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The pathogenesis of idiopathic nephrotic syndrome (INS) is as yet unknown, but several lines of evidence indicate that the immune system may play a crucial pathogenic role in non-genetic INS. The most important of these are, first, the effectiveness of therapy based on immunosuppression and, second, a vast body of data derived both from experimental models and from patient studies that implicate T cells and more recently B cells as major players in INS pathogenesis. However, recent findings also suggest a direct role of podocytes as drivers of the disease process, and the interplay between the glomerulus and the immune system is still being elucidated. In this review we provide an overview of current knowledge on the role of different components of the immune system in determining disease. Advances in our understanding of the pathogenesis of INS may help drive new, more tailored therapeutic approaches.

X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.In this Evidence-Based Guideline on X-linked hypophosphataemia, the authors identify the criteria for diagnosis of this disease, provide guidance for medical and surgical treatment and explain the challenges of follow-up.

Renal tubular acidosis (RTA) comprises a group of disorders in which excretion of hydrogen ions or reabsorption of filtered HCO 3 is impaired, leading to chronic metabolic acidosis with normal anion gap. In the current review, the focus is placed on the most common type of RTA, Type 1 RTA or Distal RTA (dRTA), which is a rare chronic genetic disorder characterized by an inability of the distal nephron to secrete hydrogen ions in the presence of metabolic acidosis. Over the years, knowledge of the molecular mechanisms behind acid secretion has improved, thereby greatly helping the diagnosis of dRTA. The primary or inherited form of dRTA is mostly diagnosed in infancy, childhood, or young adulthood, while the acquired secondary form, as a consequence of other disorders or medications, can happen at any age, although it is more commonly seen in adults. dRTA is not as “benign” as previously assumed, and can have several, highly variable long-term consequences. The present review indeed reports and summarizes both clinical symptoms and diagnosis, long-term outcomes, genetic inheritance, epidemiology and current treatment options, with the aim of shedding more light onto this rare disorder. Being a chronic condition, dRTA also deserves attention in the transition between pediatric and adult nephrology care, and as a rare disease it has a place in the European and Italian rare nephrological diseases network.

Dysregulation of the alternative complement pathway plays a pathogenic role in dense-deposit disease (also known as membranoproliferative glomerulonephritis type II). This letter reports the use of eculizumab in a patient with this disease. To the Editor: Dense-deposit disease (also known as membranoproliferative glomerulonephritis type II) is a rare glomerulopathy characterized by electron-dense deposits in the glomerular basement membrane as well as the glomerular deposition of complement. Within 10 years, the disease progresses to end-stage kidney disease in approximately 50% of patients, and it frequently recurs after kidney transplantation. Dysregulation of the alternative complement pathway, resulting from mutations in the factor H gene or the activation of autoantibodies, plays a pathogenic role in the disease. In animal models, the uncontrolled activation of C5 contributes substantially to renal lesions. 1 Such studies provide the rationale for . . .

Key Points Healthy mitochondria are essential for normal kidney function; mitochondrial cytopathies can result in renal disease and mitochondrial damage has a role in the pathophysiology of acute kidney injury (AKI) Although mitochondrial diseases are characterized by maternal inheritance, many mitochondrial disorders are caused by mutations in nuclear genes and are inherited according to classic Mendelian rules Most mitochondrial diseases with kidney involvement cause tubular defects; however, mutations in the coenzyme Q 10 biosynthesis pathway and the mtDNA 3243 A>G mutation primarily cause glomerular disease Diagnosis of genetic mitochondrial disorders increasingly relies on new sequencing techniques, but thorough biochemical and clinical characterization of patients is essential to guide these analyses In AKI, mitochondrial dysfunction precedes and participates in the physiopathology of tissue damage; mitochondrial biogenesis might represent a crucial step in the recovery phase Potential therapies that target mitochondrial dynamics, mitophagy and/or mitochondrial biogenesis might limit renal damage during AKI and promote recovery of kidney function Healthy mitochondria are essential for normal kidney function and mitochondrial dysfunction has been implicated in various types of renal disorders, both inherited and acquired. In this article, the authors review mitochondrial cytopathies with renal manifestations and the role of mitochondrial dysfunction in acute kidney injury (AKI). Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q 10 (CoQ 10 ) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ 10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue.

Steroid-sensitive nephrotic syndrome (SSNS) is a rare condition that develops primarily in preadolescent children after the age of 1 year. Since the 1950s, oral corticosteroids have been the mainstay of treatment of all children presenting with nephrotic syndrome, with most patients responding within 4 weeks to an oral course of prednisone (PDN). However, corticosteroids have important side effects and 60–80 % of patients relapse, developing frequently relapsing or steroid-dependent forms. For these reasons, many patients require second-line steroid-sparing immunosuppressive medications that have considerably improved relapse-free survival, while avoiding many PDN-related toxicities. Since most patients will eventually heal from their disease with a normal kidney function, the morbidity of SSNS is primarily related to side effects of drugs that are used to maintain prolonged remission. Therefore, treatment is essentially based on balancing the use of different drugs to achieve permanent remission with the lowest cumulative number of side effects. Treatment choice is based on the severity of SSNS, on patient age, and on drug tolerability. This review provides an update of currently available therapeutic strategies for SSNS.

Antinephrin autoantibodies occur in adults with minimal change disease and children with idiopathic nephrotic syndrome and appear to be disease activity markers. Their binding at slit diaphragms may induce podocyte dysfunction.

BackgroundA pathogenic role of B cells in non-genetic nephrotic syndrome has been suggested by the efficacy of rituximab, a B cell depleting antibody, in maintaining a prolonged remission. However, little information is available on B cell homeostasis in nephrotic syndrome patients.MethodsWe retrospectively analyzed by flow cytometry the distribution of different B cell subpopulations in 107 steroid-sensitive and in 6 genetic steroid-resistant nephrotic syndrome pediatric patients, compared with age- and sex-matched controls.ResultsFifty-one steroid-sensitive patients at disease onset, before starting immunosuppression, presented significantly increased levels of total, transitional, memory, and switched memory B cells compared to controls. Oral immunosuppression strongly affected transitional and mature B cell levels in 27 patients in relapse and also in 29 patients in remission, whereas memory B cells were significantly higher compared to controls during relapse, despite the immunosuppressive treatment, and were normalized only in patients in remission. Children with genetic forms of steroid-resistant nephrotic syndrome presented no differences in B cell profile from controls.ConclusionsOur study indicates that memory B cells, more than other B cell subsets, are increased and appear to be pathogenically relevant in steroid-sensitive nephrotic syndrome pediatric patients.

Key Points OCRL mutations cause Lowe syndrome, an X-linked disease characterized by congenital cataracts, central nervous system involvement and renal Fanconi syndrome; the only available treatments are surgery for cataracts and symptomatic care for renal dysfunction OCRL encodes a 5-phosphatase that acts preferentially on phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ), a phosphoinositide with a pivotal role in intracellular trafficking; disease-causing mutations occur throughout the OCRL gene, but mainly in exons 9–15, which encode the catalytic domain Mutations in OCRL also cause Dent disease 2, a milder condition that results in renal Fanconi syndrome similar to that of Dent disease 1, caused by mutations in the gene that encodes the endosomal chloride channel ClC-5 OCRL localizes mainly in endolysosomal compartments; its dysfunction causes an accumulation of PI(4,5)P 2 resulting in delayed recycling of receptors required for protein reabsorption and impairment of the lysosomal–autophagic pathway Mouse and zebrafish animal models of Lowe syndrome are available, but these do not fully recapitulate the manifestations of Lowe syndrome Areas for future research include the mechanisms underlying the tissue selective manifestations of Lowe syndrome and Dent disease 2 as well as the identification of effective therapeutic strategies Dysfunction of endolysosomal pathways can lead to generalized dysfunction of the proximal tubule. Here, De Matteis and colleagues describe the role of the inositol polyphosphate 5-phosphatase, OCRL, in the endolysosomal pathway and how mutations in the encoding gene lead to the clinical manifestations of Lowe syndrome and Dent disease 2. Lowe syndrome is an X-linked disease that is characterized by congenital cataracts, central hypotonia, intellectual disability and renal Fanconi syndrome. The disease is caused by mutations in OCRL , which encodes an inositol polyphosphate 5-phosphatase (OCRL) that acts on phosphoinositides — quantitatively minor constituents of cell membranes that are nonetheless pivotal regulators of intracellular trafficking. In this Review we summarize the considerable progress made over the past decade in understanding the cellular roles of OCRL in regulating phosphoinositide balance along the endolysosomal pathway, a fundamental system for the reabsorption of proteins and solutes by proximal tubular cells. We discuss how studies of OCRL have led to important discoveries about the basic mechanisms of membrane trafficking and describe the key features and limitations of the currently available animal models of Lowe syndrome. Mutations in OCRL can also give rise to a milder pathology, Dent disease 2, which is characterized by renal Fanconi syndrome in the absence of extrarenal pathologies. Understanding how mutations in OCRL give rise to two clinical entities with differing extrarenal manifestations represents an opportunity to identify molecular pathways that could be targeted to develop treatments for these conditions.

Nephropathic cystinosis (NC) is a rare disease caused by mutations in the CTNS gene encoding for cystinosin, a lysosomal transmembrane cystine/H + symporter, which promotes the efflux of cystine from lysosomes to cytosol. NC is the most frequent cause of Fanconi syndrome (FS) in young children, the molecular basis of which is not well established. Proximal tubular cells have very high metabolic rate due to the active transport of many solutes. Not surprisingly, mitochondrial disorders are often characterized by FS. A similar mechanism may also apply to NC. Because cAMP has regulatory properties on mitochondrial function, we have analyzed cAMP levels and mitochondrial targets in CTNS −/− conditionally immortalized proximal tubular epithelial cells (ciPTEC) carrying the classical homozygous 57-kb deletion ( delCTNS −/− ) or with compound heterozygous loss-of-function mutations ( mutCTNS − / − ). Compared to wild-type cells, cystinotic cells had significantly lower mitochondrial cAMP levels ( delCTNS − / − ciPTEC by 56% ± 10.5, P  < 0.0001; mutCTNS − / − by 26% ± 4.3, P  < 0.001), complex I and V activities, mitochondrial membrane potential, and SIRT3 protein levels, which were associated with increased mitochondrial fragmentation. Reduction of complex I and V activities was associated with lower expression of part of their subunits. Treatment with the non-hydrolysable cAMP analog 8-Br-cAMP restored mitochondrial potential and corrected mitochondria morphology. Treatment with cysteamine, which reduces the intra-lysosomal cystine, was able to restore mitochondrial cAMP levels, as well as most other abnormal mitochondrial findings. These observations were validated in CTNS -silenced HK-2 cells, indicating a pivotal role of mitochondrial cAMP in the proximal tubular dysfunction observed in NC.