Statins in the treatment of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease affecting all ethnic groups [1]. It is the fourth most common cause of end-stage renal disease. ADPKD is characterized by progressive development of cysts in renal tubular epithelial cells that gradually compress the adjacent parenchyma. Human and experimental data provide strong evidence that increased tubular cell proliferation and fluid secretion associated with tubulointerstitial inflammation play a crucial role in the progression of ADPKD [2]. The cholesterol-lowering drugs 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, so-called statins, have anti-proliferative, anti-inflammatory and anti-oxidant effects independent of cholesterol lowering [3, 4]. Statins inhibit the mevalonate pathway, which is important not only for cholesterol synthesis, but also for cell-signaling processes. Statins have beneficial effects in experimental models of chronic renal disease [5–10]. Moreover, they have been shown to improve endothelial function in patients with diabetes mellitus [11], nephrotic syndrome [12] and ADPKD [13]. Thus, it can be hypothesized that statins would have beneficial effects on slowing the progression of ADPKD. The first study to investigate the effects of a statin on the progression of polycystic kidney disease was performed 20 years ago [14]. In this study by Gile et al. [14], lovastatin significantly decreased cystic kidney size, the volume of density of cysts and the serum urea nitrogen level in heterozygous male Han:SPRD rats, an animal model of ADPKD. Similarly, in a more recent study, Zafar et al. [15] reported that lovastatin therapy demonstrated structural benefits, such as decreased kidney weight and cyst volume density, and functional benefits, including increased renal blood flow (RBF) and decreased BUN, in this rat model of ADPKD. In this issue of NDT, Zand et al. [16] investigated the effect of simvastatin on RBF in patients with ADPKD with mild (n = 11) and moderate (n = 10) renal dysfunction. The mean age of the patients was 47 years. The mean glomerular filtration rate (GFR), measured by iothalamate clearance, was 86.4 ± 15.8 mL/min in the mild renal dysfunction group, while it was 47.1 ± 11.7 min/min in the moderate renal dysfunction group. Four weeks of therapy with simvastatin 40 mg daily did not change RBF as determined by the para-amino-hippurate (PAH) clearance and magnetic resonance (MR) scanning. The results of this short-term study are in contrast with a previous study by van Dijk et al. [17], which showed a significant improvement in effective renal plasma flow (ERPF) as measured by PAH clearance. Ten normocholesterolemic ADPKD patients with a mean age of 35 years were included in this double-blind cross-over study. The patients were treated in random order for 4 weeks with 40 mg simvastatin or placebo daily. It was demonstrated that after treatment with simvastatin, GFR, as determined by inulin clearance, significantly increased from 124 ± 4 to 132 ± 6 mL/min (P < 0.05) and ERPF increased significantly from 494 ± 30 to 619 ± 67 mL/min (P < 0.05) [17]. The major differences between these two studies are the ages and the baseline kidney functions of the patients. The patients were older and had worse kidney function in the study by Zand et al. [16]. These factors may have affected the results. In a 6-month study of 16 ADPKD patients with a mean age of 39.4 ± 10.6 years and with well-preserved kidney function (creatinine clearances >80 mL/min/1.73 m2), Namli et al. [13] investigated the effect of simvastatin 40 mg daily treatment on endothelial dysfunction as measured by high-resolution brachial artery ultrasound. The endothelial-dependent dilatation significantly increased after 1 month of simvastatin therapy. Moreover, an additional significant increase in endothelial-dependent dilatation was observed after 6 months of statin therapy. This study, like the van Dijk et al. study [17], underlines the importance of early treatment in order to attain the beneficial effects of statins. Fassett et al. [18] conducted a randomized open-label trial on 49 patients with ADPKD to investigate to effect of pravastatin 20 mg on kidney function and urinary protein excretion. The mean age of the patients was 53 years in the pravastatin group and 49 years in the control group. The estimated GFR (eGFR) was 58.5 ± 18.2 mL/min/1.73 m2 in the pravastatin group and 49.9 ± 23.2 in the control group. No significant change in markers of kidney function or urinary protein excretion was observed between groups over 2 years of follow-up. The relatively older age of the patients with lower GFRs may have affected the outcome of the study. Statins are expected to have more benefit if started at an early stage of the disease. Cadnapaphornchai et al. [19] performed the only randomized placebo-controlled clinical trial investigating the effects of a statin, pravastatin, in patients with ADPKD. The study was conducted in young patients (ages 8–22 years) with ADPKD who were receiving an angiotensin-converting enzyme (ACE) inhibitor, lisinopril. The study enrolled 110 patients and 91 patients completed the trial. The patients randomized to treatment with pravastatin demonstrated significantly less increase in height-corrected total kidney volume as compared with patients randomized to placebo. This study emphasizes the importance of early intervention, before the development of severe structural disease, in patients with ADPKD. Two landmark trials on ADPKD have been published in recent years [20, 21]. The first is the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial, which showed that the vasopressin receptor antagonist tolvaptan was effective in slowing the increase in total kidney volume and the decline in kidney function in patients with an estimated creatinine clearance of ≥60 mL/min [20]. The second is the HALT-PKD trial, which investigated the efficacy and safety of combined treatment with an ACE inhibitor (lisinopril) and an angiotensin receptor blocker (telmisartan) versus treatment with lisinopril alone, as well as standard versus rigorous blood pressure targets. Although the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume, rigorous blood pressure control (90/60–110/75 mmHg) was associated with a slower increase in total kidney volume as compared with standard blood pressure control (120/70–130/80 mmHg) in patients with ADPKD [21]. It seems that a multidrug approach is needed in the management of patients with ADPKD, not only to slow the progression of renal disease, but also to decrease the cardiovascular complications, the major cause of morbidity and mortality in these patients [22]. Aggressive blood pressure control with an ACE inhibitor or an angiotensin receptor blocker forms the basis of this therapy. The addition of tolvaptan is expected to provide supplementary benefit in decreasing the decline of renal function in these patients. Will statins find a place in the therapeutic armamentarium of this disease? We need large randomized controlled trials in order to determine a clear answer to this question. Until we get this evidence, using a statin in the management of patients with ADPKD will remain the physician's personal choice. None declared. (See related article by Zand et al. Renal hemodynamic effects of the HMG-CoA reductase inhibitors in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2016; 31: 1290–1295)