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Diuretic Use and ESRD, Precipitating Factor or Epiphenomenon
AJH
2005; 18:739 –740
EDITORIAL
Epidemiology
Diuretic Use and ESRD, Precipitating Factor or Epiphenomenon Muhammad Akram and Donal Reddan
I
n this issue of the American Journal of Hypertension, Hawkins and Houston1 report a potential relationship between diuretic use and acceleration of end-stage renal disease (ESRD) incidence. The study aim was to determine whether changes in diuretic use patterns were predictive of the emergence of ESRD in the United States. By using data fusion, an infrequently used statistical analysis technique, the researchers demonstrated that increasing diuretic use is directly associated with an accelerated time-lagged increase in growth of ESRD incidence in United States. They reported this in the context of an inverse correlation between the significant decline in ageadjusted cardiovascular mortality and the concurrent rise in the incidence of ESRD. Diuretics reduce intravascular volume depletion2 and, consequently, can adversely affect glomerular filtration rate, especially when renal autoregulation is impaired in hypertensive and azotemic patients. Thus, the hypothesis presented in this article is biologically plausible. However, extrapolation from the higher serum creatinine levels reported in diuretic-treated patients in clinical trials, such as European Working Party on High Blood pressure in the Elderly (EWPHE),3 Systolic Hypertension in Europe (SYST-EUR), 4 Systolic Hypertension in the Elderly Program (SHEP),5 and Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),6 to the greater incidence of ESRD in the US population is overstated and may be misleading. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers also cause increases in serum creatinine, yet there is evidence that they delay ESRD. One important potential confounder in the authors’ conclusion, as they acknowledge, is survival bias. Specifically, because of the concurrent reduction in cardiovascular mortality in the general population, patients with chronic kidney disease who might have previously died of cardiovascular complications, now have a greater chance
See related articles on pages 744 and 750
Received February 7, 2005. First decision March 10, 2005. Accepted March 12, 2005. From the Department of Nephrology, Merlin Park Hospital, University College Galway, Ireland Hospital, Galway, Ireland. © 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
of surviving until after ESRD develops. The argument by them that cardiovascular morbidity should increase in the dialysis population if survival bias were present, seems reasonable. However, cardiovascular morbidity is not comprehensively recorded in United States Renal Data System (USRDS) data and the levels of severity of cardiovascular disease are not adequately represented. It is also notable that levels of comorbidity are so high among ESRD patients that a modest further increase may be difficult to appreciate. Finally, the possibility that “better cardiovascular care” could lead to less comorbidity and improved survival should not be discounted. Another potential problem with their analysis is indication bias. Patients with advanced Chronic Kidney Disease (CKD) have an increased likelihood of developing ESRD and are often prescribed diuretic treatment for indications such as volume overload and peripheral edema. This raises the possibility that the deterioration in renal function ascribed to diuretic therapy instead reflects the inexorable progression of advanced CKD that would have occurred whether or not diuretics were used. This hypothesis attributes the increase in ESRD incidence to increased diuretic use because they are observed to occur consecutively, yet the alternative explanation of increased diuretic prescription occurring as a consequence of progressive CKD symptoms, which may not be ascertained by insensitive markers such as serum creatinine, is not adequately considered. Several lines of evidence illustrate benefits of diuretic therapy. Thiazide diuretics have antihypertensive efficacy that is comparable to other drug classes.7–11 Moreover, they significantly reduce the risk of cardiovascular and cerebrovascular diseases.8,10,12,13 For example, ALLHAT demonstrated that diuretic-based therapy provided similar cardiovascular protection as newer agents10 and were possibly superior in preventing secondary cardiovascular outcomes.10 Furthermore, thiazide diuretics are among the most widely used drugs in the management of hypertension and are relatively inexpensive. Based on this evi-
Address correspondence and reprint requests to Dr. Donal Reddan, University College Galway, Department of Nephrology, Unit 1, Merlin Park Hospital, Galway, Ireland; e-mail: dreddan@ eircom.net 0895-7061/05/$30.00 doi:10.1016/j.amjhyper.2005.03.729
740
EDITORIAL
dence, they have specific indications in African Americans, in the elderly, in patients with edema, and with congestive heart failure.14,15 The investigators provide reasonable evidence of a plausible potential link between increased diuretic usage and ESRD. Whether a causal relationship really does exist needs to be studied further in large-scale randomized control trials of diuretic therapy in patients with established CKD. Development of ESRD or advanced CKD is a relatively rare outcome in general population trials and, consequently, such studies are generally underpowered for renal outcomes. Therefore, the design and execution of required prospective studies will be challenging. The evidence for the therapeutic and mortality benefits of diuretic-based therapy is available, and the treatments are time-tested. Concerns arising from the exploratory retrospective data presented by Hawkins and Huston1 could have significant implications for healthcare worldwide. Although this hypothesis is provocative, more supportive scientific evidence is required before it should significantly influence clinical practice.
References 1.
2.
3.
4.
5.
Hawkins RG, Houston MC: Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States? Am J Hypertens 2005;18:744 –749. Freis ED, Reda, DJ, Materson BJ: Volume (weight loss) and blood pressure response following thiazide diuretics. Hypertension 1988; 12:244. Fletcher A, Amery A, Birkenhager W, Bulpitt C, Clement D, de Leeuw P, Deruyterre ML, de Schaepdryver A, Dollery C, Fagard R: Risks and benefits in the trials of European Working Party on High Blood pressure in the Elderly. J Hypertens 1991;9:225–230. Voyaki SM, Staessen JA, Thijs L, Wang JG, Efstratopoulos AD, Birkenhager WH, de Leeuw PW, Leonetti G, Nachev C, Rodicio JL, Tuomilehto J, Fagard R: Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. J Hypertens 2001;19:511–519. Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, Jerome; Cohen B, Davis R, Frost P, Smith W, Gonzalez N,
AJH–June 2005–VOL. 18, NO. 6
6.
7.
8.
9.
10.
11.
12. 13.
14.
15.
Guthrie GP, Oberman A, Rutan G, Probstfield JL, Stamler J, for the SHEP Cooperative Research Group: Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program: Arch Intern Med 1998;158:741–751. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997. Medical Research Council Working Party: MRC trial of treatment of mild hypertension: principal results. Br Med J (Clin Res Ed) 1985;291:97. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Wester PO, Hedner T, de Faire U: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751–1756. Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM: Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calciumchannel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000;356:366. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2927. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ: Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583–592. Medical Research Council trial of treatment of hypertension in older adults. principal results. MRC Working Party. BMJ 1992;304:405. Messerli FH, Grossman E, Goldbourt U: Are -blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279:1903. 1999 World Health Organization–International Society of Hypertension: Guidelines for the management of hypertension. Guidelines subcommittee. J Hypertens 1999;17:151. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157:2413.
2005; 18:739 –740
EDITORIAL
Epidemiology
Diuretic Use and ESRD, Precipitating Factor or Epiphenomenon Muhammad Akram and Donal Reddan
I
n this issue of the American Journal of Hypertension, Hawkins and Houston1 report a potential relationship between diuretic use and acceleration of end-stage renal disease (ESRD) incidence. The study aim was to determine whether changes in diuretic use patterns were predictive of the emergence of ESRD in the United States. By using data fusion, an infrequently used statistical analysis technique, the researchers demonstrated that increasing diuretic use is directly associated with an accelerated time-lagged increase in growth of ESRD incidence in United States. They reported this in the context of an inverse correlation between the significant decline in ageadjusted cardiovascular mortality and the concurrent rise in the incidence of ESRD. Diuretics reduce intravascular volume depletion2 and, consequently, can adversely affect glomerular filtration rate, especially when renal autoregulation is impaired in hypertensive and azotemic patients. Thus, the hypothesis presented in this article is biologically plausible. However, extrapolation from the higher serum creatinine levels reported in diuretic-treated patients in clinical trials, such as European Working Party on High Blood pressure in the Elderly (EWPHE),3 Systolic Hypertension in Europe (SYST-EUR), 4 Systolic Hypertension in the Elderly Program (SHEP),5 and Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),6 to the greater incidence of ESRD in the US population is overstated and may be misleading. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers also cause increases in serum creatinine, yet there is evidence that they delay ESRD. One important potential confounder in the authors’ conclusion, as they acknowledge, is survival bias. Specifically, because of the concurrent reduction in cardiovascular mortality in the general population, patients with chronic kidney disease who might have previously died of cardiovascular complications, now have a greater chance
See related articles on pages 744 and 750
Received February 7, 2005. First decision March 10, 2005. Accepted March 12, 2005. From the Department of Nephrology, Merlin Park Hospital, University College Galway, Ireland Hospital, Galway, Ireland. © 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
of surviving until after ESRD develops. The argument by them that cardiovascular morbidity should increase in the dialysis population if survival bias were present, seems reasonable. However, cardiovascular morbidity is not comprehensively recorded in United States Renal Data System (USRDS) data and the levels of severity of cardiovascular disease are not adequately represented. It is also notable that levels of comorbidity are so high among ESRD patients that a modest further increase may be difficult to appreciate. Finally, the possibility that “better cardiovascular care” could lead to less comorbidity and improved survival should not be discounted. Another potential problem with their analysis is indication bias. Patients with advanced Chronic Kidney Disease (CKD) have an increased likelihood of developing ESRD and are often prescribed diuretic treatment for indications such as volume overload and peripheral edema. This raises the possibility that the deterioration in renal function ascribed to diuretic therapy instead reflects the inexorable progression of advanced CKD that would have occurred whether or not diuretics were used. This hypothesis attributes the increase in ESRD incidence to increased diuretic use because they are observed to occur consecutively, yet the alternative explanation of increased diuretic prescription occurring as a consequence of progressive CKD symptoms, which may not be ascertained by insensitive markers such as serum creatinine, is not adequately considered. Several lines of evidence illustrate benefits of diuretic therapy. Thiazide diuretics have antihypertensive efficacy that is comparable to other drug classes.7–11 Moreover, they significantly reduce the risk of cardiovascular and cerebrovascular diseases.8,10,12,13 For example, ALLHAT demonstrated that diuretic-based therapy provided similar cardiovascular protection as newer agents10 and were possibly superior in preventing secondary cardiovascular outcomes.10 Furthermore, thiazide diuretics are among the most widely used drugs in the management of hypertension and are relatively inexpensive. Based on this evi-
Address correspondence and reprint requests to Dr. Donal Reddan, University College Galway, Department of Nephrology, Unit 1, Merlin Park Hospital, Galway, Ireland; e-mail: dreddan@ eircom.net 0895-7061/05/$30.00 doi:10.1016/j.amjhyper.2005.03.729
740
EDITORIAL
dence, they have specific indications in African Americans, in the elderly, in patients with edema, and with congestive heart failure.14,15 The investigators provide reasonable evidence of a plausible potential link between increased diuretic usage and ESRD. Whether a causal relationship really does exist needs to be studied further in large-scale randomized control trials of diuretic therapy in patients with established CKD. Development of ESRD or advanced CKD is a relatively rare outcome in general population trials and, consequently, such studies are generally underpowered for renal outcomes. Therefore, the design and execution of required prospective studies will be challenging. The evidence for the therapeutic and mortality benefits of diuretic-based therapy is available, and the treatments are time-tested. Concerns arising from the exploratory retrospective data presented by Hawkins and Huston1 could have significant implications for healthcare worldwide. Although this hypothesis is provocative, more supportive scientific evidence is required before it should significantly influence clinical practice.
References 1.
2.
3.
4.
5.
Hawkins RG, Houston MC: Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States? Am J Hypertens 2005;18:744 –749. Freis ED, Reda, DJ, Materson BJ: Volume (weight loss) and blood pressure response following thiazide diuretics. Hypertension 1988; 12:244. Fletcher A, Amery A, Birkenhager W, Bulpitt C, Clement D, de Leeuw P, Deruyterre ML, de Schaepdryver A, Dollery C, Fagard R: Risks and benefits in the trials of European Working Party on High Blood pressure in the Elderly. J Hypertens 1991;9:225–230. Voyaki SM, Staessen JA, Thijs L, Wang JG, Efstratopoulos AD, Birkenhager WH, de Leeuw PW, Leonetti G, Nachev C, Rodicio JL, Tuomilehto J, Fagard R: Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. J Hypertens 2001;19:511–519. Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, Jerome; Cohen B, Davis R, Frost P, Smith W, Gonzalez N,
AJH–June 2005–VOL. 18, NO. 6
6.
7.
8.
9.
10.
11.
12. 13.
14.
15.
Guthrie GP, Oberman A, Rutan G, Probstfield JL, Stamler J, for the SHEP Cooperative Research Group: Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program: Arch Intern Med 1998;158:741–751. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997. Medical Research Council Working Party: MRC trial of treatment of mild hypertension: principal results. Br Med J (Clin Res Ed) 1985;291:97. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, Wester PO, Hedner T, de Faire U: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751–1756. Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM: Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calciumchannel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000;356:366. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2927. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ: Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583–592. Medical Research Council trial of treatment of hypertension in older adults. principal results. MRC Working Party. BMJ 1992;304:405. Messerli FH, Grossman E, Goldbourt U: Are -blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279:1903. 1999 World Health Organization–International Society of Hypertension: Guidelines for the management of hypertension. Guidelines subcommittee. J Hypertens 1999;17:151. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157:2413.