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Detecting and managing patients with type 2 diabetic kidney disease: Proteinuria and cardiovascular disease
Kidney International, Vol. 66, Supplement 92 (2004), pp. S97–S98
Detecting and managing patients with type 2 diabetic kidney disease: Proteinuria and cardiovascular disease WILLIAM E. MITCH, SHAHNAZ SHAHINFAR, TANIA Z. DICKSON, DICK DE ZEEUW, and ZHONGXIN ZHANG University of Texas Medical Branch, Galveston, Texas; Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, New Jersey; and Department of Clinical Pharmacology, Groningen University Medical Centre, Groningen, The Netherlands
METHODS The RENAAL study included 1513 patients with T2DM and nephropathy from 28 countries, with a mean follow-up of 3.4 years [4]. Methods and inclusion/exclusion criteria are described elsewhere [4]. Patients were stratified according to baseline proteinuria of <2 or >2g/g creatinine. Patients were randomized to either losartan or placebo on a background of conventional antihypertensive therapy to achieve a goal blood pressure of <140/90 mm Hg. The prespecified CKD end point was a composite of the time to doubling of serum creatinine, end-stage renal disease (ESRD), or death. There also was a secondary prespecified cardiovascular morbidity and mortality end point consisting of myocardial infarction, stroke, first hospitalization for CHF or unstable angina, coronary or peripheral artery revascularization, or CV death. All end points were adjudicated by an independent, blinded committee. Proteinuria was utilized as a marker of CKD progression, CVD risk, and treatment response. Multivariate COX proportional hazards models were used to evaluate the relationship between CKD and CVD. Baseline covariates used in the model were CVD history, CHF history, age, gender, smoking, race, weight, seated diastolic and systolic blood pressures (SiDBP, SiSBP), MAP, pulse pressure, total cholesterol, estimated GFR, hemoglobin, HBA1 c , albuminuria, and treatment allocation. Changes in proteinuria at six months were utilized to predict CVD risk and treatment responses.
Detecting and managing patients with type 2 diabetic kidney disease: Proteinuria and cardiovascular disease. Background. The increasing prevalence of type 2 diabetes (T2DM) places more patients at risk for developing chronic kidney disease (CKD) or cardiovascular (CV) events. Effective therapy for CKD or CV disease (CVD) requires a method of identifying affected patients and monitoring the effectiveness of therapy. Methods. We tested the predictive value of proteinuria for identifying patients at risk for progressive CDK and CVD, and monitoring treatment was determined using RENAAL study results. Results. Baseline proteinuria identified patients at risk for progressive CKD and CVD. Suppression of proteinuria was associated with decreased likelihood of CKD or CVD. Conclusion. Proteinuria identifies the risk of CKD and CVD, and can be used to monitor the effectiveness of therapy.
Epidemiologic analyses have uncovered two factors affecting CKD patient care: CKD prevalence is larger than suspected, with >10 million United States adults having significant kidney damage, and the risk of CVD and mortality is sharply increased by CKD [1]. More than half the United States patients receiving dialysis treatment have T2DM, and the number of estimated diabetics worldwide (>150 million) is expected to double within 25 years [2]. The association of CKD and CVD and T2DM raises clinically relevant questions. Is there a reliable marker of CKD and CVD, and can the response to therapy be monitored by a simple measurement? Additionally, is nephropathy linked to increased CVD risk? Results from the RENAAL study yield insight into the identification and monitoring of CKD and CVD in patients with T2DM and nephropathy [2, 3].
RESULTS Baseline characteristics for the treatment groups were similar [2, 3]. Proteinuria was a strong predictor of CKD and CVD, and the relationship was almost linear. Proteinuria >3 g/g increased the risk for the CKD composite end point 5.2-fold, and ESRD alone by 8.1-fold compared with proteinuria <1.5 g/g. Additionally, the risk
Key words: albuminuria, cardiovascular disease, type 2 diabetes, nephropathy, angiotensin receptor blocker. C
2004 by the International Society of Nephrology
S-97
S-98
Mitch et al: ARBs suppress kidney and cardiovascular disease
for the CVD composite was 1.92-fold higher, and the CHF risk was 2.7-fold higher in those with greater proteinuria. Change in proteinuria at six months strongly predicted CKD and CVD risk; a 30% increase in proteinuria was associated with a risk increase for the CKD composite (54%), ESRD (141%), CVD composite (7%), and CHF (17%). A reduction in proteinuria during the same time period was associated with a risk reduction for the CKD composite (43%), ESRD (52%), CVD composite (32%), and CHF (44%). DISCUSSION Angiotensin-receptor blockers delay progressive CKD in patients with T2DM and nephropathy [4, 5]. RENAAL results indicate that monitoring proteinuria identifies patients at risk and their response to treatment. Furthermore, the beneficial effects of losartan on CKD or CVD, although affecting the kidney and heart, are not due solely to lowering blood pressure. Limitations of the analyses include the post hoc assignment of proteinuria cutoffs [2, 3], and associations cannot prove a cause-effect relationship about proposed mechanisms. Other methods that suppress proteinuria (e.g., low protein diets) might help evaluate whether these drugs protect the kidney via greater suppression of protein-
uria, but again, responses to dietary changes could benefit CKD and CVD damage in other ways [6]. CONCLUSION Proteinuria is an effective identifier of patient risk for CKD or CVD. As such, monitoring proteinuria is warranted when treating type 2 diabetic patients. Reprint requests to William E. Mitch, M.D., Division of Nephrology, Department of Medicine, 4.124 John Sealy Annex, 301 University Blvd., 0569, Galveston, TX 77555–0569. E-mail: [email protected]
REFERENCES 1. HARNETT JD, PARFREY PS: Cardiac disease in uremia. Sem Nephrol 14:245–252, 1994 2. DE ZEEUW D, REMUZZI G, PARVING H-H, et al: Proteinuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110:921–927, 2004 3. DE ZEEUW D, REMUZZI G, PARVING H-H, et al: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 65:2309–2320, 2004 4. BRENNER BM, COOPER ME, DE ZEEUW D, et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869, 2001 5. LEWIS EJ, HUNSICKER LG, CLARKE WR, et al: Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860, 2001 6. MITCH WE, REMUZZI G: Diets for patients with chronic kidney disease, still worth prescribing. J Am Soc Nephrol 15:234–237, 2004
Detecting and managing patients with type 2 diabetic kidney disease: Proteinuria and cardiovascular disease WILLIAM E. MITCH, SHAHNAZ SHAHINFAR, TANIA Z. DICKSON, DICK DE ZEEUW, and ZHONGXIN ZHANG University of Texas Medical Branch, Galveston, Texas; Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, New Jersey; and Department of Clinical Pharmacology, Groningen University Medical Centre, Groningen, The Netherlands
METHODS The RENAAL study included 1513 patients with T2DM and nephropathy from 28 countries, with a mean follow-up of 3.4 years [4]. Methods and inclusion/exclusion criteria are described elsewhere [4]. Patients were stratified according to baseline proteinuria of <2 or >2g/g creatinine. Patients were randomized to either losartan or placebo on a background of conventional antihypertensive therapy to achieve a goal blood pressure of <140/90 mm Hg. The prespecified CKD end point was a composite of the time to doubling of serum creatinine, end-stage renal disease (ESRD), or death. There also was a secondary prespecified cardiovascular morbidity and mortality end point consisting of myocardial infarction, stroke, first hospitalization for CHF or unstable angina, coronary or peripheral artery revascularization, or CV death. All end points were adjudicated by an independent, blinded committee. Proteinuria was utilized as a marker of CKD progression, CVD risk, and treatment response. Multivariate COX proportional hazards models were used to evaluate the relationship between CKD and CVD. Baseline covariates used in the model were CVD history, CHF history, age, gender, smoking, race, weight, seated diastolic and systolic blood pressures (SiDBP, SiSBP), MAP, pulse pressure, total cholesterol, estimated GFR, hemoglobin, HBA1 c , albuminuria, and treatment allocation. Changes in proteinuria at six months were utilized to predict CVD risk and treatment responses.
Detecting and managing patients with type 2 diabetic kidney disease: Proteinuria and cardiovascular disease. Background. The increasing prevalence of type 2 diabetes (T2DM) places more patients at risk for developing chronic kidney disease (CKD) or cardiovascular (CV) events. Effective therapy for CKD or CV disease (CVD) requires a method of identifying affected patients and monitoring the effectiveness of therapy. Methods. We tested the predictive value of proteinuria for identifying patients at risk for progressive CDK and CVD, and monitoring treatment was determined using RENAAL study results. Results. Baseline proteinuria identified patients at risk for progressive CKD and CVD. Suppression of proteinuria was associated with decreased likelihood of CKD or CVD. Conclusion. Proteinuria identifies the risk of CKD and CVD, and can be used to monitor the effectiveness of therapy.
Epidemiologic analyses have uncovered two factors affecting CKD patient care: CKD prevalence is larger than suspected, with >10 million United States adults having significant kidney damage, and the risk of CVD and mortality is sharply increased by CKD [1]. More than half the United States patients receiving dialysis treatment have T2DM, and the number of estimated diabetics worldwide (>150 million) is expected to double within 25 years [2]. The association of CKD and CVD and T2DM raises clinically relevant questions. Is there a reliable marker of CKD and CVD, and can the response to therapy be monitored by a simple measurement? Additionally, is nephropathy linked to increased CVD risk? Results from the RENAAL study yield insight into the identification and monitoring of CKD and CVD in patients with T2DM and nephropathy [2, 3].
RESULTS Baseline characteristics for the treatment groups were similar [2, 3]. Proteinuria was a strong predictor of CKD and CVD, and the relationship was almost linear. Proteinuria >3 g/g increased the risk for the CKD composite end point 5.2-fold, and ESRD alone by 8.1-fold compared with proteinuria <1.5 g/g. Additionally, the risk
Key words: albuminuria, cardiovascular disease, type 2 diabetes, nephropathy, angiotensin receptor blocker. C
2004 by the International Society of Nephrology
S-97
S-98
Mitch et al: ARBs suppress kidney and cardiovascular disease
for the CVD composite was 1.92-fold higher, and the CHF risk was 2.7-fold higher in those with greater proteinuria. Change in proteinuria at six months strongly predicted CKD and CVD risk; a 30% increase in proteinuria was associated with a risk increase for the CKD composite (54%), ESRD (141%), CVD composite (7%), and CHF (17%). A reduction in proteinuria during the same time period was associated with a risk reduction for the CKD composite (43%), ESRD (52%), CVD composite (32%), and CHF (44%). DISCUSSION Angiotensin-receptor blockers delay progressive CKD in patients with T2DM and nephropathy [4, 5]. RENAAL results indicate that monitoring proteinuria identifies patients at risk and their response to treatment. Furthermore, the beneficial effects of losartan on CKD or CVD, although affecting the kidney and heart, are not due solely to lowering blood pressure. Limitations of the analyses include the post hoc assignment of proteinuria cutoffs [2, 3], and associations cannot prove a cause-effect relationship about proposed mechanisms. Other methods that suppress proteinuria (e.g., low protein diets) might help evaluate whether these drugs protect the kidney via greater suppression of protein-
uria, but again, responses to dietary changes could benefit CKD and CVD damage in other ways [6]. CONCLUSION Proteinuria is an effective identifier of patient risk for CKD or CVD. As such, monitoring proteinuria is warranted when treating type 2 diabetic patients. Reprint requests to William E. Mitch, M.D., Division of Nephrology, Department of Medicine, 4.124 John Sealy Annex, 301 University Blvd., 0569, Galveston, TX 77555–0569. E-mail: [email protected]
REFERENCES 1. HARNETT JD, PARFREY PS: Cardiac disease in uremia. Sem Nephrol 14:245–252, 1994 2. DE ZEEUW D, REMUZZI G, PARVING H-H, et al: Proteinuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110:921–927, 2004 3. DE ZEEUW D, REMUZZI G, PARVING H-H, et al: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 65:2309–2320, 2004 4. BRENNER BM, COOPER ME, DE ZEEUW D, et al: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869, 2001 5. LEWIS EJ, HUNSICKER LG, CLARKE WR, et al: Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860, 2001 6. MITCH WE, REMUZZI G: Diets for patients with chronic kidney disease, still worth prescribing. J Am Soc Nephrol 15:234–237, 2004