- Journal Details
- Format
- Journal
- eISSN
- 2224-4018
- First Published
- 31 Dec 2013
- Publication timeframe
- 4 times per year
- Languages
- English
Statins essentially are cholesterol-lowering drugs that are extensively prescribed for primary and secondary prevention of cardiovascular disease. Compelling evidence suggests that the beneficial effects of statins may not only be due to its ability to control cholesterol levels but also due to a pleiotropic cholesterol-independent anti-inflammatory, antioxidant, endothelial-protective and plaque-stabilizing activity. Along this line, statins may also exert acute and long-term effects on renal function. We present a narrative literature review that summarizes arguments in favor of or against the preventive and/or therapeutic use of statins in kidney-related diseases or complications. We also highlight the ongoing controversy regarding statin therapy in chronic and end-stage kidney disease.
Key words
- statins
- acute kidney injury
- chronic kidney disease
- rhabdomyolysis
- contrast-induced nephropathy
- cardiorenal syndrome
- end-stage renal disease
We made a review almost two years ago and we extended the study search up to November 2017 and have included the most recent publications. Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors and constitute the first-line drug treatment if exercise and a low-fat diet fail to correct hypercholesterolemia. This way, statins substantially contribute to reduce morbidity and mortality in patients at the highest risk of cardiovascular events.[1] All available statins have similar pharmacology, established efficacy in terms of a dose-dependent beneficial effect on plasma cholesterol concentrations, and a comparable range and severity of adverse events. Atorvastatin and rosuvastatin are drugs with high cholesterol-lowering efficacy as compared with lovastatin, simvastatin, pravastatin, and fluvastatin, which have less cholesterol-lowering potency.
Apart from an intrinsic cholesterol-lowering effect, statins also exhibit anti-inflammatory, antioxidant, and plaque-stabilizing capacities that act in concert to prevent other than cardiovascular damage.[1,2] In particular, statins may affect the kidneys via cholesterol-related and -unrelated mechanisms, resulting in potential acute and long-term benefit on the renal function.[2,3]
We reviewed the literature on statin use for prevention and treatment of various acute or chronic kidney(-related) disorders. Statins are highlighted as a novel therapeutic approach with reference to potential beneficial or harmful effects.
AKI complicating cardiac surgery is often multifactorial, leaving the precise impact of statins open to speculation.[4] Statins probably act by inhibiting post-operative inflammatory processes.[3] Compared with statin-naive subjects, patients taking statins indeed had reduced levels of circulating C-reactive protein, tumor necrosis factor alpha, myeloperoxidase, and pro-inflammatory interleukin (IL)-1, IL-6, and IL-8 and higher concentrations of the anti-inflammatory IL-10.[5] In addition, many other factors must be considered such as concomitant disease (
Statin treatment and post cardiac surgery AKI AKI: acute kidney injury; RRT: renal replacement therapy; CKD: chronic kidney disease.Author (year) Study design Patients included (n) Effect on AKI Mortality Huffmyer (2009) Observational 1,557 Less need for RRT Decreased Virani (2010) Observational 3,001 Reduced AKI incidence No effect Argalious (2010) Observational 10,648 No effect No effect Nemati (2015) Observational 1,064 No effect No effect Mithani (2011) Observational 2,104 No effect No effect Wang (2015) Meta-analysis and meta-regression 59,777 Reduced AKI incidence No effect Zeng (2016) Randomized, placebo-controlled 1,922 Higher incidence of AKI No effect Billings (2016) Randomized, placebo-controlled 199 no difference in AKI but more AKI in statin-naive patients and CKD No effect Park (2016) Randomized, placebo-controlled 200 No effect No effect
A retrospective analysis of the electronic records of 57,246 patients who underwent elective non-cardiac surgery failed to show that preoperative statin therapy in doses routinely used to treat hypercholesterolemia changed the incidence of AKI, postoperative dialysis, or hospital mortality[15] Pan
Exposure to iodinated contrast during coronary angiography and associated coronary interventions may cause acute and persistent worsening of kidney function and is associated with increased mortality. Advanced age, diabetes, congestive heart failure, CKD, hemodynamic instability, and type and volume of contrast may all precipitate the development of CIN.[17] Previous research accentuated that adequate intravenous hydration with iso-osmolar crystalloids and limiting the amount of low-osmolar and iso-osmolar contrast are crucial for prevention of CIN. Several trials in various clinical conditions, including acute coronary syndromes, examined the effect of different types of statins, high-
Important bidirectional interactions exist between heart and kidney disease. Acute or chronic dysfunction of the heart or kidneys can induce acute or chronic dysfunction in the other organ.[20] For instance, patients with heart failure with a deteriorating glomerular filtration rate have higher mortality. Inversely, patients with CKD have an increased risk of heart failure, which is responsible for up to 50 percent mortality. This “vicious liaison” is known as the CRS. Oxidative stress, endothelial dysfunction, and vascular inflammation are pathophysiological factors that are strongly related to the CRS. The pleiotropic effects of statins on cardiovascular processes, particularly their anti-inflammatory/antioxidant potential and capacity to improve nitric oxide bioavailability, support a benefit on the progression of chronic kidney and heart failure.[21]
Cardiovascular disease is the most frequent cause of premature death in early stage CKD. A recent Cochrane review found that statin therapy consistently prevented major cardiovascular events and lowered mortality in patients with CKD not requiring dialysis and without cardiovascular disease at baseline.[22] Statin-related effects on stroke and progression of CKD were less evident.[22] However, high-efficacy statin therapy (atorvastatin 80 mg or rosuvastatin 20/40 mg) was associated with a significant decrease of the risk of stroke in patients with CKD.[23] Few trials reported data on individual adverse events leaving doubt on the safety of chronic statin treatment in CKD.[24]
The pleiotropic properties of statins, though theoretically promising for preventing aminoglycoside toxicity, have only been explored in experimental settings. Ozbek
A large retrospective cohort study comparing long-term statin users with a matched group of nonusers found an association between statin treatment and an increased incidence of acute and chronic renal disease.[27] A recently published systematic review and meta-analysis including 143,888 adult patients showed that statins did not prevent AKI, modestly decreased proteinuria, and attenuated the decline in glomerular filtration rate only in adult patients not receiving dialysis.[28]
Compared with low-efficacy drugs, treatment with high-efficacy statins has been associated with a 13% increased hazard for developing severe renal failure, which remained consistent across specific populations at risk (ischemic heart disease, diabetes, and CKD).[29]
Statins are associated with skeletal muscle complaints, ranging from mild serum creatine kinase elevations and myalgia to severe muscle weakness, muscle cramps, myositis and rhabdomyolysis.[30] Amongst others, CKD is a common risk factor for the development of statin-induced myopathy. Patients with CKD may become more prone to this invalidating and potential life-threatening complication when other significant risk factors (
One case report described acute rhabdomyolysis and purpura fulminans in a patient who had used pravastatin for 3 years and developed CKD.[31] However, the patient was highly aged and had received several hemodialysis sessions prior to presentation.
Some case studies reported a link between statins and (sub) acute tubulo-interstitial nephritis.[32,33] Nephritis was biopsy-proven, resolved after discontinuing statin treatment, responded to steroids, and relapsed after re-challenging the patient with a statin. A dose-dependent class effect was suggested but not proven. Statin-induced tubulo-interstitial nephritis is probably underreported because it evolves insidiously in patients who are prone to develop AKI for other reasons (
The effects of statins in patients with CKD remain uncertain. In 2003, the Kidney Disease Outcomes Quality Initiative (KDOQI) dyslipidemia guidelines recommended statin therapy in all patients with CKD, irrespective of dialysis need, targeting a low-density lipoprotein cholesterol (LDL-C) concentration below 100 mg/dL.[34] Sharp reduction of LDL-C with daily simvastatin plus ezetimibe safely reduced the incidence of major atherosclerotic events but did not slow the 5-year kidney disease progression in a wide range of patients with advanced CKD.[35] Moreover, the high-efficacy statins atorvastatin[36] and rosuvastatin[37] substantially lowered the LDL-C levels but had no statistically significant effect on cardiovascular death, non-fatal myocardial infarction, and stroke in patients with end-stage renal disease (ESRD) (
Large well-conducted RCTs did not demonstrate any benefit of pre- or peri-operative statin treatment in patients undergoing various types of cardiac surgery. For unknown reasons, statins may even harm the kidneys in this particular patient population. A potential renal protective effect of preoperative statin therapy after major non-cardiac surgery is suggested by observational studies but not confirmed by RCTs. Statins arguably exert protective effects on the kidney in a general adult population and on the cardiovascular system in patients with CKD who do not require dialysis. Adjunctive therapy with statins can dose-dependently prevent CIN and attenuate the CRS. Whether statins affect stroke risk and progression of CKD is less evident. Statin-related rhabdomyolysis remains of concern. High-efficacy agents may harm the kidney in patients with vascular compromise and CKD. Also, statins are relatively contra-indicated in patients with ESRD.
Taken together, statins are of undisputed efficacy for treatment of hypercholesterolemia and have a prominent role in primary and secondary prevention of cardiovascular disease. However, there is currently insufficient evidence to recommend routine use of these agents for kidney protection.
Statin treatment and post cardiac surgery AKI
| Author (year) | Study design | Patients included (n) | Effect on AKI | Mortality |
|---|---|---|---|---|
| Huffmyer (2009) | Observational | 1,557 | Less need for RRT | Decreased |
| Virani (2010) | Observational | 3,001 | Reduced AKI incidence | No effect |
| Argalious (2010) | Observational | 10,648 | No effect | No effect |
| Nemati (2015) | Observational | 1,064 | No effect | No effect |
| Mithani (2011) | Observational | 2,104 | No effect | No effect |
| Wang (2015) | Meta-analysis and meta-regression | 59,777 | Reduced AKI incidence | No effect |
| Zeng (2016) | Randomized, placebo-controlled | 1,922 | Higher incidence of AKI | No effect |
| Billings (2016) | Randomized, placebo-controlled | 199 | no difference in AKI but more AKI in statin-naive patients and CKD | No effect |
| Park (2016) | Randomized, placebo-controlled | 200 | No effect | No effect |
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