Cochrane for Clinicians
Putting Evidence into Practice
Statins for Non-Dialysis Chronic Kidney Disease
Am Fam Physician. 2010 Jan 1;81(1):27-29.
A 62-year-old man with hypertension and a glomerular filtration rate (GFR) of 40 mg per minute has a low-density lipoprotein (LDL) cholesterol level of 120 mg per dL (3.11 mmol per L). He asks if he should be on a cholesterol-lowering medication.
Do statins improve outcomes in patients with non-dialysis chronic kidney disease (CKD)?
When taken over a five-year period, statins significantly reduce all-cause mortality (number needed to treat [NNT] = 56), cardiovascular mortality (NNT = 86), and nonfatal cardiovascular events (NNT = 25).1 (Strength of Recommendation = A, based on consistent and good-quality patient-oriented evidence). In a small subset of studies spanning two to 60 months, statins reduced proteinuria, but did not slow the decline of renal function. Adverse effects of treatment are negligible.1
CKD is defined as a GFR of less than 60 mg per minute persisting beyond three months, or any evidence of kidney damage regardless of the GFR (e.g., proteinuria, abnormal urine sediment, abnormal renal imaging).2 CKD is a secondary cause of dyslipidemia. Once the kidney disease is optimally treated, the LDL cholesterol goal is less than 100 mg per dL (2.59 mmol per L).1,2 Statins are ideal to achieve this goal.
The authors of this Cochrane review examined the benefits of statins for patients with non-dialysis CKD.1 Although 26 studies were included in the meta-analysis, roughly 98 percent of the mortality statistics are weighted to three studies (with 16,824 of the 25,017 participants) that involved treatment with 40 mg of pravastatin (Pravachol). Patients in these studies were predominantly middle-aged to older men with moderately elevated cholesterol levels. The authors concluded that the mortality benefits from statins were comparable with those in the general population. Another meta-analysis by these authors looked at patients on dialysis, and concluded that statins did not confer a mortality benefit.3 However, patients taking statins had similar rates of rhabdomyolysis and elevated liver function tests as the control group, and statins conferred some improvement in the incidence of nonfatal cardiovascular events. The studies' durations may have been too short to detect a difference in mortality. Another systematic review of statins in patients with kidney transplants found one study with similar results.4
Statins should be used in patients with chronic kidney disease. The National Kidney Foundation (NKF) has made several revisions to their Kidney Disease Outcomes Quality Initiative since 2002, and the guidelines on diagnosis are best described in a recent NKF publication.2 These guidelines recommend calculation of the GFR using the Modification of Diet in Renal Disease Study equation (available at http://www.kidney.org/professionals/KDOQI/gfr_calculator.cfm). Proteinuria is an early sign of kidney damage, is easiest to diagnose with a urine dipstick of 1+ protein, and should be confirmed by two albumin-to-creatinine spot urine samples taken one to two weeks apart.
In addition to screening for dyslipidemias and treating with statins, once CKD is diagnosed, the NKF recommends: ultrasound imaging of the kidneys to rule out structural disease; examination of urine sediment; anemia studies for hemoglobin levels less than 12 g per dL (120 g per L) in women or 13.5 g per dL (135 g per L) in men (also including red blood cell indices, iron studies, reticulocyte count, and fecal occult blood testing, but not an erythropoietin level); nutritional assessment; and evaluation of bone disease (parathyroid hormone, calcium, phosphorus, 25-hydroxyvitamin D).2
Background: Dyslipidemia is common in patients with chronic kidney disease (CKD) and contributes to cardiovascular disease and worsening renal function. Statins are widely used in non-dialysis dependent CKD (pre-dialysis), even though evidence favoring their use is lacking.
Objectives: To evaluate the benefits and harms of statins in patients with CKD who were not receiving renal replacement therapy.
Search Strategy: The authors searched Medline, EMBASE, and CENTRAL (in The Cochrane Library), and hand-searched reference lists of textbooks, articles, and scientific proceedings.
Selection Criteria: Randomized controlled trials (RCTs) and quasi-RCTs comparing statins with placebo, no treatment, or other statins in adult patients with pre-dialysis CKD.
Data Collection and Analysis: Two authors independently assessed study quality and extracted data. Results were expressed as mean difference (MD) for continuous outcomes (lipids, creatinine clearance, and proteinuria) and risk ratio (RR) for dichotomous outcomes (all-cause mortality, cardiovascular mortality, fatal and nonfatal cardiovascular events, elevated liver enzymes, rhabdomyolysis, and withdrawal rates) with 95% confidence intervals (CIs).
Main Results: Twenty-six studies (25,017 participants) comparing statins with placebo were identified. Total cholesterol levels decreased significantly with statins (18 studies, 1,677 patients: MD = −41.48 mg per dL; 95% CI, −49.97 to −33.99). Similarly, low-density lipoprotein cholesterol decreased significantly with statins (16 studies, 1,605 patients: MD = −42.38 mg per dL; 95% CI, −50.71 to −34.05). Statins decreased the risk of all-cause deaths (21 RCTs, 18,781 patients; RR = 0.81; 95% CI, 0.74 to 0.89) and cardiovascular deaths (20 studies, 18,746 patients; RR = 0.80; 95% CI, 0.70 to 0.90). Statins decreased 24-hour urinary protein excretion (six studies, 311 patients; MD = −0.73 g per 24 hours; 95% CI, −0.95 to −0.52), but there was no significant improvement in creatinine clearance, which is a surrogate marker of renal function (11 studies, 548 patients; MD = 1.48 mL per minute; 95% CI, −2.32 to 5.28). The incidence of rhabdomyolysis, elevated liver enzymes, and withdrawal rates due to adverse events (well known complications of statins use) were not significantly different between patients receiving statins and placebo.
Authors' Conclusions: Statins significantly reduced the risk of all-cause and cardiovascular mortality in patients with CKD who were not receiving renal replacement therapy. They do not impact the decline in renal function as measured by creatinine clearance, but may reduce protein excretion in urine. Statins appear to be safe in this population. Guideline recommendations on hyperlipidemia management in patients with CKD could therefore be followed, targeting higher proportions of patients receiving a statin, with appropriate monitoring of adverse events.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).
Treatment guidelines emphasize avoidance of nephrotoxic drugs (most notably, nonsteroidal anti-inflammatory drugs) and correction of any obstructive pathologies.2 Angiotensin-converting enzyme (ACE) inhibitors are the treatment of choice for patients with CKD and hypertension, or for normotensive patients with proteinuria. Transient increases of serum creatinine by 20 percent and potassium by 0.5 mEq per L are usually acceptable. Angiotensin receptor blockers (ARBs) should be used if ACE inhibitors are not tolerated. The combination of ACE inhibitors and ARBs, although conceptually attractive, did not prove advantageous in a recent large randomized controlled trial.5 Dihydropyridine calcium channel blockers have been shown to decrease proteinuria and may be good second-line agents.2
Anemia also is common with CKD. The updated 2007 NKF guidelines recommend using erythropoiesis-stimulating agents to achieve a target hemoglobin level of 11 to 12 g per dL (110 to 120 g per L), not to exceed 13 g per dL (130 g per L [in 2006, the U.S. Food and Drug Administration set the goal at 10 to 12 g per dL]).2 Erythropoiesis-stimulating agents are associated with increased death and cardiovascular events when used to correct hemoglobin level above 13 g per dL. Oral iron supplementation in patients with non-dialysis CKD is recommended if plasma ferritin levels are less than 100 ng per mL (224.70 pmol per L) or transferrin saturation is less than 16 percent.
Metabolic derangement is common in non-dialysis CKD. Hyperkalemia should be managed with medication adjustment and appropriate therapy. Oral sodium bicarbonate may be useful for chronic metabolic acidosis (i.e., serum bicarbonate levels less than 22 mEq per L) to protect bones and muscle.2 Dietary phosphorus should be restricted to 800 to 1,000 mg per day when the phosphorus serum level exceeds 4.6 mg per dL (1.49 mmol per L). Calcium-based phosphate binders may be used if parathyroid hormone and phosphorus levels remain elevated despite restriction. Over-the-counter vitamin D is recommended when serum 25-hydroxyvitamin D is less than 30 ng per dL (74.88 nmol per L). In contrast with NKF guidelines, a recent meta-analysis states that more biologically active, prescription vitamin D analogues (e.g., calcitriol [Rocaltrol]) are expensive and confer little benefit.6 NKF guidelines recommend preparation for kidney replacement therapy (dialysis and transplantation) when the GFR declines to less than 30 mg per minute (i.e., stage 4 renal impairment).2
1. Navaneethan SD, Pansini F, Perkovic V, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2009;(2):CD007784.
2. Greenberg A, Cheung AK, Coffman TM, eds. Primer on Kidney Diseases. 5th ed. Philadelphia, Pa.: Saunders; 2009.
3. Navaneethan SD, Nigwekar SU, Perkovic V, Johnson DW, Craig JC, Strippoli GF. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst Rev. 2009;(2):CD004289.
4. Navaneethan SD, Perkovic V, Johnson DW, Nigwekar SU, Craig JC, Strippoli GF. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst Rev. 2009;(2):CD005019.
5. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):547–553.
6. Palmer SC, McGregor DO, Macaskill P, Craig JC, Elder GJ, Strippoli GF. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med. 2007;147(12):840–853.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Hitzeman presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab007784.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
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