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Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.
Chung, EY, Ruospo, M, Natale, P, Bolignano, D, Navaneethan, SD, Palmer, SC, Strippoli, GF
The Cochrane database of systematic reviews. 2020;(10):CD007004
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Abstract
BACKGROUND Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014. OBJECTIVES To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia). SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD. DATA COLLECTION AND ANALYSIS Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE. MAIN RESULTS Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists. AUTHORS' CONCLUSIONS The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.
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Effect of different types of statins on kidney function decline and proteinuria: a network meta-analysis.
Esmeijer, K, Dekkers, OM, de Fijter, JW, Dekker, FW, Hoogeveen, EK
Scientific reports. 2019;(1):16632
Abstract
Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than others remains unclear. We performed a network meta-analysis of randomized controlled trials (RCT) to investigate which statin most effectively reduces kidney function decline and proteinuria. We searched MEDLINE, Embase, Web of Science, and the Cochrane database until July 13, 2018, and included 43 RCTs (>110,000 patients). We performed a pairwise random-effects meta-analysis and a network meta-analysis according to a frequentist approach. We assessed network inconsistency, publication bias, and estimated for each statin the probability of being the best treatment. Considerable heterogeneity was present among the included studies. In pairwise meta-analyses, 1-year use of statins versus control reduced kidney function decline by 0.61 (95%-CI: 0.27; 0.95) mL/min/1.73 m2 and proteinuria with a standardized mean difference of -0.58 (95%-CI:-0.88; -0.29). The network meta-analysis for the separate endpoints showed broad confidence intervals due to the small number available RCTs for each individual comparison. In conclusion, 1-year statin use versus control attenuated the progression of kidney function decline and proteinuria. Due to the imprecision of individual comparisons, results were inconclusive as to which statin performs best with regard to renal outcome.
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The effect of SGLT-2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.
Piperidou, A, Sarafidis, P, Boutou, A, Thomopoulos, C, Loutradis, C, Alexandrou, ME, Tsapas, A, Karagiannis, A
Journal of hypertension. 2019;(7):1334-1343
Abstract
: 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.
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The amino acid mutations of the podocin in proteinuria: a meta-analysis.
Lu, L, Sun, XM, Yin, Y, Huang, YF, Wang, M, Wan, H, Wei, LB, Xiao, W
Renal failure. 2015;(8):1329-37
Abstract
While many previous studies have reported an association between the single-nucleotide polymorphisms (SNPs) of the podocin and proteinuria occurred, a conclusive relationship has not been defined in every oligoallelic state of amino acid (AA) mutations in podocin. In this study, we performed a meta-analysis of the published data to investigate the impact of the oligoallelic AA mutations of the podocin on proteinuria; a total 16 AA mutations were investigated for oligoallelic pathogenicity. Despite significant heterogeneity within some of the comparisons, the results revealed significantly higher risks of proteinuria in early-onset (onset age <16) individuals for five mutations (P118L, R138Q, R168H, V180M, and V260E), and in all onset ages individuals for five mutations (R138Q, G140X, R229Q, V260E, and V290M) compared to non-variant individuals. We also tested the steroid response in individuals with R229Q and E237Q. No statistically significant differences in the two mutations carrier rate were observed between steroid resistance patients and controls. No AA mutation was selected for meta-analysis on the recurrence of proteinuria after renal transplantation as lack of control data. In conclusion, our meta-analysis tested the pathogenicity of the oligoallelic AA mutations in podocin and suggested the potential causative mutations, and the alleles showing an association with protein susceptibility. The sensitivity and specificity of each causative mutation are pending further testing.
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Effect of N- and T-type calcium channel blocker on proteinuria, blood pressure and kidney function in hypertensive patients: a meta-analysis.
Thamcharoen, N, Susantitaphong, P, Wongrakpanich, S, Chongsathidkiet, P, Tantrachoti, P, Pitukweerakul, S, Avihingsanon, Y, Praditpornsilpa, K, Jaber, BL, Eiam-Ong, S
Hypertension research : official journal of the Japanese Society of Hypertension. 2015;(12):847-55
Abstract
The combination of a calcium channel blocker (CCB) and a blocker of the renin-angiotensin-aldosterone system (RAAS) is recommended in clinical practice guidelines. L/N- and L/T-type CCBs might provide an additional effect on lowering proteinuria. Therefore, we conducted a meta-analysis to assess the efficacy of L/N- and L/T-type CCBs in hypertensive patients with proteinuria. We searched MEDLINE, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for single-arm studies and randomized controlled trials (RCTs) that examined the effect of L/N- and L/T-type CCBs as add-on therapy compared with standard antihypertensive regimen for proteinuria on hemodynamic and kidney-related parameters in hypertensive patients with proteinuria. Random-effect model meta-analyses were used to compute changes in the outcomes of interest. We identified 17 RCTs, representing 1905 patients. By meta-analysis, L/N- and L/T-type CCB add-on therapy did not yield significant changes in systolic and diastolic blood pressure compared with standard treatment, but there was a significant lowering of the pulse rate. However, L/N- and L/T-type CCBs resulted in a significant standardized net decrease in albuminuria and proteinuria (-1.01; 95% confidence interval (CI), -1.78 to -0.23; P=0.01), and a standardized net improvement in the estimated glomerular filtration rate and serum creatinine (0.23; 95% CI, 0.11 to 0.35, P<0.001; and -0.25; 95% CI, -0.46 to -0.03; P=0.02, respectively). Despite no additional lowering effect on blood pressure, L/N- and L/T-type CCBs combined with a blocker of the RAAS provided a decrease in proteinuria and improvement in kidney function. Further studies are required to establish the long-term kidney benefits of this combination therapy.
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Correlation between serum 25(OH)D values and lupus disease activity: an original article and a systematic review with meta-analysis focusing on serum VitD confounders.
Sahebari, M, Nabavi, N, Salehi, M
Lupus. 2014;(11):1164-77
Abstract
Notwithstanding that several original studies and some systematic reviews have been undertaken on the subject "correlation between serum values of vitamin D (VitD) and lupus disease activity," there is still no consensus on the importance of sectional measurement of serum VitD in the prediction of disease activity and important confounders in estimation of serum VitD. Medline, Web of Knowledge, and Scopus databases were searched from 1995 to 2013. The following medical subject heading (MeSH) terms and/or text words were used: "Vitamin D" OR "25OHD" OR "25(OH)D" combined with "systemic lupus erythematosus" OR "lupus" OR "SLE." References cited in the identified articles were also manually searched. Human studies in any language were included. Original research on this topic was also carried out on 82 lupus patients, considering important VitD confounders according to our systematic review and we included them in the meta-analysis. A total of 35 studies were registered for this study. Only 11 of these pointed to this correlation by Pearson test. The pooled Pearson correlation (r) of associations between disease activity and VitD was -0.365 (95% CI: -0.536, -0.165) with significant heterogeneity (p = 0.001 I (2 )= 93%). Sensitivity analysis resulted in no significant differences. The most important adjustable confounders considered by researchers were drugs, especially hydroxychloroquine, prednisolone and supplementary VitD, body mass index (BMI) and proteinuria or renal function. Only proteinuria was reported to influence VitD concentration strongly. BMI was another probable influencing factor. Our original research presented no correlation between VitD and SLEDAI (p = 0.68, r s = 0.003). This meta-analysis demonstrated that most of the studies on the relationship between VitD and lupus disease activity that found no correlation did not present the details of the statistics. However, analyzing 11 studies, most of which found a reverse correlation and reported it in detail, and our study found a weak reverse correlation between those two items. Systematic review of confounders showed that BMI, medications and kidney involvement were the most remarkable ones reported by researchers.
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Meta-analysis: the efficacy and safety of paricalcitol for the treatment of secondary hyperparathyroidism and proteinuria in chronic kidney disease.
Han, T, Rong, G, Quan, D, Shu, Y, Liang, Z, She, N, Liu, M, Yang, B, Cheng, G, Lv, Y, et al
BioMed research international. 2013;:320560
Abstract
INTRODUCTION Previous studies have demonstrated the safety and efficacy of using Paricalcitol for the treatment of secondary hyperparathyroidism (SHPT) in patients on dialysis. The aim of the current meta-analysis was to assess the safety and efficacy of Paricalcitol for the management of SHPT in patients with chronic kidney disease (CKD) not yet on dialysis. A secondary aim was to determine if sufficient data was available to assess the effect of Paricalcitol for the management of proteinuria. METHODS A meta-analysis was conducted using the Cochrane Collaboration's RevMan 4.2 software. RESULTS Paricalcitol is effective in lowering PTH in patients with CKD not yet on dialysis and is also effective in lowering proteinuria in diabetic CKD patients. However, we uncovered a safety signal identifying an elevated calcium phosphate product and a trend towards the development of hypercalcemia. A phosphate elevation was not demonstrated because the target used in the clinical studies was a P > 5.5 mg/dl, a value appropriate for dialysis patients and not CKD patients. CONCLUSION Although Paricalcitol is effective in lowering PTH, we advise caution in the use of any active Vitamin D analogues in patients with CKD because of the potential risk of exacerbating vascular calcification.
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Active vitamin D treatment for reduction of residual proteinuria: a systematic review.
de Borst, MH, Hajhosseiny, R, Tamez, H, Wenger, J, Thadhani, R, Goldsmith, DJ
Journal of the American Society of Nephrology : JASN. 2013;(11):1863-71
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Abstract
Despite renin-angiotensin-aldosterone system blockade, which retards progression of CKD by reducing proteinuria, many patients with CKD have residual proteinuria, an independent risk factor for disease progression. We aimed to address whether active vitamin D analogs reduce residual proteinuria. We systematically searched for trials published between 1950 and September of 2012 in the Medline, Embase, and Cochrane Library databases. All randomized controlled trials of vitamin D analogs in patients with CKD that reported an effect on proteinuria with sample size≥50 were selected. Mean differences of proteinuria change over time and odds ratios for reaching ≥15% proteinuria decrease from baseline to last measurement were synthesized under a random effects model. From 907 citations retrieved, six studies (four studies with paricalcitol and two studies with calcitriol) providing data for 688 patients were included in the meta-analysis. Most patients (84%) used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker throughout the study. Active vitamin D analogs reduced proteinuria (weighted mean difference from baseline to last measurement was -16% [95% CI, -13% to -18%]) compared with controls (+6% [95% CI, 0% to +12%]; P<0.001). Proteinuria reduction was achieved more commonly in patients treated with an active vitamin D analog (204/390 patients) than control patients (86/298 patients; OR, 2.72 [95% CI, 1.82 to 4.07]; P<0.001). Thus, active vitamin D analogs may further reduce proteinuria in CKD patients in addition to current regimens. Future studies should address whether vitamin D therapy also retards progressive renal functional decline.
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Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts.
Afshinnia, F, Wilt, TJ, Duval, S, Esmaeili, A, Ibrahim, HN
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2010;(4):1173-83
Abstract
BACKGROUND Obesity is a risk factor for the progression of chronic kidney disease (CKD). The impact of weight loss on proteinuria and renal function is less clear. We aimed to determine the effect of intentional weight loss on proteinuria and kidney function. METHODS Three bibliographic databases including Medline, Cochrane and SCUPOS as well as reference list of articles were searched. We included randomized and non-randomized controlled trials as well as single-arm trials published in English through May 2009 which examined urinary protein among obese or overweight adults before and after weight loss interventions including dietary restriction, exercise, anti-obesity medications and bariatric surgery. Study characteristics and methodological quality of trials were assessed. RESULTS Five hundred twenty-two subjects from five controlled and eight uncontrolled trials were included. Weight loss interventions were associated with decreased proteinuria and microalbuminuria by 1.7 g [95% confidence interval (95% CI), 0.7 to 2.6 g] and 14 mg (95% CI, 11 to 17 mg), respectively (P < 0.05). Meta-regression showed that, independent of decline in mean arterial pressure, each 1 kg weight loss was associated with 110 mg (95% CI, 60 to 160 mg, P < 0.001) decrease in proteinuria and 1.1 mg (95% CI, 0.5 to 2.4 mg, P = 0.011) decrease in microalbuminuria, respectively. The decrease was observed across different designs and methods of weight loss. Only bariatric surgery resulted in a significant decrease in creatinine clearance. CONCLUSIONS Weight loss is associated with decreased proteinuria and microalbuminuria. There were no data evaluating the durability of this decrease or the effect of weight loss on CKD progression.
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The effect of n-3 long-chain polyunsaturated fatty acid supplementation on urine protein excretion and kidney function: meta-analysis of clinical trials.
Miller, ER, Juraschek, SP, Appel, LJ, Madala, M, Anderson, CA, Bleys, J, Guallar, E
The American journal of clinical nutrition. 2009;(6):1937-45
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Abstract
BACKGROUND Chronic kidney disease is a major worldwide problem. Although epidemiologic and experimental studies suggest that n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation may prevent or slow the progression of kidney disease, evidence from clinical trials is inconsistent. OBJECTIVE The objective was to combine evidence from controlled clinical trials to assess the effect of n-3 LCPUFA supplementation on the change in urine protein excretion (UPE) and on glomerular filtration rate (GFR). DESIGN We performed a meta-analysis of clinical trials that tested the effect of n-3 LCPUFA supplementation on UPE, a marker of kidney damage, and on GFR, a marker of kidney function. A random-effects model was used to pool SD effect size (Cohen's d) across studies. RESULTS Seventeen trials with 626 participants were included in the meta-analysis. Most trials focused on patients with a single underlying diagnosis: IgA nephropathy (n = 5), diabetes (n = 7), or lupus nephritis (n = 1). The dose of n-3 LCPUFAs ranged from 0.7 to 5.1 g/d, and the median follow-up was 9 mo. In the pooled analysis, there was a greater reduction in UPE in the n-3 LCPUFA group than in the control group: Cohen's d for all trials was -0.19 (95% CI: -0.34, -0.04; P = 0.01). In a patient with 1 g UPE/d , this corresponds to a reduction of 190 mg/d. Effects on GFR were reported in 12 trials. The decline in GFR was slower in the n-3 LCPUFA group than in the control group, but this effect was not significant (0.11; 95% CI: -0.07, 0.29; P = 0.24). CONCLUSIONS In our meta-analysis, use of n-3 LCPUFA supplements reduced UPE but not the decline in GFR. However, small numbers of participants in trials, different methods of assessing proteinuria and GFR, and inconsistent data reporting limit the strength of these conclusions. Large, high-quality trials with clinical outcomes are warranted.