Michael van Husen

New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome

Although many children with idiopathic nephrotic syndrome (INS) respond initially to steroid therapy, repeated courses for patients with relapses often cause significant steroid toxicity. Patients with frequent relapses who develop steroid dependency thus require alternative treatment. The first such options have been considered to be cyclophosphamide or levamisole, although the latter is no longer available in many countries. There is also an increasing body of data indicating that mycophenolic acid (MPA) may be an alternative for these patients. Calcineurin inhibitors (cyclosporine A or tacrolimus) are usually effective and often used after cytotoxic treatment, but long-term treatment with these agents is necessary, raising concerns of a possible accumulation of side effects. Some patients show a tendency to relapse even on such maintenance regimens, and some even have a refractory course that creates a medical dilemma. For this situation, recent data indicate that monoclonal antibodies directed to B-cells (e.g. rituximab) may have some effect and that such drugs may also prove to be a therapeutic option in less complicated cases. Patients that do not respond to steroid treatment need genetic testing and a renal biopsy since focal segmental glomerulosclerosis (FSGS) may be present. Treatment options include pulse methylprednisolone, often in addition to calcineurin inhibitors, mainly in the form of cyclosporine, but tacrolimus has also come into recent favor. Some studies have found cytotoxic treatment, especially intravenous cyclophosphamide, to be effective in steroid resistant nephrotic syndrome, but it seems to be inferior to calcineurin inhibitors. MPA and rituximab have also been used in children with primary FSGS, but the response seems to be inferior to that in patients with steroid sensitive nephrotic syndrome. Taken together, INS in both steroid-sensitive and steroid-resistant patients is a potentially complicated disorder, and despite a wide arsenal of immunological interventions, some patients have a treatment refractory course. Prospective studies or at least standardized treatment for complicated cases is urgently needed.

Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

BACKGROUND AND OBJECTIVES This study evaluated the relevance of complement factor H (CFH)-related protein (CFHR) 1 deficiency in pediatric patients with atypical hemolytic uremic syndrome (aHUS) by evaluating both the frequency of deletions in CFHR1 and the presence of complement factor H (CFH) antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 116 patients (mainly from central Europe) and 118 healthy blood donors were included from 2001 to 2012. The presence of CFHR1 gene deletions was determined in 90 pediatric patients with aHUS and 118 controls by an easy, fast, and cheap PCR assay; 100 patients with aHUS and 42 controls were tested for CFH antibodies by ELISA. Questionnaires were administered to evaluate the clinical and laboratory data. RESULTS Homozygous deletion in CFHR1 was detected in 32% of the patients with aHUS tested, compared with 2.5% of controls (P<0.001). CFH antibodies were present in 25% of the patients and none of the controls. CFH antibodies were detected in 82% of patients with homozygous CFHR1 gene deletion and in 6% of patients without. CFH antibody-positive patients with aHUS showed a significantly lower platelet nadir at disease onset and significantly less frequent involvement of the central nervous system than did antibody-negative patients. Antibody-positive patients also received plasma therapy more often. CONCLUSION Homozygous deletion in CFHR1 is strongly associated with occurrence of CFH antibodies in pediatric patients with aHUS. However, despite this apparent genetic disease predisposition, it cannot be considered an exclusive cause for aHUS. Initial presentation of Shiga toxin-negative HUS with severe thrombocytopenia and no central nervous system complications in pediatric patients is especially suspicious for CFH antibody aHUS.

Fibroblast growth factor 23 and bone metabolism in children with chronic kidney disease

Fibroblast growth factor 23 (FGF23) is a circulating protein that regulates the renal reabsorption of phosphate and also inhibits 1-alpha-hydroxylase production. In adults FGF23 is increased in chronic kidney disease (CKD) and is an important prognostic factor for cardiovascular morbidity. In order to gain insight into the role of FGF23 and other biochemical variables of bone metabolism in children we studied 69 patients at different stages of CKD. FGF23 was found to be significantly elevated in stage 3 compared with stages 1 and 2 of CKD, preceding significant hyperphosphatemia in stage 4 disease. The highest levels of FGF23 were found in stage 5 compared with stages 1 and 2 CKD. The levels of FGF23 positively correlated with parathyroid hormone and phosphate concentrations and negatively with 1,25-dihydroxyvitamin D, the estimated glomerular filtration rate, and tubular phosphate reabsorption. Using multivariate analysis, hyperphosphatemia and low estimated glomerular filtration rate remained the most significant factors. Thus we found that FGF23 likely has an important role in pediatric calcium and phosphate homeostasis, and in vitamin D metabolism, even at an early stage of CKD. Further studies are needed to clarify the role of FGF23 on the pathogenesis of renal osteodystrophy and its impact on cardiovascular morbidity in pediatric patients with CKD.

Immediate postoperative intensive care treatment of pediatric combined liver-kidney transplantation: outcome and prognostic factors.

Background. Studies reporting the immediate pediatric intensive care unit (PICU) treatment after combined liver-kidney transplantation (CLKT) are scarce, although this period is pivotal for survival and long-term outcome. Methods. We retrospectively analyzed all pediatric CLKT performed in our center between 1998 and 2010. Results. Sixteen patients underwent 17 CLKT at a median age of 5.3 years (range, 1.3–15.9 years). Median body weight at CLKT was 17.7 kg (range, 9.2–55 kg). Underlying diagnosis was primary hyperoxaluria type 1 in nine patients and autosomal recessive polycystic kidney disease in seven patients. Median time on PICU was 8.5 days (range, 3–68 days); however, patients with primary hyperoxaluria type 1 had a significantly longer stay (P=0.031). Median duration of ventilation was 1 day; however, five patients required ventilation for 25 to 52 days. Continuous veno-venous hemofiltration was applied in nine patients due to delayed kidney graft function, volume overload, or high plasma oxalate. Overall, the survival rate after CLKT was 100% and long-term outcome was very good at a mean follow-up of 3.6 years (range, 0.5–12.2 years). Waiting time, donor age, and donor-to-recipient weight ratio were found to be significant risk factors for an extended PICU stay (P=0.02, 0.0031, and 0.014, respectively). Conclusions. Immediate postoperative course after CLKT may be challenging and complex. However, excellent results can be achieved, even in small children.

Elevated serum levels of B-cell activating factor in pediatric renal transplant patients

BackgroundB-cells are increasingly recognized as important players in alloimmunity. B cell-activating factor (BAFF) and its receptor BAFF-R are essential for B-cell differentiation and survival. Data on BAFF levels in pediatric renal transplant (RT) patients are scarce.ObjectiveIt is known from adult data that elevated BAFF levels correlate with an unfavorable outcome in bone marrow and kidney recipients. To analyze this hypothesis in pediatric renal transplant patients we performed a cross-sectional analysis of serum BAFF levels, lymphocyte surface BAFF-R expression, and clinical variables in a cohort of 43 pediatric renal transplant patients.MethodsWe studied serum BAFF, CD19+ B-, and FoxP3+ regulatory T-cells (Tregs) and BAFF-R expression in 43 children 2.9 (0.1–12.4) years after RT on maintenance immunosuppression. Twenty-two healthy children and 19 children with chronic kidney disease stage 5 (CKD5) served as controls.ResultsBAFF levels were significantly higher in RT patients than in healthy children (1,435±574 vs 894±189 pg/mL; p<0.0001) whereas numbers of B-cells and Tregs were significantly lower. BAFF-R expression on B-cells was decreased after RT (531±334 vs 707±257 MFI; p<0.005), BAFF inversely correlated with BAFF-R (r=-0.5022, p<0.006), but not with B-cell count. BAFF was elevated in CKD5 patients (1,276±294 pg/mL). In RT patients BAFF was significantly higher in those with eGFR <60 ml/min/1.73m2 (1,553±447 vs 1,234±323 pg/mL; p=0.02). BAFF levels and BAFF-R expression did not correlate with HLA antibody status, time after transplantation, age or gender of the patients.ConclusionSerum BAFF concentrations were significantly elevated in pediatric RT patients. They correlated with decreased BAFF-R expression on CD19+ B-cells and impaired allograft function. Our findings of a dysregulated BAFF/BAFF-R axis may be of clinical relevance after renal transplantation and therefore underline the importance of further research into BAFF-dependent mechanisms.

High prevalence of renal dysfunction in children after liver transplantation: non-invasive diagnosis using a cystatin C-based equation

BACKGROUND Chronic kidney disease (CKD) has been increasingly shown to be a negative prognostic factor after liver transplantation (Ltx). Creatinine-based glomerular filtration rate (GFR) formulas are notoriously insensitive. In children, non-invasive determination of GFR by measurement of serum cystatin C is feasible and repeatedly correlated to the gold standards of GFR measurements. The aim of our study was to determine GFR using cystatin C (GFR(cys)) in comparison with conventional calculated creatinine clearance (GFR(crea)) in the long-term follow-up after paediatric liver transplantation (pLtx) in a large number of patients. METHODS GFR of 168 children following liver transplantation was determined using cystatin C (GFR(cys)) and the Schwartz formula (GFR(crea)). In order to evaluate risk factors for CKD, a logistic regression analysis was performed. A multivariate model was applied to assess the impact of immunosuppressive treatment. RESULTS The mean follow-up after transplantation was 7.8 (0.44-15.72) years. Due to a high overestimation of GFR as demonstrated in a Bland-Altman plot, only three patients with CKD stages 2-3 were detected with GFR(crea) compared with 34 with GFR(cys) (P < 0.001). Thus, prevalence of CKD with GFR((cys)) < 90 mL/min/1.73 m2; was 30.4%, 7.6% and 27% in patients with 5, 10 and > 10 years of follow-up, respectively. Patients on cyclosporine had a significantly lower GFR than patients on tacrolimus. Logistic regression analysis did not show any significant risk factor for the development of CKD. CONCLUSIONS The cystatin C equation is a non-invasive and sensitive diagnostic tool to detect renal dysfunction in children after Ltx at an early stage. The choice of first-line calcineurin inhibitor has an important impact on the development of CKD.

Difficult-to-treat idiopathic nephrotic syndrome: established drugs, open questions and future options

The idiopathic nephrotic syndrome in childhood can be classified according to the International Study of Kidney Disease in Children (ISKDC) based on the response to steroids. Typically, steroid-sensitive nephrotic syndrome (SSNS) is characterised by minimal changes in disease (MCD) histology, whereas in steroid-resistant nephrotic syndrome (SRNS) focal segmental glomerulosclerosis (FSGS) is the most prevalent lesion. Patients with SSNS may develop frequent relapses and/or steroid dependency, which can be difficult to treat. New studies confirm the value of calcineurin inhibitors (CNIs) and mycophenolic acid in preventing relapses of SSNS. Rituximab also plays an important role, but many questions regarding initial dosing, repetitions of courses, and long-term side effects remain unclear. SRNS, especially when unresponsive to treatment, can lead to chronic kidney disease. In particular, treatment with CNIs has improved the prognosis and recent data indicate that treatment can even be discontinued in many patients with full remission. In CNI-unresponsive SRNS, rituximab is less effective than in SSNS and the role of other biologicals (such as ofatumumab, abatacept, and others) remains unclear. A significant proportion of children with FSGS have genetic causes and most patients do not respond to immunosuppression, although individual patients with partial and even complete response have been documented. Future studies should evaluate treatments leading to long-term remission without maintenance immunosuppression in SSNS; in both genetic and immune-mediated SRNS, novel options to decrease the number of treatment-unresponsive patients seem mandatory, as they are at a high risk of developing end-stage renal disease.

Fibroblast growth factor 23 and calcium phosphate homeostasis after pediatric renal transplantation

van Husen M, Lehnhardt A, Fischer A‐K, Brinkert F, Loos S, Oh J, Kemper MJ. Fibroblast growth factor 23 and calcium phosphate homeostasis after pediatric renal transplantation.