Current issues of ACP Journal Club are published in Annals of Internal Medicine


Etiology

Reduced glomerular filtration rate was associated with increased death, cardiovascular events, and hospitalization

PDF

ACP J Club. 2005 Mar-Apr;142:50. doi:10.7326/ACPJC-2005-142-2-050

Related Content in this Issue
• Companion Abstract and Commentary: Renal impairment increased mortality and cardiovascular complications after myocardial infarction


Clinical Impact Ratings

GIM/FP/GP: 4 stars

Cardiology: 5 stars

Nephrology: 6 stars


Source Citation

Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. [PubMed ID: 15385656]


Abstract

Question

What is the relation of the severity of renal impairment to the risk for all-cause mortality, cardiovascular (CV) events, and hospitalization?

Methods

Design: Cohort study with 2.84-year follow-up.

Setting: The Kaiser Permanente of Northern California health care system, San Francisco Bay area.

Patients: 1 120 295 patients who were ≥ 20 years of age (mean age 52 y, 55% women) and had ≥ 1 outpatient measurement of serum creatinine levels between January 1, 1996, and December 31, 2000. Exclusion criteria were kidney transplantation or maintenance dialysis.

Risk factors: The Modification of Diet and Renal Disease (MDRD) equation was used to estimate baseline glomerular filtration rate (GFR). The Kaiser Permanente regional laboratory serum creatinine measurement was calibrated with the laboratory used to derive the MDRD equation. GFR was divided into 5 categories (< 15, 15 to 29, 30 to 44, 45 to 59, and ≥ 60 mL/min per 1.73 m2of body surface). Other risk factors were age, sex, race or ethnicity, and comorbid illnesses (including coronary disease, stroke or transient ischemic attack, heart failure, peripheral arterial disease, diabetes mellitus, hypertension, dyslipidemia, lung or liver disease, cancer, and dementia).

Outcomes: All-cause mortality, CV events (hospitalization for coronary disease, heart failure, stroke, or peripheral arterial disease), and hospitalization.

Main results

Risk for all-cause mortality, CV events, and hospitalizations increased with decreasing estimated GFRs (Table). The adjusted risk for all-cause mortality ranged from a 17% increase with an estimated GFR 45 to 59 mL/min per 1.73 m2 to 600% with a GFR < 15 mL/min per 1.73 m2. The presence of proteinuria was also an independent predictor of all-cause mortality (adjusted hazard ratio [HR] 1.3, 95% CI 1.3 to 1.4), CV events (HR 1.3, CI 1.2 to 1.3), and hospitalization (HR 1.4, CI 1.4 to 1.4).

Conclusion

Reduced estimated glomerular filtration rate was associated with increased risk for all-cause mortality, cardiovascular events, and hospitalization.

Source of funding: National Institute for Diabetes, Digestive, and Kidney Diseases.

For correspondence: Dr. A.S. Go, Kaiser Permanente of Northern California, Oakland, CA, USA. E-mail alan.s.go@kp.org.


Table. Association of estimated glomerular filtration rate (GFR) with risk for death, cardiovascular events, and hospitalization*

Outcomes Adjusted hazard ratio (95% CI)†
GFR < 15 mL/min per 1.73 m2 GFR 15 to 29 mL/min per 1.73 m2 GFR 30 to 44 mL/min per 1.73 m2 GFR 45 to 59 mL/min per 1.73 m2
All-cause mortality 5.9 (5.4 to 6.5) 3.2 (3.1 to 3.4) 1.8 (1.7 to 1.9) 1.2 (1.1 to 1.2)
Any cardiovascular event 3.4 (3.1 to 3.8) 2.8 (2.6 to 2.9) 2.0 (1.9 to 2.1) 1.4 (1.4 to 1.5)
Any hospitalization 3.1 (3.0 to 3.3) 2.1 (2.0 to 2.2) 1.5 (1.5 to 1.5) 1.1 (1.1 to 1.1)

*Patients with GFR ≥ 60 mL/min per 1.73 m2 were the reference group. CI defined in Glossary.
†Adjusted for age sex, income, education, dialysis, coronary disease, heart failure, stroke or transient ischemic attack, hypertension, dyslipidemia, cancer, serum albumin level ≤ 3.5 g/dL, dementia, cirrhosis or liver disease, lung disease, proteinuria, and previous hospitalizations.


Commentary

Patients with renal insufficiency are easily identifiable, using equations that estimate GFR based on serum creatinine. In recent years, numerous studies have suggested that patients with estimated lower GFR have a higher incidence of future CV events and mortality than those with normal GFR. The large, well-done studies by Go and Anavekar and their colleagues confirm this both in the general population and in patients presenting with acute MI. For example, in the study by Go and colleagues, the age-standardized rate of death per 100 person-years in the general population was 14.1 when the estimated GFR was < 15 mL/min per 1.73 m2 and was 11.4, 4.8, and 1.1 when the estimated GFR was 15 to 29, 30 to 44, and 45 to 59 mL/min per 1.73 m2, respectively. Similar trends were also present for CV and hospitalization outcomes. These findings in large numbers of patients, throughout an entire range of GFRs, highlight the clinical and public health importance of this condition.

How can practitioners prevent future morbidity and mortality in these patients? It is evident that patients with moderate reductions of GFR (GFR 30 to 59 mL/min per 1.73 m2) benefit from established CV protective interventions, such as statins and angiotensin-converting enzyme inhibitors (1, 2). Given their high incidence of future CV events, patients with low GFR may derive an even greater benefit in absolute terms than does the general population. Thus, the importance of using such medications in these patients cannot be overemphasized, and observed deficiencies in health care must be remedied (3). Unfortunately, a number of clinical trials testing CV protective interventions deliberately excluded patients with more marked reductions in GFR. In addition, a recent large trial showed that hemodialysis patients were unresponsive to the benefits of statins (4). Thus, whether patients with GFR < 30 have a similar response to CV agents proven beneficial in the general population remains to be clarified.

In patients with GFR < 30 mL/min per 1.73 m2, is there any role for the treatment of potential novel risk factors that become pronouced with GFR decline? The studies by Go and Anavekar and their collegues both describe a “dose-dependent,” independent association between decrements in GFR and future CV events. The risk in patients with GFR < 30 mL/min per 1.7 3m2 was more than 3-fold that of patients with preserved GFR. These associations persisted after adjustment for established cardiovascular risk factors and other relevant comorbid conditions. Proposed novel mechanisms potentially amenable to therapeutic intervention include elevated calcium-phosphate product, hyperhomocysteinemia, anemia, and inflammation. However, whether low GFR is causally related to CV disease remains controversial. For example, in the study by Anavekar and colleagues, a portion of the independent association between low GFR and future CV events is expected to be noncausal residual confounding from such factors as concomitant renal vascular disease, generalized atherosclerosis, and renal hypoperfusion. Thus, while promising, the potential to reduce the burden of CV disease by treating unique renal pathogenic mechanisms remains uncertain. The CV benefits of erythropoietin and phosphate binders in these patients are the subject of ongoing clinical trials, and their results will inform both patient care and the causality debate.

Amit X. Garg, MD, MA, FRCPC
London Health Sciences Centre
London, Ontario, Canada


References

1. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation. 2004;110:1557-63. [PubMed ID: 15364796]

2. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134:629-36. [PubMed ID: 11304102]

3. Nissenson AR, Collins AJ, Hurley J, et al. Opportunities for improving the care of patients with chronic renal insufficiency: current practice patterns. J Am Soc Nephrol. 2001;12:1713-20. [PubMed ID: 11461944]

4. Wanner C, Krane V, Marz W, et al. Randomized controlled trial on the efficacy and safety of atorvastatin in patients with type 2 diabetes on hemodialysis (4D study): demographic and baseline characteristics. Kidney Blood Press Res. 2004;27:259-66. Epub 2004 Aug 16. [PubMed ID: 15316128]