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.

Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression.

BACKGROUND: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS: The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Artificial intelligence in glomerular diseases.

In this narrative review, we focus on the application of artificial intelligence in the clinical history of patients with glomerular disease, digital pathology in kidney biopsy, renal ultrasonography imaging, and prediction of chronic kidney disease (CKD). With the development of natural language processing, the clinical history of a patient can be used to identify a computable phenotype. In kidney pathology, digital imaging has adopted innovative deep learning algorithms (DLAs) that can improve the predictive capability of the examined lesions. However, at this time, these applications can only be used in research because there is no recognized validation to replace the conventional diagnostic applications. Kidney ultrasonography, used in the clinical examination of patients, provides information about the progression of kidney damage. Machine learning algorithms (MLAs) with promising results for the early detection of CKD have been proposed, but, still, they are not solid enough to be incorporated into the clinical practice. A few tools for glomerulonephritis, based on MLAs, are available in clinical practice. They can be downloaded on computers and cellular phones but can only be applied to uniracial cohorts of patients. To improve their performance, it is necessary to organize large consortia with multiracial cohorts. Finally, in many studies MLA development has been carried out using retrospective cohorts. The performance of the models might differ in retrospective cohorts compared to real-world data. Therefore, the models should be validated in prospective external large cohorts.

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

Epigenetic dysregulation in neuroblastoma: A tale of miRNAs and DNA methylation.

In neuroblastoma, the epigenetic landscape is more profoundly altered in aggressive compared to lower grade tumors and the concomitant hypermethylation of many genes, defined as "methylator phenotype", has been associated with poor outcome. DNA methylation can interfere with gene expression acting at distance through the methylation or demethylation of the regulatory regions of miRNAs. The multiplicity of miRNA targets may result in the simultaneous alteration of many biological pathways like cell proliferation, apoptosis, migration and differentiation. We have analyzed the methylation status of a set of miRNAs in a panel of neuroblastoma cell lines and identified a subset of hypermethylated and down-regulated miRNAs (miRNA 34b-3p, miRNA 34b-5p, miRNA34c-5p, and miRNA 124-2-3p) involved in the regulation of cell cycle, apoptosis and in the control of MYCN expression. These miRNAs share, in part, some of the targets whose expression is inversely correlated to the methylation and expression of the corresponding miRNA. To simulate the effect of the demethylation of miRNAs, we transfected the corresponding miRNA-mimics in the same cell lines and observed the down-regulation of a set of their target genes as well as the partial block of the cell cycle and the activation of the apoptotic pathway. The epigenetic alterations of miRNAs described in the present study were found also in a subset of patients at high risk of progression. Our data disclosed a complex network of interactions between epigenetically altered miRNAs and target genes, that could interfere at multiple levels in the control of cell homeostasis.

In a retrospective international study, circulating miR-148b and let-7b were found to be serum markers for detecting primary IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a worldwide disease characterized by the presence of galactose-deficient IgA1 deposits in the glomerular mesangium. A kidney biopsy for diagnosis is required. Here, we measured two miRNAs (let-7b and miR-148b), previously identified as regulators of the O-glycosylation process of IgA1, in serum samples from patients with IgAN and healthy blood donors (controls) recruited in an international multicenter study. Two predictive models, based on these miRNAs, were developed and the diagnostic accuracy of the combined biomarkers was assessed by the area under the receiver operating characteristic (ROC) curve (AUC) carried out in three steps. In a training study, the combined miRNAs were able to discriminate between 100 patients with IgAN and 119 controls (AUC, 0.82). A validation study confirmed the model in an independent cohort of 145 patients with IgAN and 64 controls (AUC, 0.78). Finally, in a test study, the combined biomarkers were able to discriminate patients with IgAN from 105 patients affected by other forms of primary glomerulonephritis, supporting the specificity (AUC, 0.76). Using the same study design, we also performed two subgroup analyses (one for Caucasians and one for East Asians) and found that race-specific models were the best fit to distinguish IgAN patients from controls. Thus, serum levels of the combined miRNA biomarker, let-7b and miR-148b, appears to be a novel, reliable, and noninvasive test to predict the probability of having IgAN.

Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis.

BACKGROUND: The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & POPULATION: Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system [RAS] blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome. PREDICTOR: 9-month change in proteinuria. OUTCOME: Doubling of serum creatinine level, end-stage renal disease, or death. RESULTS: Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI, -19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32). LIMITATIONS: Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events. CONCLUSIONS: Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings.

Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy.

IgAN (IgA nephropathy) is the most common form of primary glomerulonephritis worldwide and has a strong genetic component. In this setting, DNA methylation could also be an important factor influencing this disease. We performed a genome-wide screening for DNA methylation in CD4(+) T-cells from IgAN patients and found three regions aberrantly methylated influencing genes involved in the response and proliferation of CD4(+) T-cells. Two hypomethylated regions codified genes involved in TCR (T-cell receptor) signalling, TRIM27 (tripartite motif-containing 27) and DUSP3 (dual-specificity phosphatase 3), and an hypermethylated region included the VTRNA2-1 (vault RNA 2-1) non-coding RNA, also known as miR-886 precursor. We showed that the aberrant methylation influences the expression of these genes in IgAN patients. Moreover, we demonstrated that the hypermethylation of the miR-886 precursor led to a decreased CD4(+) T-cell proliferation following TCR stimulation and to the overexpression of TGFß (transforming growth factor ß). Finally, we found a Th1/Th2 imbalance in IgAN patients. The IL (interleukin)-2/IL-5 ratio was notably higher in IgAN patients and clearly indicated a Th1 shift. In conclusion, we identified for the first time some specific DNA regions abnormally methylated in IgAN patients that led to the reduced TCR signal strength of the CD4(+) T-cells and to their anomalous response and activation that could explain the T-helper cell imbalance. The present study reveals new molecular mechanisms underlying the abnormal CD4(+) T-cell response in IgAN patients.

Potential role of effector memory T cells in chronic T cell-mediated kidney graft rejection.

BACKGROUND: Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. METHODS: RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The results were validated in an independent set of kidney biopsies. RESULTS: We identified 616 and 243 differentially expressed genes with a fold change ≥1.5 and a false discovery rate <0.05 in chronic and acute TCMR, respectively. Pathway analysis revealed upregulation of OX40 signalling. This pathway is involved in the generation of CD8+ effector memory T cells and the upregulation of killer cell lectin-like receptor G1 (KLRG-1), B lymphocyte-induced maturation protein 1 (BLIMP-1) and CD25, which characterize CD8+ effector memory T cells. However, the enhanced OX40 signalling pathway was specific to chronic TCMR; a significant increase of KLRG-1+/CD8+ and BLIMP-1+/CD8+ was only detected in these specimens. CONCLUSIONS: These results suggest the involvement of memory-committed CD8+ effector T cells in chronic TCMR. The generation of effector memory T cells is mediated by the OX40 gene pathway, and could be considered a future target for the specific treatment of chronic TCMR.

microRNAs in glomerular diseases from pathophysiology to potential treatment target.

miRNAs are regulators of gene expression in diverse biological and pathological courses in life. Their discovery may be considered one of the most important steps in the story of modern biology. miRNAs are packed within exosomes and released by cells for cellular communications; they are present in bodily fluids. Their study opens the way for understanding the pathogenetic mechanisms of many diseases; furthermore, as potential candidate biomarkers, they can be measured in bodily fluids for non-invasive monitoring of disease outcomes. The present review highlights recent advances in the role of miRNAs in the pathogenesis of primary and secondary glomerulonephritides such as IgA nephropathy, focal segmental glomerular sclerosis, lupus nephritis and diabetic nephropathy. The identification of reciprocal expression of miRNAs and their target genes provides the molecular basis for additional information on the pathogenetic mechanisms of kidney diseases. Finally, recent findings demonstrate that miRNAs can be considered as potential targets for novel drugs.

Role of let-7b in the regulation of N-acetylgalactosaminyltransferase 2 in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is characterized by aberrant O-glycosylation in the hinge region of IgA1. The early step in O-glycan formation is the attachment of N-acetylgalactosamine (GalNAc) to the serine/threonine of the hinge region; the process is catalysed by UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2). In our previous work, the microarray analysis on peripheral blood mononuclear cells (PBMCs) identified an upregulated miRNA called let-7b. METHODS: To study the molecular mechanisms in which let-7b was involved, we performed a bioinformatic analysis to predict their target genes. To validate biologically let-7b targets, we performed transient transfection experiments ex vivo using PBMCs from an independent group of IgAN patients and healthy blood donors (HBDs). RESULTS: Bioinformatic analysis revealed that GALNT2 is the potential target of let-7b. We found this miRNA significantly upregulated in PBMCs of IgAN patients compared with HBDs. Then, we demonstrated in ex-vivo experiments that let-7b decreased GALNT2 levels in PBMCs of IgAN patients, whereas the loss of let-7b function in PBMCs of HBDs led to an increase of GALNT2 mRNA and its protein level. Finally, we found that upregulation of let-7b occurred also in B-lymphocytes from IgAN patients. CONCLUSIONS: Our results give novel additional information on the abnormal O-glycosylation process of IgA1 in IgAN patients. This study provides evidence for another important miRNA-based regulatory mechanism of the O-glycosylation process in which the deregulated expression of let-7b is associated with altered expression of GALNT2. This finding could be taken into consideration for new therapeutic approaches in IgAN because other serum glycosylated proteins do not display abnormal glycosylation.

Kidney and urine cell transcriptomics in IgA nephropathy and lupus nephritis: a narrative review.

This narrative review sheds light on the use of transcriptomics in the analysis of kidney biopsies and urinary cell samples from patients with immunoglobulin A nephropathy or lupus nephritis. The conventional methods of examining kidney biopsy through light microscopy, immunofluorescence and electron microscopy provide valuable clinical information for diagnosis and prognosis but have some limitations that transcriptomics can address. Some recent studies have reported that kidney transcriptomics has uncovered new molecular biomarkers implicated in the inflammatory process induced by the deposition of circulating immune complexes in the investigated kidney diseases. In addition, transcriptomics applied to urinary cells mirrors the inflammatory process that occurs in the kidney. This means that we can study urinary cell transcriptomics in clinical practice to diagnose the stage of the inflammatory process. Furthermore, the transcriptomics of urinary cells can be used to make therapy decisions during patient follow-up to avoid the stress of a second kidney biopsy. The studies analyzed in this review have a significant limitation. Biomarkers have been identified in small cohorts of patients but none of them has been validated in independent external cohorts. Further prospective studies in large cohorts of patients are necessary for accurate and complete validation. Only after that can these biomarkers be widely used in clinical practice.

Human renal stem/progenitor cells repair tubular epithelial cell injury through TLR2-driven inhibin-A and microvesicle-shuttled decorin.

Acute kidney injury (AKI) is emerging as a worldwide public health problem. Recent studies have focused on the possibility of using human adult renal stem/progenitor cells (ARPCs) to improve the repair of AKI. Here we studied the influence of ARPCs on the healing of cisplatin-injured renal proximal tubular epithelial cells. Tubular, but not glomerular, ARPCs provided a protective effect promoting proliferation of surviving tubular cells and inhibiting cisplatin-induced apoptosis. The recovery effect was specific to tubular ARPCs, occurred only after damage sensing, and was completely cancelled by TLR2 blockade on tubular ARPCs. Moreover, tubular, but not glomerular, ARPCs were resistant to the apoptotic effect of cisplatin. Tubular ARPCs operate mainly through the engagement of TLR2, the secretion of inhibin-A protein, and microvesicle-shuttled decorin, inhibin-A, and cyclin D1 mRNAs. These factors worked synergistically and were essential to the repair process. The involvement of tubular ARPC-secreted inhibin-A and decorin mRNA in the pathophysiology of AKI was also confirmed in transplant patients affected by delayed graft function. Hence, identification of this TLR2-driven recovery mechanism may shed light on new therapeutic strategies to promote the recovery capacity of the kidney in acute tubular damage. Use of these components, derived from ARPCs, avoids injecting stem cells.

A comparative study of covariance selection models for the inference of gene regulatory networks.

MOTIVATION: The inference, or 'reverse-engineering', of gene regulatory networks from expression data and the description of the complex dependency structures among genes are open issues in modern molecular biology. RESULTS: In this paper we compared three regularized methods of covariance selection for the inference of gene regulatory networks, developed to circumvent the problems raising when the number of observations n is smaller than the number of genes p. The examined approaches provided three alternative estimates of the inverse covariance matrix: (a) the 'PINV' method is based on the Moore-Penrose pseudoinverse, (b) the 'RCM' method performs correlation between regression residuals and (c) 'ℓ(2C)' method maximizes a properly regularized log-likelihood function. Our extensive simulation studies showed that ℓ(2C) outperformed the other two methods having the most predictive partial correlation estimates and the highest values of sensitivity to infer conditional dependencies between genes even when a few number of observations was available. The application of this method for inferring gene networks of the isoprenoid biosynthesis pathways in Arabidopsis thaliana allowed to enlighten a negative partial correlation coefficient between the two hubs in the two isoprenoid pathways and, more importantly, provided an evidence of cross-talk between genes in the plastidial and the cytosolic pathways. When applied to gene expression data relative to a signature of HRAS oncogene in human cell cultures, the method revealed 9 genes (p-value<0.0005) directly interacting with HRAS, sharing the same Ras-responsive binding site for the transcription factor RREB1. This result suggests that the transcriptional activation of these genes is mediated by a common transcription factor downstream of Ras signaling. AVAILABILITY: Software implementing the methods in the form of Matlab scripts are available at: http://users.ba.cnr.it/issia/iesina18/CovSelModelsCodes.zip.

Abnormal miR-148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy.

Aberrant O-glycosylation in the hinge region of IgA1 characterizes IgA nephropathy. The mechanisms underlying this abnormal glycosylation are not well understood, but reduced expression of the enzyme core 1, ß1,3-galactosyltransferase 1 (C1GALT1) may contribute. In this study, high-throughput microRNA (miRNA) profiling identified 37 miRNAs differentially expressed in PBMCs of patients with IgA nephropathy compared with healthy persons. Among them, we observed upregulation of miR-148b, which potentially targets C1GALT1. Patients with IgA nephropathy exhibited lower C1GALT1 expression, which negatively correlated with miR-148b expression. Transfection of PBMCs from healthy persons with a miR-148b mimic reduced endogenous C1GALT1 mRNA levels threefold. Conversely, loss of miR-148b function in PBMCs of patients with IgA nephropathy increased C1GALT1 mRNA and protein levels to those observed in healthy persons. Moreover, we found that upregulation of miR-148b directly correlated with levels of galactose-deficient IgA1. In vitro, we used an IgA1-producing cell line to confirm that miR-148b modulates IgA1 O-glycosylation and the levels of secreted galactose-deficient IgA1. Taken together, these data suggest a role for miRNAs in the pathogenesis of IgA nephropathy. Abnormal expression of miR-148b may explain the aberrant glycosylation of IgA1, providing a potential pharmacologic target for IgA nephropathy.

Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD.

BACKGROUND: The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope. METHODS: We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m2/yr) and those of the clinical end point (doubling of serum creatinine, GFR <15 ml/min per 1.73 m2, or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m2, baseline urine albumin-to-creatinine ratio [UACR] per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m2/yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero. RESULTS: There was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR [-0.05 to 0.03]; baseline UACR [-0.02 to 0.04]; CKD progression rate [-0.07 to 0.02]). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR [0.02 to 0.11]; baseline UACR [-0.11 to -0.02]; CKD progression rate [0.01 to 0.15]). CONCLUSIONS: These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations.

A meta-analysis of GFR slope as a surrogate endpoint for kidney failure.

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min-1 per 1.73 m2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25-0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression.

Activated innate immunity and the involvement of CX3CR1-fractalkine in promoting hematuria in patients with IgA nephropathy.

A hallmark of immunoglobulin A nephropathy (IgAN) is episodes of gross hematuria coinciding with mucosal infections that can represent the disease-triggering event. Here we performed a whole genomic screen of IgAN patients during gross hematuria to clarify the link between mucosal antigens and glomerular hematuria. Modulated genes showed a clear involvement of the intracellular interferon signaling, antigen-presenting pathway, and the immunoproteasome. The mRNA and protein level of the chemokine receptor characterizing cytotoxic effector lymphocytes, CX3CR1, was upregulated. In vitro antigenic stimulation of peripheral blood mononuclear cells from IgAN patients, healthy blood donors, and other nephropathies with microscopic hematuria showed that only in IgAN patients was CX3CR1 enhanced in a dose-dependent manner. A significantly higher amount of glomerular and urinary fractalkine, the only ligand of CX3CR1, was also found in IgAN patients with recurrent episodes of gross hematuria compared with other patients with microscopic or no hematuria. This suggests a predisposition for cytotoxic cell extravasation only in patients with recurrent gross hematuria. Thus, we found a defect in antigen handling in peripheral blood mononuclear cells of IgAN patients with a specific increase of CX3CR1. This constitutive upregulation of glomerular and urinary fractalkine suggests an involvement of the CX3CR1-fractalkine axis in the exacerbation of gross hematuria.

Randomized clinical study to evaluate the effect of personalized therapy on patients with immunoglobulin A nephropathy.

Background: Randomized controlled trials (RCTs) have been conducted, stratifying idiopathic immunoglobulin A nephropathy (IgAN) patients based on the laboratory findings [serum creatinine, estimated glomerular filtration rate (eGFR) and daily proteinuria]. In contrast, data from kidney biopsy have been used only for clinical diagnosis. Therefore, IgAN patients with active or chronic renal lesions have been receiving the same therapy in experimental and control arms of randomized clinical trials (RCTs). Methods: Our clinical study of IgAN (CLIgAN) is a multicentre, prospective, controlled and open-label RCT based on patients' stratification at the time of their kidney biopsy. We will consider, first, the type of renal lesions, followed by serum creatinine values, eGFR and proteinuria. Primary and secondary endpoints will be monitored. Then, we will determine whether personalized therapy can slow the decline of renal function and delay end-stage kidney disease. Results: We will enrol 132 IgAN patients with active renal lesions (66 patients per arm) in the first RCT (ACIgAN). They will receive corticosteroids combined with renin-angiotensin system blockers (RASBs) or only RASBs. A total of 294 IgAN patients with chronic or moderate renal lesions at high or very high risk of chronic kidney disease (147 patients per arm) will be enrolled in the second RCT (CHRONIgAN), in which they will receive dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, combined with RASBs, or RASBs alone. Conclusion: Using this approach, we hypothesize that patients could receive personalized therapy based on renal lesions to ensure that the right drug gets to the right patient at the right time.

Erratum: Randomized clinical study to evaluate the effect of personalized therapy on patients with immunoglobulin A nephropathy.

[This corrects the article DOI: 10.1093/ckj/sfab263.].