Role of Podocyte in Kidney Disease.

Podocytes are epithelial cells lining the outer surface of the renal glomerular capillaries and they play a pivotal role in maintaining the structural and functional integrity of the glomerular filtration barrier. Podocytes react to injury in various ways and any injury to these highly specialized cells can progress to podocyte dysfunction, resulting in a group of proteinuric renal diseases called podocytopathies. Podocytopathies include a wide spectrum of primary and secondary kidney diseases, including minimal change disease, diffuse mesangial sclerosis, focal segmental glomerulosclerosis, collapsing glomerulopathy, diabetic, membranous and lupus nephropathies. Etiologically, they can be idiopathic, genetic or secondary to infections and drugs, metabolic diseases, hemodynamic factors or associated with various immune and non-immune systemic diseases. This manuscript provides a basic understanding of podocyte structure, causes of podocyte injury, response to the injury and the subsequent progression to podocytopathies. The pathogenesis of these diseases is set around podocytes. The clinical and morphological manifestations, the commonality and heterogeneity of these podocytopathies are also discussed. As our knowledge of podocyte biology improves, so will our treatment avenues with a more podocyte-centric personalized approach.

The pivotal role of glucose transporter 1 in diabetic kidney disease.

Diabetes mellitus (DM) is a significant public health problem. Diabetic kidney disease (DKD) is the most common complication of DM, and its incidence has been increasing with the increasing prevalence of DM. Given the association between DKD and mortality in patients with DM, DKD is a significant burden on public health resources. Despite its significance in DM progression, the pathogenesis of DKD remains unclear. Aberrant glucose uptake by cells is an important pathophysiological mechanism underlying DKD renal injury. Glucose is transported across the bilayer cell membrane by a glucose transporter (GLUT) located on the cell membrane. Multiple GLUT proteins have been identified in the kidney, and GLUT1 is one of the most abundantly expressed isoforms. GLUT1 is a crucial regulator of intracellular glucose metabolism and plays a key pathological role in the phenotypic changes in DKD mesangial cells. In an attempt to understand the pathogenesis of DKD better, we here present a review of studies on the role of GLUT1 in the development and progression of DKD.

Advances in primary glomerulonephritis.

Primary glomerulonephritis comprises several renal-limited diseases that can cause haematoproteinuria, chronic kidney disease, nephrosis and end stage kidney disease. The most common of these are IgA nephropathy (IgAN), primary membranous nephropathy (PMN), Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD). Although rare, these diseases cause a significant burden to health care systems, given the high cost of treating End Stage Kidney Disease (ESKD) with dialysis or transplantation. Until recently, the pathogenesis of primary gloerulonephritis has remained obscure. However, recent advances in understanding of how these diseases evolve has led to the introduction of novel therapeutic agents. Trials are underway or have recently completed that have huge implications for the standard of care for the primary glomerulonephritidies, and should dramatically reduce the number of patients who progress onto end stage kidney disease. This article reviews the international Kidney Disease Improving Global Outcomes (KDIGO) guidelines for the treatment of IgAN, PMN, FSGS and MCD, as well as recent research on pathogenesis and treatment.

Five-Year study on renal outcomes in biopsy-proven focal segmental glomerulosclerosis patients in Shiraz, Iran.

Background: Focal segmental glomerulosclerosis (FSGS) is a prevalent glomerular disease that often leads to nephrotic syndrome. It is characterized by consolidating a portion of the glomerular capillary tuft connected to Bowman's capsule. This retrospective cohort study aimed to determine the demographic characteristics, risk factors, and prognostic indicators associated with FSGS in Shiraz, Iran. Methods: The study included 53 primary FSGS patients aged over 18 years who were referred to clinics affiliated with Shiraz University of Medical Sciences. Data were collected through a comprehensive data-gathering sheet encompassing demographic information, medical history, laboratory test results, and histopathological findings. Statistical analysis was performed using SPSS 18, considering a significance level of p<0.05. Results: A five-year follow-up was conducted on the 53 patients, with the mean age of 41.0±13.3 years. The most common FSGS variants observed were "not otherwise specified" (NOS, 13.2%) and tip variant (7.5%). Older patients exhibited higher disease activity, whereas remission rates were higher among younger individuals (P=0.012). Patients achieving remission had lower creatinine and Pro/Cr ratios and higher glomerular filtration rates (p<0.05). Treatment involving a combination of corticosteroids and mycophenolate mofetil showed a significant correlation with remission (P=0.036). Conclusion: Older patients with higher creatinine levels, higher Pro/Cr ratios, and lower glomerular filtration rates at disease onset may require more aggressive treatment. Combination therapy with mycophenolate mofetil and corticosteroids yields better outcomes, leading to increased remission rates. These findings provide valuable insights for managing FSGS patients.

Zinc Deficiency Causes Glomerulosclerosis and Renal Interstitial Fibrosis Through Oxidative Stress and Increased Lactate Metabolism in Rats.

Chronic kidney disease (CKD) is a highly prevalent condition characterized by renal fibrosis as its ultimate manifestation. Zinc deficiency is closely associated with CKD, evidenced by its link to renal fibrosis. Recently, local lactic acidosis has been demonstrated to promote renal fibrosis. Under zinc-deficient conditions, mitochondrial function is compromised and abnormal lactate metabolism might be induced potentially. However, it remains unclear whether zinc deficiency leads to renal fibrosis through local lactic acidosis. Zinc deficiency rat models were successfully established by feeding zinc-deficient diet. Western blot, qPCR, IHC, and other experiments were employed to investigate the key markers and molecular mechanisms of glomerulosclerosis and renal interstitial fibrosis. Our results indicate that zinc deficiency reduces specific markers of podocytes (podocalyxin, WT1, and nephrin) and activates the Wnt3a/ß-catenin pathway, a key pathway in podocyte injury. Concurrently, glomerulosclerosis is indicated by increased urinary microalbumin and serum creatinine levels along with histological alteration observed through PAS and Masson staining in zinc-deficient rats. Furthermore, various degrees of upregulation for several markers of interstitial fibrosis including α-SMA, FN1 and collagen III are also revealed. These findings were further confirmed by Masson staining and IHC. Additionally, alterations in four markers in the EMT process, N-cadherin, E-cadherin, Vimentin, and snail, were consistent with expectations. We then confirmed the activation of the non-canonical TGF-ß1 pathway known as the PI3K/AKT/mTOR pathway. An elevation in renal ROS levels accompanied by increased mitochondrial marker cytochrome C expression as well as an elevated NADH/NAD + ratio is also observed within the kidneys. Furthermore, the activity of both MMP/TIMP system and fibrinolytic system was abnormally enhanced under zinc deficiency conditions. Finally, we find zinc supplementation could significantly ameliorate relevant pathological alterations induced by zinc deficiency. These results collectively point that zinc deficiency causes podocyte damage ultimately resulting in glomerulosclerosis via accumulation of ROS and induces interstitial fibrosis via lactic acidosis.

A Case Report on Primary Collapsing Glomerulopathy in a Filipino Post-partum Female and An Updated Review of Literature.

Collapsing Glomerulopathy (CG) is a rare entity presenting as nephrotic syndrome and rapidly progressive renal deterioration. It has been first identified among African-American patients and subsequently dubbed HIV-associated nephropathy after a number of patients with HIV were found to have CG. It has re-emerged recently among patients with COVID-19. To our knowledge, this is the first case of primary collapsing glomerulopathy in the country to be published. The case is a 36-year-old Filipino female admitted due to bipedal edema which started 2 weeks post-partum. She has no comorbidities and social history was negative for illicit drug use. Initial work up showed hypoalbuminemia and diffuse hepatic disease on ultrasound. She was referred to a gastroenterologist where albumin infusion and paracentesis was done but with no improvement. She developed anasarca and was admitted. Paracentesis obtained minimal ascitic fluid. Serum ascites albumin gradient was low and baseline laboratories showed high creatinine, hypoalbuminemia, and albuminuria. 24-hour urine protein was 11 grams, ANA and anti-DsDNA were negative and c3 and c4 levels were normal. Hepatitis profile was negative for infection. Abdominal CT scan revealed multiple hypoenhancing lesions. Tumor markers CA-125, CA 19-9 and CA 15-3 were high. Breast ultrasound showed simple breast cyst. Gynecology consult was called where pap smear was negative for atypical cells. Surgery service recommended monitoring for the pancreatic and breast lesions. Kidney biopsy was delayed due to new onset bacterial pneumonia. COVID-19 RT-PCR test was negative. Patient was discharged improved with no edema. On follow up, the kidney biopsy result came out to be collapsing glomerulopathy. HIV test was then done and was negative. Bipedal edema and albuminuria recurred. She was started on tacrolimus. She has been on regular follow up and currently has no edema, no proteinuria and normal creatinine level. This is an interesting case as the primary glomerular disease has been masked by the earlier laboratory findings which led us to think of liver disease then a paraneoplastic nephrotic syndrome. Ultimately, the renal biopsy revealed the diagnosis. This serves as an index case for primary collapsing glomerulopathy in a Filipino patient on remission after being treated with tacrolimus.

Clinical characteristics and favorable treatment responses of recurrent focal segmental glomerulosclerosis or steroid-resistant nephrotic syndrome in children after kidney transplantation.

BACKGROUND: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. METHODS: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. RESULTS: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. CONCLUSIONS: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents.

Long-term outcomes of adults with FSGS in the German Chronic Kidney Disease cohort.

Background: Focal segmental glomerulosclerosis (FSGS) can lead to kidney failure in adults. This study examines the progression of FSGS in the German Chronic Kidney Disease (GCKD) cohort. Methods: The GCKD study (N = 5217), a prospective cohort, included 159 patients with biopsy-confirmed FSGS recruited from 2010 to 2012. Baseline was defined as the first study visit. Adjudicated endpoints included a composite kidney endpoint (CKE), including an estimated glomerular filtration rate (eGFR) decrease >40%, eGFR <15 ml/min/1.73 m2 or initiation of kidney replacement therapy and combined major adverse cardiovascular events (MACE), including non-fatal myocardial infarction or stroke and all-cause mortality. Associations between baseline demographics, laboratory data, comorbidity and CKE and MACE were analysed using the Cox proportional hazards regression model. Results: The mean age at baseline was 52.1 ± 13.6 years, with a disease duration of 4.72 years (quartile 1: 1; quartile 3: 6) before joining the study. The median urinary albumin:creatinine ratio (UACR) at baseline was 0.7 g/g (IQR 0.1;1.8), while mean eGFR was 55.8 ± 23 ml/min/1.73 m2. Based on clinical and pathological features, 69 (43.4%) patients were categorized as primary FSGS, 55 (34.6%) as secondary FSGS and 35 (22%) as indeterminate. Over a follow-up of 6.5 years, 44 patients reached the composite kidney endpoint and 16 individuals had at least one MACE. UACR ≥0.7 g/g was strongly associated with both the composite kidney endpoint {hazard ratio [HR] 5.27 [95% confidence interval (CI) 2.4-11.5]} and MACE [HR 3.37 (95% CI 1.05-10.82)] compared with <0.7 g/g, whereas a higher eGFR at baseline (per 10 ml/min) was protective for both endpoints [HR 0.8 (95% CI 0.68-0.95) and HR 0.63 (95% CI 0.46-0.88), respectively]. Patients with secondary FSGS experienced a greater rate of eGFR decline than patients with primary FSGS. Conclusions: Lower eGFR and higher albuminuria are key risk factors for kidney disease progression and cardiovascular events in patients with FSGS.

A family with neuronal intranuclear inclusion disease with focal segmental glomerulosclerosis.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events. METHODS: Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis. RESULTS: ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case. CONCLUSIONS: This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS.

Relapse during and after regular single-dose rituximab treatment in adult patients with steroid-dependent nephrotic syndrome.

BACKGROUND: Rituximab is widely used in patients with steroid-dependent nephrotic syndrome. However, information on the effect of long-term rituximab treatment is limited. This study examined the efficacy of rituximab during and after treatment in adult patients with steroid-dependent nephrotic syndrome. METHODS: This retrospective cohort study included 30 patients with steroid-dependent nephrotic syndrome. Patients received regular single-dose rituximab (500 mg) intravenously every 6 months. Discontinuation of rituximab was considered after four to six doses if there was no recurrence of nephrotic syndrome. Glucocorticoid discontinuation with remission, first relapse after rituximab initiation, and relapse after regular rituximab treatment discontinuation were evaluated. RESULTS: The median age was 38 (range 18-67) years. Of 30 patients, 13 and 17 were men and women, respectively. Prior to rituximab treatment, the median number of nephrotic syndrome relapses in the patients was 5 (range 2- > 20). The 1 year discontinuation rate of glucocorticoids with remission was 83%. All patients discontinued glucocorticoid treatment at least once until 3 years and 7 months. The 1 and 2 year relapse rates after initiation of rituximab treatment were 0% and 3%, respectively. 25 patients discontinued regular rituximab treatment after a median number of six (4-12) doses. Six patients relapsed after discontinuing rituximab, and the 1 and 2 year relapse rates after the last regular rituximab treatment were 9% and 25%, respectively. CONCLUSION: All patients with steroid-dependent nephrotic syndrome who received rituximab could discontinue glucocorticoid treatment with remission, and three-fourths of the patients remained in remission for > 2 years after discontinuing rituximab treatment.

Clinical Course of Nonresponders With Recurrent Focal Segmental Glomerulosclerosis After Pediatric Kidney Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation and is associated with poor graft survival. Patients who do not achieve remission (nonresponders) have an especially poor graft survival. However, the characteristics that may affect graft survival in nonresponders are unknown. This study aimed to determine the clinical characteristics associated with graft survival in nonresponders. METHODS: We retrospectively collected the clinical records of patients with FSGS and an age at onset <16 years who experienced posttransplant recurrence of FSGS at six hospitals in Japan from 1993 to 2018. RESULTS: Eight nonresponders with recurrent FSGS were enrolled in this study. The median time to recurrence after kidney transplantation was 1 day (interquartile range, 1-2 days). All patients received therapeutic plasma exchange and methylprednisolone pulse therapy. Rituximab was used as an add-on therapy in three patients. Five patients lost their graft within 2 years after kidney transplantation (rapid group). In contrast, three patients had much longer graft survival (nonrapid group). We compared the clinical characteristics of the rapid and nonrapid groups. Proteinuria tended to be lower in the nonrapid group at the third and subsequent months of therapy. The rapid group had persistent nephrotic syndrome. The rate of reduction in proteinuria was lower in the rapid group than in the nonrapid group. CONCLUSIONS: Our study suggests that persistent nephrotic syndrome and a low rate of reduction in proteinuria may predict rapid progression to graft failure in nonresponders.

The effect of porang (Amorphophallus muelleri) extract on renal histopathological changes.

Diabetes mellitus is a chronic condition defined by elevated blood sugar levels (hyperglycemia). This condition can lead to complications such as nephropathy, which is histologically shown with glomerulosclerosis. Glucomannan, a component of Amorphophallus muelleri, offers numerous health benefits, but its direct therapeutic effect on glomeruli remains uncertain. Male Wistar rats which were taken with random sampling (n = 30) were distributed into six distinct groups. All groups, excluding Group N, received 125 mg/kg BW single intraperitoneal dose of alloxan. Group N received a single dose of PBS 125 mg/kg BW. After 7 days, Group K + was induced with acarbose at a dose of 50 mg/70 kg BW (adjusted using a factor of 0.018) orally per day. Groups N and K - induced with 1% CMC Na at 0.2 mL/0.1 kg orally per day. While Group P1, P2, and P3 were orally given A. muelleri ethanolic extract orally per day at a dose of 100, 200, and 400 mg/kg BW. The following 50 days of treatment, the Wistar rats were euthanized, and their kidney was preserved for histological slides that were stained with hematoxylin and eosin. The oral administration of A. muelleri ethanolic extract in alloxan-induced diabetic rats led to a significant decrease in the average of glomerulosclerosis instances when compared to the K - group. The most effective dose was observed at 400 mg/kg BW per day. A. muelleri administration leads to a reduction in glomerulosclerosis occurrences, suggesting its potential as a therapeutic approach for reducing complications probability linked to hyperglycemia.

Idiopathic nodular glomerulosclerosis: a case report.

Idiopathic nodular glomerulosclerosis (ING) is a rare condition characterized by poor renal prognosis. The pathophysiology remains incompletely understood. Histologically, it closely resembles diabetic nephropathy. The development of this disease seems to be influenced by factors such as metabolic syndrome, particularly hypertension and glucose intolerance, along with active smoking. We report a case of ING in an obese 71-year-old male patient who had a long history of untreated hypertension and smoking. The patient underwent conservative treatment involving the administration of an angiotensin-2 receptor antagonist and dapagliflozin, resulting in favorable disease progression. Additional therapeutic measures, such as discontinuation of smoking and efforts toward weight loss, are strongly advised. Furthermore, regular screening for diabetes in the follow-up is crucial, as it can play a pathophysiological role in the disease and may manifest at a later stage, as observed in our clinical case.

Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease.

Elevated interferon (IFN) signaling is associated with kidney diseases including COVID-19, HIV, and apolipoprotein-L1 (APOL1) nephropathy, but whether IFNs directly contribute to nephrotoxicity remains unclear. Using human kidney organoids, primary endothelial cells, and patient samples, we demonstrate that IFN-γ induces pyroptotic angiopathy in combination with APOL1 expression. Single-cell RNA sequencing, immunoblotting, and quantitative fluorescence-based assays reveal that IFN-γ-mediated expression of APOL1 is accompanied by pyroptotic endothelial network degradation in organoids. Pharmacological blockade of IFN-γ signaling inhibits APOL1 expression, prevents upregulation of pyroptosis-associated genes, and rescues vascular networks. Multiomic analyses in patients with COVID-19, proteinuric kidney disease, and collapsing glomerulopathy similarly demonstrate increased IFN signaling and pyroptosis-associated gene expression correlating with accelerated renal disease progression. Our results reveal that IFN-γ signaling simultaneously induces endothelial injury and primes renal cells for pyroptosis, suggesting a combinatorial mechanism for APOL1-mediated collapsing glomerulopathy, which can be targeted therapeutically.

Discovery of pyridazinone derivatives bearing tetrahydroimidazo[1,2-a]pyrazine scaffold as potent inhibitors of transient receptor potential canonical 5 to ameliorate hypertension-induced renal injury in rats.

Transient receptor potential canonical 5 (TRPC5) is a calcium-permeable non-selective cation channel involved in various pathophysiological processes, including renal injury. Recently, GFB-887, an investigational pyridazinone TRPC5 inhibitor, demonstrated significant therapeutic potential in a Phase II clinical trial for focal segmental glomerulosclerosis (FSGS), a rare and severe form of chronic kidney disease (CKD). In the current study, based on the structure of GFB-887, we conducted extensive structural modification to explore novel TRPC5 inhibitors with desirable drug-like properties and robust nephroprotective efficacy. A series of pyridazinone derivatives featuring a novel tetrahydroimidazo[1,2-a]pyrazine scaffold were synthesized and their activities were evaluated in HEK-293 cells stably expressing TRPC5 using a fluorescence-based Ca2+ mobilization assay. Among these compounds, compound 12 is turned out to be a potent TRPC5 inhibitor with apparent affinity comparable to the parent compound GBF-887. Compound 12 is highly selective on TRPC4/5 over TRPC3/6/7 and hERG channels, along with acceptable pharmacokinetic properties and a favorable safety profile. More importantly, in a rat model of hypertension-induced renal injury, oral administration of compound 12 (10 mg/kg, BID) efficaciously reduced mean blood pressure, inhibited proteinuria, and protected podocyte damage. These findings further confirmed the potential of TRPC5 inhibitors on the CKD treatment and provided compound 12 to be a valuable tool for exploring TRPC4/5 pathophysiology.

INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death.

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)-a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression.

Design and baseline characteristics of the Finerenone, in addition to standard of care, on the progression of kidney disease in patients with Non-Diabetic Chronic Kidney Disease (FIND-CKD) randomized trial.

BACKGROUND AND HYPOTHESIS: Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney, and cardiovascular outcomes in patients with CKD and T2D in two Phase 3 outcome trials. The FIND-CKD study investigates the effect of finerenone in adults with CKD without diabetes. METHODS: FIND-CKD (NCT05047263 and EU CT 2023-506897-11-00) is a randomized, double-blind, placebo-controlled Phase 3 trial in patients with CKD of non-diabetic aetiology. Adults with a urinary albumin-creatinine ratio (UACR) of ≥ 200 to ≤3500 mg/g and eGFR ≥ 25 to <90 mL/min/1.73 m2 receiving a maximum tolerated dose of a renin-angiotensin-system (RAS) inhibitor were randomized 1:1 to once daily placebo or finerenone 10 or 20 mg depending on eGFR above or below 60 mL/min/1.73 m2. The primary efficacy outcome is total eGFR slope, defined as the mean annual rate of change in eGFR from baseline to Month 32. Secondary efficacy outcomes include a combined cardiorenal composite outcome comprising time to kidney failure, sustained ≥57% decrease in eGFR, hospitalization for heart failure, or cardiovascular death, as well as separate kidney and cardiovascular composite outcomes. Adverse events are recorded to assess tolerability and safety. RESULTS: Across 24 countries, 3231 patients were screened and 1584 were randomized to study treatment. The most common causes of CKD were chronic glomerulonephritis (57.0%) and hypertensive/ischaemic nephropathy (29.0%). Immunoglobulin A nephropathy was the most common glomerulonephritis (26.3% of the total population). At baseline, mean eGFR and median UACR were 46.7 mL/min/1.73 m2 and 818.9 mg/g, respectively. Diuretics were used by 282 participants (17.8%), statins by 851 (53.7%), and calcium channel blockers by 794 (50.1%). SGLT2 inhibitors were used in 16.9% of patients; these individuals had a similar mean eGFR (45.6 vs 46.8 mL/min/1.73 m2) and slightly higher median UACR (871.9 vs 808.3 mg/g) compared to those not using SGLT2 inhibitors at baseline. CONCLUSIONS: FIND-CKD is the first Phase 3 trial of finerenone in patients with CKD of non-diabetic aetiology.

C4d expression in focal segmental glomerulosclerosis.

BACKGROUND: There is a little information about of expression of C4d (complement fragment) in Focal segmental glomerulosclerosis (FSGS) subtypes. Our aim was to determine the expression of C4d in FSGS subtypes in percutaneous native renal biopsies in a second-level hospital and its correlation with clinical, biochemical and histological variables. MATERIAL AND METHODS: A retrospective study in paraffin blocks of patients with biopsy with FSGS aged 16-65 years, indistinct sex, not diabetic or obese. Immunohistochemistry was performed for C4d and their expression was analyzing in non-sclerosed glomerular capillaries (GC) and sclerosis areas (SA). Clinical and biochemical variables were recorded. The cases were divided into C4d positive and C4d negative groups and compared. The correlation between C4d staining scores in CG and SA with clinical and biochemical variables were analyzed. RESULTS: Twenty samples were analyzed, 4 for each subtype. At the time of biopsy average age 38.8 ±â€¯18.6 years, 65% male, 8.7% were hypertension. The percentage of positivity for C4d was 40% in GC, 30% SA and 35% in mesangium. The highest expression was for cellular and collapsing subtypes. C4d positivity cases had increased proteinuria (p = 0.035). A significant correlation was found between percentage of C4d expression in CG with SA (p = 0.012) and SA with tubular atrophy and interstitial fibrosis (p < 0.05). CONCLUSIONS: C4d expression in FSGS predominated in the cellular and collapsing subtypes, which translates complement activation. C4d is a possible surrogate marker in GSFS.