Reduction Of Proteinuria Research Articles

RGD-HSA-TAC nanoparticles targeted delivery of tacrolimus and attenuation of podocyte injury in diabetic kidney disease

BackgroundDiabetic kidney disease (DKD) is a prevalent and severe complication of diabetes and plays a pivotal role in the pathogenesis and progression of DKD. However, the current clinical application of the treatment methods does not yield effective results. Tacrolimus has been utilized in the management of immune-mediated and genetic-mediated nephropathy, with an emphasis on the restoration of podocyte cytoskeletal integrity and inhibition of apoptosis. The clinical management of diabetic nephropathy with tacrolimus remains challenging because of the risk of worsening hyperglycemia and infection.ResultsWe developed two RGD-HSA-TAC nanoparticles designed for targeted delivery of tacrolimus to podocytes. Administration of SANPs and CNPs resulted in elevated levels of tacrolimus in podocytes, leading to a reduction in podocyte damage and albuminuria in diabetic nephropathy mice. Furthermore, the use of SANPs and CNPs resulted in a decrease in tacrolimus accumulation in the pancreas, lymph nodes, and thymus, thereby reducing the potential to exacerbate hyperglycemia and infection. Importantly, compared to tacrolimus alone, both SANPs and CNPs demonstrated superior therapeutic efficacy, with CNPs exhibiting a greater advantage over SANPs.ConclusionsCompared to tacrolimus, SANPs and CNPs demonstrated superior therapeutic efficacy and a reduced incidence of adverse effects in the treatment of diabetic nephropathy.Graphical abstract

Proteinuria and tubular cells: Plasticity and toxicity.

Proteinuria is the most robust predictive factors for the progression of chronic kidney disease (CKD), and interventions targeting proteinuria reduction have shown to be the most effective nephroprotective treatments to date. While glomerular dysfunction is the primary source of proteinuria, its consequences extend beyond the glomerulus and have a profound impact on tubular epithelial cells. Indeed, proteinuria induces notable phenotypic changes in tubular epithelial cells and plays a crucial role in driving CKD progression. This comprehensive review aims to elucidate the mechanisms involved in the tubular handling of proteins and explore the potential effects of proteinuria on the function of tubular epithelial cells. This paper is a narrative review. Litterature review was performed on PubMed from its inception until 2024, focusing on the effects of proteinuria on tubular cells. The review highlights the toxic effects of plasma proteins on tubular epithelial cells through signal transduction pathways, as well as endoplasmic reticulum stress activation, oxidative stress, and metabolic alterations. Additionally, it provides an updated understanding of the dynamic phenotypic changes occurring within the nephron in response to proteinuria. By examining the intricate interplay between proteinuria and tubular epithelial cells, this review sheds light on key factors contributing to CKD progression and unveils potential targets for therapeutic interventions.

Stem cells prevent long-term deterioration of renal function after renal artery revascularization in a renovascular hypertension model in rats

Partial stenosis of the renal artery causes renovascular hypertension (RVH) and is accompanied by chronic renal ischemia, resulting in irreversible kidney damage. Revascularization constitutes the most efficient therapy for normalizing blood pressure (BP) and has significant benefits for renal function; however, the tissue damage caused by chronic hypoxia is not fully reversed. Mesenchymal stem cells (MSCs) have produced discrete results in minimizing RVH and renal tissue and functional improvements since the obstruction persists. This study aimed to evaluate the effects of administration of MSCs in combination with renal artery revascularization in rats subjected to RVH. The following groups were evaluated: control (SHAM), hypertensive (2K-1C), hypertensive treated with MSCs (MSC), hypertensive subjected to revascularization (REV), and hypertensive subjected to revascularization and treatment with MSCs (REV + MSC). The animals were followed up for 10 weeks. The animals in the MSC group received cell infusions at the 3rd, 5th, 7th and 9th weeks. In the REV and REV + MSC groups, the clip was removed by the 6th week (revascularization), and in the REV + MSC group, MSCs infusion was performed at the 6th and 8th weeks. Tail systolic blood pressure (SBP) was measured weekly, and histological parameters and renal function were evaluated at the end of the protocol. The clipped animals developed RVH, deterioration of total renal function (50% decrease in creatinine clearance), and significant proteinuria (15x increase). Treatment with MSCs had no detectable beneficial effects on kidney function or SBP. REV resulted in normalization of BP and a significant but partial reduction in proteinuria (80% vs. 2K-1C), but areas with renal fibrosis persisted. The combination of the two treatments was effective at normalizing all renal parameters as well as reversing proteinuria, reducing the number of ischemic glomeruli and atrophic tubules, indicating an improvement of the renal parenchyma. The results suggest that therapy with MSCs associated with revascularization can potentially help in the full recovery of renal function in the long term in patients with RVH.

Use of SGLT2i in Non-Diabetic Kidney Transplant Recipients.

The potential anti-proteinuric effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) is of special interest in kidney transplantation. Its benefits have been demonstrated in diabetic kidney transplant recipients (KTRs). We analyzed the efficacy and safety of SGLT2i in non-diabetic KTRs collecting clinical and analytical data at baseline and 6 months after the introduction of the drug. We performed a unicenter observational study including all non-diabetic KTRs who were prescribed SGLT2i as antiproteinuric therapy. We analyzed clinical and analytical data at baseline and after 6 months of starting SGLT2i. We included 22 patients (68.2% men), median age 58 years, with a median post-transplant period of 67 months. Hypertension was present in 95% of the patients, 90% had dyslipidemia, and 68.2% were receiving treatment with renin-angiotensin-aldosterone system blockade agents plus antialdosterone drugs. The most used SGLT2i was dapagliflozin (91%). The median baseline creatinine was 2.1 (1.48 to 2.85) mg/dL, estimated glomerular filtrate rate (eGFR) 31 (23.7 to 45,2) mL/min, and urinary protein/creatinine ratio 1.68 (0.58 to 2.9) g/g. After 6 months of follow-up, we found a significant reduction in proteinuria (1.68 to 1.06 g/g, P = .025), as well as a reduction in uric acid and high-density lipoprotein (HDL). There was a mild significant reduction in eGFR (31 to 28.5 mL/min, P = .001), which was greater in patients with recurrence of the underlying disease or chronic rejection. The drug was discontinued in two patients (9.1%): one due to a urinary tract infection (UTI) and another one due to hemodialysis initiation. There were no cardiovascular events or death. The use of SGLT2i in our cohort was effective to reduce proteinuria in non-diabetic KTRs after 6 months of treatment with an acceptable safety profile.

Blood Pressure Management Strategies and Podocyte Health.

Hypertension (HTN) is one of the key global cardiovascular risk factors, which is tightly linked to kidney health and disease development. Podocytes, glomerular epithelial cells that play a pivotal role in maintenance of the renal filtration barrier, are significantly affected by increased glomerular capillary pressure in HTN. Damage or loss of these cells causes proteinuria, which marks the initiation of the HTN-driven renal damage. It goes without saying that effective blood pressure (BP) management should not only mitigate cardiovascular risks but also preserve renal function by protecting podocyte integrity. This review offers a comprehensive examination of current BP management strategies and their implications for podocyte structure and function and emphasizes strategies for the reduction of proteinuria in HTN. We explore primary and secondary antihypertensive agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics, as well as newer therapies (sodium-glucose cotransporter-2 blocking and endothelin receptor antagonism), emphasizing their mechanistic roles in safeguarding podocytes and curtailing proteinuria.

Cellular cross-talk drives mesenchymal transdifferentiation in diabetic kidney disease.

While changes in glomerular function and structure may herald diabetic kidney disease (DKD), many studies have underscored the significance of tubule-interstitial changes in the progression of DKD. Indeed, tubule-interstitial fibrosis may be the most important determinant of progression of DKD as in many forms of chronic glomerulopathies. The mechanisms underlying the effects of tubular changes on glomerular function in DKD have intrigued many investigators, and therefore, the signaling mechanisms underlying the cross-talk between tubular cells and glomerular cells have been the focus of investigation in many recent studies. Additionally, the observations of slowing of glomerular filtration rate (GFR) decline and reduction of proteinuria by recent drugs such as SGLT-2 blockers, whose primary mechanism of action is on proximal tubules, further strengthen the concept of cross-talk between the tubular and glomerular cells. Recently, the focus of research on the pathogenesis of DKD has primarily centered around exploring the cross-talk between various signaling pathways in the diabetic kidney as well as cross-talk between tubular and glomerular endothelial cells and podocytes with special relevance to epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). The focus of this review is to provide a general description of cell-to-cell cross-talk in the diabetic kidney and to highlight these concepts with evidence in relation to the physiology and pathophysiology of DKD.

Which Immunosuppressive Therapy should be used in Primary Membranous Glomerulonephritis?

Background: Different results have been reported on immunosuppressive treatments in patients with primary membranous nephropathy. In recent years, it has been determined that antiPLA2R antibodies can be used for the diagnosis of primary membranous glomerulonephritis. The aim of this study was to investigate the treatment responses of patients with primary membranous glomerulonephritis determined by the presence of PLA2-R antibody. Patients and Methods: Sixty patients (M:29, F:31) with membranous glomerulonephritis were retrospectively investigated. The presence of glomerular PLA2R antibodies were investigated by immunohistochemical method from the pathological specimen. Those patients were treated with immunosuppressants (methylprednisolon, cyclophosphamide, cyclosporine, azathioprine), and angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB). The treatments were carried out with different combinations. The success of the treatment was defined as complete (<0.3g/day), partial (<3.5g/day or at least 50% reduction) or unresponsive (insufficient reduction) according to the reduction in proteinuria. In the patients, progression risks (low, moderate, high) were divided according to proteinuria and creatinine clearance. The results of immunosuppressive treatments were statistically analyzed, and p<0.05 was accepted significant. Results Glomerular PLA2R antibodies were positive in 50 cases (87.7%), negative in 7 cases (12.2%). The mean duration of treatment of the patients was 23 months (6-58 months). With the treatment of PLA2R antibody-positive patients, 29% developed complete remission, 56% partial remission, and 15% did not respond. Complete remission was achieved only by steroid plus cyclophosphamide or cyclosporine combinations. The overall response (complete plus partial) rates were similar (respectively, 91% and 89%) in cyclophosphamide or cyclosporine treatment with steroids. The reduction rates in proteinuria were 70.6% in patients using cyclophosphamide, steroid, and ARB, and 79.5% in patients using cyclosporine, steroid, and ARB; there was no difference between them (P=0.67). In patients with positive PLA2R antibodies, the risk of progression was low in 25%, moderate in 29%, and high in 46%. When the treatment responses were examined, a lower rate of complete remission and higher partial remission were found in the high-risk group than in the low-risk group. However, overall response rates were not different in risk groups. Conclusion In primary membranous glomerulonephritis, only cyclophosphamide or combinations of cyclosporine and steroids provided complete remission. The complete plus partial response rates were similar in all risk groups.

Early reduction in total cholesterol to high-density lipoprotein cholesterol ratio predicts hydroxychloroquine efficacy in treating IgA nephropathy

Background Hydroxychloroquine (HCQ) effectively improves lipid levels in patients with autoimmune diseases. This study aimed to examine the effect of HCQ on lipid profiles in patients with immunoglobulin A (IgA) nephropathy (IgAN) and determine whether alterations in lipid profiles can predict the efficacy of HCQ. Methods This study retrospectively analyzed 77 patients, and the total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) decline rate after 3 months of HCQ treatment was selected as a predictor based on receiver operating curve analysis. Patients were then divided into low and high TC/HDL-C decline rate groups based on the optimal cutoff value. The Cox proportional hazard model and Kaplan–Meier curve were used to evaluate the value of the TC/HDL-C decline rate in predicting the efficacy of HCQ in patients with IgAN. Results Patients in the high TC/HDL-C decline rate group with ≥50% decrease in proteinuria from baseline experienced a significant improvement during the follow-up. Kaplan–Meier analysis revealed that a high TC/HDL-C decline rate was strongly associated with a higher proteinuria reduction rate in patients with IgAN. Furthermore, multivariate Cox analysis indicated that a higher reduction in the TC/HDL-C ratio (hazard ratio: 2.314; 95% confidence interval: 1.234–4.340; p = 0.009) was an independent predictive indicator for achieving ≥50% reduction in proteinuria with HCQ therapy in IgAN. Conclusion HCQ effectively improves lipid profiles in patients with IgAN, and an early decrease in the TC/HDL-C ratio serves as a predictor of better outcomes in patients treated with HCQ.

Efficacy and safety of rituximab in primary IgA nephropathy: a retrospective study.

The study aimed to evaluate the efficacy and safety of rituximab (RTX) in primary IgA nephropathy (IgAN). A retrospective review was conducted on the medical records of 22 patients diagnosed with primary IgAN who received RTX treatment. The clinical data, including blood tests, urine examinations and estimated glomerular filtration rate (eGFR), were analyzed at four time point: baseline, 3months, 6months and 12months. Adverse events were also recorded. Our study included 9 male and 13 female participants. The level of serum albumin significantly increased after three months with RTX applied (P < 0.01). Furthermore, we observed a significant reduction in microalbuminuria and urine albumin-to-creatinine ratio at twelve months (P < 0.01). However, there was no change in serum creatinine (P = 0.08), urinary red blood cell (P = 0.11) or eGFR (P = 0.09) during the course of one year. Two cases achieved complete remission, while eleven cases experienced partial remission, resulting in an overall remission rate of 50.0%. During the treatment period, three patients developed infections and two patients encountered infusion-related adverse reactions. In our retrospective study, RTX demonstrated a significant improvement in serum albumin levels and a reduction in proteinuria among primary IgAN patients. Although no statistically significant difference was observed in terms of renal function, there was an observable trend towards improvement. Therefore, we propose that RTX may be an alternative treatment option for primary IgAN patients who cannot tolerate glucocorticoids or immunosuppressants.

Pharmacokinetic Aspects of Hydroxychloroquine and Its Relationship to Efficacy in Immunoglobulin A Nephropathy

Introduction: Hydroxychloroquine (HCQ) is recommended for Chinese patients with immunoglobulin A nephropathy (IgAN). This study aimed to investigate the pharmacokinetics of HCQ in the treatment of IgAN and its relationship with therapeutic efficacy. Methods: This prospective study included 49 IgAN patients treated with HCQ, who were divided into effective and ineffective groups based on HCQ treatment efficacy after 6 months, defined as a reduction in proteinuria of at least 50% from baseline. The concentrations of HCQ and its metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry. The relationships between the concentrations of HCQ and its metabolites and therapeutic efficacy were analyzed using linear correlation analysis and logistic regression. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of HCQ and its metabolite concentrations. Results: Following 6 months of treatment with HCQ, patients in the effective group exhibited increased concentrations of HCQ (p = 0.022) and desethylchloroquine (DCQ) (p = 0.015). The results of the Spearman’s correlation analysis indicated a positive correlation between alterations in proteinuria and concentrations of HCQ (r = 0.328, p < 0.05) and DCQ (r = 0.267, p < 0.05). Univariate and multivariate logistic regression analyses indicated that efficacy was significantly correlated with HCQ (odds ratio 1.008, 95% CI: 1.001–1.014) and DCQ (odds ratio 1.064, 95% CI: 1.010–1.121) concentrations. ROC curves indicated that an HCQ concentration of 442.6 ng/mL and a DCQ concentration of 42.7 ng/mL exhibited the optimal capacity to predict efficacy (p < 0.05). Conclusion: The blood concentrations of HCQ and its metabolite DCQ may be significant factors for evaluating therapeutic efficacy in IgAN patients.

Tacrolimus to belatacept conversion in proteinuric kidney transplant recipients.

Proteinuria is associated with worse allograft outcomes in kidney transplant recipients (KTRs) and treatment strategies are limited. We examined the outcomes of calcineurin inhibitor (CNI) to belatacept conversion in proteinuric KTRs. In a pilot phase II single-arm multicenter prospective trial, we recruited adult KTRs >6 months post-kidney transplantation with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m2 and proteinuria >1 g/day. Patients were converted from CNI to belatacept. The primary outcome was a 25% reduction in proteinuria at 12 months. A total of 15 KTRs were recruited who had pre-conversion median (interquartile range) proteinuria of 1.8 (IQR 1.4 - 3.5) g/g and estimated glomerular filtration rate (eGFR) of 48 (IQR 32 - 52.5) ml/min/1.73m2. At 12 months post-conversion, median proteinuria was 1.4 (IQR 0.4 - 2.2) g/g (P = 0.068) and eGFR was maintained at 43 (34 - 54.5) ml/min/1.73m2. The primary outcome of at least a 25% reduction in proteinuria occurred in 53% (8/15) at 12 months. Abbreviated IBOX scores predicting 7-year graft survival were also stable at 1-year post-conversion compared to baseline. At extended follow-up at 5 years, both proteinuria and eGFR remained stable at 0.69 (0.24 - 2.15) g/g and 39 (31 - 57) ml/min/1.73m2, respectively. CNI to belatacept conversion was associated with preserved allograft function in KTRs with significant proteinuria. These findings need to be confirmed in a larger randomized clinical trial. https://clinicaltrials.gov/, identifier NCT0232740.

Parvovirus B19-related membranoproliferative glomerulonephritis presenting with positive glomerular staining for nephritis-associated plasmin receptor: a case report and review of the literature.

Several cases of glomerulonephritis occurring after infection with human parvovirus B19 (PVB19) have been reported. However, the pathogenesis and clinicopathological features of PVB19-related glomerulonephritis remain elusive. We describe the case of a 34year-old woman who showed nephrotic syndrome and microscopic hematuria 10days after PVB19 infection. Blood pressure and renal function were within normal ranges. Laboratory tests showed positive results for anti-PVB19 immunoglobulin (Ig)M antibody and complement 3 (C3) hypocomplementemia. Antibody to streptolysin O (ASO) was slightly elevated, but bacterial cultures yielded no colonies. Light microscopy of renal biopsy was compatible with membranoproliferative glomerulonephritis (MPGN). Immunofluorescence microscopy showed intense staining for C3 and faint staining for IgG on the glomerular capillary wall and paramesangial area. Electron micrography showed subendothelial electron-dense deposits (EDDs), but hump-shaped subepithelial EDDs were not evident. PBV19-DNA was absent from renal tissue. Moreover, glomeruli showed positive staining for nephritis-associated plasmin receptor (NAPlr) and plasmin activity with similar distribution. Around 6months after PVB19 infection, levels of anti-PVB19 IgM antibody spontaneously tuned negative with an apparent reduction of proteinuria and improvement of hypocomplementemia, although ASO level remained unchanged. This appears to represent the first description of positive glomerular staining for NAPlr in MPGN after PVB19 infection. Based on a review of 27 cases, including our own case, the MPGN lesions could be attributable to PVB19 infection. Clinicopathological features of this case were incompatible with post-streptococcal acute glomerulonephritis. We presume that a PBV19-derived glomerular pathogen that cross-reacts with anti-NAPlr antibody might be involved in the development of PVB19-related MPGN.

SGLT2 inhibitors in preventing progression of chronic kidney disease in patients with type 2 diabetes: a literature review

IntroductionType 2 diabetes mellitus (T2DM) is an increasing health concern, and diabetic kidney disease (DKD) affects 30–40% of patients with diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective medications used in the treatment of T2DM, which not only improve glycemic control but also slow the progression of diabetic kidney disease (DKD), reducing the risk of renal and cardiovascular complications. They work by decreasing glomerular hyperfiltration and alleviating inflammation in the kidneys. Clinical studies have demonstrated significant therapeutic benefits, including a reduction in albuminuria and improvement in renal function. In the future, the development of new drug classes, such as Nrf2 activators and RAS inhibitors, which are currently under clinical investigation, may further advance the treatment of DKD, offering a more personalized approach to therapy. This article reviews the current knowledge on SGLT2i and their impact on the progression of DKD, the future prospects for therapies in managing diabetes and its complications. Aim of the Study: The aim of this study was to gather and analyze available scientific publications regarding the effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on slowing the progression of chronic kidney disease (CKD) in patients with T2DM and to determine the future of therapy based on new reports and research into emerging drug classes. Materials and Methods: We conducted a review and analysis of the literature available in the PubMed database, using keywords such as SGLT2 inhibitors, gliflozins, chronic kidney disease, type 2 diabetes.

The Complement System: An Important New Therapeutic Target in IgA Nephropathy

Background: IgA nephropathy is the most common primary glomerular disease worldwide, and it is an important cause of end-stage kidney disease. Until recently, there were not any treatments of proven benefit, and care of patients with IgAN primarily involved supportive measures. Within the past few years, however, multiple new drugs have shown promise in clinical trials. Summary: Among the new drugs, several complement inhibitory drugs have demonstrated efficacy at reducing proteinuria, and there is a strong rationale for expecting that these agents will be effective at slowing progression of the disease. Furthermore, anticomplement drugs target a part of the immune system that is not directly blocked by other classes of immunosuppressive agents. One of the new drugs, iptacopan, is a selective inhibitor of the alternative pathway. Preliminary results from a phase 3 study of iptacopan in IgA nephropathy demonstrated that treatment is associated with a rapid reduction in proteinuria, and the drug recently received accelerated approval from the Food and Drug Administration. Additional drugs that have been tested in IgA nephropathy include agents that block the complement cascade at the levels of C3 and C5. Complement activation in the kidneys of IgA nephropathy patients generates biomarkers that can be detected in the blood, urine, and kidney biopsies. If multiple complement inhibitory drugs receive approval for IgA nephropathy, these biomarkers may be useful for selecting the most appropriate drug for an individual patient. Complement biomarkers may also be useful for monitoring a patient’s response to treatment. Key Messages: Several complement inhibitors are currently in clinical trials for IgAN. Iptacopan recently received accelerated approval for the indication and complement inhibitory drugs will likely become an integral part of the treatment for this disease in the near future. As these drugs become available in the clinic, it will be important to develop biomarkers that can guide clinicians to the best drug for an individual patient.

Endothelin receptor antagonists in chronic kidney disease.

Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ETAreceptor andangiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.

First real-world evidence of sparsentan efficacy in patients with IgA nephropathy treated with SGLT2 inhibitors.

Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach. A total of 23 patients with IgAN were treated with sparsentan via the Managed Access Programme between December 2023 and August 2024. The patients were stable on maximum tolerated doses of renin-angiotensin system (RAS) and SGLT2 inhibitors, with an estimated glomerular filtration rate (eGFR) >30mL/min/1.73m² and a urine protein/creatinine ratio (UPCR) >0.75g/g. In the 23 patients, median (IQR) baseline eGFR (CKD-EPI) was 42mL/min/1.73m2 (32-63) and median baseline UPCR was 1.5g/g (0.9-1.8). After initiation of sparsentan, UPCR significantly decreased (P<0.0001) to a median of 0.85g/g (0.42-1.15) in the 2-week follow-up and further declined (P=0.001) to a median of 0.60g/g (0.32-0.82) after 14 weeks, equivalent to a relative reduction in proteinuria up to 62% (45-74). A similar significant reduction was observed for the urine albumin/creatinine ratio. No drug-related serious adverse events were reported. In this real-world setting, sparsentan shows a significant impact on proteinuria, leading to a relative reduction of 62% in UPCR after 14 weeks and beyond, even in patients already receiving SGLT2 inhibitors.

Efficacy and safety of dapagliflozin in patients with CKD: real-world experience in 93 Italian renal clinics.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are recommended for reducing the renal and cardiovascular risk in patients with chronic kidney disease (CKD) based on the positive results reported by clinical trials. However, real-world data on the efficacy and the safety of these drugs in CKD population followed in nephrology setting are lacking. We report the effects of dapagliflozin in CKD patients by using data collected during a learning program in which 105 nephrologists added dapagliflozin (10mg/day) to consecutive patients referred to their renal clinics. Efficacy endpoints were the albuminuria change and the determinants of an albuminuria decline ≥30%. Adverse events were also collected. A total of 1724 patients with CKD (age 67.4±13.2 years, 72.8% males, diabetes 59.9%, eGFR 43.5±17.4ml/min/1.73 m2, severe albuminuria 70.1%) received dapagliflozin for 4±1 months. Dapagliflozin significantly reduced body weight (-1.3kg), eGFR (-0.27ml/min/month), and blood pressure (-3.6/-1.7mmHg). Albuminuria declined by 25.1% (95%CI 23.0-27.2) from 500mg/day [IQR 225-1425] to 320mg/day [IQR 100-900]. Albuminuria reduction was ≥30% in 48.3% of patients, 0-29% in 37.6% while it increased in 14.1% of patients. At logistic regression analysis, older age, female sex, use of mineralocorticoid receptor antagonist, higher eGFR, and higher albuminuria were all significant predictors of albuminuria decline ≥30%. We collected 46 side effects leading to drug discontinuation in 36 patients (2%), with acute kidney injury and urinary tract infection being the most frequent adverse events. We provide evidence of the anti-proteinuric efficacy of short-term dapagliflozin in the presence of good safety profile in patients with CKD followed in nephrology.

Efficacy and safety of guselkumab in patients with active lupus nephritis: results from a Phase 2, randomized, placebo-controlled study.

Evaluate the efficacy and safety of guselkumab, an interleukin (IL)-23 inhibitor, in a Phase 2, multicentre, randomized, double-blind, placebo-controlled study of patients with active lupus nephritis (LN). Adults (18-75 years) with active LN (Class III-IV proliferative nephritis [kidney biopsy] and urine protein-to-creatinine ratio [UPCR)] of ≥ 1 mg/mg despite standard-of-care therapy) were randomized (1:1; planned sample = 60) to receive intravenous infusions of guselkumab 400 mg or placebo at Weeks 0, 4, and 8, then subcutaneous injections (guselkumab 200 mg or placebo) at Week12 and every 4 weeks through Week48 in addition to their background therapy. The primary end point was achievement of ≥ 50% decrease in proteinuria from baseline at Week24. Major secondary endpoints (Week24) were achievement of complete renal response (CRR), sustained reduction in steroid dose (≤10 mg/day prednisone/equivalent) from Weeks 16-24, UPCR <0.5 mg/mg; <0.75 mg/mg, time to achieving CRR, and time to treatment failure. Safety was assessed through end-of-study. Following enrolment challenges (COVID-19 pandemic; Ukraine/Russia crisis), the sponsor terminated the study early; 33 participants were randomized (placebo, n = 16; guselkumab, n = 17). At Week24, 56.3% (9/16) in the placebo group and 35.3% (6/17) in the guselkumab group achieved the primary end point. No apparent differences were observed in the secondary endpoints. Through end-of-study, 75% of placebo patients and 71% of guselkumab patients reported ≥1 adverse event; most were mild-to-moderate severity. Guselkumab+background therapy did not demonstrate superior reduction in proteinuria vs placebo+background in this small cohort of patients with active LN. Safety results were consistent with the known safety profile of guselkumab. clinicaltrials.gov: NCT04376827.

Combined Therapy with Azathioprine, Prednisone, and Enalapril in Children with IgAN and IgAVN.

Background: The aim of this study was to evaluate the efficacy of 1-year treatment in children with IgAN and IgAVN using azathioprine, prednisone, and enalapril (AZA+PRED+E) combined with a control kidney biopsy. Methods: This study consists of 68 children diagnosed via kidney biopsy with Oxford classification. The study group included 36 children (15 IgAN, 21 IgAVN) treated with AZA+PRED+E (according to the protocol with a control kidney biopsy); and the control group included 32 children (21 IgAN, 11 IgAVN) who were treated with enalapril alone during one year after kidney biopsy. Results: After 1 year of combined therapy, a significant reduction in both proteinuria (proteinuria = 0 in 35 patients from the study group) and hematuria in the study group was found. It was confirmed that the Δ proteinuria between the start and end of treatment in IgAN and IgAVN patients from the study group was significantly higher than the Δ proteinuria between the start and end of treatment in the control IgAN and IgAVN group treated with enalapril (30.7 ± 43.6 vs. 8.7 ± 8.7; p = 0.015; 68.2 ± 58.3 vs. 19.3 ± 20.3; p = 0.008 respectively). In the Oxford classification a high frequency of improvement in E and T in the study group after treatment was observed. Conclusions: Patients with higher proteinuria and a higher MESTC score require consideration of the strategy of immunosuppressive treatment so that therapy with AZA+PRED+E may be used as a personal treatment plan for children with these diseases.

Multi-stain deep learning prediction model of treatment response in lupus nephritis based on renal histopathology.

The response of the kidney after induction treatment is one of the determinants of prognosis in lupus nephritis, but effective predictive tools are lacking. Here, we sought to apply deep learning approaches on kidney biopsies for treatment response prediction in lupus nephritis. Patients who received cyclophosphamide or mycophenolate mofetil as induction treatment were included and the primary outcome was 12-month treatment response, complete response defined as 24h urinary protein under 0.5 g with normal estimated glomerular filtration rate or within 10% of normal range. The model development cohort included 245 patients (880 digital slides), and the external test cohort had 71 patients (258 digital slides). Deep learning models were trained independently on hematoxylin and eosin, periodic acid-Schiff, periodic Schiff-methenamine silver and Masson's trichrome stained slides at multiple magnifications and integrated to predict the primary outcome of complete response to therapy at 12 months. Single-stain models showed area under the curves of 0.813, 0.841, 0.823, and 0.862, respectively. Further, integration of the four models into a multi-stain model achieved area under the curves of 0.901 and 0.840 on internal validation and external testing, respectively, which outperformed conventional clinicopathologic parameters including estimated glomerular filtration rate, chronicity index and reduction in proteinuria at three months. Decisive features uncovered by visualization uncovered for model prediction included tertiary lymphoid structures, glomerulosclerosis, interstitial fibrosis and tubular atrophy. Our study demonstrated the feasibility of utilizing deep learning on kidney pathology to predict treatment response for lupus patients. Further validation is required before the model could be implemented for risk stratification and to aid in making therapeutic decisions in clinical practice.