The sGC Activator Runcaciguat Has Kidney Protective Effects and Prevents a Decline of Kidney Function in ZSF1 Rats.

Chronic kidney disease (CKD) progression is associated with persisting oxidative stress, which impairs the NO-sGC-cGMP signaling cascade through the formation of oxidized and heme-free apo-sGC that cannot be activated by NO. Runcaciguat (BAY 1101042) is a novel, potent, and selective sGC activator that binds and activates oxidized and heme-free sGC and thereby restores NO-sGC-cGMP signaling under oxidative stress. Therefore, runcaciguat might represent a very effective treatment option for CKD/DKD. The potential kidney-protective effects of runcaciguat were investigated in ZSF1 rats as a model of CKD/DKD, characterized by hypertension, hyperglycemia, obesity, and insulin resistance. ZSF1 rats were treated daily orally for up to 12 weeks with runcaciguat (1, 3, 10 mg/kg/bid) or placebo. The study endpoints were proteinuria, kidney histopathology, plasma, urinary biomarkers of kidney damage, and gene expression profiling to gain information about relevant pathways affected by runcaciguat. Furthermore, oxidative stress was compared in the ZSF1 rat kidney with kidney samples from DKD patients. Within the duration of the 12-week treatment study, kidney function was significantly decreased in obese ZSF1 rats, indicated by a 20-fold increase in proteinuria, compared to lean ZSF1 rats. Runcaciguat dose-dependently and significantly attenuated the development of proteinuria in ZSF1 rats with reduced uPCR at the end of the study by -19%, -54%, and -70% at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo treatment. Additionally, average blood glucose levels measured as HbA1C, triglycerides, and cholesterol were increased by five times, twenty times, and four times, respectively, in obese ZSF1 compared to lean rats. In obese ZSF1 rats, runcaciguat reduced HbA1c levels by -8%, -34%, and -76%, triglycerides by -42%, -55%, and -71%, and cholesterol by -16%, -17%, and -34%, at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo. Concomitantly, runcaciguat also reduced kidney weights, morphological kidney damage, and urinary and plasma biomarkers of kidney damage. Beneficial effects were accompanied by changes in gene expression that indicate reduced fibrosis and inflammation and suggest improved endothelial stabilization. In summary, the sGC activator runcaciguat significantly prevented a decline in kidney function in a DKD rat model that mimics common comorbidities and conditions of oxidative stress of CKD patients. Thus, runcaciguat represents a promising treatment option for CKD patients, which is in line with recent phase 2 clinical study data, where runcaciguat showed promising efficacy in CKD patients (NCT04507061).

Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney disease.

Oxidative stress is a key concept in basic, translational, and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. Although attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically have gained further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells, and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular antioxidative glutathione stores. Vanin-1-deficient mice were shown to be protected against oxidative stress damage. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress-related acute or chronic kidney injury as well. By studying renal ischemia-reperfusion injury in Col4α3-/- (Alport syndrome) mice and in vitro hypoxia-reoxygenation in human proximal tubular cells we found that treatment with a selective and potent Vanin-1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigation and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.

Effects of Finerenone Combined with Empagliflozin in a Model of Hypertension-Induced End-Organ Damage.

INTRODUCTION: The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in CKD patients with type 2 diabetes. Clinical data analyzing the potential value of a combination therapy are currently limited. We therefore investigated cardiorenal protection of respective mono- and combination therapy in a preclinical model of hypertension-induced end-organ damage. METHODS: Cardiovascular (CV) morbidity and mortality were studied in hypertensive, N(ω)-nitro-L-arginine methyl ester-treated, renin-transgenic (mRen2)27 rats. Rats (10- to 11-week-old females, n = 13-17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Key outcome parameters included mortality, proteinuria, plasma creatinine and uric acid, blood pressure, and cardiac and renal histology. RESULTS: Placebo-treated rats demonstrated a 50% survival rate over the course of 7 weeks. Drug treatment resulted in variable degrees of survival benefit, most prominently in the low-dose combination group with a survival benefit of 93%. Monotherapies of finerenone or empagliflozin dose-dependently reduced proteinuria, while low-dose combination revealed an early, sustained, and over-additive reduction in proteinuria. Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone coadministration in the combination arm. Low-dose combination but not respective low-dose monotherapies significantly reduced plasma creatinine and plasma uric acid after 6 weeks. Treatment with finerenone and the low-dose combination significantly decreased systolic blood pressure after 5 weeks. There was a dose-dependent protection from cardiac and kidney fibrosis and vasculopathy with both agents, while low-dose combination therapy was more efficient than the respective monotherapy dosages on most cardiorenal histology parameters. DISCUSSION/CONCLUSIONS: Nonsteroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer CV protection in preclinical hypertension-induced cardiorenal disease. Combination of these 2 independent modes of action at low dosages revealed efficacious reduction in important functional parameters such as proteinuria and blood pressure, plasma markers including creatinine and uric acid, cardiac and renal lesions as determined by histopathology, and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations.

Direct Blood Pressure-Independent Anti-Fibrotic Effects by the Selective Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone in Progressive Models of Kidney Fibrosis.

INTRODUCTION: The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in chronic kidney disease patients with type 2 diabetes. Precise molecular mechanisms responsible for these benefits are incompletely understood. Here, we investigated potential direct anti-fibrotic effects and mechanisms of nonsteroidal MR antagonism by finerenone or SGLT2 inhibition by empagliflozin in 2 relevant mouse kidney fibrosis models: unilateral ureter obstruction and sub-chronic ischemia reperfusion injury. METHODS: Kidney fibrosis was induced in mice via unilateral ureteral obstruction or ischemia. In a series of experiments, mice were treated orally with the MR antagonist finerenone (3 or 10 mg/kg), the SGLT2 inhibitor empagliflozin (10 or 30 mg/kg), or in a direct comparison of both drugs. Interstitial myofibroblast accumulation was quantified via alpha-smooth muscle actin and interstitial collagen deposition via Sirius Red/Fast Green staining in both models. Secondary analyses included the assessment of inflammatory cells, kidney mRNA expression of fibrotic markers as well as functional parameters (serum creatinine and albuminuria) in the ischemic model. Blood pressure was measured via telemetry in healthy conscious compound-treated animals. RESULTS: Finerenone dose-dependently decreased pathological myofibroblast accumulation and collagen deposition with no effects on systemic blood pressure and inflammatory markers in the tested dose range. Reduced kidney fibrosis was paralleled by reduced kidney plasminogen activator inhibitor-1 (PAI-1) and naked cuticle 2 (NKD2) expression in finerenone-treated mice. In contrast, treatment with empagliflozin strongly increased urinary glucose excretion in both models and reduced ischemia-induced albuminuria but had no effects on kidney myofibroblasts or collagen deposition. DISCUSSION/CONCLUSION: Finerenone has direct anti-fibrotic properties resulting in reduced myofibroblast and collagen deposition accompanied by a reduction in renal PAI-1 and NKD2 expression in mouse models of progressive kidney fibrosis at blood pressure-independent dosages.

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators.

The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.

After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy.

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.

Identification of platelet-derived growth factor C as a mediator of both renal fibrosis and hypertension.

Platelet-derived growth factors (PDGF) have been implicated in kidney disease progression. We previously found that PDGF-C is upregulated at sites of renal fibrosis and that antagonism of PDGF-C reduces fibrosis in the unilateral ureteral obstruction model. We studied the role of PDGF-C in collagen 4A3-/- ("Alport") mice, a model of progressive renal fibrosis with greater relevance to human kidney disease. Alport mice were crossbred with PDGF-C-/- mice or administered a neutralizing PDGF-C antibody. Both PDGF-C deficiency and neutralization reduced serum creatinine and blood urea nitrogen levels and mitigated glomerular injury, renal fibrosis, and renal inflammation. Unexpectedly, systolic blood pressure was also reduced in both Alport and wild-type mice treated with a neutralizing PDGF-C antibody. Neutralization of PDGF-C reduced arterial wall thickness in the renal cortex of Alport mice. Aortic rings isolated from anti-PDGF-C-treated wildtype mice exhibited reduced tension and faster relaxation than those of untreated mice. In vitro, PDGF-C upregulated angiotensinogen in aortic tissue and in primary hepatocytes and induced nuclear factor κB (NFκB)/p65-binding to the angiotensinogen promoter in hepatocytes. Neutralization of PDGF-C suppressed transcript expression of angiotensinogen in Alport mice and angiotensin II receptor type 1 in Alport and wildtype mice. Finally, administration of neutralizing PDGF-C antibodies ameliorated angiotensin II-induced hypertension in healthy mice. Thus, in addition to its key role in mediating renal fibrosis, we identified PDGF-C as a mediator of hypertension via effects on renal vasculature and on the renin-angiotensin system. The contribution to both renal fibrosis and hypertension render PDGF-C an attractive target in progressive kidney disease.

Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy.

The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m2: 6-month corticosteroid monotherapy; GFR=30-59 ml/min per 1.73 m2: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m2 during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; P=0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively; P=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m2 did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.

Intensive Supportive Care plus Immunosuppression in IgA Nephropathy.

BACKGROUND: The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain. METHODS: We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio <0.2 [with both protein and creatinine measured in grams] and a decrease in the estimated glomerular filtration rate [eGFR] of <5 ml per minute per 1.73 m(2) of body-surface area from baseline) and a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) at the end of the trial. The primary end points were analyzed with the use of logistic-regression models. RESULTS: The run-in phase was completed by 309 of 337 patients. The proteinuria level decreased to less than 0.75 g of urinary protein excretion per day in 94 patients. Of the remaining 162 patients who consented to undergo randomization, 80 were assigned to the supportive-care group, and 82 to the immunosuppression group. After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the immunosuppression group, had a full clinical remission (P=0.01). A total of 22 patients (28%) in the supportive-care group and 21 (26%) in the immunosuppression group had a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) (P=0.75). There was no significant difference in the annual decline in eGFR between the two groups. More patients in the immunosuppression group than in the supportive-care group had severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment. One patient in the immunosuppression group died of sepsis. CONCLUSIONS: The addition of immunosuppressive therapy to intensive supportive care in patients with high-risk IgA nephropathy did not significantly improve the outcome, and during the 3-year study phase, more adverse effects were observed among the patients who received immunosuppressive therapy, with no change in the rate of decrease in the eGFR. (Funded by the German Federal Ministry of Education and Research; STOP-IgAN ClinicalTrials.gov number, NCT00554502.).

Urinary Biomarkers in the Prediction of Prognosis and Treatment Response in IgA Nephropathy.

BACKGROUND/AIMS: The addition of immunosuppression to supportive care reduces proteinuria in a subset of patients with IgA nephropathy (IgAN) but is associated with an increased rate of adverse events. The present work investigates whether urinary biomarkers are able to identify subjects who benefit from immunosuppression and to predict the progression of disease in a sub-cohort of the STOP-IgAN trial. METHODS: Urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), calprotectin, and the product of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 (TIMP2•IGFBP7) were measured in all available urine samples obtained at the time point of enrollment in the STOP-IgAN trial (n=113). RESULTS: Biomarker concentrations in both the overall study population and the subgroup with additional immunosuppression did not differ in subjects reaching vs. not reaching full clinical remission, eGFR loss ≥ 15, or 30 ml/min/1.73 m2 over the 3-year trial phase (p> 0.05 each). Receiver-operating characteristic curves showed a poor predictive accuracy of each biomarker for the above-mentioned parameters in the overall study population (areas under the curve ≤0.611). Accordingly, there was neither a significant correlation of any biomarker and adverse outcome in linear regression analysis, nor between biomarker concentrations at enrollment and change in the eGFR over the 3-year observation period. CONCLUSION: NGAL, KIM-1, calprotectin, and [TIMP-2]•[IGFBP7] had neither a prognostic value for the progression of IgAN, nor for the response to immunosuppression in the present sub-cohort of the STOP-IgAN trial. The search for appropriate biomarkers for an individualized treatment strategy in IgAN continues.

Renal outcomes of STOP-IgAN trial patients in relation to baseline histology (MEST-C scores).

BACKGROUND: The Oxford classification of IgA nephropathy (IgAN) defines histologic criteria (MEST-C) that provide prognostic information based on the kidney biopsy. There are few data on the predictive impact of this classification in randomized clinical trial settings. METHODS: We performed an exploratory analysis of MEST-C scores in 70 available renal biopsies from 162 randomized STOP-IgAN trial participants and correlated the results with clinical outcomes. Analyses were performed by researchers blinded to the clinical outcome of the patients. Biopsies had been obtained 6.5 to 95 (median 9.4) months prior to randomization. RESULTS: Mesangial hypercellularity (M1) associated with higher annual eGFR-loss during the 3-year trial (M1: - 5.06 ± 5.17 ml/min/1.73 m2, M0: - 0.79 ± 4.50 ml/min/1.73 m2, p = 0.002). An M0-score additionally showed a weak association with full clinical remission, whereas the percentage of patients losing ≥15 ml/min/1.73 m2 over the 3-year trial phase was higher among those scored as M1. Among patients with additional immunosuppression, ESRD occurred more frequently in patients when tubulointerstitial fibrosis (T1/2) was present (T1/2 = 33%, T0 = 0%, p = 0.008). In patients receiving supportive care only, ESRD frequencies were similar (T1/2 = 18%, T0 = 7%, p = 0.603). At randomization, eGFR was significantly lower when tubulointerstitial fibrosis was present (T1/2: 45.2 ± 15.7 ml/min/1.73 m2, T0: 74.6 ± 28.2 ml/min/1.73 m2, p < 0.0001). Endocapillary hypercellularity (E), and glomerular segmental sclerosis (S) were not associated with any clinical outcome parameter. In the analyzed cohort, patients with glomerular crescents (C1/2 scores) in their biopsies were more likely to develop ESRD during the 3-year trial phase, but this trend was only significant in patients under supportive care. CONCLUSIONS: This secondary analysis of STOP-IgAN biopsies indicates that M1, T1/2 and C1/2 scores associate with worse renal outcomes.

The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective.

Chronic Kidney Disease (CKD) is a highly prevalent disease with a substantial medical need for new and more efficacious treatments. The Nitric Oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine monophosphate (cGMP) signaling cascade regulates various kidney functions. cGMP directly influences renal blood flow, renin secretion, glomerular function, and tubular exchange processes. Downregulation of NO/sGC/cGMP signaling results in severe kidney pathologies such as CKD. Therefore, treatment strategies aiming to maintain or increase cGMP might have beneficial effects for the treatment of progressive kidney diseases. Within this article, we review the NO/sGC/cGMP signaling cascade and its major pharmacological intervention sites. We specifically focus on the currently known effects of cGMP on kidney function parameters. Finally, we summarize the preclinical evidence for kidney protective effects of NO-donors, PDE inhibitors, sGC stimulators, and sGC activators.

Role of platelet-derived growth factor-CC in capillary rarefaction in renal fibrosis.

We have identified platelet-derived growth factor (PDGF)-CC as a potent profibrotic mediator in kidney fibrosis and pro-angiogenic mediator in glomeruli. Because renal fibrosis is associated with progressive capillary rarefaction, we asked whether PDGF-CC neutralization in fibrosis might have detrimental anti-angiogenic effects leading to aggravated peritubular capillary loss. We analyzed capillary rarefaction in mice with and without PDGF-CC neutralization (using genetically deficient mice and neutralizing antibodies), in three different models of renal interstitial fibrosis, unilateral ureteral obstruction, unilateral ischemia-reperfusion, Col4a3-deficient (Alport) mice, and healthy animals. Independent of the effect of PDGF-CC neutralization on renal fibrosis, we found no difference in capillary rarefaction between PDGF-CC-neutralized mice and mice with intact PDGF-CC. We also found no differences in microvascular leakage (determined by extravasation of Evans Blue Dye) and in renal relative blood volume quantified using in vivo microcomputed tomography. PDGF-CC neutralization had no effects on renal microvasculature in healthy animals. Capillary endothelium did not express PDGF receptor-α, suggesting that potential PDGF-CC effects would have to be indirect. PDGF-CC neutralization or deficiency was not associated with preservation or accelerated loss of peritubular capillaries, suggesting no significant pro-angiogenic effects of PDGF-CC during renal fibrosis. From a clinical perspective, the profibrotic effects of PDGF-CC outweigh the pro-angiogenic effects and, thus, do not limit a potential therapeutic use of PDGF-CC inhibition in renal fibrosis.

Con: STOP immunosuppression in IgA nephropathy.

A comprehensive supportive therapy approach constitutes the mainstay treatment of IgA nephropathy (IgAN) patients. In our recent Supportive versus immunosuppressive Therapy Of Progressive IgA Nephropathy (STOP-IgAN) trial, we systematically selected for patients at high risk of a progressive disease course and evaluated the effect of immunosuppression, combined with supportive care, on renal end points in these patients. There was a higher rate of full clinical remission and transient proteinuria reduction in immunosuppressed patients. However, deterioration of renal function (i.e. number of patients with an estimated glomerular filtration rate (eGFR) decrease of at least 15 mL/min over the 3-year trial phase) was remarkably slow in both groups, compared with previous studies, and was not slowed further by adding immunosuppression to supportive care. Here, we address several concerns raised on the design and interpretation of our trial. In our randomized patients, we confirmed a lower baseline proteinuria to be predictive of clinical remission in IgAN. However, the observed transient drop in proteinuria in the immunosuppressed patients did not translate into an improved overall renal outcome in these patients. Although longer follow-up would be desirable, there was not even a trend for the eGFR course to diverge between our two treatment arms during the trial phase. Finally, it is important to note that we excluded specific infrequent patient groups during our run-in phase. Therefore, IgAN patients with a rapidly progressing course and those with persistent proteinuria >3.5 g/day would require further evaluation regarding potential benefits of immunosuppressive therapies.

Nonsteroidal antagonists of the mineralocorticoid receptor.

PURPOSE OF REVIEW: The broad clinical use of steroidal mineralocorticoid receptor antagonists (MRAs) is limited by the potential risk of inducing hyperkalemia when given on top of renin-angiotensin system blockade. Drug discovery campaigns have been launched aiming for the identification of nonsteroidal MRAs with an improved safety profile. This review analyses the evidence for the potential of improved safety profiles of nonsteroidal MRAs and the current landscape of clinical trials with nonsteroidal MRAs. RECENT FINDINGS: At least three novel nonsteroidal MRAs have reportedly demonstrated an improved therapeutic index (i.e. less risk for hyperkalemia) in comparison to steroidal antagonists in preclinical models. Five pharmaceutical companies have nonsteroidal MRAs in clinical development with a clear focus on the treatment of chronic kidney diseases. No clinical data have been published so far for MT-3995 (Mitsubishi), SC-3150 (Daiichi-Sankyo), LY2623091 (Eli Lilly) and PF-03882845 (Pfizer). In contrast, data from two clinical phase II trials are available for finerenone (Bayer) which demonstrated safety and efficacy in patients with heart failure and additional chronic kidney diseases, and significantly reduced albuminuria in patients with diabetic nephropathy. Neither hyperkalemia nor reductions in kidney function were limiting factors to its use. SUMMARY: Novel, nonsteroidal MRAs are currently tested in clinical trials. Based on preclinical and first clinical data, these nonsteroidal MRAs might overcome the limitations of today's steroidal antagonists.

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹°), with heterogeneity detected only at the PSMB9/TAP1 locus (I²â€Š= 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻4). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²8). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.

BACKGROUND: Maintenance therapy, often with azathioprine or mycophenolate mofetil, is required to consolidate remission and prevent relapse after the initial control of lupus nephritis. METHODS: We carried out a 36-month, randomized, double-blind, double-dummy, phase 3 study comparing oral mycophenolate mofetil (2 g per day) and oral azathioprine (2 mg per kilogram of body weight per day), plus placebo in each group, in patients who met response criteria during a 6-month induction trial. The study group underwent repeat randomization in a 1:1 ratio. Up to 10 mg of prednisone per day or its equivalent was permitted. The primary efficacy end point was the time to treatment failure, which was defined as death, end-stage renal disease, doubling of the serum creatinine level, renal flare, or rescue therapy for lupus nephritis. Secondary assessments included the time to the individual components of treatment failure and adverse events. RESULTS: A total of 227 patients were randomly assigned to maintenance treatment (116 to mycophenolate mofetil and 111 to azathioprine). Mycophenolate mofetil was superior to azathioprine with respect to the primary end point, time to treatment failure (hazard ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), and with respect to time to renal flare and time to rescue therapy (hazard ratio, <1.00; P < 0.05). Observed rates of treatment failure were 16.4% (19 of 116 patients) in the mycophenolate mofetil group and 32.4% (36 of 111) in the azathioprine group. Adverse events, most commonly minor infections and gastrointestinal disorders, occurred in more than 95% of the patients in both groups (P = 0.68). Serious adverse events occurred in 33.3% of patients in the azathioprine group and in 23.5% of those in the mycophenolate mofetil group (P = 0.11), and the rate of withdrawal due to adverse events was higher with azathioprine than with mycophenolate mofetil (39.6% vs. 25.2%, P = 0.02). CONCLUSIONS: Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy. (Funded by Vifor Pharma [formerly Aspreva]; ALMS ClinicalTrials.gov number, NCT00377637.).

Platelet-derived growth factor (PDGF)-C neutralization reveals differential roles of PDGF receptors in liver and kidney fibrosis.

Platelet-derived growth factors (PDGF) are key mediators of organ fibrosis. We investigated whether PDGF-C(-/-) mice or mice treated with neutralizing PDGF-C antibodies are protected from bile duct ligation-induced liver fibrosis, and we compared the effects with those of PDGF-C deficiency or neutralization on kidney fibrosis induced by unilateral ureteral obstruction. Unexpectedly, and in contrast to kidney fibrosis, PDGF-C deficiency or antagonism did not protect from liver fibrosis or functional liver impairment. Furthermore, the hepatic infiltration of monocytes/macrophages/dendritic cells and chemokine mRNA expression (CC chemokine ligand [CCL]5, CCL2, and CC chemokine receptor 2 [CCR2]) remained unchanged. Transcript expression of PDGF ligands increased in both liver and kidney fibrosis and was not affected by neutralization of PDGF-C. In kidney fibrosis, PDGF-C deficiency or antagonism led to reduced expression and signaling of PDGF-receptor (R)-α- and PDGFR-ß-chains. In contrast, in liver fibrosis there was either no difference (PDGF-C(-/-) mice) or even an upregulation of PDGFR-ß and signaling (anti-PDGF-C group). Finally, in vitro studies in portal myofibroblasts pointed to a predominant role of PDGF-B and PDGF-D signaling in liver fibrosis. In conclusion, our study revealed significant differences between kidney and liver fibrosis in that PDGF-C mediates kidney fibrosis, whereas antagonism of PDGF-C in liver fibrosis appears to be counteracted by significant upregulation and increased PDGFR-ß signaling. PDGF-C antagonism, therefore, may not be effective to treat liver fibrosis.