The integrity of the filtration barrier of the kidney relies on the proper composition of podocyte interdigitating foot processes. Their architecture is supported by a complex actin-cytoskeleton. Following podocyte stress or injury, podocytes encounter structural changes, including rearrangement of the actin network and subsequent effacement of the foot processes. Immunosuppressive drugs, which are currently used as treatment in proteinuric kidney diseases, have been shown to exert not only immune-mediated effects. This review will focus on the direct effects of glucocorticoids, cyclosporine A, tacrolimus, mycophenolate mofetil, and rituximab on podocytes by regulation of Ca2+ ion channels and consecutive downstream signaling which prevent cytoskeletal rearrangements and ultimately proteinuria. In addition, the efficacy of these drugs in genetic nephrotic syndrome will be discussed.

In recent years functional multiphoton (MP) imaging of vital mouse tissues and stimulation emission depletion (STED) imaging of optically cleared tissues allowed new insights into kidney biology. Here, we present a novel workflow where MP imaging of calcium signals can be combined with super-resolved STED imaging for morphological analysis of the slit diaphragm (SD) within the same glomerulus. Mice expressing the calcium indicator GCaMP3 in podocytes served as healthy controls or were challenged with two different doses of nephrotoxic serum (NTS). NTS induced glomerular damage in a dose dependent manner measured by shortening of SD length. In acute kidney slices (AKS) intracellular calcium levels increased upon disease but showed a high variation between glomeruli. We could not find a clear correlation between intracellular calcium levels and SD length in the same glomerulus. Remarkably, analysis of the SD morphology of glomeruli selected during MP calcium imaging revealed a higher percentage of completely disrupted SD architecture than estimated by STED imaging alone. Our novel co-imaging protocol is applicable to a broad range of research questions. It can be used with different tissues and is compatible with diverse reporters and target proteins.

The problem is the chronic relapsing course of the disease in about 80% of patients of which more than half of the cases develop frequent relapses and steroid dependency. This requires repeated therapy with glucocorticoids accompanied by several side effects, or the use of steroid-sparing alternatives and puts the affected families under considerable pressure. A subset of patients even develops multidrug-dependent or multidrug-resistant nephrotic syndrome. International clinical practice recommendations guide the management of such situations (1)Trautmann A. Vivarelli M. Samuel S. et al.IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistantnephrotic syndrome.Pediatr Nephrol. 2020; 35 (https://doi.org/10.1007/s00467-020-04519-1): 1529-1561Crossref PubMed Scopus (0) Google Scholar,2)Trautmann A. Boyer O. Hodson E. et al.IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome.Pediatr Nephrol. 2023; 38 (https://doi.org/10.1007/s00467-022-05739-3): 877-919Crossref PubMed Scopus (49) Google Scholar). However, do we really know what we are doing? Despite countless mechanistic and therapy-optimizing studies, the pathogenesis of nephrotic syndrome in childhood is not only elusive, but also simply not yet understood. It remains to be seen whether the current enthusiastic discussion regarding the role of anti-nephrin antibodies in the development of nephrotic syndrome will turn iNS into an antibody-mediated nephrotic syndrome. The same uncertainty exists with regard to the effectiveness of the drugs used. The most common justification for their use is simply their clinically proven efficacy in the majority of cases. At this point, we realize that the cause of iNS is multifactorial including membrane selectivity, oxidative stress, circulating factors, complement, interleukins, immune cells, antibodies and regulatory immunoglobulins (3)Vincenti F. Angeletti A. Ghiggeri G.M. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs.Front Immunol. 2023; 141167741https://doi.org/10.3389/fimmu.2023.1167741Crossref PubMed Scopus (2) Google Scholar). With that in mind, it does not sound conceivable that one single form of therapy can help all patients. Recently, the chimeric monoclonal anti-CD20 antibody rituximab has gained great attention, especially as rescue therapy in complicated courses of iNS that cannot be controlled by other steroid-sparing agents (2)Trautmann A. Boyer O. Hodson E. et al.IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome.Pediatr Nephrol. 2023; 38 (https://doi.org/10.1007/s00467-022-05739-3): 877-919Crossref PubMed Scopus (49) Google Scholar,4)Chan E.Y. Yap D.Y. Colucci M. et al.Use of Rituximab in Childhood Idiopathic nephrotic Syndrome.Clin J Am Soc Nephrol. 2023; 18 (https://doi: 10.2215/CJN.08570722): 533-548Crossref Scopus (10) Google Scholar). The treatment effect is temporary, and many children require additional courses of rituximab. A series of well-performed studies even propose rituximab as first line steroid-sparing option (5)Liu S. Gui C. Lu Z. et al.The Efficacy and Safety of Rituximab for Childhood Steroid-Dependent Nephrotic Syndrome: A Systematic Review and Meta-Analysis.Front Pediatr. 2021; 9 (https://doi: 10.3389/fped.2021.728010)728010Crossref Scopus (2) Google Scholar). Rituximab depletes all circulating B-cell subsets (but not the bone-marrow resident plasma cells), and B cell recovery is associated with the risk of relapse (4)Chan E.Y. Yap D.Y. Colucci M. et al.Use of Rituximab in Childhood Idiopathic nephrotic Syndrome.Clin J Am Soc Nephrol. 2023; 18 (https://doi: 10.2215/CJN.08570722): 533-548Crossref Scopus (10) Google Scholar). Currently, it is not clear, if newer humanized anti-CD20 antibodies such as ofatumumab or obinutuzumab may have superior efficacy compared to rituximab in children with iNS (6)Basu B. Angeletti A. Islam B. et al.New and old anti-CD20 monoclonal antibodies for nephrotic syndrome. Where we are?.Front Immunol. 2022; 13805697https://doi.org/10.3389/fimmu.2022.805697Crossref Scopus (15) Google Scholar). In this issue of Kidney International Reports, Angeletti and co-workers address the aspect of antibody-mediated disease and report on their experience with a combined rituximab and daratumumab treatment in a cohort of multidrug-resistant and multidrug-dependent patients suffering from non-genetic nephrotic syndrome (7)Angeletti A, Bin S, Kajana X, et al. Combined Rituximab and Daratumumab Treatment in difficult to Treat nephrotic Syndrome Cases. Kidney Intl Rep, in pressGoogle Scholar). Daratumumab is a fully human monoclonal anti-CD38 antibody, depleting long-lived CD38 positive plasma cells that are not affected by rituximab. Combined therapy results in profound depletion of the entire B-cell spectrum and causes prolonged reduction in serum IgM that is supposed to play a pathogenic role in nephrotic-range proteinuria via classical complement activation (3)Vincenti F. Angeletti A. Ghiggeri G.M. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs.Front Immunol. 2023; 141167741https://doi.org/10.3389/fimmu.2023.1167741Crossref PubMed Scopus (2) Google Scholar,8)Trachtman H. Laskowski J. Lee c et al.Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.Am J Renal Physiol. 2021; (F505-F516. https://doi:10.1152/ajprenal.00041.2021)Crossref Scopus (18) Google Scholar). The reported clinical success is impressive: six out of seven multidrug-resistant patients went into partial (N=2) or complete remission (N=4) and the relapse-free survival after 12 months doubled in multidrug-dependent patients despite withdrawal of oral immunosuppressive drugs. Not less important is the absence of infectious complications and only one significant hypogammaglobulinemia in the follow-up period of 9 to 28 months. Thus, global depletion of B cells may be a promising treatment attempt in difficult-to-treat cases of non-genetic nephrotic syndrome. In this respect, the real-life character of the study, which included a very heterogeneous patient population of different ages (3 to 24 years), different histologies, different disease courses and previous therapies, is to be seen as a strength. However, we are aware that only a very small group of patients with iNS is candidate for global B-cell depletion as most patients respond to steroid-sparing immunosuppressive therapy and those requiring rituximab as rescue show a satisfactory response in 30-90% of the cases. However, the study leaves a number of questions unanswered, which require further clarification in the future.1)Rituximab is supposed to generate a disease-modifying effect (4)Chan E.Y. Yap D.Y. Colucci M. et al.Use of Rituximab in Childhood Idiopathic nephrotic Syndrome.Clin J Am Soc Nephrol. 2023; 18 (https://doi: 10.2215/CJN.08570722): 533-548Crossref Scopus (10) Google Scholar), that seems to increase with repeated doses and might be irrespective of B-cell recovery. In the present study, a subset of patients had already been treated with rituximab before and it remains unclear whether this could have had an effect on the clinical outcome. Could the sustained effect also be true for daratumumab alone? Could the combination of both agents result in an even more pronounced sustained effect? What would this mean for potential further dosing, when plasma cells and IgM levels recover? Is recovery of target cells a helpful finding in decision-making for repeated dosing, at all? Could maintenance mycophenolate mofetil treatment following global B-cell depletion induce long-term disease remission as has been shown for rituximab alone (9)Basu B. Erdmann S. Sander a et al.Long-Term Efficacy and Safety of Rituximab Versus Tacrolimus in Children with Steroid Dependent Nephrotic Syndrome.Kidney Int Rep. 2023; 8 (https://doi.org/10.1016/j.ekir.2023.05.022): 1575-1584Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar)?2)We cannot yet assess the extent to which antibodies contribute to the development of the disease. In the present study, the recovery of IgM levels was associated with a higher risk of relapse. Would the complement activating property of IgM antibodies open the door for complement blockade? Unfortunately, no kidney biopsies were available from all patients at baseline and none after the start of treatment that could provide information on glomerular IgM deposits and local complement activation. The rising IgM levels could also merely be a surrogate parameter of the recurring CD38 positive plasma cells. Do we have enough mechanistic evidence to indicate global B-cell depletion? This leads to the next aspect that is of special concern for pediatric nephrologists.3)Is global B-cell depletion safe in pediatric patients? There were no safety concerns in the present study but the cohort was rather small. There is some evidence supporting the view that rituximab is safe for most children, but we fear the rare and potentially serious adverse events such as lung injury, multifocal leukoencephalopathy or viral reactivations (4)Chan E.Y. Yap D.Y. Colucci M. et al.Use of Rituximab in Childhood Idiopathic nephrotic Syndrome.Clin J Am Soc Nephrol. 2023; 18 (https://doi: 10.2215/CJN.08570722): 533-548Crossref Scopus (10) Google Scholar). How is the risk of especially young children to develop sustained neutropenia and hypogammaglobulinemia in global B-cell depletion?4)How should we assess the finding that anti-nephrin antibody levels were not affected by global B-cell depletion in the present study? The finding might be due to an analytical problem. Assuming it was a reproducible result, would that call into question the impact of anti-nephrin antibodies and the indication for B-cell depleting therapy in total? Do we need more data on immune cell profiles and their signaling dynamics in iNS? We have come a long way and yet somehow we are still at the beginning. That is no reason to despair, but it is an absolute motivation to keep going. It currently seems to be an exciting time, as we can expect groundbreaking research into the pathophysiology and treatment of childhood INS in the near future. Combined Rituximab and Daratumumab Treatment in Difficult-to-Treat Nephrotic Syndrome CasesKidney International ReportsPreviewIdiopathic nephrotic syndrome (NS) is characterized by severe proteinuria, hypoalbuminemia, and/or edema and affects about 1 to 3 per 100,000 children and young adults.1 Corticosteroids represent the first line therapy for primary NS, leading to disease remission in 70% to 80% of cases.2 However, 70% to 80% may relapse after steroid withdrawal, and approximately 10% to 30% of patients have steroid-resistant NS. Treatment of steroid-resistant NS includes calcineurin inhibitors, mycophenolate mofetil, and anti-CD20 monoclonal antibodies (rituximab or obinutuzumab) used alone or in combination. Full-Text PDF Open Access

Background Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. Methods Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2–5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. Results M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. Conclusions Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Mammalian kidneys filter enormous volumes of water and small solutes, a filtration driven by the hydrostatic pressure in glomerular capillaries, which is considerably higher than in most other tissues. Interdigitating cellular processes of podocytes form the slits for fluid filtration connected by the membrane-like slit diaphragm cell junction containing a mechanosensitive ion channel complex and allow filtration while counteracting hydrostatic pressure. Several previous publications speculated that podocyte processes may display a preferable orientation on glomerular capillaries instead of a random distribution. However, for decades, the controversy over spatially oriented filtration slits could not be resolved due to technical limitations of imaging technologies. Here, we used advanced high-resolution, three-dimensional microscopy with high data throughput to assess spatial orientation of podocyte processes and filtration slits quantitatively. Filtration-slit-generating secondary processes preferentially align along the capillaries’ longitudinal axis while primary processes are preferably perpendicular to the longitudinal direction. This preferential orientation required maturation in development of the mice but was lost in mice with kidney disease due to treatment with nephrotoxic serum or with underlying heterologous mutations in the podocyte foot process protein podocin. Thus, the observation that podocytes maintain a preferred spatial orientation of their processes on glomerular capillaries goes well in line with the role of podocyte foot processes as mechanical buttresses to counteract mechanical forces resulting from pressurized capillaries. Future studies are needed to establish how podocytes establish and maintain their orientation and why orientation is lost under pathological conditions.

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca 2+ -actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca 2+ concentration ([Ca 2+ ] i ), the experimental design was repeated in mice expressing podocyte-specific Ca 2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca 2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca 2+ ] i imaging in podocytes showing decreased Ca 2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca 2+ ] i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.

ABSTRACT Mammalian kidneys filter enormous volumes of water and small solutes, a filtration driven by the very high hydrostatic pressure in glomerular capillaries. Interdigitating cellular processes of podocytes form the slits for fluid filtration. They are connected by the membrane-like slit diaphragm cell junction containing a mechanosensitive ion channel complex and allow filtration while counteracting hydrostatic pressure. Using high-resolution microscopy, we show that filtration-slit-generating secondary processes preferentially align along the capillaries’ longitudinal axis while primary processes are preferably perpendicular to the longitudinal direction. The preferential orientation requires maturation in development and is lost in disease states. We demonstrate that loss of proper orientation might contribute to impaired filtration by collapsing of the filtration slits and reducing the mechanical stability of podocyte processes. Together, these data suggest that podocytes sense mechanical strain to utilize circumferential hoop stress balancing the massive mechanical strain generated from fluid flow over the filtration slit.

Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF’s active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p < 0.05) affected expression of 351 genes in podocytes. Gene Ontology term enrichment analysis particularly clustered terms related to actin and inflammation-related cell death. Indeed, quantification of the actin cytoskeleton of BSA treated podocytes revealed a significant increase of thickness and number of actin filaments after treatment with MPA. Further, MPA significantly reduced TNFα and cycloheximide induced cell death. MPA has a substantial effect on the transcriptome of podocytes in vitro, particularly including functional clusters related to non-immune cell dependent mechanisms. This may provide a molecular basis for direct beneficial effects of MPA on the structural integrity and survival of podocytes under pro-inflammatory conditions.

In recent years functional multiphoton imaging of viable mouse tissue and STED imaging of optically cleared tissues allowed new insights into kidney biology. Here, we present a novel workflow where multiphoton imaging of calcium signals in podocytes is, in the same glomerulus, correlated with super-resolved STED imaging and analysis of the slit diaphragm (SD) morphology. Mice expressing the calcium indicator GCaMP3 exclusively in podocytes served as healthy controls and were challenged with two different doses of nephrotoxic serum (NTS). NTS-induced SD architecture damage increased in a dose-dependent manner, whereas intracellular calcium levels exhibited a wide range of variation and showed no correlation with SD damage in the same glomerulus. Our co-imaging protocol is applicable to a broad range of research questions as it is suitable for other tissues and compatible with a variety of reporters and tissue antigens. Translational statement The combination of multiphoton and super-resolution microscopy identifies the modulation of signaling pathways and resolves the changes in ultrastructure in disease states in the same glomeruli. Using our new method, we can compare functional and morphological data to investigate the degree of correlation to reveal novel underlying pathomechanism. This knowledge can improve our ability to draw conclusions from human kidney biopsies, in which the ultrastructure will be assessed more-often by routine super-resolution microscopy in the future.

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.

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.

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.

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.

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.

Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood and traditionally considered as a self-limiting disease. However, renal involvement can unfavorably determine long-term prognosis. The reported regimens to treat HSP nephritis (HSPN) are diverse, indicating that the most effective treatment remains controversial.

Childhood steroid-dependent (SDNS) and frequently relapsing (FRNS) nephrotic syndromes often require long term immunosuppressive therapy to maintain remission. Successful discontinuation of maintenance therapy remains to be a challenge with these children. In the following article, we report our experience on patients after discontinuation of steroid-sparing immunosuppressive maintenance therapy (IT). Thereby, we retrospectively reviewed all patients between 2006 and 2016 with a relapsing course of steroid-sensitive nephrotic syndrome (SDNS or FRNS) treated with steroid-sparing maintenance immunosuppressive medication. Patient data of a total of 24 patients were recorded for a median time of 53.5 (11.2 - 112) months. In 11 patients, therapy was discontinued at physician's discretion. Thereafter, 8 of 11 patients (group A) relapsed after a median time of 2.21 (0.23 - 9.17) months, and IT was restarted. The remaining 3 patients (group B) maintained in long-term remission for a median time of 26.9 (17.7 - 32.1) months until the end of observation. Neither age, at initial episode nor at discontinuation or duration of IT, differed significantly between the groups of patients with relapse after discontinuation of IT, compared to those without. There was a trend towards a shorter relapse-free interval before discontinuation in group A than in group B (35.7 vs. 44.1 months). All patients who restarted IT again attained a stable remission until the last follow-up and did not show any further relapse. These results demonstrate that a failed discontinuation attempt does not put the patient's future remission at risk.