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.

Response to cyclosporine in steroid-resistant nephrotic syndrome: discontinuation is possible.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is still regarded as a serious disease although treatment with cyclosporine (CSA) has improved outcome. However, the duration of treatment in responders is unclear, and treatment of patients with genetic causes is a matter of debate. METHODS: Thirty-six patients with SRNS were studied retrospectively. Median age at presentation was 3.2 (range, 0.06-15.0) and median follow-up 15.5 years (range, 1.8-27.7), respectively; 23 (64%) had focal segmental glomerulosclerosis (FSGS) on biopsy. In 33/36 patients (92%), genetic testing was performed for at least three most common genes known to be mutated in SRNS. RESULTS: Nineteen patients (53%), especially those with minimal change nephrotic syndrome (MCNS) at initial biopsy (p < 0.002), entered complete remission with CSA monotherapy, including one patient with compound heterozygous NPHS1 and dominant ACTN4 mutation, respectively. Ten patients entered partial remission (28%, all FSGS), including two with NPHS2 mutations. Seven patients (six FSGS, one MCNS) did not respond to treatment. In 15 of 19 responders to CSA, treatment was stopped after a median of 3.1 years (range, 0.5-14) and no further relapses occurred in 11/15 (73%) patients with median follow-up of 9.7 years. CONCLUSIONS: CSA monotherapy is effective in SRNS. Discontinuation of CSA is possible in many patients with complete remission.

Renal osteodystrophy in children: pathogenesis, diagnosis and treatment.

PURPOSE OF REVIEW: Disturbances in calcium-phosphate homeostasis play an important role in children with chronic kidney disease, and not only cause renal osteodystrophy but also result in increased cardiovascular morbidity and mortality. This review outlines the current aspects in the pathogenesis, diagnostic approach and treatment of renal osteodystrophy. RECENT FINDINGS: The pathogenesis of renal osteodystrophy is under strong influence of the fibroblast growth factor 23/Klotho system, which is able to enhance phosphate excretion and reduce calcitriol synthesis in the kidney. Fibroblast growth factor 23 increases tissue calcinosis and is cardiotoxic, and is independently associated with mortality. Despite improvement in diagnostic imaging (bone density measurements), determination of biomarkers, mainly parathyroid hormone, still plays a central role. New treatment options resulted in improved bone health and also a reduction in mortality was achieved in adults with calcium-free phosphate binders. Substitution of active and inactive vitamin D is important and also has a beneficial effect on proteinuria. SUMMARY: Knowledge about the biochemical and molecular mechanisms of renal osteodystrophy is increasing dramatically and has an impact not only to bone health but also overall morbidity and mortality. This will ultimately translate into further improved diagnostic approaches and novel treatment options.

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 calcium phosphate homeostasis after pediatric renal transplantation.

FGF23 is a circulating factor regulating TPR and is increased in CKD. After RT, it seems to induce phosphorus wasting in adults. Data on FGF23 after PRT are scarce. Parameters of bone metabolism including calcium, phosphate, 25-(OH) vitamin D, 1,25-(OH)(2) vitamin D, alkaline phosphatase, PTH, and FGF23 were analyzed in 57 children after PRT and 11 controls. Median time after PRT was 25.9 (range 2-135) months. eGFR after PRT ranged from 15 to 175 mL/min/1.73 qm. Mean (±s.e.) FGF23 and PTH levels were significantly elevated compared with controls (146 ± 30 vs. 43 ± 3 ng/L, p = 0.001 and 182 ± 42 vs. 74 ± 18 ng/L, p = 0.004, respectively). Highest FGF23 levels were found in children with an eGFR below 60 mL/min*1.73 sqm (280 ± 69 vs. 62 ± 5 ng/L, p = 0.001), but significantly elevated values were already present in CKD2T. In a multivariate analysis, eGFR, PTH, calcium, and phosphate were significantly associated with FGF23. In a subgroup of 17 patients (29.8%) with persistent hypophosphatemia, phosphate levels were significantly associated with FGF23 and not with PTH. FGF23 is increased in children after PRT, especially in patients with chronic allograft dysfunction, and seems to be a more sensitive marker of dysregulated calcium phosphate homeostasis than PTH.

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

BACKGROUND: B-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. OBJECTIVE: It 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. METHODS: We 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. RESULTS: BAFF 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/1.73m(2) (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. CONCLUSION: Serum 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.

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.

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.

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.

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.

Outcome in preterm small for gestational age infants compared to appropriate for gestational age preterms at the age of 2 years: a prospective study.

OBJECTIVES: To investigate the effects of small for gestational age (SGA) in preterm infants on growth and development until the age of 22 months. STUDY DESIGN: Seventy-four preterm infants being born SGA (birth weight <10th percentile) were compared with 74 appropriate for gestational age (AGA) infants matched prospectively according to gestational age with respect to growth parameters and neurodevelopment (using Griffiths developmental scores) at the age of 22 months corrected age. RESULTS: Birth weight was significantly lower in SGA-infants compared to AGA-infants (1503 g (430-2205 g) versus 1995 g (680-3300 g); P<0.0001 (median and range)). There were no significant differences regarding the median gestational age (34 weeks), gender distribution, mode of delivery, umbilical artery pH, and APGAR-scores. Mean Griffiths-scores did not differ significantly between both groups (96.7% versus 97.6%). Developmental retardation was diagnosed in 9 SGA-infants versus 10 AGA-infants. Within the total group a positive correlation was observed between gestational age and developmental scoring. Body weight, head circumference, and height were significantly lower in SGA-infants at 22 months corrected age. CONCLUSION: No significant differences regarding neurodevelopmental outcome at 22 months were observed between SGA- and AGA-infants. SGA-infants did not show catch-up growth.