Decoding myofibroblast origins in human kidney fibrosis.

Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1-3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis.

A new alternative: inhibiting complement activation in patients with IgA nephropathy.

Mesangial complement C3 deposits, reflecting alternative and possibly lectin pathway activation, are characteristic in biopsies of patients with IgA nephropathy (IgAN). A recent randomized controlled trial tested the efficacy and safety of iptacopan, a factor B inhibitor, in patients with IgAN. Iptacopan dose-dependently reduced proteinuria, and there was a pronounced decrease of urinary C5b-9. This offers the perspective of "personalizing" therapy, which would be a unique feature of this novel approach to IgAN. A phase III clinical trial (APPLAUSE-IgAN) is ongoing.

Factor XI inhibition in hemodialysis patients: the safer anticoagulation?

Chronic hemodialysis patients exhibit an excessive cardiovascular risk and a marked increase in both thromboembolism and bleeding episodes. Factor XI inhibition may provide anticoagulation, with a low risk of bleeding, and several factor XI inhibitors, including fesomersen, an antisense oligonucleotide, are under development. Recently, a phase 2 study of fesomersen showed a good safety profile in chronic hemodialysis patients and suggested that clotting rates of the arteriovenous fistula and the dialysis circuit are lower.

A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases was published in 2021. Since then, the pace of drug development for glomerular diseases has accelerated, due in large part to rapidly accumulating insights into disease pathogenesis from genetic and molecular studies of afflicted patients. To keep the Glomerular Diseases Guideline as current as possible, KDIGO made a commitment to the nephrology community to provide periodic updates, based on new developments for each disease. After the 2021 guideline was published, two novel drugs received regulatory approval for the management of lupus nephritis, leading to the first KDIGO guideline update. Herein, an executive summary of the most important guideline changes from the Lupus Nephritis chapter is provided as a quick reference.

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated Vasculitis.

In 2021, the Kidney Disease: Improving Global Outcomes (KDIGO) Guideline for the Management of Glomerular Diseases was published. KDIGO is committed to providing the nephrology community with periodic updates, based on new developments for each disease. For patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), avacopan received regulatory approval in late 2021, leading to this KDIGO guideline update. In addition, the evidence supporting a lower-dose glucocorticoid induction regimen or even complete replacement of glucocorticoids has become stronger. Herein, an executive summary of the most important guideline changes from the AAV chapter is provided as a quick reference.

The role of desmoglein-2 in kidney disease.

Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The kidney is exposed to various mechanical stimuli and stress, yet little is known about kidney desmosomes. In healthy kidneys, we found desmosomal proteins located at the apical-junctional complex in tubular epithelial cells. In four different animal models and patient biopsies with various kidney diseases, desmosomal components were significantly upregulated and partly miss-localized outside of the apical-junctional complexes along the whole lateral tubular epithelial cell membrane. The most upregulated component was desmoglein-2 (Dsg2). Mice with constitutive tubular epithelial cell-specific deletion of Dsg2 developed normally, and other desmosomal components were not altered in these mice. When challenged with different types of tubular epithelial cell injury (unilateral ureteral obstruction, ischemia-reperfusion, and 2,8-dihydroxyadenine crystal nephropathy), we found increased tubular epithelial cell apoptosis, proliferation, tubular atrophy, and inflammation compared to wild-type mice in all models and time points. In vitro, silencing DSG2 via siRNA weakened cell-cell adhesion in HK-2 cells and increased cell death. Thus, our data show a prominent upregulation of desmosomal components in tubular cells across species and diseases and suggest a protective role of Dsg2 against various injurious stimuli.

Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial.

BACKGROUND: IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35-90 mL/min per 1·73 m2, and persistent proteinuria (urine protein-creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed. FINDINGS: Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported. INTERPRETATION: A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product. FUNDING: Calliditas Therapeutics.

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial.

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

Reduction of Endothelial Glycocalyx on Peritubular Capillaries in Chronic Kidney Disease.

In chronic kidney disease (CKD), peritubular capillaries undergo anatomic and functional alterations, such as rarefaction and increased permeability. The endothelial glycocalyx (EG) is a carbohydrate-rich gel-like mesh, which covers the luminal surface of endothelial cells. It is involved in many regulatory functions of the endothelium, including vascular permeability. Herein, we investigated ultrastructural alterations of the EG in different murine CKD models. Fluorescence staining using different lectins with high affinity to components of the renal glycocalyx revealed a reduced binding to the endothelium in CKD in the animal models, and there were similar finding in human kidney specimens. Lanthanum Dysprosium Glycosamino Glycan adhesion staining technique was used to visualize the ultrastructure of the glycocalyx in transmission electron microscopy. This also enabled quantitative analyses, showing a significant reduction of the EG thickness and density. In addition, mRNA expression of proteins involved in glycocalyx biology, synthesis, and turnover (ie, syndecan 1 and glypican 1), which are main components of the glycocalyx, and exostosin 2, involved in the synthesis of the glycocalyx, were significantly up-regulated in endothelial cells isolated from murine CKD models. Visualization of glycocalyx using specific transmission electron microscopy analyses allows qualitative and quantitative analyses and revealed significant pathologic alterations in peritubular capillaries in CKD.

Use of Analog and Human Insulin in a European Hemodialysis Cohort With Type 2 Diabetes: Associations With Mortality, Hospitalization, MACE, and Hypoglycemia.

RATIONALE & OBJECTIVE: Poor glycemic control may contribute to the high mortality rate in patients with type 2 diabetes receiving hemodialysis. Insulin type may influence glycemic control, and its choice may be an opportunity to improve outcomes. This study assessed whether treatment with analog insulin compared with human insulin is associated with different outcomes in people with type 2 diabetes and kidney failure receiving hemodialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: People in the Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) study with kidney failure commencing hemodialysis and type 2 diabetes being treated with insulin within 288 dialysis facilities between 2007 and 2009 across 7 European countries. Study participants were followed for 3 years. People with type 1 diabetes were excluded using an established administrative data algorithm. EXPOSURE: Treatment with an insulin analog or human insulin. OUTCOME: All-cause mortality, major adverse cardiovascular events (MACE), all-cause hospitalization, and confirmed hypoglycemia (blood glucose<3.0mmol/L sampled during hemodialysis). ANALYTICAL APPROACH: Inverse probability weighted Cox proportional hazards models to estimate hazard ratios for analog insulin compared with human insulin. RESULTS: There were 713 insulin analog and 733 human insulin users. Significant variation in insulin type by country was observed. Comparing analog with human insulin at 3 years, the percentage of patients experiencing end points and adjusted hazard ratios (AHR) were 22.0% versus 31.4% (AHR, 0.808 [95% CI, 0.66-0.99], P=0.04) for all-cause mortality, 26.8% versus 35.9% (AHR, 0.817 [95% CI, 0.68-0.98], P=0.03) for MACE, and 58.2% versus 75.0% (AHR, 0.757 [95% CI, 0.67-0.86], P<0.001) for hospitalization. Hypoglycemia was comparable between insulin types at 14.1% versus 15.0% (AHR, 1.169 [95% CI, 0.80-1.72], P=0.4). Consistent strength and direction of the associations were observed across sensitivity analyses. LIMITATIONS: Residual confounding, lack of more detailed glycemia data. CONCLUSIONS: In this large multinational cohort of people with type 2 diabetes and kidney failure receiving maintenance hemodialysis, treatment with analog insulins was associated with better clinical outcomes when compared with human insulin. PLAIN-LANGUAGE SUMMARY: People with diabetes who are receiving dialysis for kidney failure are at high risk of cardiovascular disease and death. This study uses information from 1,446 people with kidney failure from 7 European countries who are receiving dialysis, have type 2 diabetes, and are prescribed either insulin identical to that made in the body (human insulin) or insulins with engineered extra features (insulin analog). After 3 years, fewer participants receiving analog insulins had died, had been admitted to the hospital, or had a cardiovascular event (heart attack, stroke, heart failure, or peripheral vascular disease). These findings suggest that analog insulins should be further explored as a treatment leading to better outcomes for people with diabetes on dialysis.

Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group.

The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.

Interactive exploration of adverse events and multimorbidity in CKD.

BACKGROUND AND HYPOTHESIS: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. METHODS: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. RESULTS: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort.

BACKGROUND: The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. METHODS: Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. RESULTS: A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. CONCLUSIONS: In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.

The Role of Platelet-Derived Growth Factor in Focal Segmental Glomerulosclerosis.

BACKGROUND: FSGS is the final common pathway to nephron loss in most forms of severe or progressive glomerular injury. Although podocyte injury initiates FSGS, parietal epithelial cells (PECs) are the main effectors. Because PDGF takes part in fibrotic processes, we hypothesized that the ligand PDGF-B and its receptor PDGFR- ß participate in the origin and progression of FSGS. METHODS: We challenged Thy1.1 transgenic mice, which express Thy1.1 in the podocytes, with anti-Thy1.1 antibody to study the progression of FSGS. We investigated the role of PDGF in FSGS using challenged Thy1.1 mice, 5/6 nephrectomized mice, Col4 -/- (Alport) mice, patient kidney biopsies, and primary murine PECs, and challenged Thy1.1 mice treated with neutralizing anti-PDGF-B antibody therapy. RESULTS: The unchallenged Thy1.1 mice developed only mild spontaneous FSGS, whereas challenged mice developed progressive FSGS accompanied by a decline in kidney function. PEC activation, proliferation, and profibrotic phenotypic switch drove the FSGS. During disease, PDGF-B was upregulated in podocytes, whereas PDGFR- ß was upregulated in PECs from both mice and patients with FSGS. Short- and long-term treatment with PDGF-B neutralizing antibody improved kidney function and reduced FSGS, PEC proliferation, and profibrotic activation. In vitro , stimulation of primary murine PECs with PDGF-B recapitulated in vivo findings with PEC activation and proliferation, which was inhibited by PDGF-B antibody or imatinib. CONCLUSION: PDGF-B-PDGFR- ß molecular crosstalk between podocytes and PECs drives glomerulosclerosis and the progression of FSGS. PODCAST: This article contains a podcast at.

Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Clinical Trials in CKD.

SIGNIFICANCE STATEMENT: Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. BACKGROUND: Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. METHODS: Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. RESULTS: Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were -0.41 (95% Bayesian Credible Interval, -0.64 to -0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and -0.06 (95% Bayesian Credible Interval, -0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. CONCLUSIONS: In Phase 2 trials of CKD with sample sizes of 100-200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

IgA nephropathy: the lectin pathway and implications for targeted therapy.

Many patients with immunoglobulin A nephropathy (IgAN) progress to kidney failure even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system-particularly the lectin and alternative pathways of complement-has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. This review will focus on the lectin pathway. The examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (1 of 6 pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients.

Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy.

The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.

International Society of Nephrology first consensus guidance for preclinical animal studies in translational nephrology.

Preclinical tests in animal models are key steps in early drug development. Consequently, the International Society of Nephrology held a consensus meeting that connected experts in the global kidney community in order to provide guidance on optimal management of translational animal studies for the development of new drugs to treat kidney disease, entitled "TRANSFORM; TRAnslational Nephrology Science FOR new Medications." The meeting covered various themes, including the following: (i) selection of disease model; (ii) pharmacokinetics; (iii) interventions in late preclinical models; (iv) choice of animal; (v) statistical power; (vi) organoids and organ-on-a-chip models; and (vii) reporting of results. This guidance is the first to be provided on the optimal conduct of translational animal studies for the development of new drugs to treat kidney disease. These recommendations are designed to accelerate development of new drugs for efficacious treatment of kidney diseases, and to improve the prognosis and quality of life of patients with a variety of kidney diseases.

DNA binding protein YB-1 is a part of the neutrophil extracellular trap mediation of kidney damage and cross-organ effects.

Open-heart surgery is associated with high morbidity, with acute kidney injury (AKI) being one of the most commonly observed postoperative complications. Following open-heart surgery, in an observational study we found significantly higher numbers of blood neutrophils in a group of 13 patients with AKI compared to 25 patients without AKI (AKI: 12.9±5.4 ×109 cells/L; non-AKI: 10.1±2. 9 ×109 cells/L). Elevated serum levels of neutrophil extracellular trap (NETs) components, such as dsDNA, histone 3, and DNA binding protein Y-box protein (YB)-1, were found within the first 24 hours in patients who later developed AKI. We could demonstrate that NET formation and hypoxia triggered the release of YB-1, which was subsequently shown to act as a mediator of kidney tubular damage. Experimentally, in two models of AKI mimicking kidney hypoperfusion during cardiac surgery (bilateral ischemia/reperfusion (I/R) and systemic lipopolysaccharide (LPS) administration), a neutralizing YB-1 antibody was administered to mice. In both models, prophylactic YB-1 antibody administration significantly reduced the tubular damage (damage score range 1-4, the LPS model: non-specific IgG control, 0.92±0.23; anti-YB-1 0.65±0.18; and in the I/R model: non-specific IgG control 2.42±0.23; anti-YB-1 1.86±0.44). Even in a therapeutic, delayed treatment model, antagonism of YB-1 ameliorated AKI (damage score, non-specific IgG control 3.03±0.31; anti-YB-1 2.58±0.18). Thus, blocking extracellular YB-1 reduced the effects induced by hypoxia and NET formation in the kidney and significantly limited AKI, suggesting that YB-1 is part of the NET formation process and an integral mediator of cross-organ effects.