Significant Reduction In Proteinuria Research Articles

Kidney and Metabolic Phenotypes in Glycogen Storage Disease Type-I Patients.

Patients and Methods: A retrospective chart review of 32 GSD- I patients, followed at the American University of Beirut Medical Center, between 2007 and 2018 was conducted. Diagnosis was confirmed by enzymatic and/or genetic studies. Clinical presentation, growth, and kidney outcome were assessed. All patients were evaluated for body mass index, blood parameters of metabolic control including uric acid, alanine, lactic acid, and triglycerides in blood. Kidney evaluation included creatinine clearance, microalbuminuria, citraturia, and calciuria as well as urine microalbumin/creatinine ratio.Results: Almost one third of GSD-I patients developed microalbuminuria. This was detected below 7 months of age in 36% of patients who required early treatment with ACEI with significant reduction in albuminuria. Kidney stones were present in 6% and were associated with hypercalciuria and hypocitraturia. Poor metabolic control reflected by hyperuricemia, lactic acidosis, and hyperalaninemia were noted only in patients who developed microalbuminuria.Conclusion: Glomerular injury may appear in early infancy in poorly controlled patients. Adequate metabolic control and ACEI therapy may improve kidney outcome in GSD I patients. Plasma alanine appears to be a promising and reliable marker reflecting metabolic control in GSD-I patients.

AB0373 TREATMENT OF SLE WITH THE IMMUNOPROTEASOME INHIBITOR KZR-616: RESULTS FROM THE FIRST 4 COHORTS OF THE MISSION STUDY, AN OPEN-LABEL PHASE 1B DOSE ESCALATION TRIAL

Background:Non-specific proteasome inhibitors, such as bortezomib (BTZ), target the constitutive proteasome and immunoproteasome and are approved treatments for multiple myeloma1. BTZ has also been used to treat systemic lupus erythematosus (SLE) and lupus nephritis (LN); however, treatment emergent adverse events (TEAEs), such as gastrointestinal (GI) effects, hematologic abnormalities, asthenia and peripheral neuropathy, limit its use as a long-term treatment option for chronic autoimmune disease2. KZR-616 is a first-in-class selective immunoproteasome inhibitor and is highly active in murine SLE3. Subcutaneous (SC) administration of KZR-616 (30 and 45 mg weekly [QW]) was demonstrated as safe and well-tolerated, and successfully achieved target levels of immunoproteasome inhibition in healthy volunteers4, 5.Objectives:We report the preliminary safety and efficacy of KZR-616 in the first 4 cohorts of the Phase 1b portion of Study KZR-616-002 in patients with active SLE (NCT03393013).Methods:SLE patients (per SLICC Classification Criteria) with SLEDAI ≥4 despite stable background immunosuppressant, anti-malarial, and/or corticosteroid (≤20 mg prednisone equivalent) therapy in this open-label multicentric dose-escalation trial received KZR-616 at doses of 45mg (Cohort 1), 60mg (Cohort 2), or 30mg with escalation to 60mg (Cohorts 2a and 2b) SC weekly through Week 13 (W13) with 12 weeks of follow-up. Efficacy measures included SLEDAI, Cutaneous Lupus Erythematous Disease Area and Severity Index, 28 tender and swollen joint counts, Physicians Global Assessment, Patient Global Assessment, and Patient Assessment of Pain, in evaluable patients (those who received ≥1 month of KZR-616).Results:As of 16 January 2020, 33 patients had enrolled and received at least 1 dose of KZR-616. The majority of TEAEs have been mild or moderate with no reported peripheral neuropathy, prolonged GI-related AEs, and no clinically significant laboratory AEs. There were 3 treatment emergent SAEs, one each of thrombotic microangiopathy (Cohort 2), localized herpes zoster (Cohort 2a), and systemic inflammatory response syndrome (Cohort 2a) with the latter 2 patients completing the full 13 weeks of treatment after resolution. When compared to baseline, improvement in all measures of disease activity were seen at W13 and maintained or improved during the follow-up period, and 94% of evaluable patients had improvements on at least 2 measures/assessments of disease activity. A single patient with active class IV/V nephritis was enrolled on prednisone 10 mg, leflunomide 10 mg, and hydroxychloroquine 200mg/day; nephrotic-range proteinuria at baseline (3.85 g/day) decreased to 0.6 g/day 4 weeks after the last dose of KZR-616.Conclusion:Weekly subcutaneous administration of KZR-616 at 45 and 60 mg was safe and well-tolerated. Evidence of disease suppression at W13 in active SLE patients on stable background therapy was observed. In addition, one study participant with active proliferative nephritis was enrolled with significant reduction in proteinuria. The Phase 2 portion of this study in active proliferative LN is open for enrollment.

26-LB: Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease: A Multicenter, Randomized, Parallel Study

Aim: This trial aimed to assess the effects of exenatide, a GLP-1RA, on renal outcomes in patients with T2DM and DKD. Methods: We performed a randomized, parallel study conducted in 4 general hospitals. T2DM patients with an eGFR≥30mL/min/1.73m2 and macroalbuminuria, defined as 24h-urinary albumin-creatinine ratio (UAER) >0.3g/24h, were randomized 1:1 to receive exenatide twice daily plus glargine or lispro insulin plus glargine for 24 weeks. The primary outcome was percentage change in 24h-UAER after 24 weeks of intervention comparing to baseline measurement. The secondary outcomes included the percentage change in urinary ACR, change in 24h-UAER, ACR, HbA1c, FPG, body weight and blood pressure. The safety outcomes include rates of hypoglycemia, adverse events and change in eGFR during the follow up. Results: Between March 2016 and April 2019, 92 patients were randomized and took at least one dose of study drug. The mean age of the participants was 56 years. At baseline, the median 24h-UAER was 1512.0 mg/24h (IQR 782.5-2818.0), and mean eGFR was 70.4 mL/min/1.73 m2 (SD 23.4). After 24 weeks, exenatide reduced the percentage change of the 24h-UAER (difference between groups was 29.7%, p=0.0255), the percentage change of ACR (difference between groups was 28.4%, p=0.0395) and the absolute change of ACR (difference between groups was 607.8 mg/g, p=0.0209) but had no significant difference on the absolute change of 24h-UAER than the control group. Meanwhile, the body weight declined by 1.3kg with exenatide (difference between groups was 2.7kg, p=0.0001). There was no difference between two groups on the change in HbA1c, FPG, blood pressure or eGFR. Comparing to the control group, lower frequency of hypoglycemia as well as more gastrointestinal adverse events were in intervention group. Conclusions: Exenatide twice daily plus glargine for 24 weeks resulted in significant reduction of albuminuria in T2DM patients with DKD. Disclosure X. Wang: None. Q. Zhang: None. M. Guan: None. S. Sheng: None. W. Mo: None. M. Zou: None. J. Li: None. J. Bi: None. X. Tang: None. J. He: None. G. Xu: None. P. Li: None. H. Zhang: None. Y. Xue: None.

2220-PUB: Renal Outcomes Associated with Canagliflozin 100mg and with Intensification of SGLT2 Inhibitor Therapy Switching to Canagliflozin 300mg in Patients with Type 2 Diabetes Mellitus in a Real-World Setting: The Renal-WECAN Study

The aim of this multicentric retrospective study was to assess in a real-world setting kidney outcomes associated with canagliflozin 100 mg/d (CANA100), as add-on to the background antihyperglycemic therapy, and with the intensification of SGLT2 inhibitor (SGLT2i) therapy by switching to canagliflozin 300 mg/d (CANA300) in patients with T2DM. 583 patients were included, 279 with CANA100 (eGFR 86.5 ml/min, eGFR<60 12.3%, albuminuria >30 mg/g 25.7%) and 304 with CANA 300 (eGFR 84.9 ml/min, eGFR<60 9.1%, albuminuria >30 mg/g 20.7%). Median follow-up periods in both cohorts were 9.1 and 15.4 months respectively. The primary outcomes of the study were changes in eGFR, albuminuria and systolic BP (SBP) over the follow-up time. CANA100 was associated to significant reductions in eGFR (-2 ml/min) and SBP (-4.8 mmHg). In those patients with SBP>140 mmHg, CANA 100 lowered SBP levels by 14.9 mmHg. No significant changes in albuminuria were observed. However, in the subset of patients with baseline albuminuria >30 mg/gr, there was a significant decrease in median albuminuria. In the second cohort, patients with prior background SGLT2i therapy switched to CANA300. Significant reductions in eGFR (-1.8 ml/min), SBP (-3.2 mmHg), and median albuminuria (from 8.1 to 5.8 mg/g) were observed over the follow-up period. In those patients with SBP>140 mmHg, CANA 300 lowered SBP levels by 15.9 mmHg. In the subset with baseline albuminuria >30 mg/g, there was a significant decrease in median albuminuria. No significant changes in anti-hypertensive medications were observed over the follow-up. There was a low rate of adverse events related to volume depletion. In summary, CANA100 (as add-on therapy) and CANA300 (switching from CANA100 or other SGLT2i) significantly decreased SBP and modestly reduced eGFR. A significant reduction in albuminuria was observed with CANA300. Disclosure J.J. Gorgojo-Martinez: Advisory Panel; Self; Abbott, AstraZeneca, Grunenthal Group, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Mundipharma International, Novo Nordisk Inc., Pfizer Inc. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Mundipharma International, Novo Nordisk Inc. M.A. Gargallo-Fernandez: Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi. A. Galdon: Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Mundipharma International, Novo Nordisk Inc. T. Antón-Bravo: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Mundipharma International, Novo Nordisk Inc. M. Brito-Sanfiel: Advisory Panel; Self; Abbott, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Almirall, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Esteve, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mylan, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi-Aventis. J.E.M. Wong-Cruz: None.

Combined rituximab and plasmapheresis or plasma exchange for focal segmental glomerulosclerosis in adult kidney transplant recipients: a meta-analysis.

To demonstrate the efficacy of combined rituximab and plasmapheresis (PP)/plasma exchange (PE) therapy for focal segmental glomerulosclerosis in transplanted kidneys (ptFSGS). We searched MEDLINE, SCOPUS, and Cochrane Library for eligible publications. Only observational studies or clinical trials containing patients' age > 18years were included for full-text extraction. A total of eight observational studies (n = 85) were included in meta-analyses. With a median follow-up of 18months (IQR 4.4), combination therapy of RTX-PP/PE in patients with ptFSGS resulted in overall remission rate of 72.7% (95% CI 52.3-86.6%) with a significant reduction of proteinuria and serum creatinine levels. Complete remission was 41.0%, while partial remission was 31.7%. The mean difference of serum creatinine levels between pre- and post-treatment was - 0.65mg/dL (95% CI - 1.15 to - 0.14). The mean difference of the degree of proteinuria between pre- and post-treatment was - 4.79g/day (95% CI - 7.02 to - 2.56). Subgroup analyses were performed after adjusted for study year, type of intervention, and primary pre-transplant lesion. Patients with recurrent FSGS tended have lesser reduction in the degree of proteinuria compared to patients with de novo FSGS. Incidence of serious adverse events with combined RTX-PP/PE therapy was 0.12 event/year. We conclude that combined RTX-PP/PE therapy may be considered as an alternative treatment of ptFSGS in achieving remission by lowering proteinuria and serum creatinine levels. However, the efficacy of combined RTX-PP/PE therapy must be confirmed in randomized-controlled trials.

SAT-398 LOW DOSE OF RITUXIMAB IS CLINICALLY AND COST EFFECTIVE IN PRIMARY MEMBRANOUS NEPHROPATHY

B cells are thought to be involved in the pathogenesis of Primary Membranous nephropathy(IMN) and therapies targeting B cells may have a role. Though cyclophosphamide based therapies were traditionally used, targeting B cells with Rituximab and thereby depleting antibody production has been suggested as an alternative and possibly more effective therapy1. Most of the studies have extrapolated the dose used in treating B cell lymphoproliferative diseases in a four weekly dose of 375mg/m2. There have even been suggestions that mega doses may be more effective by preventing epitope spreading2. At the same time, clinical efficacy with a single dose has also been reported3. We studied the role of a single low dose of 100mg Rituximab in decreasing CD19 B cells, proteinuria, renal functions and antiphospholipid 2 receptor antibody titres (Anti PLA2R) in IMN. A single centre, prospective observational study was conducted at a tertiary care centre in South India over a six month period. Biopsy proven cases of IMN with proteinuria >8g/day and eGFR >30ml/min/m2 who did not receive previous therapy with cyclophosphamide or calcineurin inhibitors received Inj. Rituximab 100 mg as monotherapy after informed consent along with Angiotensin 11 receptor blockers, statins and diuretics. Dose of antihypertensive drugs were targeted to keep blood pressure <140/90 mmHg. CD 19 counts were measured at baseline, at 4 weeks,12 weeks and 24weeks following Rituximab. Anti PLA2R titres were also measured at baseline and if elevated, periodically. Other baseline parameters like serum albumin, total cholesterol and proteinuria were also recorded at baseline and at intervals mentioned above. Five patients including 3 males with a mean age of 55+/-2 years were studied. Mean serum creatinine at baseline was 1.3+/-0.6 mg/dl. Baseline 24 hour proteinuria was 10.2+/-1.8g.Four patients were PLA2R negative and one was positive. Following 100mg of rituximab, CD19 counts were suppressed in all patients at 1 month. Four patients attained partial remission by 3 months and were in complete remission by 6months. One patient had transient decrease in proteinuria and Anti PLA2R titres but relapsed by 2nd month and thereafter failed to respond. At the end of 24 weeks significant reduction in proteinuria along with normal serum albumin and total cholesterol were observed in 4 patients. Among those who responded, proteinuria at the end of 24 weeks came down to an average of 1.08+/-0.5g/day(p<0.005). There were a limited number of minor side-effects. Though initial cluster of differentiation 19 (CD19)+ B cell were depleted in all patients at 4 weeks(count <1%), repopulation of CD19+ B cells occurred in 4 patients by 3 months. Clinical remission could be achieved at the end of 24 weeks in 4 of our patients. Lack of response in one patient despite initial fall in PLA2R titres and CD19 count could be explained due to PLA2R epitope spreading. A single dose of 100mg Rituximab was sufficient to suppress the CD 19 count to less than 1% at 4 weeks. Targetting further doses depending on whether repopulation of CD19 Bcells occur and Anti PLA2R titres become elevated could limit the cumulative dose of rituximab, be cost effective and decrease toxicity. These observations may need to be confirmed by larger, preferably multicentre trials.

Artan Çocukluk Çağı Obezitesi ve Fokal Segmental Glomeruloskleroz (FSGS): İki Olgu Sunumu

Çocuklarda nefrotik sendrom nedeni olarak en sık minimal değişiklik hastalığı olarak gözlemlenirken, ikinci sırayı fokal segmental glomerüloskleroz (FSGS) almaktadır. FSGS primer veya sekonder nedenlere bağlı oluşabilmektedir. Sekonder nedenler arasında morbid obezite sıklığının gittikçe arttığı dikkati çekmektedir. Yapılan çalışmalarda vücut ağırlığındaki düşüşün proteinüride azalma ile ilişkilendirildiği gösterilmiştir. Bu amaçla obezite ile ilişkili FSGS olan adölesan iki olgunun tıbbi tedavisi ve diyet yönetimi makalede tartışılacaktır.

THE RENOPROTECTIVE EFFECTS OF SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITORS IN DIABETES MELLITUS

Objective: Diabetic Kidney Disease is a serious microvascular complication of diabetes mellitus and the leading cause of end-stage-renal-disease in Western countries. New therapeutic agents are needed to delay its onset and progression. Recent literature suggests that sodium-glucose co-transporter 2 inhibitors may have renoprotective effects. Our aim was to systematically review the effect of SGLT2-inhibitors on albuminuria and proteinuria in patients with diabetes. Design and method: Studies were identified by search in major electronic databases, clinical trial registers and other sources of gray literature. We included RCTs of currently approved SGLT2-inhibitors with a duration of >/=12 weeks. The primary outcome was the between-groups difference in the proportional (%) change of albuminuria or proteinuria between baseline and end-of-treatment. Results: SGLT-2 inhibitors were associated with statistically significant reduction in albuminuria compared to placebo or active control (WMD −25.39%, 95% CI −34.17 to −16.62) (15 studies, n = 17,540 patients). When trials were stratified according to the level of baseline albuminuria, reduction in UACR was more prominent in RCTs in patients with moderately (−40.78%, −63.21 to −18.34) or severely increased albuminuria (−36.40%, −51.53 to −21.26). Only one study reported data for urine protein to creatinine ratio (UPCR). SGLT2- inhibitors reduced systolic and diastolic blood pressure by 4.43 mmHg (95% CI −5.24 to −3.63) and 1.81 mmHg (95% CI −2.38 to −1.23) respectively. Conclusions: SGLT2-inhibitors reduced UAE compared to placebo or active treatment in patients with diabetes. Future RCTs assessing hard renal outcomes are expected to fully elucidate the clinical value of SGLT2-inhibitors as a therapeutic option for diabetic nephropathy.

The effect of SGLT-2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

: Diabetic kidney disease is a serious microvascular complication of diabetes mellitus and the leading cause of end-stage renal disease in western countries. New therapeutic agents are needed to delay its onset and progression. Recent literature suggests that sodium-glucose cotransporter 2 (SGLT-2) inhibitors may have renoprotective effects. Our aim was to systematically review the effect of SGLT-2 inhibitors on albuminuria and proteinuria in patients with diabetes mellitus. Studies were identified by search in major electronic databases, clinical trial registers, and sources of gray literature. We included randomized controlled trials of currently approved SGLT-2 inhibitors with a duration of at least 12 weeks. The primary outcome was the between-groups difference in the proportional (%) change of albuminuria or proteinuria between baseline and end of treatment. SGLT-2 inhibitors were associated with statistically significant reduction in albuminuria compared to placebo or active control [weighted mean difference (WMD) -25.39%, 95% confidence interval (CI) -34.17 to -16.62] (15 studies, N = 17 540 patients). When trials were stratified according to the level of baseline albuminuria, reduction in urine albumin-to-creatinine ratio was more prominent in randomized controlled trials in patients with moderately (WMD -40.78%, 95% CI -63.21 to -18.34) or severely increased albuminuria (WMD -36.40%, 95% CI -51.53 to -21.26). Only one study reported data for urine protein-to-creatinine ratio. Finally, SGLT-2 inhibitors reduced systolic and diastolic blood pressure by 4.43 mmHg (95% CI -5.24 to -3.63) and 1.81 mmHg (95% CI -2.38 to -1.23), respectively.

Role of Nox4 in Angiotensin II‐Mediated Changes in Volume Dynamics and Nitric Oxide Production in Podocytes

Nitric oxide (NO) is a powerful vasodilator that serves important functions in the kidney such as regulation of renal hemodynamics, pressure natriuresis, and diuresis. Significant reduction in NO production has been found to play a role in the pathogenesis of hypertension. Our recent studies revealed that Angiotensin II (Ang II), in addition to causing a release of calcium, stimulates NO production in the glomerular podocytes. This signaling pathway can be also triggered by extracellular application of hydrogen peroxide (H2O2) and is significantly reduced with the development of salt‐sensitive hypertension and kidney injury in Dahl salt‐sensitive (SS) rats (Palygin et al., Nitric Oxide, 2018). Recently, using a knock out of NADPH oxidase 4 (Nox4) in SS rats (SSNox4−/−), one of the primary source of renal reactive oxygen species (ROS) and specifically H2O2 we described the reduction in intracellular calcium activation in podocytes as well as H2O2 production in isolated glomeruli in response to Ang II (Ilatovskaya et al., J Am Soc Nephrol. 2018). Overall, SSNox4−/− rats displayed a protective phenotype with a significant reduction of albuminuria, glomeruli injury and reduction in the elevation of blood pressure under high salt challenge (Cowley et al., Hypertension, 2016). Here we used this model to characterize the effects of alterations in the balance in the relationship between ROS and NO production in podocytes and establish the relation between Nox4 and glomerular/podocyte volume dynamics. The in vivo concentration of H2O2, measured by biosensors amperometry as catalase sensitive current, was significantly reduced in both cortex and medullar parts of the SSNox4−/− rat kidney compared to wild type SS rats, indicating a direct association between Nox4 and the production of renal ROS. We found that acute application of Ang II promoted opposite changes in glomeruli and podocyte volumes, where glomeruli volume decreased, and podocyte volume increased approximately by 18% in SS rats. Overall, SSNox4−/− rats exhibited an increase in total NO production (by 16% to compare with SS), calculated using confocal microscopy as a total integral of NO fluorescent transient (DAF‐FM dye) in the population of podocytes within a freshly isolated glomerulus. In SSNox4−/− rats the elevation in NO together with declining in H2O2 levels directly correlated with an increase of podocyte volume in response to Ang II (13% vs. SS control). We anticipate a rapid podocyte volume change dependent on intracellular NO production and reflecting the ability of these cells to dynamically regulate the permeability of glomeruli filtration barrier. Thus far, we can conclude that in the absence of Nox4 the podocytes shift the ROS production in response to Ang II towards the increase of intracellular NO bioavailability and a decrease of renal H2O2 production. This mechanism may play a key role in the protection of glomeruli form oxidative stress and elevation of blood pressure during the development of salt‐sensitive hypertension.Support or Funding InformationNHLBI R35 HL135749; P01 HL116264; AHA 18PRE34030127; ADA 1‐15‐BS‐172; DK‐020595 Pilot &amp; Feasibility projectThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dipeptidyl Peptidase 4 Inhibition Ameliorates Chronic Kidney Disease in a Model of Salt-Dependent Hypertension.

Cardiovascular diseases frequently coexist with chronic kidney disease that constitutes a major determinant of outcome in patients with heart failure. Dysfunction of both organs is related to chronic inflammation, endothelial dysfunction, oxidative stress, and fibrosis. Widespread expression of serine protease DPP4 that degrades varieties of substrates suggests its involvement in numerous physiological processes. In this study, we tested the effects of selective DPP4 inhibition on the progression of renal disease in a nondiabetic model of hypertensive heart disease using Dahl salt-sensitive rats. Chronic DPP4 inhibition positively affected renal function with a significant reduction in albuminuria and serum creatinine. DPP4 inhibition attenuated the inflammatory component by reducing the expression of NF-κB, TNFα, IL-1β, IL-6, and MCP-1. Kidney macrophages expressed GLP-1R, and DPP4 inhibition promoted macrophage polarization toward the anti-inflammatory M2 phenotype. Finally, high degrees of NADPH oxidase 4 expression and oxidation of nucleic acids, lipids, and proteins were reduced upon DPP4 inhibition. Our study provides evidence of renoprotection by DPP4 inhibition in a nondiabetic hypertension-induced model of chronic cardiorenal syndrome, indicating that DPP4 pathway remains a valid object to study in the context of chronic multiorgan diseases.

The Effects of Novel Antidiabetic Drugs on Albuminuria in Type 2 DiabetesMellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The effects of novel antidiabetic drugs, including sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors, on albuminuria in patients with type 2 diabetes mellitus (T2DM) are still controversial. Therefore, we performed a meta-analysis to evaluate the effects of novel antidiabetic drugs on albuminuria in patients with T2DM. We conducted a random-effects meta-analysis of randomized controlled trials (RCTs) by searching the MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases up to 16 August 2018. The effects of novel antidiabetic drugs on albuminuria were evaluated as percent changes from baseline to follow-up urinary albumin excretion/urinary albumin to creatinine ratio (UAE/UACR) levels in both the intervention and control groups. Data regarding percent changes were used to generate weighted mean differences (WMDs) and 95% confidence intervals (CIs). In this meta-analysis, 26 RCTs involving 14,929 patients were included. Pooled analysis suggested that SGLT-2 inhibitors (WMD - 26.23%, 95% CI - 35.90 to - 16.56; p < 0.00001) and GLP-1 receptor agonists (WMD - 13.85%, 95% CI - 15.96 to - 11.74; p < 0.00001) were associated with a significant reduction in albuminuria compared with other conventional therapies or placebo. DPP-4 inhibitors (WMD - 6.19%, 95% CI - 14.03 to 1.66; p = 0.12) were not significantly associated with lower albuminuria than other conventional therapies or placebo. This meta-analysis indicates that SGLT-2 inhibitors and GLP-1 receptor agonists were associated with a reduction in albuminuria compared with other conventional therapies or placebo, while DPP-4 inhibitorswere not associated with albuminuria-reducing effects compared with other conventional therapies or placebo.

The Role for Protein Restriction in Addition to Renin-Angiotensin-Aldosterone System Inhibitors in the Management of CKD

In experimental studies a low-protein diet (LPD) and renin-angiotensin-aldosterone system (RAAS) inhibitors are both reported to slow the progression of chronic kidney disease (CKD) and reduce proteinuria. RAAS activity contributes to increased blood pressure, fluid retention, and positive sodium balance, but also to kidney damage by enhancing glomerular capillary filtration pressure and synthesis of profibrotic molecules such as transforming growth factor β. It has been well established that an LPD decreases glomerular hyperfiltration and the generation of uremic toxins, as well as the burden of acid load, phosphorus, and sodium. In different animal CKD models, a significant reduction in proteinuria and glomerulosclerosis has been achieved when an RAAS inhibitor and LPD were combined. To date, high-quality intervention trials investigating this combined strategy are lacking. We summarize the experimental and clinical studies that have examined a potential additive action of these therapies on CKD progression. We outline potential mechanisms of action and additive efficacy of an LPD and RAAS inhibitors in CKD, with a particular emphasis on phosphate levels, uremic toxin production, acid load, and salt intake. Finally, although the evidence is inadequate to recommend combining RAAS inhibitors and an LPD to slow the progression of CKD, we provide a perspective to support a large-scale randomized clinical trial to study this combination.

Lenalidomide as a Beneficial Treatment Option for Renal Impairment Caused by Light Chain Deposition Disease

Light chain deposition disease (LCDD) is a rare systemic disorder caused by the deposition of light chain immunoglobulins, which often results in renal impairment associated with either nephrotic syndrome or asymptomatic proteinuria. B-cell neoplasms, such as multiple myeloma and lymphoproliferative disorders, are well-known underlying diseases in LCDD. Some chemotherapy regimens have been reported, but both evidence-based treatment and management for LCDD have yet to be established. We herein report three cases of LCDD treated with lenalidomide-based therapy, resulting in hematologic responses accompanied by a significant reduction in proteinuria and improvement in the renal function. We recommend lenalidomide-based therapy for renal impairment caused by LCDD.

Intervention using vitamin D for elevated urinary albumin in type 2 diabetes mellitus (IDEAL-2 Study): study protocol for a randomised controlled trial

BackgroundThe prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. T2DM is associated with serious macro- and microvascular complications. In particular, diabetic kidney disease (DKD), which begins with excessive urinary albumin excretion, has a significant impact on affected individuals and is costly to healthcare services. Inhibition of the renin–angiotensin–aldosterone system (RAAS) with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) significantly reduces albuminuria in diabetes, but this effect is not observed in all those treated. Active vitamin D analogues have been observed to be reno-protective through inhibition of RAAS in animal and human studies. Therefore, it can be hypothesised that an active vitamin D analogue will have an additional benefit to ACEI/ARB treatment for albuminuria reduction in DKD.MethodsThe planned study is an ongoing non-blinded randomised controlled parallel-group trial examining the impact, in individuals with T2DM, of the addition of bioactive vitamin D (calcitriol) to RAAS inhibition treatment using ACI or ARB on urinary albumin excretion over a period of 26 weeks. The primary outcome measure is the urinary albumin creatinine ratio. It is planned for the study to recruit 320 participants. Other outcome measures of interest include 24-h urine albumin (24 h UA) excretion, estimated glomerular filtration rate (eGFR), blood pressure and quality of life. Safety will be assessed throughout.DiscussionIf the addition of calcitriol to RAAS inhibition with ACEI or ARB safely results in a significant reduction in albuminuria, the study adds to the body of evidence supporting a role for vitamin D in reno-protection, will inform clinical practice and could result in significant reduction of healthcare costs associated with DKD.Trial registrationISRCTN, ISRCTN86739609. Registered on 7 June 2017. ClinicalTrials.gov, NCT03216564. Registered on 13 July 2017.

Renal protective effect of SGLT2 inhibitor dapagliflozin alone and in combination with irbesartan in a rat model of diabetic nephropathy

Considering the complementary mechanisms of SGLT2 inhibitors and angiotensin inhibitors on kidney, it is postulated that combination of both agents could afford greater protection against diabetic renal injury. So, we investigated renal protective effects of SGLT2 inhibitor, dapagliflozin, alone and in combination with irbesartan in a rat model of diabetic nephropathy. Diabetic rats, injected with nicotinamide-streptozotocin, were treated orally for 12 weeks with either vehicle, dapagliflozin 2 mg/kg/day, irbesartan 30 mg/kg/day, or combination of both drugs; respectively. Biochemical analysis included blood glucose, HbA1c, urinary albumin excretion, creatinine clearance, TGF-β1, sRAGE, oxidative markers, and histopathological examination of kidneys. Treatment with dapagliflozin, irbesartan, and especially their combination, produced significant reduction in albuminuria, improved renal function parameters, increased sRAGE level and improved inflammatory and oxidative markers, together with amelioration of renal histopathological changes. Beside glycemic control, dapagliflozin produced higher sRAGE levels than irbesartan, suggesting that inhibition of AGE-RAGE axis is important in its renoprotective action. Combination of dapagliflozin and irbesartan produced more remarkable protective effects on renal function and structure, than use of either agent alone. It is concluded that, combination of SGLT2 inhibitor, dapagliflozin and ARB, irbesartan could offer more effective renal protection and represent a promising therapeutic option for management of diabetic nephropathy.

PROSPECTS OF NEPHROPROTECTION AGAINST TYPE 2 DIABETES USING THE DPP-4 INHIBITOR VILDAGLIPTIN

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which increases morbidity and mortality. Accumulated evidence, mostly experimental ones that DPP-4 inhibitors have non-glycemic tissue effects including renal protection. Clinical data confirming these effects are insufficient. This makes it relevant to study the influence of iDPP-4 on the renal function in patients with Type 2 diabetes.To study the effects of iDPP vildagliptin on glycemic, metabolic and renal parameters in patients with type 2 diabetes with CKD 1–2 receiving insulin therapy 44 patients were randomized to continue therapy with insulin or insulin + vildagliptin at a dose of 50 mg/day, with the evaluation of results in 6 months.In group of vildagliptin therapy a significant decrease of HbA1c, postprandial glycemia, diastolic blood pressure, HOMA-IR, insulin demand and a reduction in the frequency of hypoglycemia occurred. The positive dynamics of indicators of glomerular functions of the kidney were noted in this group - a significant reduction in albuminuria and a significant increase in eGFR by cystatin C and decreased urinary excretion of type IV collagen. The findings suggest the positive effect of vildagliptin on metabolic status and indicators of glycaemia and hemodynamics as earlier confirmed in clinical studies and the ability of vildagliptin independent from glycemic effects to slow the development of glomerular dysfunction in patients with type 2 diabetes and the initial manifestations of DN.

An integrin antagonist (MK‐0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model

Multiple integrins have been implicated in modulating renal function. Modulation of integrin function can lead to pathophysiological processes associated with diabetic nephropathy such as alterations in the glomerular filtration barrier and kidney fibrosis. The complexity of these pathophysiological changes implies that multiple integrin subtypes might need to be targeted to ameliorate the progression of renal disease. To address this hypothesis, we investigated the effects of MK‐0429, a compound that was originally developed as an αvβ3 inhibitor for the treatment of osteoporosis, on renal function and fibrosis. We demonstrated that MK‐0429 is an equipotent pan‐inhibitor of multiple av integrins. MK‐0429 dose‐dependently inhibited podocyte motility and also suppressed TGF‐β‐induced fibrosis marker gene expression in kidney fibroblasts. Moreover, in the obese ZSF1 rat model of diabetic nephropathy, chronic treatment with MK‐0429 resulted in significant reduction in proteinuria, kidney fibrosis, and collagen accumulation. In summary, our results suggest that inhibition of multiple integrin subtypes might lead to meaningful impact on proteinuria and renal fibrosis in diabetic nephropathy.

Comparison of effects of benidipine and amlodipine on clinical and biochemical parameters in hypertensive patients: an observational study

Background: Hypertension is a widespread public health problem and a major risk factor for cardiovascular disease. Amlodipine, a calcium channel blocker, dilates arterioles by blocking L-type calcium channels. Benidipine inhibits L, N, and T type calcium channels. We compared the efficacy of Amlodipine and benidipine on blood pressure, pulse rate, proteinuria and lipid profile in hypertensive patients.Methods: The study was an observational, prospective, open label comparison. Eligible hypertensives were given either amlodipine (5mg/d) or benidipine (4mg/d). Clinical features and laboratory parameters were recorded initially and after 3 months. Adverse events were recorded with the help of a questionnaire. Compliance was assessed by return pill count.Results: Out of 35 patients, recruited for study, 16 received amlodipine and 17 were treated with benidipine and two were lost during follow up. Both the groups were well matched in terms of age, body weight, clinical findings and laboratory values. Both the drugs significantly (P &lt;0.05) reduced systolic (142±16 to 138±15 vs.148±16 to 134±14mmHg) and diastolic blood pressure (81±9 to 79±7). In the Amlodipine group the pulse rate after treatment tended to be higher than before (70±9 to 72±10bpm). In the Benidipine group there was decrease in pulse-rate after treatment (69±9 to 67±9). Unlike Amlodipine, Benidipine significantly (P&lt;0.05) decreased urinary protein excretion (1.0±1.2 to 1.1±1.4 vs. 1.4±2.5 to 1.1±1.7g/g-Cr) and serum triglycerides (125±25 to 120±23 vs 130±26 to 115±21mg/dl).Conclusions: In this study, amlodipine and benidipine were found to be be equally effective anti-hypertensive in patients with stage 1 hypertension. However, there was significant reduction in proteinuria and serum triglycerides in Benidipine group as compared to Amlodipine group. Benidipine may be a better alternative to existing calcium channel blockers.

Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model.

Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout db/db mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (P<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, α-smooth muscle actin, connective tissue growth factor, collagen I, and TGF-β; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, n=4; at 20 weeks: 364±18 with vehicle, n=7, and 536±12 with LPAR inhibition, n=7; P<0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.