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Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy

Abstract Aims/Introduction We aimed to evaluate the potential benefits and adverse effects of adding a mineralocorticoid receptor antagonist (MRA) to angiotensin‐converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB), as standard treatment in patients with diabetic nephropathy. Materials and Methods We scanned the Embase, PubMed and Cochrane Central Register of Controlled Trials databases for human clinical trials published in English until June 2016, evaluating renal outcomes in patients with diabetic nephropathy. Results A total of 18 randomized controlled trials involving 1,786 patients were included. Compared with ACEI/ARB alone, co‐administration of MRA and ACEI/ARB significantly reduced urinary albumin excretion and the urinary albumin–creatinine ratio (mean difference −69.38, 95% confidence intervals −103.53 to −35.22, P < 0.0001; mean difference −215.74, 95% confidence intervals −409.22 to −22.26, P = 0.03, respectively). A decrease of blood pressure was also found in the co‐administration of MRA and ACEI/ARB groups. However, we did not observe any improvement in the glomerular filtration rate. There was a significant increase in the risk of hyperkalemia on the addition of MRA to ACEI/ARB treatment (relative risk 3.74, 95% confidence intervals 2.30–6.09, P < 0.00001). Conclusions These findings suggest that co‐administration of MRA and ACEI/ARB has beneficial effects on renal outcomes with increasing the incidence of hyperkalemia.


INTRODUCTION
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) in developed countries, and its prevalence has increased dramatically over the past decades. Although there has been a significant progress in slowing the progression of DN, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes 1,2 . However, a failure to achieve adequate anti-albuminuric renoprotective effects even after the administration of renin-angiotensin-aldosterone system inhibitors has been reported. An inadequate blockade of aldosterone could be one of the reasons why longterm administration of renin-angiotensin-aldosterone system inhibitors has not been effective in patients with DN. Mineralocorticoid receptor (MR) blockade is emerging as a new paradigm in diabetes 3 . In a number of animal models of type 1 and type 2 diabetes, studies have shown a beneficial effect of spironolactone, a MR antagonist (MRA), as well as that of the more selective MRA, eplerenone [4][5][6][7] . The effects of these agents in reducing albuminuria or urinary albumin excretion (UAE) and inhibiting the progression of DN have been evaluated in clinical trials, with small sample sizes. Finerenone is a novel non-steroidal MRA with a higher selectivity towards the MR compared with spironolactone, and a stronger MR-binding affinity compared with eplerenone. The addition of finerenone to angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) therapy resulted in an improvement of the urinary albumin-creatinine ratio (UACR) in patients with DN 8 . However, the risk of life-threatening hyperkalemia after MRA treatment in patients with DN could severely limit the clinical use of this drug.
Although a number of studies have examined the effects of spironolactone on DN, to date, no meta-analysis has been carried out to examine all MRAs, especially the novel MRAs, and their impact on DN progression. The objectives of the present study were to analyze the renal outcomes, the efficacy and the safety of adding an MRA to ACEI/ARB treatment of patients with DN, and to increase the understanding of dual blockade with co-administration of MRA and ACEI/ARB in this patient population.

Search strategies
The Embase, PubMed and Cochrane Central Register of Controlled Trials databases (up to June 2016) were searched for clinical trials published in English, involving human subjects and evaluating the effect of MR blockade in patients with DN. The search terms used were 'spironolactone,' 'eplerenone,' 'finerenone,' 'mineralocorticoid receptor antagonist' 'aldactone,' 'mineralocorticoid receptor blockade,' 'aldosterone antagonist,' 'diabetic nephropathy,' 'albuminuria' 'glomerular filtration rate' and 'proteinuria.' The search was supplemented by reviewing lists of references, manual searching of relevant journals and by direct correspondence with authors. Case reports, commentaries, review articles, abstracts, case series and single-group cohort studies were excluded from this review. All subjects were patients with DN, and there were no restrictions on sample size or duration of follow up. The end-points identified in these studies included changes in UAE, UACR, glomerular filtration rate (GFR), systolic blood pressure (SBP) and diastolic blood pressure (DBP). Adverse effects, such as hyperkalemia, were also reviewed.

Data collection
Two reviewers (LJS and YNS) independently carried out data extraction. The search strategy was used to obtain titles and abstracts of studies relevant to the review. The reviewers independently assessed the retrieved abstracts and the full text, rejecting studies that did not meet the inclusion criteria. Disagreements between the reviewers were resolved by consensus or by a third investigator (GRJ).
Data on the first author, year and country of publication, study design, classification of MRA, treatment duration, sample size, and study end-point were collected. The indexes of renal outcome (UAE, UACR, GFR) and BP were extracted. Furthermore, data on safety and adverse events, including hyperkalemia, were also included.

Assessment of risk of bias
The risk of bias in the included studies was assessed independently by two authors (LJS and YNS). Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other potential sources of bias were assessed using the risk of bias assessment tool, and discrepancies were resolved by discussion with a third investigator (GRJ).

Statistical analysis
Analyses were carried out using Revman 5.3 (The Cochrane Collaboration, London, UK). For dichotomous outcomes (hyperkalemia), results were expressed as relative risks (RR) with 95% confidence intervals (CI). Continuous variables (UAE, UACR, BP and GFR) were analyzed using the mean difference (MD) and 95% CI. Statistical heterogeneity was measured using the I 2 -statistic and the v 2 -test. Heterogeneity was not considered to be significant when I 2 was <50%, whereas I 2 > 50% was considered an indication of statistically significant heterogeneity among the included studies. Data were pooled using a fixed-effects model when I 2 was <50%. We chose the randomeffects model to analyze data when I 2 was >50%. A P-value <0.05 for any test or model was considered statistically significant.
Sensitivity analyses (excluding 1 study at a time) were carried out to assess the contribution of the individual trials to the pooled effect estimates by sequentially omitting each trial. Forest plots were used for graphic representation of the data.

Search results
The combined search of the Embase, PubMed and Cochrane Central Register of Controlled Trials databases identified 772  citations. We excluded 429 articles after a review of the title and abstract, and 270 articles because of a duplication of studies; 73 articles were retrieved for a detailed evaluation, and 18 randomized controlled trials (RCTs) involving 1,786 patients satisfying the inclusion criteria were finally analyzed in a metaanalysis published between 2002 and 2015. The process used to select studies for the meta-analysis is shown in Figure 1. Table 1 shows the baseline characteristics of patients with DN in each trial included in the present study.

Risk of bias
The risks of bias in the included studies are shown in Figures 2 and 3. Random sequence generation was unclear in seven studies, and allocation concealment was adequate in four out of 18 trials (22.2%) and unclear in the remaining 14 studies (77.8%).
Blinding of participants was unclear in three studies, and outcome assessors blinding was clear in only one study. Incomplete outcome was clear in 14 studies (77.8%) and unclear in three studies. There was selective reporting in 14 studies. Seven studies were unclear in other biases. Publication bias was not evident in the present study.

DISCUSSION
The present findings show that MRA plus ACEI/ARB therapy, compared with ACEI/ARB monotherapy, significantly improved the UAE and UACR in patients with DN. We also observed a significant reduction in the SBP and DBP in the present study population. However, MRA plus ACEI/ARB therapy does not seem to improve the GFR, which is an important index of renal function. There was a significant difference in the incidence of hyperkalemia between the MRA plus ACEI/ ARB therapy patients and the ACEI/ARB monotherapy patients.
DN is a leading cause of chronic kidney disease worldwide. Although efforts have been made to develop novel therapeutic approaches, DN remains a severe disease condition with high rates of morbidity and mortality. An inadequate blockade of aldosterone might fail to achieve adequate anti-albuminuric effects in patients with DN. Studies show that renin-angiotensin-aldosterone system blockade with ACEI/ARB alone sometimes does not achieve adequate renoprotective effects and does not reduce the progression of kidney disease, despite therapy 27 . There is increasing evidence suggesting that the use of MRA in combination with ACEI/ARB has a protective effect on CKD patients; however, this combination treatment still requires further investigation 28,29 . Several studies have reported the effects of spironolactone therapy on renal outcomes in patients with CKD [30][31][32] . The available data confirmed the protective effects of MRA plus ACEI/ARB treatment on major renal events in CKD patients; however, these studies were not limited to DN patients and did not include a novel MRA, such as finerenone. The present study focused on a 'DN' population, and specifically analyzed three MRAs including finerenone. The current data about finerenone on DN are very limited, only one study was involved in our analysis, so our pool results were consistent with previous studies. UAE and UACR are considered important markers for proteinuria. Increased UAE or UACR can accelerate the progression of DN, and a reduction in UAE or UACR has been associated with a favorable effect on renal outcome. Our pooled analysis of these studies showed a significant improvement in the UAE and UACR after MRA plus ACEI/ARB therapy compared with their values after ACEI/ARB monotherapy. The overall findings are consistent, to a certain extent, with previous studies. In 2006, Epstein et al. 25 reported that compared with ACEI monotherapy, co-administration of eplerenone with an ACEI significantly reduced the UACR in patients with DN; however, we did not include this RCT in our UACR analysis, because we were unable to obtain detailed data from the authors. Some studies showed beneficial effects of MRAs on  proteinuria; however, these studies did not include data for a combined MRA plus ACEI/ARB treatment. Therefore, we did not include these studies in our analysis 33,34 . Thus, the present analysis was limited owing to insufficient data on proteinuria parameters in the trials included in this study. Additionally, the number of the trials included in this study was too small.  Further RCTs are necessary to investigate the validity of our conclusions.
The GFR is an important index for the evaluation of renal function. We observed that co-administration of MRA and ACEI/ARB had no impact on GFR compared with ACEI/ARB monotherapy in patients with DN. However, the present results might have been affected by the fact that just 11 RCTs in our analysis reported the GFR, whereas GFR data were not reported in a number of the reviewed trials, and others reported GFR data but did not provide complete information. While discussing the GFR findings, it is important to note that the GFR was only examined in the context of a study population with DN, and this has not been extensively studied in other populations. It seems plausible that co-administration of MRA and ACEI/ARB maintain a relatively stable GFR in patients with DN.
Control of BP is another crucial factor in the treatment of DN, and is associated with survival and renal prognosis. Our pooled analysis of 10 RCTs showed a significant reduction in SBP and DBP after MRA and ACEI/ARB therapy, compared with ACEI/ARB monotherapy. In three RCTs, we observed a reduction in SBP and DBP compared with the baseline BP. Improved BP control after a combination therapy significantly reduces the elevated systemic blood pressure to the glomeruli, which can lead to beneficial effects on renal outcome, specifically, proteinuria, and GFR 35,36 .
As the evidence supporting the use of MRA in the treatment of DN accumulates, the question of safety arises, particularly given the pre-existing risk of hyperkalemia. In a recent narrative review, Mavrakanas 3 analyzed the effects of MRA combined with ACEI/ARB in patients with DN. That review included just nine trials, and confirmed that combined treatment increased the risk of hyperkalemia. We carried out an analysis of the development of hyperkalemia, even though each trial included in our analysis defined hyperkalemia differently. We confirmed that the risk of hyperkalemia was significantly higher after MRA and ACEI/ARB therapy compared with that after ACEI/ARB monotherapy in patients with DN. This finding is consistent with previous studies. Some studies have reported on the safety of including MRA in the treatment of DN or end-stage renal disease population treated with ACEI/ ARB 25,37 . For example, Epstein et al. 25 found that eplerenone plus ACEI had no significant effect on serum potassium levels compared with ACEI monotherapy in patients with DN. The most likely explanation is the careful selection of patients, with the exclusion of patients with a previous event of hyperkalemia. There are reports that finerenone with ACEI did not change potassium levels in patients with DN 25 . Furthermore, co-administration of MRA and ACEI/ARB in patients with DN should be carried out under appropriate laboratory surveillance.
The present study had several limitations. First, the short study duration designed to assess surrogate end-points might affect the results. Further limitations include the relatively small sample size, and the limited or absent long-term follow-up data on the cumulative effects of MRA and ACEI/ARB therapy on study end-points. In addition, some relevant data were not available or complete. More detailed information is required to clarify the effect of MRA on renal outcome. Second, although   our statistical analyses suggested a low probability of publication bias, which remains a concern. Selection bias cannot be completely ruled out, as we only retrieved articles from English-language journals and published trials. Third, although most studies were RCTs, there were cross-over design studies, and some trials did not report their study methods in enough detail to determine the methods used and the trial quality. Finally, heterogeneity was found in some of our analyses, and a single, heavily weighted study could confuse the outcomes of the present meta-analysis.
In conclusion, the co-administration of MRA and ACEI/ ARB in patients with DN confers greater renoprotection compared with ACEI/ARB alone. However, the inclusion of MRA to the ACEI/ARB therapy results in a higher incidence of hyperkalemia, suggesting that co-administration of MRA and ACEI/ARB, under appropriate laboratory surveillance, might be a reasonable treatment option in these patients.
The potential effects of MRA remain unclear and require further clarification. The majority of studies focused on spironolactone, whereas studies on DN involving new MRAs, such as finerenone, are currently limited. Large-scale, multicenter, randomized, double-blind, placebo-controlled trials are required to provide new insights into the effects of MRA, as a therapeutic agent, on the renal outcomes in patients with DN.
ACKNOWLEDGMENT This work was supported by Scientific Research grant (No. 13YJ15) from Xinhua Hospital.

DISCLOSURE
The authors declare no conflict of interest.