Antiproteinuric Effect In Patients Research Articles

#1549 The effect of sglt2 inhibitors (dapaglifozin) on albuminuria in patients of diabetic nephropathy above standard of care

Abstract Background and Aims Albuminuria is the hallmark of diabetic nephropathy (DN) and progression of albuminuria denotes declining renal functions culminating in End Stage Renal Disease. Intensive blood glucose control (HbA1c <7%), intensive blood pressure control (<130/90 mmHg), blockade of Renin Angiotensin Aldosterone System (RAAS) by Angiotensin converting enzyme inhibitors (ACE-i) and Angiotensin receptor blockers (ARBs) constitute the standard line of care for treatment of DN with proteinuria. Sodium Glucose cotransporter 2 inhibitors (SGLT2i) are drugs are recently introduced for proteinuria reduction with no data available in this part of the world. Hence, I, observed the antiproteinuric effect of SGLT2i in patients who have type2 diabetes mellitus (T2DM) with albuminuria and who are already on maximum doses of ACE-I or ARBs. My study population was on dapaglifozin due to easy availability and low cost. Method it is an observational study including patients who attended the out-patient clinic of Nephrology, at Medica Hospital, Kolkata between July 2022 to February 2023. Inclusion criteria: Exclusion criteria: Quantitative estimation of urine albumin was performed using the VITROS Chemistry Products mALB Reagent along with the VITROS Chemistry Products Calibrator Kit 24 on the VITROS 5,1 FS Chemistry System and the VITROS 5600 Integrated System. Blood sugar was measured by glucose oxidase method. eGFR by CKD EPI equation. Statistical Methodology Continuous variables were presented with mean and standard deviation and tested for normal distribution by the Kolmogorov-Smirnov test. Categorical variables were summarized using frequency and percentages. For testing of related samples, Wilcoxon sign ranked test is used. Statistical analyses were performed using the SPSS software with version 26.0. Results A total of 100 patients were included in the study, of which 3 patients were lost to follow up and 2 patients discontinued the study at 3 months due to fall in eGFR below 25 ml/min/1.73 m2 and 4 patients discontinued after 3 months because of fungal genital infections. After Dapaglifozin administration, a significant reduction in Urine Albumin-creatinine ratio (UACR) was observed, by a percentage decrease of 37.3% (p<0.001) at 3 months and of 70.2% (p<0.001) at 6 months from baseline. Similarly, there was an acute reduction in eGFR from baseline. A percentage decrease by 5.16% (p<0.001) was observed at 3 months & a decrease by 5.69% (p<0.001) at 6 months from baseline. Conclusion Conventional approaches reduce but have not been able to stop disease progression in Diabetic Kidney Disease (DKD). SGLT2i can protect against the onset of DKD, slow disease progression independently. They have an antiproteinuric effect in patients with diabetic nephropathy which was sustained throughout the follow-up period in my study. Studies have also shown that SGLT2i reduce major adverse cardiovascular events in patients with T2DM and established cardiovascular disease. With the new results of EMPA-KIDNEY trial, SGLT2i are being used at even lower eGFR (<25 ml/min/1.73 m2 till on hemodialysis) and such vast health benefits, invention of SGLT2i are is a boon to the mankind.

Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease

Reductions in albuminuria of more than 30% are considered a strong marker of delay of chronic kidney disease (CKD) progression. Single renin-angiotensin system (RAS) blockade represents the cornerstone of CKD treatment. However, as CKD progression still occurs, other nephroprotective options were explored; mineralocorticoid receptor antagonists (MRA) were tested with generally positive results. We conducted a systematic review and meta-analysis on the effects of MRAs on albuminuria/proteinuria, and adverse events, such as change in renal function and hyperkalemia incidence. A detailed search in electronic databases, clinical trial registries and grey literature was performed to retrieve randomized controlled trials (RCTs) in which administration of an MRA alone or on-top of ACEi/ARB was compared with placebo or active treatment. Of the 45 initially identified reports, 31, with 2767 participants, were included in analysis of the primary outcome. The use of MRAs (alone or on top of RAS blockade) compared with placebo decreased urine albumin-to-creatinine ratio (UACR) by -24.55% (95% CI -29.57 to -19.53%), urine protein-to-creatinine ratio (UPCR) by -53.93% (95% CI -79% to -28.86%) and 24 h albumin excretion by -32.47% (95% CI -41.1 to -23.85%). MRAs also reduced UACR by -22.48% (95% CI -24.51 to -20.44%) compared with calcium-channel-blockers (CCBs), whereas no differences were found compared with a second ACEi/ARB or nonpotassium-sparing diuretics. Addition of an MRA was associated with change in estimated glomerular filtration rate (eGFR) of -2.38 ml/min per 1.73 m (95% CI -3.51 to -1.25), rise in potassium by 0.22 mEq/l (95% CI 0.16-0.28 mEq/l) and a 2.6-fold increase in hyperkalemia risk (RR 2.63, 95% CI 1.69-4.08) compared with placebo/active control. Use of MRAs alone or on top of RAS blockade confers important antiproteinuric effects in patients with CKD, with a slight increase in mean potassium levels.

EFFECTS OF MINERALOCORTICOID RECEPTOR ANTAGONISTS IN PROTEINURIC KIDNEY DISEASE

Objective: Reductions in albuminuria of >30% are considered a strong marker of delay of chronic kidney disease (CKD) progression. Single renin-angiotensin-system (RAS)-blockade represents the cornerstone of CKD treatment. However, as CKD progression still occurs, other nephroprotective options were explored; mineralocorticoid-receptor-antagonists (MRA) were tested with generally positive results. Design and method: We conducted a systematic review and meta-analysis on the effects of MRAs on albuminuria/proteinuria, and adverse events, such as change in renal function and hyperkalemia incidence. A detailed search in electronic databases, clinical trial registries and grey literature was performed to retrieve randomized controlled trials (RCTs) in which administration of an MRA alone or on-top of ACEi/ARB was compared to placebo or active treatment. Results: Of the 45 initially identified reports, 31, with 2767 participants, were included in analysis of the primary outcome. Compared to placebo, MRAs decreased urine albumin-to-creatinine ratio (UACR) by −24.55% (95%CI −29.57 to −19.53%), urine protein-to-creatinine ratio (UPCR) by −53.93% (95%CI −79% to −28.86%) and 24hour albumin excretion by −32.47% (95%CI −41.1 to −23.85%). MRAs also reduced UACR by −22.48% (95%CI −24.51 to −20.44%) compared to calcium-channel-blockers (CCBs), while no differences were found compared to a second ACEi/ARB or other diuretics. Addition of an MRA was associated with change in estimated-glomerular-filtration-rate (eGFR) of −2.38 mL/min/1.73m2 (95%CI −3.51 to −1.25), rise in potassium by 0.22mEq/L (95%CI 0.16 to 0.28mEq/L) and a 2.5-fold increase in hyperkalemia risk (RR 2.63, 95%CI 1.69 to 4.08). Conclusions: Addition of MRAs confers an additive antiproteinuric effect in patients with CKD, with a slight increase in mean potassium levels.

Baroreflex activation therapy in patients with prior renal denervation.

Both baroreflex activation therapy (BAT) and renal denervation modulate sympathetic activity. The aim of this study was to systematically investigate whether additive modulation of autonomic nervous system by BAT lowers blood pressure (BP) in patients who still suffer from uncontrolled resistant hypertension despite prior renal denervation. From 2012 to January 2015, patients treated with BAT for uncontrolled resistant hypertension, who prior received renal denervation were consecutively analyzed in four German centers for hypertension. Analyses of office BP, 24-h ambulatory BP, central hemodynamics, parameters of renal function were performed. A total of 28 patients, who underwent renal denervation at least 5 months before and still suffer from uncontrolled BP, were subsequently treated with BAT. The office SBP decreased from 182 ± 28 to 163 ± 27 mmHg (P < 0.01) with a responder rate of 68% (office SBP reduction ≥10 mmHg) at month 6, whereas the number of prescribed antihypertensive drug classes remained unchanged (6.2 ± 1.5 vs. 6.0 ± 1.7, P = 0.30). Serum creatinine, estimated glomerular filtration rate and cystatin C remained stable (P = 1.00, P = 0.41 and P = 0.22, respectively), whereas albuminuria was significantly reduced by a median of -29% (P = 0.02). Central SBP (-15 ± 24 mmHg, P = 0.047) and end systolic pressure (-14 ± 20 mmHg, P = 0.03) were significantly reduced. The present data demonstrate that BAT may exert BP-lowering as well as antiproteinuric effects in patients with prior renal denervation. However, precise evaluation of BAT effects in patients with prior renal denervation will need randomized controlled trials using sham procedures.

Effect of pentoxifylline on microalbuminuria in diabetic patients: a randomized controlled trial.

Background. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with anti-inflammatory properties. Human studies have proved its antiproteinuric effect in patients with glomerular diseases, but this study was designed to assess the effects of add-on pentoxifylline to available treatment on reduction of microalbuminuria in diabetic patients without glomerular diseases. Methods. In a double-blind placebo-controlled, randomized study we evaluated the influence of pentoxifylline on microalbuminuria in type 2 diabetic patients. 40 diabetic patients with estimated glomerular filtration rate (eGFR) of more than 60 mL/min/1.73 m2 in eight weeks and microalbuminuria were randomized to two groups which will receive pentoxifylline 1200 mg/day or placebo added to regular medications for 6 months. albuminuria; eGFR was evaluated at three- and six-month follow-up period. Results. Baseline characteristics were similar between the two groups. At six months, the mean estimated GFR and albuminuria were not different between two groups at 3- and 6-month follow-up. Trend of albumin to creatinine ratio, systolic and diastolic blood pressure, and eGFR in both groups were decreased, but no significant differences were noted between two groups (P value > 0.05). Conclusion. Pentoxifylline has not a significant additive antimicroalbuminuric effect compared with placebo in patients with type 2 diabetes with early stage of kidney disease; however, further clinical investigations are necessary to be done.

The Safety and Short-Term Efficacy of Aliskiren in the Treatment of Immunoglobulin A Nephropathy – A Randomized Cross-Over Study

BackgroundLaboratory research and previous study suggest that aliskiren, a direct renin inhibitor, has anti-proteinuric effects. We conducted a randomized crossover study to evaluate the anti-proteinuric effect of aliskiren in patients with immunoglobulin A (IgA) nephropathy.MethodsWe studied 22 patients with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Patients were randomized to either oral aliskiren 300 mg/day or placebo for 16 weeks and then crossed over to the other treatment arm after a washout period. Proteinuria, estimated glomerular filtration rate (eGFR), blood pressure, and serum potassium were monitored.ResultsAfter aliskiren treatment, there was a significant reduction in proteinuria in 4 weeks (1.76±0.95 to 1.03±0.69 g:g-Cr, p<0.0001), which remained at a low level throughout the treatment period. There was a significant difference in proteinuria between the aliskiren and placebo groups from 4 to 16 weeks after treatment (p<0.01 for all comparisons). After aliskiren treatment, there were modest but statistically significant reductions in eGFR (57.2±29.1 to 54.8±29.3 ml/min/1.73 m2, p = 0.013) and diastolic blood pressure (72.6±12.3 to 66.2±11.2 mmHg, p<0.0001). None of the patient developed severe hyperkalemia (serum potassium ≥6.0 mmol/l) during the study period.ConclusionsAliskiren has anti-proteinuric effect in patients with IgA nephropathy and persistent proteinuria despite ACE inhibitor or ARB. Further studies are needed to confirm the renal protecting effect of direct renin inhibition in chronic proteinuric kidney diseases.Trial Registration ClinicalTrials.gov NCT00870493

Aldosterone and progression of kidney disease

Experimental evidence indicates that aldosterone, besides its mineralcorticoid properties, directly contributes to accelerate renal damage through promotion of cell growth, fibrosis and inflammation. As a consequence, attenuation of growth-promoting and fibroproliferative effects of aldosterone might contribute to slow progression of chronic renal injury. Preliminary clinical observations have documented that aldosterone blockers added to angiotensin-converting enzyme inhibitor- and/or angiotensin receptor blocker-based regimens exerted significant antiproteinuric effects in patients with diabetic and nondiabetic nephropathies. Further studies in larger cohorts are now required to definitively address the safety and efficacy of aldosterone antagonism in patients with chronic kidney diseases.

Effect of Pentoxifylline in Addition to Losartan on Proteinuria and GFR in CKD: A 12-Month Randomized Trial

Pentoxifylline potently inhibits cell proliferation, inflammation, and extracellular matrix accumulation. Human studies have proved its antiproteinuric effect in patients with glomerular diseases. Its benefit in addition to angiotensin receptor blockade in patients with chronic kidney disease is not clear. Randomized controlled study. 85 patients with estimated glomerular filtration rate (eGFR) of 10 to 60 mL/min/1.73 m(2) and proteinuria with protein greater than 500 mg/g of creatinine on treatment with losartan, 100 mg/d, for longer than 6 months were screened in National Taiwan University Hospital. In the first stage (12 months), group 1 served as control and group 2 was administered pentoxifylline. In the second stage (6 months), both groups were administered pentoxifylline. The pentoxifylline dose was 400 mg twice daily for patients with eGFR of 30 to 60 mL/min/1.73 m(2) or once daily for patients with eGFR of 10 to 29 mL/min/1.73 m(2). Proteinuria and eGFR. Proteinuria was assessed as total protein-creatinine ratio, eGFR was computed by using the Modification of Diet in Renal Disease Study equation. 27 and 29 patients were randomly assigned to groups 1 and 2, respectively. In the first stage, pentoxifylline decreased median proteinuria from 1,140 to 800 mg/g (median change, -23.9%) compared with 1,410 to 1,810 mg/g (median change, 13.8%) in the control group. The difference between groups was 38.7% (95% confidence interval, 25.7 to 51.6; P < 0.001). The change in proteinuria was related to the change in urinary tumor necrosis factor alpha and monocyte chemoattractant protein 1 excretion (R = 0.64 and R = 0.55, respectively; P < 0.001 for both). In the second stage, pentoxifylline reproduced the change in proteinuria in group 1. Small sample size, disease of late stages, open-labeled study. Pentoxifylline added to losartan therapy for 1 year decreased proteinuria in patients with CKD stages 3 to 5. A large-scale clinical trial is necessary to confirm this result.

Oral Calcitriol for the Treatment of Persistent Proteinuria in Immunoglobulin A Nephropathy: An Uncontrolled Trial

Laboratory research and previous retrospective study suggest that vitamin D and its analogues have profound effects on immune system function and glomerular mesangial cell proliferation. We conducted an open-label study to evaluate the antiproteinuric effect of calcitriol on proteinuria in patients with immunoglobulin A (IgA) nephropathy. Open-label prospective uncontrolled trial. 10 patients (3 men) with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy in a tertiary referral center. Calcitriol, 0.5 microg, twice weekly for 12 weeks. Changes in proteinuria, renal function, serum transforming growth factor beta (TGF-beta) and angiotensin II levels. After calcitriol treatment, there was a significant overall decrease in proteinuria with time by using a general linear model with repeated measures (P = 0.03). There was a progressive decrease in urine protein-creatinine ratio from 1.98 +/- 0.74 to 1.48 +/- 0.81 g/g (P = 0.007) during the first 6 weeks that persisted throughout the study period. No significant change in blood pressure or renal function was noted. There was a simultaneous decrease in serum TGF-beta level, and percentage of decrease in serum TGF-beta level significantly correlated with percentage of change in proteinuria (Spearman r = 0.643; P = 0.02). Serum angiotensin II level did not change throughout the study. One patient experienced transient hypercalcemia that normalized after a dosage decrease. No other major adverse effect was reported. This small study is uncontrolled and does not examine the long-term effect of calcitriol therapy. Twice-weekly oral calcitriol has a modest antiproteinuric effect in patients with IgA nephropathy and persistent proteinuria despite angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy. Additional studies are needed to confirm the renal protecting effect of calcitriol in patients with chronic proteinuric kidney diseases.

Effect of cyclosporin A on renal function in patients with glomerulonephritis

Cyclosporin A ( CsA) plays a confounding part in the treatment of nephrotic syndrome. Renal hemodynamics and glomerular permselectivity were investigated in patients with glomerulonephritis to analyse the antiproteinuric action of CsA and to differentiate between nephrotoxic and immunosuppressive effects. We studied 19 patients with nephrotic syndrome after 6 months of treatment with CsA (membranous glomerulonephritis-MGN, n = 10; focal segmental sclerosing glomerulonephritis - FSGN, n = 5; minimal changes glomerulonephritis - MCGN, n = 4). Patients were studied three times within 3 weeks with (A) and without (B) CsA treatment (A-B-A'). Blood pressure, creatinine, proteinuria, C(In), C(PAH), C(Dex) were measured (analysis according to the model of Deen et al., Am J Physiol. 1985; 249 : 374). GFR (C (In)) increased significantly after withdrawal of CsA from 54 +/- 7.3 to 64 +/- 8.5 ml/min (p < 0.01). Proteinuria increased after withdrawal of cyclosporin (B) between 21 % (MGN) and 45 % (FSGN). After withdrawal of CsA (B) there was no change of FC(dex) in patients with MGN and FSGN. Withdrawal of CsA in patients with MCGN induced a significant decrease in glomerular selectivity in the high molecular range. These data demonstrate that CsA is able to induce even in the short term a significant increase in glomerular permselectivity in MCGN. The acute effects on GFR predominantly determined the acute antiproteinuric effects in patients with MGN and FSGN.

Glurenorm in diabetic nephropathy: effects on renal function and vascular endothelium

Study of the effects of glurenorm, an oral sugar- reducing drug, on renal function and vascular endothelium in patients with noninsulin-dependent diabetes mellitus at different stages of diabetic involvement of the kidneys, including those with chronic renal insufficiency, revealed that glurenorm in therapeutic doses had no nephrotoxic effect; moreover, it maintained the filtration function of the kidneys even in patients with the initial stage of chronic renal insufficiency (with blood serum creatinine of up to 200 mmol/liter. Therapy with glurenorm for 3 and 6 months caused a reliable reduction of the production of thromboxane A, a vasoconstrictor, this probably improving the intrarenal hemodynamics, and exerting an antiproteinuric effect in patients with manifest diabetic nephropathy. At the same time, glurenorm therapy did not appreciably influence the production of factors released by vascular endothelium (prostacyclin and endothelin-1). Hence, a detailed study of renal function and vascular endothelium in patients with type II diabetes demonstrated that administration of glurenorm to patients with manifest renal involvement was not only safe, but even favorably affected the intrarenal hemodynamics and had an antiproteinuric effect.

Effect of captopril on heavy proteinuria in patients with various glomerular diseases.

The effect of captopril on proteinuria was evaluated in twenty patients with various glomerular diseases excreting heavy proteinuria (> 3.0 g/day). Captopril in a daily dose of 37.5 mg was administered orally three times a day to all patients and they were followed for eight weeks. Twenty-four hour urinary excretion of protein, creatinine, sodium, selective protein index (SPI), and blood chemistry including serum electrolytes were measured every two weeks. Twenty-four hour urinary protein excretion per gram creatinine started to fall within two weeks of captopril administration and became nearly stable after four weeks of therapy (p < 0.05). Mean 24-hour urinary protein excretion decreased significantly from a pretreatment value of 9.0 +/- 6.0 gm/gm of cr. to 4.4 +/- 3.5 gm/gm of cr. after eight weeks of captopril treatment. The serum albumin level increased progressively at six and eight weeks after the captopril treatment period and was significantly higher than the pretreatment value (p < 0.05). The decrease in proteinuria did not coincide with a fall in blood pressure or any changes in creatinine clearance. We conclude that captopril does have a significant antiproteinuric effect in patients excreting heavy proteinuria with various glomerular diseases. However, the long term therapeutic efficacy and any renal protective effect of this drug remain to be proven.