From microalbuminuria to hyperhomocysteinemia
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EDITORIAL From microalbuminuria to hyperhomocysteinemia In 1979, Mogensen and Vittinghus in Denmark used a sensitive radioimmunoassay to measure urine albumin, and reported in this journal that exercise provoked transient albuminuria in patients with diabetes mellitus for 2 to 11 years, but not in normal subjects nor in those with diabetes for less than one year [1]. From this observation the concept of microalbuminuria gradually emerged, a concept which nephrologists embraced quickly and developed thor- oughly. Microalbuminuria predicts the development of diabetic nephropathy and is an independent risk factor for cardiovascular mortality in type 1 and type 2 diabetes [2]. Its relationship to other major renodestructive diseases is less clear [3]. Microalbuminuria can be reduced by angio- tensin converting enzyme inhibitors [4], a class of drugs that retard the progression of diabetic kidney disease. The general theory is that microalbuminuria represents an early and sensitive marker of vascular abnormalities, including those of the glomerular capillary wall. Also in 1979, Wilcken and Gupta [5] in Australia recon- firmed that hyperhomocysteinemia occurs in chronic renal failure, an observation made earlier by Cohen, Patel and Kornhauser [6]. Both groups linked this abnormality to the accelerated atherosclerosis attributed to chronic renal fail- ure. Nephrologists remained largely unaware or uninspired by this concept, but eventually accepted it and are now developing it systematically. Hyperhomocysteinemia is now established as an independent risk factor for cardiovascular disease with or without chronic renal failure [7]. In patients with chronic renal failure, high homocysteine concentra- tions can be reduced by folic acid and other B vitamins [8], a class of agents which are now being tested to retard the progression of atherosclerotic disease. The general theory is that hyperhomocysteinemia causes oxidative injury to the vascular wall [9], presumably including glomerular capillar- ies. In this issue of Kidney International, Hoogeveen et al [10] bring these two threads together by establishing a firm link between microalbuminuria and hyperhomocysteinemia in the Hoorn Study, a population-based survey of glucose tolerance and cardiovascular risks conducted in Hoorn, the Netherlands between 1989 and 1992. In a cross sectional study of a random population sample of 680 Dutch men and women between the ages of 50 and 75 years, the risk of microalbuminuria increased with higher homocysteine con- centrations independent of other determinants. After ad- justment for age, gender and other classical risk factors, the odds ratio for microalbuminuria was 1.33 per 5 mmol/liter increment in total homocysteine concentration. The Hoorn Study is interesting because it brings together two investigative themes, and provocative because it indi- cates a possible role for homocysteine in the production of microalbuminuria. The study was not prospective and the question arises whether the findings represent a simple association between two surrogates. As the authors point out, it is conceivable that hyperhomocysteinemia and mi- croalbuminuria may arise from a common insult. Also tenable statistically, although unattractive biologically, is the possibility that microalbuminuria causes hyperhomo- cysteinemia. Regardless of the interpretation, the reason- ably ample number of subjects, the extensiveness of the data and the thoroughness of the analysis combine to provide a compelling association around which much more work still needs to be done. The Hoorn Study addressed the involvement of angio- tensin converting enzyme inhibitors as best it could, but did not investigate the role of B vitamins. Recent attention has focused on folate deficiency in the production of several chronic diseases that range from the familiar megaloblastic anemias to neural tube defects, neuropsychiatric distur- bances, and more recently, vascular disorders. Low folate levels may also promote carcinogenesis. If high homocys- teine levels, which are commonly associated with low or relatively low folate levels, are causally related to mi- croalbuminuria, then diabetic nephropathy and potentially other renal disorders’ dysfunction may need to be added to the list of conditions to which folic acid deficiency predis- poses. This would be a shift from the currently prevailing paradigm that hyperhomocysteinemia may mediate some of the complications of chronic renal failure but not its causes. By extension, folic acid should take its place alongside ACE inhibitors on the list of agents in need of testing for potential usefulness in retarding the progression of chronic renal failure as well as its complications. Such a trial would require scientific altruism because of the lack of commercial potential. For the moment, the Hoorn Study is welcome as a fertile observation that raises many questions which nephrologists may want to develop further in labo- ratory and clinical investigations. KILLIAN ROBINSON and VINCENT W. DENNIS Cleveland Clinic Foundation Cleveland, Ohio, USA Key words: diabetic nephropathy, cardiovascular disease, angiotensin converting enzyme, chronic renal failure, folic acid. © 1998 by the International Society of Nephrology Kidney International, Vol. 54 (1998), pp. 281–282 281
Transcript of From microalbuminuria to hyperhomocysteinemia
EDITORIAL
From microalbuminuria to hyperhomocysteinemia
In 1979, Mogensen and Vittinghus in Denmark used asensitive radioimmunoassay to measure urine albumin, andreported in this journal that exercise provoked transientalbuminuria in patients with diabetes mellitus for 2 to 11years, but not in normal subjects nor in those with diabetesfor less than one year [1]. From this observation theconcept of microalbuminuria gradually emerged, a conceptwhich nephrologists embraced quickly and developed thor-oughly. Microalbuminuria predicts the development ofdiabetic nephropathy and is an independent risk factor forcardiovascular mortality in type 1 and type 2 diabetes [2].Its relationship to other major renodestructive diseases isless clear [3]. Microalbuminuria can be reduced by angio-tensin converting enzyme inhibitors [4], a class of drugs thatretard the progression of diabetic kidney disease. Thegeneral theory is that microalbuminuria represents an earlyand sensitive marker of vascular abnormalities, includingthose of the glomerular capillary wall.
Also in 1979, Wilcken and Gupta [5] in Australia recon-firmed that hyperhomocysteinemia occurs in chronic renalfailure, an observation made earlier by Cohen, Patel andKornhauser [6]. Both groups linked this abnormality to theaccelerated atherosclerosis attributed to chronic renal fail-ure. Nephrologists remained largely unaware or uninspiredby this concept, but eventually accepted it and are nowdeveloping it systematically. Hyperhomocysteinemia is nowestablished as an independent risk factor for cardiovasculardisease with or without chronic renal failure [7]. In patientswith chronic renal failure, high homocysteine concentra-tions can be reduced by folic acid and other B vitamins [8],a class of agents which are now being tested to retard theprogression of atherosclerotic disease. The general theoryis that hyperhomocysteinemia causes oxidative injury to thevascular wall [9], presumably including glomerular capillar-ies.
In this issue of Kidney International, Hoogeveen et al [10]bring these two threads together by establishing a firm linkbetween microalbuminuria and hyperhomocysteinemia inthe Hoorn Study, a population-based survey of glucosetolerance and cardiovascular risks conducted in Hoorn, theNetherlands between 1989 and 1992. In a cross sectionalstudy of a random population sample of 680 Dutch menand women between the ages of 50 and 75 years, the risk of
microalbuminuria increased with higher homocysteine con-centrations independent of other determinants. After ad-justment for age, gender and other classical risk factors, theodds ratio for microalbuminuria was 1.33 per 5 mmol/literincrement in total homocysteine concentration.
The Hoorn Study is interesting because it brings togethertwo investigative themes, and provocative because it indi-cates a possible role for homocysteine in the production ofmicroalbuminuria. The study was not prospective and thequestion arises whether the findings represent a simpleassociation between two surrogates. As the authors pointout, it is conceivable that hyperhomocysteinemia and mi-croalbuminuria may arise from a common insult. Alsotenable statistically, although unattractive biologically, isthe possibility that microalbuminuria causes hyperhomo-cysteinemia. Regardless of the interpretation, the reason-ably ample number of subjects, the extensiveness of thedata and the thoroughness of the analysis combine toprovide a compelling association around which much morework still needs to be done.
The Hoorn Study addressed the involvement of angio-tensin converting enzyme inhibitors as best it could, but didnot investigate the role of B vitamins. Recent attention hasfocused on folate deficiency in the production of severalchronic diseases that range from the familiar megaloblasticanemias to neural tube defects, neuropsychiatric distur-bances, and more recently, vascular disorders. Low folatelevels may also promote carcinogenesis. If high homocys-teine levels, which are commonly associated with low orrelatively low folate levels, are causally related to mi-croalbuminuria, then diabetic nephropathy and potentiallyother renal disorders’ dysfunction may need to be added tothe list of conditions to which folic acid deficiency predis-poses. This would be a shift from the currently prevailingparadigm that hyperhomocysteinemia may mediate someof the complications of chronic renal failure but not itscauses. By extension, folic acid should take its placealongside ACE inhibitors on the list of agents in need oftesting for potential usefulness in retarding the progressionof chronic renal failure as well as its complications. Such atrial would require scientific altruism because of the lack ofcommercial potential. For the moment, the Hoorn Study iswelcome as a fertile observation that raises many questionswhich nephrologists may want to develop further in labo-ratory and clinical investigations.
KILLIAN ROBINSON and VINCENT W. DENNISCleveland Clinic Foundation
Cleveland, Ohio, USA
Key words: diabetic nephropathy, cardiovascular disease, angiotensinconverting enzyme, chronic renal failure, folic acid.
© 1998 by the International Society of Nephrology
Kidney International, Vol. 54 (1998), pp. 281–282
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Reprint requests to Killian Robinson, M.D., Department of Cardiology,Cleveland Clinic Foundation, 9500 Euclid Ave., Desk F15, Cleveland, Ohio44195, USA.
REFERENCES1. VITTINGHUS E, MOGENSEN CE: Graded exercise and protein excretion
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2. DINNEEN SF, GERSTEIN HC: The association of microalbuminuria andmortality in non-insulin-dependent diabetes mellitus. A systematicoverview of the literature. Arch Intern Med 157:1413–1418, 1997
3. AGEWALL S, WIKSTRAND J, LJUNGMAN S, FAGERBERG B: Usefulness ofmicroalbuminuria in predicting cardiovascular mortality in treatedhypertensive men with and without diabetes mellitus. Risk FactorIntervention Study Group. Am J Cardiol 80:164–169, 1997
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7. ROBINSON K, GUPTA A, DENNIS VW, ARHEART K, CHAUDHARY D,GREEN R, VIGO P, MAYER EL, SELHUB J, KUTNER M, JACOBSEN D:Hyperhomocysteinemia confers an independent increased risk ofatherosclerosis in end-stage renal disease and is closely linked toplasma folate and pyridoxine concentrations. Circulation 94:2743–2748, 1996
8. BOSTOM AG, SHEMIN D, LAPANE KL, HUME AL, YOBURN D, NADEAU
MR, BENDICH A, SELHUB J, ROSENBERG IH: High dose B-vitamintreatment of hyperhomocysteinemia in dialysis patients. Kidney Int49:147–152, 1996
9. LOSCALZO J: The oxidant stress of hyperhomocyst(e)inemia. J ClinInvest 98:5–7, 1996
10. HOOGEVEEN EK, KOSTENSE PJ, JAGER A, HEINE RJ, JAKOBS C,BOUTER LM, DONKER AJM, STEHOUWER CDA: Serum homocysteinelevel and protein intake are related to risk of microalbuminuria: TheHoorn Study. Kidney Int 54:203–209, 1998
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