets may be conflicting, at least in part, since a high calorie intake is needed for optimal growth, whereas a low protein diet, which was believed to protect renal function, places patients at risk of low calorie intake. Dietary manipulations for optimal growth are mainly effective in infants with chronic renal failure. However, growth remains suboptimal even with an energy intake above 80% of RDA. Although a low protein diet is able to slow down the rate of deterioration in renal function in rodent studies, the results of prospective clinical studies were disappointing at least for an observation period up to three years. The conclusions out of meta-analyses of these clinical studies in adults are contradictory. The progression rate was not significantly influenced by protein restriction, whereas renal replacement therapy could be postponed. However, the latter seems to be the effect of weakening uremic symptoms during the phase of end-stage renal failure. According to our present knowledge it is not justified to prescribe special diets to children early in the course of chronic renal failure, but the composition of their nutrition should follow the general concept of an optimal mixed diet.

Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients – A single-center experience

Hoerning A, Hegen B, Wingen A‐M, Cetiner M, Lainka E, Kathemann S, Fiedler M, Timm J, Wenzel JJ, Hoyer PF, Gerner P. Prevalence of hepatitis E virus infection in pediatric solid organ transplant recipients – A single‐center experience.

Development of growth and body mass index after pediatric renal transplantation

Abstract:  Suboptimal final height and marked weight gain after renal transplantation (RTx) are common and may result in obesity. Steroid free immunosuppression has been advocated to improve growth and limit weight gain. We evaluated retrospectively the evolution of growth and body mass index (BMI) after renal transplantation to study risk factors for weight gain under steroid based treatment. Sixty‐four pediatric patients (age 9.9 ± 5.0 yr) were included in the study. To allow comparison between different age groups, standard deviation scores (SDS) for height and BMI for height age were calculated at time of transplantation and 3, 6, 9, 12, 24, 36, 48 and 60 months later. Induction immunosuppression consisted of basiliximab, cyclosporine and prednisone. Growth retardation at time of RTx was obvious with a SDS for height of −2.20 ± 1.34. Height during the first year improved to an SDS of −2.0 ± 1.27 (p < 0.01) but did further not increase in year 2 and 3. More than 40% of all patients remained 2 SDS below normal mean. SDS BMI for height age at transplantation was −0.19 ± 0.98 and increased significantly during the first 3 months after transplantation to +0.64 ± 1.07 (p < 0.01). Thereafter, BMI remained stable but did not decline to pretransplant values. A SDS BMI for height age of more than 2 SDS was observed in 2, 6, 9 and 11% of children at RTx and 1, 2 and 3 yr later respectively. BMI gain over 3 yr was significantly enhanced in children whose parents (especially the mother) were overweight. No influence of gender, BMI at RTx, dialysis modality prior to RTx or rejection episodes could be detected. We conclude that after RTx children exhibit some improvement in growth but height remains suboptimal. The BMI does increase significantly during the first months after RTx and does not return to baseline values under steroid‐based immunosuppression. Obesity (>2 SDS above normal) does not occur more often than in the normal population. The most predictive parameter of inappropriate weight gain during 3 yr is the BMI of the mother. We would speculate that steroids may play a major role in weight gain in the early phase after RTx. However, genetic or environmental factors predict the long‐term weight development.

Acute rejection episodes in pediatric renal transplant recipients with cytomegalovirus infection

Abstract:  CMV infection is the most important opportunistic virus infection after renal transplantation leading to increased patient mortality, graft loss, risk for acute rejection episodes and impaired renal function. The potential impact of prophylactic anti‐viral therapy on long‐term graft outcome is relevant. The aim of this study was to evaluate the incidence of CMV infection, its risk factors and long‐term outcome in children after renal transplantation. 103 children (mean age 10.6 ± 5.3, range 1.6–22.0 yr) were monitored weekly for pp65 for the first 6–8 wk after renal transplantation, followed by a monthly monitoring for the first year. CMV infection occurred in 23/103 children (21.1%) with 10 patients (9.7%) developing CMV disease characterized by positive pp65 in the presence of organ involvement. The CMV R−/D+ and R+/D+ serostatus was significantly associated with an increased risk of CMV infection (p < 0.0001 and p = 0.009). 14/28 R−/D+ patients developed CMV infection despite prophylactic treatment with CMV hyperimmune globulin. The incidence of acute rejection episodes after or during CMV infection was significantly increased (p = 0.003) and the D+ serostatus was significantly associated with acute rejection episodes within the first year after transplantation (p = 0.006). In summary the overall incidence of CMV infection in this single center experience is 21.1%. The D+ serostatus represents a serious risk factor for both CMV infection and acute rejection episodes. In future the potential impact of different modalities of prophylactic anti‐viral therapy on the prevention of acute rejection should be considered.

Long-term side effects of treatment with mTOR inhibitors in children after renal transplantation.

BackgroundmTOR inhibitors (mTORI) have emerged as alternative and additive immunosuppressive agents in pediatric renal transplantation (pRTx). Their immunosuppressive, anti-proliferative, and anti-neoplastic mechanisms have been described to be effective, whereas some side effects are alarming. In particular, growth and pubertal development are of concern. The aim of this study was to look for long-term side effects of mTORI therapy in pRTx.Patients and methodsThe retrospective analysis focused on side effects, growth, and pubertal development under mTORI therapy in 31 children. Eighteen children were routinely monitored for estradiol, testosterone, LH, and FSH levels.ResultsThe occurrence of bacterial infections, lymphoceles, myelosuppression, and the course of overall linear growth was comparable with other pediatric renal transplant cohorts. According to the clinical puberty status, all but one patient showed normal age-related development in parallel to normal serum hormone levels. Only one patient experienced cytomegaly virus infection under mTORI, no post-transplant lymphoproliferative disorders (PTLD) occurred.ConclusionsLong-term mTORI therapy is safe in pRTx. No negative impact on growth and pubertal development was observed.

Comprehensive analysis of glomerular mRNA expression of pro- and antithrombotic genes in atypical haemolytic-uremic syndrome (aHUS)

Atypical haemolytic–uremic syndrome (aHUS) is, in most cases, due to hereditary or acquired defects in complement regulation and a life-threatening disease. Despite the rapidly grown knowledge about the primary defects in aHUS, the pathogenesis that links complement dysregulation with microthrombus formation in aHUS is still unknown. Thus, we examined the glomerular microvascular expression of pro- and antithrombotic genes. Glomeruli were microdissected from 12 archival paraffin-embedded biopsies with aHUS and from seven control biopsies. Glomerular mRNA expression was quantified by single real-time PCR reactions after preamplification. In addition immunostains were performed for plasminogen activator inhibitor 1 (PAI-1) and for tissue plasminogen activator (tPA). Results were compared between cases and controls and with clinical data. Glomeruli in aHUS had increased mRNA expression of antifibrinolytic, prothrombotic PAI-1, antithrombotic thrombomodulin (THBD) and CD73 and decreased expression of profibrinolytic, antithrombotic tPA compared to controls. Impaired fibrinolysis due to increased microvascular expression of the antifibrinolytic PAI-1 in combination with the decreased expression of the profibrinolytic tPA seems to be a final common pathway in renal thrombotic microangiopathy that is also effective in aHUS. The concomitant induction of antithrombotic transcripts likely indicates counterregulatory efforts, demonstrating that the capillary bed is not a passive victim of complement attack. Future research should investigate if and how complement activation could induce the reported shift in the expression of PAI-1 and tPA.

Nephrectomy in an autosomal recessive polycystic kidney disease (ARPKD) patient with rapid kidney enlargement and increased expression of EGFR

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary disorder with an incidence of 1/10 000 to 1/40 000 individuals [1,2]. ARPKD is caused by mutations in the PKHD1 gene on chromosome 6p12 [3,4]. Prenatally, oligohydramnion, enlarged kidneys and lung hypoplasia with the typical Potter facies become evident. Principal histological manifestations involve the fusiform dilation of renal collecting ducts and distal tubuli as well as dysgenesis of the hepatic portal triad (so-called ductal plate malformation with congenital hepatic fibrosis and hyperplastic biliary ducts). The spectrum of the disease is highly variable ranging from severe perinatal manifestations to later onset and milder forms. Severe phenotypes are more often associated with truncating PKHD1 changes than moderately affected individuals [5,6]. Especially children with severe renal disease show a high perinatal mortality. Death is often caused by respiratory insufficiency due to lung hypoplasia and displacement of the diaphragm by bilateral renomegaly. The reported incidence of severe respiratory problems, including pneumothoraces and respiratory insufficiency, is up to 75% in patients presenting early with renal failure [7,8] and most of the children with lung hypoplasia die from respiratory insufficiency shortly after birth. Among the neonatal survivors, 30% show fast progression to renal insufficiency [2,8–11]. Another common problem in children with ARPKD, especially at onset, is arterial hypertension with a prevalence of 55–100% [8,9,11]. Volume overload due to poor renal function and hyponatraemia

Hypothyroidism mimicking chronic renal failure in reflux nephropathy

An adolescent with a history of pyelonephritis and renal scarring had antireflux surgery at the age of 2.5 years. His serum creatinine was high at the age of 14 years (133 μmol/l; glomerular filtration rate (GFR) 56 ml/min × 1.73 m2), and reflux nephropathy with chronic renal failure was diagnosed. Because of a fall in height velocity, endocrinological investigations were performed six months later which showed hypothyroidism caused by autoimmune thyroiditis. Substitution with thyroxine was started; renal function improved to normal six months later (GFR 108 ml/min × 1.73 m2). Metabolic changes of hypothyroidism led to a reduction of GFR in this patient and mimicked chronic renal failure.