The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in renal disease

Figures & data

Figure 1 Effect of statins over the isoprenyl derivatives.

Abbreviations: HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA; PI3, phosphorous triiodide; Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; PP, pyrophosphate; tRNA, transfer ribonucleic acid; LPS, lipopolysaccharide; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homologue gene family member A; NADPH, nicotinamide adenine dinucleotide phosphate; NFkB, nuclear factor-kappa B.

Table 1 Randomized trials on the use of statins in patients with chronic renal disease

Study	n	Statin	Baseline eGFR (mL/minute)	Results
JUPITER^Citation22	17,802	Rosuvastatin 20 mg versus placebo	73.3	Did not show any benefit on eGFR.
TNT^Citation25	10,001	Atorvastatin 10 mg versus 80 mg	65.6	Atorvastatin protected against the expected 5-year decline in renal function.
ASCOT-LLA^Citation26	10,305	Atorvastatin 10 mg versus placebo	69.5	Adding atorvastatin to antihypertensive medications appears to slow down age-related decline in kidney function.
ATTEMPT^Citation38	1,123	Atorvastatin 10–80 mg versus placebo	69.6	Atorvastatin improved eGFR in metabolic syndrome patients.
PLANET 1^Citation41	353	Rosuvastatin 10 mg versus 40 mg versus atorvastatin 80 mg	71.2	None of the treatments showed any protection against GFR decline in diabetes mellitus patients.
PLANET 2^Citation42	237	Rosuvastatin 10 mg versus 40 mg versus atorvastatin 80 mg	74.9	Neither treatment showed any protection against GFR decline in nondiabetic patients.
SHARP^Citation45	9,370	Simvastatin 20 mg + ezetimibe 10 mg versus placebo	26.6	No differences in renal outcomes.
LORD^Citation46	132	Atorvastatin 10 mg versus placebo	31.9	No significant change was found.

Abbreviations: n, number; eGFR, estimated glomerular filtration rate; JUPITER, the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin study; TNT, Treating to New Targets study; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm; ATTEMPT, Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes Trial; GFR, glomerular filtration rate; PLANET 1, Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease; PLANET 2, Prospective Evaluation of Proteinuria and Renal Function in Non-Diabetic Patients with Progressive Renal Disease; SHARP, Study of Heart And Renal Protection; LORD, Lipid-lowering and Onset of Renal Disease trial.

Table 2 Ongoing clinical trials on the use of statins and renal function

Study	Estimated enrollment	Statin	Baseline eGFR (mL/minute)	Endpoint
PRATO-ACS 2 study^Citation44	760	Rosuvastatin 40 mg followed by 20 mg/day versus atorvastatin (80 mg followed by 40 mg/day)	Any, except ESRD or AKI	To compare the nephroprotective effects of high-dose atorvastatin and high-dose rosuvastatin.
Anti-inflammatory and renoprotective effect of pretreatment loading dose atorvastatin in CABG^Citation61	80	Load of atorvastatin 80 mg + 40 mg	GFR >60 mL/minute	Safety and efficiency study of loading dose of atorvastatin in cardiac surgery.
Short-term atorvastatin’s effect on acute kidney injury following cardiac surgery^Citation62	820	Atorvastatin 80 mg (load), followed by 40 mg/day	Any, except ESRD	Short-term atorvastatin’s effect on acute kidney injury following cardiac surgery.
PRINCIPLE-II study^Citation63	404	Pitavastatin 4 mg/day for 7 days before angiography	eGFR ≤60 mL/minute	Preventive effect of pitavastatin on contrast-induced nephropathy in patients with renal dysfunction.
SARP study^Citation64	40	Atorvastatin 40 mg versus 10 mg	CKD stage 3–4	To evaluate the comparative effects of low-dose atorvastatin on proteinuria in patients with stage 3 or 4 chronic kidney disease.
SCIN study^Citation65	200	Load of atorvastatin 80 mg + 40 mg	Creatinine >1.3 mg/dL or GFR <60 mL/minute	To determine if statin therapy plus intravenous normal saline, in patients with CKD undergoing angiography, is superior to placebo plus intravenous normal saline therapy in the prevention of CIN.

Abbreviations: eGFR, estimated glomerular filtration rate; PRATO-ACS 2, Atorvastatin Versus Rosuvastatin on Contrast Induced Acute Kidney Injury; ESRD, end-stage renal disease; AKI, acute kidney injury; CABG, coronary artery bypass graft; GFR, glomerular filtration rate; PRINCIPLE-II, Preventive Effect of the PRetreatment With pitavastatiN on Contrast-Induced Nephropathy in Patients With RenaL Dysfunction UndErgoing Coronary Angiography/Intervention; SARP, Study of Atorvastatin Dose Dependent Reduction of Proteinuria; CKD, chronic kidney disease; SCIN, Efficacy of Statins In Prevention of CIN; CIN, contrast-induced nephropathy.

RidkerPMDanielsonEFonsecaFAJUPITER Study GroupRosuvastatin to prevent vascular events in men and women with elevated C-reactive proteinN Engl J Med2008359212195220718997196

 PubMed Web of Science ®Google Scholar

ShepherdJKasteleinJJBittnerVTreating to New Targets InvestigatorsEffect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) studyClin J Am Soc Nephrol2007261131113917942759

 PubMed Web of Science ®Google Scholar

GuptaAKChangCLCollierBThe relationship between statin therapy and progression of renal damage among 10305 hypertensive patients randomised in the ASCOT-lipid-lowering arm (LLA)Atheroscl Suppl2011121158159

 Web of Science ®Google Scholar

SandhuSWiebeNFriedLFTonelliMStatins for improving renal outcomes: a meta-analysisJ Am Soc Nephrol20061772006201616762986

 PubMed Web of Science ®Google Scholar

AstraZenecaRandomized, double-blind, 52-wk, parallel-grp, multicentre, PIIb study to evaluate effects of rosuvastatin 10 mg, rosuvastatin 40 mg and atorvastatin 80 mg on urinary protein excretion in hypercholesterolaemic diabetic patients with moderate proteinuria NLM identifier: NCT00296374

 Google Scholar

AstraZenecaRandomized, double-blind, 52-wk, parallel-grp multicentre, PIIb study to evaluate effects of rosuvastatin 10 mg, rosuvastatin 40 mg and atorvastatin 80 mg on urinary protein excretion in hypercholesterolaemic non-diabetic patients with moderate proteinuria NLM identifier: NCT00296400

 Google Scholar

BaigentCLandrayMJReithCSHARP InvestigatorsThe effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trialLancet201137797842181219221663949

 PubMed Web of Science ®Google Scholar

FassettRGRobertsonIKBallMJGeraghtyDPCoombesJSEffect of atorvastatin on kidney function in chronic kidney disease: a randomised double-blind placebo-controlled trialAtherosclerosis2010213121822420810109

 PubMed Web of Science ®Google Scholar

Randomized, double-blind, parallel-grpAtorvastatin versus rosuvastatin on contrast induced acute kidney injury (PRATO-ACS 2) study NLM identifier: NCT01870804

 Google Scholar

Randomized, double-blind, parallel-grp, anti-inflammatory and renoprotective effect of pretreatment loading dose atorvastatin in coronary artery bypass graft surgery NLM identifier: NCT01547455

 Google Scholar

Randomized, double-blind, parallel-grpShort-term atorvastatin’s effect on acute kidney injury following cardiac surgery NLM identifier: NCT00791648

 Google Scholar

Randomized, double-blind, parallel-grpPreventive effect of the pretreatment with pitavastatin on contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography/intervention (PRINCIPLE-II) study NLM identifier: NCT 01871792

 Google Scholar

Randomized, double-blind, parallel-grpStudy of atorvastatin dose dependent reduction of proteinuria(SARP) study NLM identifier: NCT 00768638

 Google Scholar

Randomized, double-blind, parallel-grpEfficacy of statins in prevention of contrast-induced nephropathy(SCIN) study NLM identifier: NCT 01071993

 Google Scholar