Antihypertensive treatments in adult autosomal dominant polycystic kidney disease: network meta-analysis of the randomized controlled trials.

BACKGROUND
Blood pressure (BP) control is one of the most important treatments of Autosomal dominant polycystic kidney disease (ADPKD). The comparative efficacy of antihypertensive treatments in ADPKD patients is inconclusive.


METHODS
Network meta-analysis was used to evaluate randomized controlled trials (RCT) which investigated antihypertensive treatments in ADPKD. PubMed, Embase, Ovid, and Cochrane Collaboration were searched. The primary outcome was estimated glomerular filtration rate (eGFR). Secondary outcomes were serum creatinine (Scr), urinary albumin excretion (UAE), systolic BP (SBP), diastolic BP (DBP), mean artery pressure (MAP) and left ventricular mass index (LVMI).


RESULTS
We included 10 RCTs with 1386 patients and six interventions: angiotensin-converting enzyme inhibitors (ACEI), Angiotensin II receptor blocker (ARB), combination of ACEI and ARB, calcium channel blockers (CCB), β-blockers and dilazep. There was no difference of eGFR in all the treatments in both network and direct comparisons. No significant differences of Scr, SBP, DBP, MAP, and LVMI were found in network comparisons. However, ACEI signiﬁcantly reduced SBP, DBP, MAP and LVMI when compared to CCB. Significantly increased UAE was observed in CCB compared with ACEI or ARB. Bayesian probability analysis found ARB ranked first in the surrogate measures of eGFR, UAE and SBP.


CONCLUSIONS
There is little evidence to detect differences of antihypertensive treatments on kidney disease progression in ADPKD patients. More RCTs will be needed in the future. Use of ARB may be an optimal choice in clinical practice.


INTRODUCTION
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by continuous enlargement of kidney cysts. ADPKD is the most common hereditary nephropathy with prevalence from 1/1000 to 1/400 [1]. ADPKD patients develop hypertension early, which increases the renal progression. ADPKD patients with hypertension have faster and greater annual rates of total kidney volume (TKV) growth, and an increased prevalence of cardiovascular complications when compared with the normotensive patients. Healthcare for ADPKD mainly focuses on hypertension to reduce mortality and morbidity. Currently, blood pressure (BP) control is one of the most important clinical treatments of ADPKD. www.impactjournals.com/oncotarget The renin-angiotensin-aldosterone system (RAAS) plays an important role in hypertension pathogenesis in ADPKD [2]. RAAS inhibitors (RASI) include Angiotensin converting enzyme inhibitor (ACEI) and Angiotensin II receptor blocker (ARB). RASIs have been proved to slow renal progression in non-diabetes chronic kidney disease (CKD), and are widely used in clinical practice of ADPKD. Besides, calcium channel blockers (CCBs), β-blockers, dilazep and the diuretics also were used in ADPKD with hypertension [3][4][5]. There was no difference in renal function between ACEI and placebo [6]. Kanno et al. [7] found CCB showed higher creatinine clearance compared with ACEI. However, a randomized controlled trial (RCT) found renal function was similar between amlodipine and enalapril [8]. Recently, the Halt Progression of Polycystic Kidney Disease studies (HALT-PKD) [1,2] observed a negative effect of the combination of ACEI and ARB on renal function compared with ACEI monotherapy.
Each RCT just contained only two or three drugs. It is hard to get a head-to-head outcome comparing the drugs of interest or get all the drugs to integrate some specific effects together [9]. This study aimed to use network and traditional meta-analysis to assess the direct and indirect effects of antihypertensive treatments in ADPKD.

RESULTS
Ten RCTs with 1,386 participants were included after assessment of 45 full-text articles and 197 records [1][2][3][4][5][6][7][8][10][11][12][13][14][15]. Electronic searching process was shown in the flowchart (Figure 1). Eight trials were two-grouped, and two trials were four-grouped. The network of included treatment comparisons was shown in Figure 2. ACEIs were the most frequently studied agents. The baseline characteristics were summarized in Table 1. The mean follow-up time was about four years (range 0.5-8 years). Male/female proportion was balanced in all trials. The hypertension criteria in the studies was > 140/90 mm Hg. Two studies [6,15] divided patients into hypertension and normal BP groups.
The overall risk of bias of the included studies was shown in Figure 3. Random sequence generation was adequate in two studies. 60% studies did not present adequate blinding. Only three studies used intention-totreat analyses. Predefined endpoints were reported fully in four studies.
Network comparisons for primary outcome eGFR were shown in Table 2. There was no difference of eGFR in all the treatments (seven studies, five treatments, Supplemental Figure 1). There was no increased eGFR with ACEI, ARB, or ACEI+ARB when compared with β-blocker or CCB either in the consistency model or in the inconsistency model. Table 3 showed network comparisons for the Scr. No significant difference was found in all the treatments (five studies, four treatments, Supplemental Figure 2). There was no decreased Scr with ACEI or ARB when compared with β-blocker or CCB either in the consistency model or in the inconsistency model. Table 4 showed the network comparisons for the UAE (seven studies, five treatments, Supplemental Figure 3). UAE in ACEI, ARB, ACEI+ARB and β-blocker did not differ, but UAE tended to be higher in CCB. There was increased UAE with CCB when compared with all the RASI treatments and β-blocker in the consistency model. However, we did not find increased UAE in CCB than β-blocker in the inconsistency model (MD 169.66, 95% CI -11.59, 351.46). Table 5 showed the network comparisons for the SBP (seven studies, five treatments, Supplemental Figure 4). No significant difference was observed in all the treatments either in the consistency model or in the inconsistency model. Table 6 showed network comparisons for the DBP (seven studies, five treatments, Supplemental Figure 5). DBP in all the treatments did not differ. Table 7 showed the network comparisons for the MAP (five studies, five treatments, Supplemental Figure 6). No significant difference was observed in all the treatments either in the consistency model or in the inconsistency model. Table 8 showed the network comparisons for the LVMI (four studies, five treatments, Supplemental Figure 7). LVMI lowering effect was similar in all the treatments either in the consistency model or in the inconsistency model.
Then we performed direct comparisons between the rigorous BP control group (target < 120/80 mmHg) and the standard BP control group (target 120/80-140/90         (Figure 6). Bayesian probability analysis found the ARB had 34% probability to be the best treatment in eGFR. The ranking sequence was shown in Table 9. ARB also ranked first in the UAE and the SBP. B-blocker ranked first in the Scr and the LVMI. ACEI+ARB ranked first in the DBP and the MAP. Sensitivity analysis of by changing different models got similar results for all the outcomes in direct   55 (-317.05, -74.83) -135.99 (-284.14, -3     comparisons. Sensitivity analysis of direct comparisons by excluding each study one by one was consistent with the former results. Heterogeneity of direct comparisons was high in the rigorous BP vs. standard BP group, because the included studies used log transformations in the results. Heterogeneity in the network comparisons was mainly from the ACEI-ARB-CCB loop, so we checked the heterogeneity through the node-splitting (Table 10). There was no significant heterogeneity in the node-splitting.

DISCUSSION
This study provided evidences for the antihypertensive treatments from 10 RCTs evaluating six interventions in adult patients with ADPKD. Overall, network comparisons and direct comparisons both indicated there was currently insufficient evidence of an association between lowering BP and the surrogate measures of kidney.
All the treatments did not differ in eGFR, Scr, SBP, DBP, MAP, and LVMI in network comparisons.
Compared with β-blocker or CCB, RASIs did not show different effects on the renal function. ACEI was not associated with significantly protective effects on eGFR and UAE when compared with placebo. However, ACEI significantly decreased SBP, DBP, MAP and LVMI when compared with CCB. Significantly increased UAE was observed in CCB compared with RASI treatments. No significant outcome was found in Dilazep compared with placebo. The rigorous BP control was associated with lower LVMI than the standard BP control. ARB may be relatively the most suitable treatment for eGFR, UAE and SBP in ADPKD.
RASIs are the first-line treatments for hypertension in ADPKD till now [16]. However, little beneficial effect of RASIs in renal function was found in ADPKD patients in the past [17]. Therapeutic effects of RASI in renal function might be limited due to massive cystic involvement. EGFR in the majority of ADPKD patients remained steady until the late stage of the disease [18]. Combination of ACEI and ARB which was supposed to solve the compensatory feedback showed similar treatment effects of eGFR and TKV when compared with the ACEI monotherapy [1,2].
UAE reflects the level of glomerular proteinuria, which is considered as a marker of glomerular injury [19]. ACEI is widely used in CKD to reduce the albuminuria mainly through lowering the intra-glomerular pressure [20]. Protective effects of ACEI were almost found in patients with chronic glomerulonephritis or proteinuria > 2 g/24h which did not always happen in ADPKD [21]. ADPKD patients were always accompanied with low levels of UAE (<2 g/24h). Therefore the anti-albuminuria effect of the ACEI still need large-scale studies to prove.
CCB was associated with increased UAE than RASIs [3,8,10]. We noticed that the CCB used in the trials was amlodipine (L-type CCB). CCBs varied in their effects of glomerular arterioles. T-or N-channel receptors mainly existed on the afferent and efferent arteriole, while L-channel receptors predominantly existed on the afferent arteriole. T-/N-channel blockade led to a reduction of intra-glomerular pressure and accordingly decreased UAE levels, while blockade of L-channel receptors led to an increase of UAE [22]. On the other hand, cytosolic Ca 2+ depletion caused by PKD1/2 mutation could activate cyclic adenosine monophosphate (cAMP) signal pathway and accelerate cystic proliferation in ADPKD [23,24]. CCB might aggravate the Ca 2+ depletion of the tubules and activate the cAMP pathway. However, this hypothesis needed to be testified.
Β-blockers treatment was limited and uncertain according to the existing outcomes. Β-blockers could inhibit RAAS activation by suppressing renin release. Evidence about β-blockers in ADPKD still needs more studies to prove.
LVMI is known as cardiovascular risk factor for morbidity or mortality in ADPKD patients [19]. Left ventricular hypertrophy frequently occurs in ADPKD patients with hypertension. LVMI decrease of hypertensive patients could bring benefits in reduced cardiovascular risk and mortality. Only rigorous BP control was found to be associated with obvious decline in LVMI compared with the standard BP control. Moreover, the HALT-PKD study found rigorous BP control could slow TKV significantly in the patients with early ADPKD [1,2]. However, the eGFR and the UAE were not significant in the rigorous BP control group.
There were few data on patient relevant endpoints, such as end stage renal disease, need for dialysis/ transplantation and mortality in addition to adverse drug effects. Zeltner et al. [4] reported no difference between ACEI vs. β-blocker in the need for dialysis/transplantation and the risk of cardiovascular events. Nutahara et al. [3] reported no difference between ARB vs. CCB in the risk of doubling of Scr.
This study had several limitations. First, the sample  Data was listed as MD with 95% CI. Effect estimates from the network meta-analysis in the consistency model occupy the bottom left part of the diagram, and the estimates from the inconsistency model occupy the top right part of the diagram. The diagonal corresponds to the comparison. The MD and 95% CI for the comparisons should be read from left to right. The data should be read from left to right in the bottom left part of the diagram, and from right to left in the top right part of the diagram. Rank 1 was the best. The bigger number of the rank, the worse rank. Rank 1 was underlined and in bold.  size of included studies was scant. Therefore, conclusions of eGFR and secondary outcomes were uncertain. Secondly, most of the ADPKD patients were prescribed with combination antihypertensive drugs. Our results were influenced inevitably by mixed drug effects. Thirdly, safety endpoints were poorly defined in included studies. Moreover, this study could not assess subgroup analysis by different ADPKD genotypes (PKD1&PKD2) with different speed of renal progression.
In conclusion, this network meta-analysis is underpowered to detect differences of antihypertensive treatments on kidney progression in ADPKD patients. More RCTs and research about T-/N-type CCBs will be needed in the future. Use of ARB in clinical practice may be an optimal choice.