Repetitive administration of rituximab can achieve and maintain clinical remission in patients with MCD or FSGS.

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are glomerulopathies associated with nephrotic syndrome. Primary forms of these diseases are treated with various regimes of immunosuppression. Frequently relapsing or glucocorticoid-dependent courses remain challenging. Here, a B-cell-depleting strategy with rituximab represents a salvage option although data are sparse in the adult population. In particular, there is limited evidence on the efficacy of restoring remission after initial successful treatment with rituximab and whether patients benefit from an individualized, relapse-based approach. We identified 13 patients who received multiple therapies with rituximab from the FOrMe-registry (NCT03949972), a nationwide registry for MCD and FSGS in Germany, or from the University Hospital of Cologne. Disease status, changes in serum creatinine, proteinuria, and time to relapse were evaluated. Relapse-free survival was compared to the patients' previous therapy regimens. Through all treatment cycles, an improvement of disease activity was shown leading to a complete remission in 72% and partial remission in 26% after 3 ([Formula: see text]0.001) and 6 months ([Formula: see text]0.001). Relapse-free survival increased from 4.5 months (95%-CI 3-10 months) to 21 months (95%-CI 16-32 months) ([Formula: see text]0.001) compared to previous immunosuppression regimens with no loss in estimated glomerular filtration over time (p = 0.53). Compared to continuous B-cell depletion, an individualized relapse-based approach led to a reduced rituximab exposure and significant cost savings. Relapse-based administration of rituximab in patients with MCD/FSGS with an initial good clinical response did not result in a decreased efficacy at a median follow-up duration of 110 months. Thus, reinduction therapies may provide an alternative to continuous B-cell-depletion and reduce the long-term side effects of continuous immunosuppression.

A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.

While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

Prevalence and potential relevance of hyperuricemia in pediatric kidney transplant recipients-a CERTAIN registry analysis.

BACKGROUND: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients. METHODS: This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26. RESULTS: One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented. CONCLUSION: This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated.

The impact of a needs-oriented dental prophylaxis program on bacteremia after toothbrushing and systemic inflammation in children, adolescents, and young adults with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) still leads to high mortality rates, mainly due to cardiovascular disease. One important influencing factor is persisting low-grade chronic inflammation partly maintained by gingivitis that favors transient bacteremia during daily activities such as toothbrushing. METHODS: To examine whether intensive dental prophylaxis can restore oral health, reduce the prevalence of bacteremia and degree of systemic inflammation indicated by CRP levels, we conducted this pilot study examining 30 CKD patients aged 6-26 years, 15 receiving intensive prophylaxis (IP), 15 receiving treatment as usual (TAU) serving as control group. There were three appointments for examination, each 10 ± 1 weeks apart (at baseline, after intervention periods one and two, when TAU also received IP, and the IP group stopped prophylaxis). RESULTS: The gingival index (GI) in the IP group decreased by 90% (GI 0.09; p=0.001), resulting in almost healthy gingiva. There was no significant change in CRP or prevalence of bacteremia. General prevalence of bacteremia after toothbrushing was 9.5% affecting 7 (26%) of the participants. In three participants, bacteremia dissolved after IP, in one after TAU. Two patients developed bacteremia ≥ 10 weeks after ending IP. We identified eight different bacterial species. CONCLUSIONS: We were able to show that IP can effectively treat gingivitis. It might be a promising approach to reduce systemic inflammation and subsequently lower premature cardiovascular disease, despite the lack of statistical significance. Future research requires a larger patient cohort to enable matched treatment groups with long-term follow-up and molecular detection methods for bacteremia. A higher resolution version of the Graphical abstract is available as Supplementary information.

The role of the immune system in idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.

Pediatric idiopathic steroid-sensitive nephrotic syndrome: diagnosis and therapy -short version of the updated German best practice guideline (S2e) - AWMF register no. 166-001, 6/2020.

Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts of the world. Children with steroid-sensitive nephrotic syndrome (SSNS) generally have a good prognosis regarding the maintenance of normal kidney function even in the case of frequent relapses. The course of SSNS is often complicated by a high rate of relapses and the associated side effects of repeated glucocorticoid (steroid) therapy. The following recommendations for the treatment of SSNS are based on the comprehensive consideration of published evidence by a working group of the German Society for Pediatric Nephrology (GPN) based on the systematic Cochrane reviews on SSNS and the guidelines of the KDIGO working group (Kidney Disease - Improving Global Outcomes).

Therapeutic drug monitoring of mycophenolate mofetil in pediatric patients: novel techniques and current opinion.

Introduction: Mycophenolate mofetil (MMF) is an ester prodrug of the immunosuppressant mycophenolic acid (MPA) and is recommended and widely used for maintenance immunosuppressive therapy in solid organ and stem-cell transplantation as well as in immunological kidney diseases. MPA is a potent, reversible, noncompetitive inhibitor of the inosine monophosphate dehydrogenase (IMPDH), a crucial enzyme in the de novo purine synthesis in T- and B-lymphocytes, thereby inhibiting cell-mediated immunity and antibody formation. The use of therapeutic drug monitoring (TDM) of MMF is still controversial as outcome data of clinical trials are equivocal. Areas covered: This review covers in great depth the existing literature on TDM of MMF in the field of pediatric (kidney) transplantation. In addition, the relevance of TDM in immunological kidney diseases, in particular childhood nephrotic syndrome is highlighted. Expert opinion: TDM of MMF has the potential to optimize therapy in pediatric transplantation as well as in nephrotic syndrome. Limited sampling strategies to estimate MPA exposure increase its feasibility. Future perspectives rather encompass approaches reflecting total immunosuppressive load than single drug TDM.

Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.

Clinical practice recommendations for recurrence of focal and segmental glomerulosclerosis/steroid-resistant nephrotic syndrome.

Recurrence of primary disease is one of the major risks for allograft loss after pediatric RTx. The risk of recurrence of FSGS/SRNS after pediatric RTx in particular can be up to 86% in idiopathic cases. There is a need for consensus recommendations on its prevention and treatment. The CERTAIN study group has therefore performed a thorough literature search based on the PICO model of clinical questions to formulate educated statements to guide the clinician in the process of decision-making. A set of educated statements on prevention and treatment of FSGS/SRNS after pediatric RTx has been generated after careful evaluation of available evidence and thorough panel discussion. We do not recommend routine nephrectomy prior to transplantation; neither do we recommend abstaining from living donation. Special attendance needs to be given to those patients who had already experienced graft loss due to FSGS/SRNS recurrence. Early PE or IA with or without high-dose CsA and/or rituximab seems to be most promising to induce remission. The educated statements presented here acknowledge that FSGS/SRNS recurrence after pediatric RTx remains a major concern and is associated with shorter graft survival or even graft loss. The value of any recommendation needs to take into account that evidence is based on cohorts that differ in ethnicity, pre-transplant history, immunosuppressive regimen, definition of recurrence (eg, clinical and/or histological diagnosis) and treatment modalities of recurrence.

Long-term data on two sisters with C3GN due to an identical, homozygous CFH mutation and autoantibodies.

C3 glomerulonephritis (C3GN) is a rare but severe form of kidney disease caused by fluid-phase dysregulation of the alternative complement pathway. Causative mutations in complement regulating genes as well as auto-immune forms of C3GN have been described. However, therapy and prognosis in individual patients remain a matter of debate and long-term data are scarce. This also applies for the management of transplant patients as disease recurrence post-transplant is frequent. Here, we depict the clinical courses of two sisters with the unique combination of an identical, homozygous mutation in the complement factor H (CFH) gene as well as autoantibodies with a clinical follow-up of more than 20 years. Interestingly, the sisters presented with discordant clinical courses of C3GN with normal kidney function in one (patient A) and end-stage kidney disease in the other sister (patient B). In patient B, eculizumab was administered immediately prior to and in the course after kidney transplantation, with the result of a stable graft function without any signs of disease recurrence. Comprehensive genetic work-up revealed no further disease-causing mutation in both sisters. Intriguingly, the auto-antibody profile substantially differed in both sisters: autoantibodies in patient A reduced the C3b deposition, while the antibodies identified in patient B increased complement activation and deposition of split products. This study underlines the concept of a personalized-medicine approach in complement-associated diseases after thorough evaluation of the individual risk profile in each patient.

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome.

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.

Peritoneal dialysis in extremely and very low-birth-weight infants.

The outcome of extremely low-birth-weight (ELBW) and very low-birth-weight (VLBW) infants has substantially improved in recent years. As acute kidney injury is frequent in these infants due to various risk factors, there is an increasing demand for renal replacement therapy in these patients. Data on that topic, however, are scarce. We review the available literature on that topic and report our experience on temporary dialysis in three extremely immature infants (two ELBW and one VLBW) with acute kidney failure. Peritoneal dialysis (PD) was performed for 19, 23, and 44 days until recovery of native renal function. At recent follow-up of 18 and 24 months, two patients are in good clinical condition with chronic kidney disease stages 1 and 4, respectively. One patient deceased at the age of 12 months due to secondary liver failure. The dialysis regimen applied in our study differed significantly from older infants with extremely short dwell times and accordingly high numbers of daily cycles. The use of rigid acute PD catheters was associated with less catheter-related complications (leakage, dislocation, and obstruction) as compared to ascites drainage catheters. In summary, PD was technically feasible and effective also in extremely immature infants, but frequent adjustments of dialysis regimens and high numbers of daily cycles posed immense efforts on both, parents and medical staff.

Pharmacodynamic Monitoring of Mycophenolic Acid Therapy: Improved Liquid Chromatography-Tandem Mass Spectrometry Method for Measuring Inosin-5'-Monophosphate Dehydrogenase Activity.

BACKGROUND: Mycophenolic acid (MPA), a powerful inhibitor of lymphocyte proliferation, is widely used in transplantation medicine and as a glucocorticoid-sparing agent in rheumatic and inflammatory diseases. As inosine-5'-monophosphate dehydrogenase (IMPDH), the target enzyme of MPA, shows high interindividual variability in its basal activity, the assessment of IMPDH activity in addition to pharmacokinetic monitoring has emerged as a strategy to individualize MPA pharmacotherapy. METHODS: A liquid chromatography-tandem mass spectrometry method was developed to measure IMPDH activity in peripheral blood mononuclear cells from lithium-heparinized blood. Stable isotope-labeled analogs of analytes were used as internal standards for the quantitative analyses of xanthosine-5'-monophosphate (XMP) and adenosine-5'-monophosphate (AMP). IMPDH activity was expressed as enzymatic production of XMP per time normalized to the AMP concentration. Validation and evaluation of the new method were performed by using blood samples from healthy volunteers (n = 10). RESULTS: Linearity was demonstrated over the concentration ranges of 0.25-80 µM for XMP and 4-80 µM for AMP (R > 0.99). Between-day and within-day assay precisions and accuracies were within the acceptance criterion of ±15%. Matrix effects were fully compensated by the coelution of internal standards. Specific and linear XMP production (R > 0.99) and the inhibition of IMPDH activity by MPA at clinically relevant doses were demonstrated. CONCLUSIONS: In this study, a liquid chromatography-tandem mass spectrometry method to measure IMPDH activity was established and fully evaluated for matrix and ion suppression effects. The method enabled precise quantification of IMPDH activity for the improvement of pharmacokinetic/pharmacodynamic therapeutic drug monitoring approaches to optimize immunosuppressive treatment with MPA.

Generation and Validation of a Limited Sampling Strategy to Monitor Mycophenolic Acid Exposure in Children With Nephrotic Syndrome.

BACKGROUND: Mycophenolate mofetil (MMF) plays an increasingly important role in the treatment of children with nephrotic syndrome, especially in steroid sparing protocols. Recent publications show the relationship of exposure to its active moiety mycophenolic acid (MPA) and clinical efficacy. Performance of full-time pharmacokinetic (PK) profiles, however, is inconvenient and laborious. Established limited sampling strategies (LSS) to estimate the area under the concentration (AUC) versus time curve of MPA (MPA-AUC) in pediatric renal transplant recipients cannot be easily transferred to children suffering from nephrotic syndrome, mainly because of the lack of concomitant immunosuppressive therapy. We therefore aimed for the generation and validation of a LSS to estimate MPA exposure to facilitate therapeutic drug monitoring in children with nephrotic syndrome. METHODS: We performed 27 complete PK profiles in 23 children in remission [mean age (±SD):12.3 ± 4.26 years] to generate and validate an LSS. Sampling time points were before administration (C0) and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after the administration of MMF. MPA was measured by enzyme multiplied immunoassay technique. There was no concomitant treatment with calcineurin inhibitors. RESULTS: Mean daily dose of MMF was 927 ± 209 mg/m of body surface area resulting in a mean MPA-AUC0-12 value of 59.2 ± 29.3 mg × h/L and a predose level of 3.03 ± 2.24 mg/L. Between-patient variability of dose-normalized MPA-AUC0-12 was high (coefficient of variation: 45.5%). Correlation of predose levels with the corresponding MPA-AUC0-12 was moderate (r = 0.59) in a subgroup of 18 patients (20 PK profiles, generation group). An algorithm based on 3 PK sampling time points during the first 2 hours after MMF dosing (estimated AUC0-12 = 8.7 + 4.63 × C0 + 1.90 × C1 + 1.52 × C2) was able to predict MPA-AUC with a low percentage prediction error (3.88%) and a good correlation of determination (r = 0.90). Validation of this algorithm in a randomized separate group of 6 patients (7 PK profiles, validation group) resulted in comparably good correlation (r = 0.95) and low percentage prediction error (5.57%). CONCLUSIONS: An abbreviated profile within the first 2 hours after MMF dosing gives a good estimate of MPA exposure in children with nephrotic syndrome and hence has the potential to optimize MMF therapy.