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Despite an increasing incidence of acute kidney injury in both high-income and low-income countries and growing insight into the causes and mechanisms of disease, few preventive and therapeutic options exist. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries. Concerted international action encompassing many medical disciplines is needed to aid early recognition and management of acute kidney injury.

BackgroundData on therapy and outcome of dense deposit disease (DDD), C3 glomerulonephritis (C3GN), and immune-complex MPGN (IC-MPGN) in children are limited.MethodsIn this retrospective single-center study from 2007 to 2019, kidney biopsies were reviewed to include patients aged <18-years with C3 glomerulopathy and IC-MPGN. Initial immunosuppression comprised prednisolone, mycophenolate mofetil (n = 51), tacrolimus (n = 11), and/or IV cyclophosphamide (n = 20). Clinicopathological features, response to therapy, and adverse outcome (eGFRcr < 15 mL/min/1.73 m2 or death) were evaluated.ResultsA total of 92 patients were classified as DDD (n = 48, 52.2%), C3GN (n = 26, 28.3%), and IC-MPGN (n = 18, 19.6%) by immunohistochemistry and electron microscopy; 8 patients with DDD were misclassified as IC-MPGN on immunofluorescence. At last follow-up (median 4.3 years), complete or partial remission occurred in 28.5, 36.1, and 16.7% patients with DDD, C3GN, and IC-MPGN, respectively. Serum albumin at onset < 2.5 g/dL (HR = 0.29, P = 0.005) and persistently low serum C3 (HR = 0.34, P = 0.02) were associated with lack of remission. The 5-year kidney survival was 62.6, 85.5, and 88.5% in patients with DDD, C3GN, and IC-MPGN, respectively (log-rank, P = 0.006). Presentation as rapidly progressive GN (HR = 11.2, P < 0.001), age > 10 years at onset (HR = 4.0, P = 0.004), and DDD (HR = 4.2, P = 0.02) were independently associated with adverse outcome; achieving remission was protective (HR = 0.04; P < 0.001).ConclusionOutcome in patients with C3 glomerulopathy and IC-MPGN was unsatisfactory, and only a small proportion of patients achieved complete or partial remission. Patients with DDD were more likely to present with rapidly progressive GN and were at higher risk of adverse outcomes, including kidney failure.

Rituximab offers an alternative approach to current immunosuppressive therapies for patients with difficult-to-treat, steroid-dependent nephrotic syndrome. Rituximab therapy has been shown to induce and maintain remission in these patients; however, most data are derived from anecdotal reports or case series. This Review provides an overview of available data on the safety and efficacy of rituximab in the treatment of paediatric and adult patients with nephrotic syndrome. Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. The best outcomes are seen in patients with steroid-dependent nephrotic syndrome who have failed to respond to multiple therapies. By contrast, the benefits of rituximab therapy are limited in patients with steroid-resistant nephrotic syndrome, particularly those with focal segmental glomerulosclerosis (FSGS). Therapy with plasma exchange and one or two doses of rituximab has shown success in patients with recurrent FSGS. Young patients and those with normal serum albumin at recurrence of nephrotic syndrome are most likely to respond to rituximab therapy. A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A 2 receptor autoantibodies, which are implicated in the pathogenesis of this disorder. Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. However, the available evidence of efficacy of rituximab therapy is derived chiefly from small case series and requires confirmation in prospective, randomized, controlled studies that define the indications for use and predictors of response to this therapy. Key Points Therapy with rituximab induces and maintains remission effectively in patients with difficult-to-treat, steroid-dependent nephrotic syndrome; sustained remission enables the reduction of steroid doses and withdrawal of calcineurin inhibitors In patients with steroid-resistant nephrotic syndrome who fail to respond to treatment with calcineurin inhibitors, the response to rituximab therapy is less efficacious Rituximab dose(s), the rate of B-cell recovery and clinical response are not closely correlated Combined therapy with rituximab and plasma exchange might be useful to prevent or treat recurrence of focal segmental glomerulosclerosis Therapy with rituximab should be considered in patients with idiopathic membranous nephropathy who fail to respond to treatment with cyclophosphamide or calcineurin inhibitors Acute infusion reactions are frequent but transient in patients who receive rituximab; serious adverse effects, including an increased risk of infections, are uncommon

In low and middle-income countries, reliable data on the epidemiology of childhood acute kidney injury (AKI) is lacking. The Global Snapshot, conducted by the ISN \"0by25\" AKI initiative, was a world-wide cross-sectional, observational study to evaluate AKI in hospitalized patients. Here we report the pediatric results of this study. We prospectively collected data on children who met the Kidney Disease Improving Global Outcomes AKI criteria during a 10-week window in late 2014. AKI risk factors, etiological factors, management and outcomes were recorded using standardized forms and protocols. Countries were classified according to their 2014 gross national income (GNI) per person into high-income countries (HIC), upper-middle income countries (UMIC) and low and low-middle income countries (LLMIC). Need for renal replacement therapy, mortality, and renal recovery were assessed 7 days after AKI diagnosis or at hospital discharge, whichever came first. 92 centers from 41 countries collected data on 354 pediatric AKI patients; 53% of the children developed AKI while hospitalized and 47% in the community. The most common etiological factors for AKI differed across GNI categories as well as between patients with community-acquired vs. hospital-acquired AKI. Children from HIC were younger, and larger proportion of AKI in this group were due to post-surgical complications vs. other etiologies when compared to other income categories. In patients with hypotension as the cause of AKI, the adjusted risk of death was almost 10-fold higher compared to patients without hypotension as an etiological factor for AKI development. Mortality was similar within AKI stages in HIC and UMIC. In LLMIC, patients with the highest AKI level of severity had higher mortality than patients in higher income categories. Patients from LLMIC and UMIC had a 57-fold and 11 fold higher adjusted risk of death, respectively, compared to patients from HIC. In resource-limited countries, pediatric AKI-associated mortality is disproportionately higher when compared to high-resource areas, especially among patients with more severe AKI.

Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.This expert Consensus Statement from the Pediatric Continuous Renal Replacement Therapy (PCRRT) workgroup presents recommendations for the management of hyperammonaemia requiring kidney replacement therapy in paediatric populations. Additional studies are needed to strengthen these recommendations, which will be reviewed every 2 years.

Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury (AKI), is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required. Of 781 patients <18-year-old of aHUS in the nationwide database from 2007 to 2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-year ( = 317) were compared to before ( = 119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity ( = 8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH), and proteinuria were evaluated in a subset. Patients presented with markedly elevated anti-FH titers (10,633.2 ± 998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-year showed better renal survival at mean 28.5 ± 27.3 months (log rank = 0.022). Mean anti-FH titers stayed 700-1,164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission [Generalized estimating equations (GEE), = 0.001]; anti-FH levels ≥1,330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; = 0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8,000 AU/ml (HR 2.23; = 0.024), time to PEX ≥14 days (HR 2.09; = 0.071) and PEX for <14 days (HR 2.60; = 0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; = 0.026); maintenance therapy reduced risk of relapses (HR 0.11; < 0.001). At 4.4±2.5 year, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38, 30, and 18%, respectively. Proteinuria and LVH occurred in 58 and 28% patients, respectively. Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.

Background Information on the course of SARS-CoV-2 infection in children with chronic kidney disease (CKD) is limited. Methods We retrospectively reviewed the presentation and outcomes of SARS-CoV-2 infection in patients with CKD followed at any of the four pediatric nephrology centers in New Delhi from April 2020 to June 2021. Outcomes, including cardiopulmonary and renal complications, were reported in relation to underlying disease category and illness severity at presentation. Results Underlying illness in 88 patients included nephrotic syndrome (50%), other CKD stages 1–4 (18.2%), CKD 5D (17%), and CKD 5T (14.8%). Thirty-two of 61 patients with symptomatic COVID-19 and 9/27 asymptomatic patients were admitted for median 10 (interquartile range 7–15) days. Seventeen (19.3%) patients developed moderate or severe COVID-19. Systemic complications, observed in 30 (34.1%), included acute kidney injury (AKI, 34.2%), COVID-19 pneumonia (15.9%), unrelated pulmonary disease (2.3%), and shock (4.5%). Nineteen (21.6%) had severe complications (AKI stage 2–3, encephalopathy, respiratory failure, shock). Eight (11%) of twelve (16.4%) patients with severe AKI required dialysis. Three (3.4%) patients, two with steroid-resistant nephrotic syndrome in relapse and one with CKD 1–4, died due to respiratory failure. Univariate logistic regression indicated that patients presenting with nephrotic syndrome in relapse or moderate to severe COVID-19 were at risk of AKI (respective odds ratio, 95%CI: 3.62, 1.01–12.99; 4.58, 1.06–19.86) and/or severe complications (respective odds ratio, 95%CI: 5.92, 1.99–17.66; 61.2, 6.99–536.01). Conclusions Children with CKD presenting with moderate-to-severe COVID-19 or in nephrotic syndrome relapse are at risk of severe complications, including severe AKI and mortality. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein.