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Vol. 14. Núm. 2.Abril 1994
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Pharmacologic treatment of early diabetic nephropathy
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NEFROLOGIA. Vol. XIV. Núm. 2, 1994 EDITORIALES Pharmacologic treatment of early diabetic nephropathy G. Jerums T. J. Allen, E. C. Hendrich Y P. G. McNally Austin Hospital. Heidelberg Victoria 3084. Australia INTRODUCTION Approximately one third of patients with type l diabetes and one fifth of patients with type II diabetes develop clinically overt DN. While the incidence of DN in type I diabetes is declining, the incidence of end-stage renal failure in type II diabetic patients has increased dramatically in the United States in recent years. The functional and structural lesions of DN develop in predisposed patients over 10 to 20 years following diagnosis, and it is not clear if there is a latent period. DN evolves through several stages which generally follow the sequence hyperfiltration, microalbuminuria, raised blood pressure, macroalbuminuria and progressive fall in glomerular filtration rate (GFR) as shown in figure 1. Apart from hyperfiltration, the concomitants of microalbuminuria include increase in serum prorenin levels 1 and apoprotein(a) levels 2. If it could be shown conclusively that increases in prorenin precede the development of microalbuminuria, it would follow that aggressive intervention would need to be considered in this subgroup of patients. Although these stages represent a continuum, they are often considered separately as incipient and overt DN. Incipient DN is defined as persistent levels of albumin excretion rate (AER) in the range 20-200 ug/min (established microalbuminuria). It may indicate the presence of renal disease rather than being a marker for its subsequent development. Overt DN occurs when AER persistently exceeds 200 ug/min and when total proteinuria exceeds 0.5 grams/24 hours. This is approximately equivalent to a positive (+) albustix test. In patients with evolving DN, AER usually increases exponentially and averages 30-40 % per year in both type I and type II diabetes 3. Results of AER measurements over several years are shown in Fig. 1.-Natural history of diabetic nephropathy in IDDM Correspondencia: Dr. D. George Jerum. Austin Hospital. Heidelberg Victoria 3084. Australia. figure 2 for a patient with progressively increasing AER, prior to and after commencement of antihypertensive therapy. The increase in AER may be explained by functional changes in renal haemodynamics and by changes in glomerular ultrastructure such as basement membrane thickening and increased mesangial volume leading to a decrease in available filtration surface 4 . In addition, both functional and structural p a r a m e t e r s , such as loss of heparan sulphate proteoglycan, may cause alterations in the permselectivity of the glomerular filter. The existence of a functional component in a l b u m i n u r i a is one reason why it is not appropriate to assume that reduction or stabilisation of AER in microalbuminuric patients is necessarily coupled to delay or amelioration of the subseq u e n t d e c l i n e in renal function 5 . A l t h o u g h an 127 NEFROPATIA DIABETICA PRECOZ 1 `ooi______.>L& . l / t. l 0 1 `0 1 2 3 4 5 6 7 B 9 10 . 0 1 2 3 4 5 6 7 8 9 l( Duration of Diabetes (yrs) Duration of Diabetes (yrs) Fig. 2.-Progression of albuminuria before and after intervention w i t h antihypertensive therapy in an individual patient. Solid circles represent n o t h e r a p y and open circles represent antihypertensive therapy. Solid line represents the regression relations h i p during no therapy (r = 0.79, p = 0.00011. Dashed line represents the lower limit of microalbuminuria 120 ug/min). Fig. 3.-Progression of AER despite improving glycaemic control in a patient studied over 16 years. increased AER is the hallmark of early DN, it should be noted that some female patients with type I diabetes may develop decreased renal function and glomerular ultrastructural changes indistinguishable from DN 6 . It should also be noted that the onset of microalbuminuria may lose most of its prognostic value in type I diabetic patients with disease duration exceeding 15 years 7. GLYCAEMIC CONTROL AND PREVENTION OF OVERT DN The respective roles of glycaemic and blood pressure control in evolving DN are shown in figure 3, which emphasise the loss of effectiveness diagrammatically of glycaemic control in the later stages of DN. Glycaemic control has been traditionally listed as a factor in preventing DN, but persuasive human data to support this have been scarce 8. Recently, two r a n d o m i s e d , prospective longterm studies from S w e d e n and the United States have shown that HbAlc levels of < 7.5 % (normal < 6.1 %) are achievable with multiple insulin injections over periods of 7.5 years 9 and 9 years 10. These studies also showed t h a t microvascular complications, including overt DN, can be delayed and possibly prevented by intensive glycaemic control. In the Swedish study, half of 102 type I diabetic patients were randomised to intensive glycaemic control and half to standard control. DN, defined as AER > 200 ug/min, developed in 1 patient on intensive treatment compared with 9 patients on standard treatment (p < 0.01). A subnormal GFR occurred in no patient in the intensive treatment g r o u p compared with 6 patients receiving standard t r e a t m e n t ( p < 0.02, 9) Similar results have been f o u n d in the much larger DCCT, which studied approximately 1400 patients, half of whom were treat e d with intensive glycaemic control 10. This study showed that development of overt DN was reduced b y approximately 50 % in the intensive control group, which maintained a mean HbAlc of 7.2 % during the study. Our own studies have shown a significant correlation between the rate of increase in AER and-mean HbAlc levels over intervals of 9 to 14 years in patients with either type I or type II diabetes 3. Atpresent, no longterm study exists to document the effects of intensified glycaemic control on the evolution of DN in type II diabetes. However, one study has shown that addition of a nocturnal dose of longacting insulin to oral hypoglycaemic therapy is better tolerated than the multiple insulin injection regimen, and results in comparable glycaemic control 11. It is important to note that AER may increase despite improving glycaemic control as shown in a patient studied for over 10 years (figure 4). This indicates that 129 C. JERUMS y cols. Fig. 4.-Relative e f f e c t i v e n e s s o f intervention in d i a b e t i c nephropathy. Y-axis represents increasing effectiveness. Grey area represents glycaemic control and hatched area represents blood pressure control. blood sugar levels are only one of a number of pathogenetic factors contributing to DN. A N T I H Y P E R T E N S I V E THERAPY IN T H E N O R M O T E N S I V E , MICROALBUMINURIC PATIENT The case for a specific protective effect of ACE inhibitors on the kidney is based on studies of experimental DN 12, which suggested that these agents lower intraglomerular pressure and also partially restore glomerular permselectivity towards normal. Short-term studies in man support the latter action of ACE inhibitors. The calcium channel blocker, diltiazem, has also been reported to exert a beneficial effect on glomerular heparan sulphate content and on albuminuria in diabetic rats 13. However, no studies of the effects of calcium channel blockade on glomerular permselectivity appear to have been done S e v e r a l studies have examined the effects of antihypertensive therapy, usually with ACE inhibitors, in normotensive, microalbuminuric patients with type I diabetes for intervals of 1 to 4 years 1 4 - 1 7 . These studies showed a reduction or stabilisation of microalb u m i n u r i a in association with a slight decrease in blood pressure l 4 or without any decrease in blood pressure. 130 G. JERUMS y cols. T h e Melbourne Diabetic Nephropathy Study dies with isotopic measurements of GFR and/or gloGroup (MDNSG) has also addressed the question 1 8 merular ultrastructure are needed to strengthen the case for ACE inhibition in normotensive microalbuof antihypertensive treatment in normotensive and hypertensive microalbuminuric patients. In this study, minuric patients. 43 type I and type II diabetic patients with persistent microalbuminuria were randomised to treatment with ANTIHYPERTENSIVE THERAPY IN OVERT DN the ACE inhibitor, perindopril, or the calcium channel blocker, nifedipine, for a period of 12 months, aiIn contrast to the lack of a clear consensus on the ming for a reduction in diastolic blood pressure of 4 choice of and threshold for antihypertensive treatmmHg in normotensive patients and a target diastolic ment in the normotensive microalbuminuric patient, blood pressure of 90 mmHg in hypertensive patients. the situation in patients with overt DN is much cleaIn this study hypertension was defined as > 160/95 19 . rer (see table l). Several studies have shown that both A significant correlation was found between the conventional antihypertensive agents and the newer change in mean blood pressure and the change in ACE inhibitors and calcium channel blockers all have AER in individual patients (r = 0.37, p = 0.02), but beneficial effects on AER and the rate of fall in GFR, there was no clear evidence that perindopril was suin proportion to their lowering of systemic blood perior to nifedipine in reducing AER. Both drugs prepressure 25-27. vented increases in AER in normotensive patients and A meta analysis has recently compared the effects decreased AER in hypertensive patients. It should be of ACE inhibitors, calcium channel blockers and noted that there has been a recent trend to use a loother agents on proteinuria and renal function in diawer threshold for the definition of hypertension in betic patients 2 8 . This study concluded that ACE inhidiabetic patients, such as 140/90 or less 20 . It is imbitors can decrease proteinuria and preserve GFR. portant to note that one month after cessation of anHowever, the analysis used pooled data from studies tihypertensive treatment, there was a rebound of AER in microalbuminuric and macroalbuminuric patients. in the total cohort, with no significant difference betFurthermore, of the 12 randomised controlled trials ween those receiving perindopril and those receiving that were analysed, 11 examined the effects of ACE nifedipine. Analysis of the rebound of AER in a subinhibition. In the absence of comparable data on calgroup of patients with a total follow-up exceeding 9 cium channel blockers and other agents, it may be years indicated that, while both drugs stabilised AER, premature to conclude that ACE inhibitors are the subsequent rates of increase in AER while off treatpreferred therapy of incipient and overt DN. ment were approximately parallel to pretreatment values 21. A second study by the MDNSG is in progress. This TREATMENT OF DYSLIPIDAEMIA IN PATIENTS is examining the effects of perindopril, nifedipine and WITH DN placebo on AER and renal function in normotensive diabetic patients with microalbuminuria. Preliminary Apart from hyperglycaemia and raised blood presresults show that both active drugs prevent increases sure, a further possible explanation for the excess in AER but no effects on GFR are yet evident. The efcardiovascular mortality associated with overt DN is fects of antihypertensive intervention in microalbuminuric diabetic patients have been the subject of two Table l. Effect of antihypertensive therapy on recent editorials 22,23. Both conclude that AER may be diabetic neohrooathv favourably influenced by ACE inhibitors in normotensive patients. However, it should be pointed out that no longterm ( > 5 yr) intervention studies exist in normotensive type I microalbuminuric patients to show that ACE inhibition preserves GFR. By contrast, a recent study of ACE inhibition, using enalapril Smg twiMiUO Macro ce daily, in normotensive microalbuminuric patients with type ll diabetes has demonstrated stabilisation of /\ 0 AER and plasma creatinine levels over 5 years 24 . 213 NT ll3 HT ll4 NT 314 HT Placebo treated patients showed an increase in AER AER */J Rate of fall of CFR &? later 1 i i i and a rise in serum creatinine levels starting from the Preferred drug ! ACE inhibitor av av -v second year of the study. However, the enalapril efNT = normotensive; HT = hypertensive; Normo = normoalbuminuria; micro fect on changes in serum creatinine levels was small, = microalbuminuria. although statistically significant. Further longterm stu132 G. JERUMS y cols dyslipidaemia29. Experimental evidence indicates that dyslipidaemia may damage the kidney but few human studies support a causative role for lipid disorders in DN. One study of the rate of decline in renal function in type 1 diabetic patients has shown a correlation with serum cholesterol levels 30 . Combined hyperlipidaemia with low HDL cholesterol is the commonest type of diabetic dyslipidaemia, and occurs particularly in patients with type II diabetes. This can be treated with lipid modifying drugs such as gemfibroril if high triglycerides and low HDL cholesterol are the main abnormalities, or w i t h HMC CoA reductase inhibitors if raised LDL cholesterol is the predominant abnormality. No data exist to allow assessment of the effects of lipid modifying therapy on AER or other aspects of DN in man. Proteinuric patients with type I diabetes have been shown to have lower HDL cholesterol levels than age and sex matched control subjects 31. Serial studies in our own laboratory have shown that increasing AER is associated with concomitant increases in apoprotein(a) levels, especially in type II diabetic patients 2. Unfortunately, no effective methods for lowering apoprotein(a) levels are available. It has been recently shown that treatment with the ACE inhibitor, fosinopril, improves lipid abnormalities in type II diabetic patients with overt DN, in association with a partial reduction in proteinuria 3 2 . In summary, the above evidence supports aggressive pharmacological intervention is warranted in patients with DN. Before the development of microa l b u m i n u r i a , emphasis should be on excellent glycaemic control. In practice, this refers to all diabetic patients since identification of DN in the prem i c r o a l b u m i n u r i c phase remains controversial. Intensive blood pressure control becomes important after AER has risen to the microalbuminuric stage. Since the usual nocturnal fall in blood pressure may be reduced in diabetic patients, it is possible that the best way of assessing blood pressure may be to use 24 hour ambulatory records 33. Lipid lowering drugs are also indicated, although the exact role of lipid disorders in the pathogenesis of DN remains to be determined. Although DN is usually considered to be irreversible in its later stages, after overt DN has developed, it is possible that early intervention with the above pharmacological agents will prevent progression to the point of irreversibility. References 1. Blankestijn PJ, Derkz FHM, Weber RFA, Schalekamp M: Plasma prorenin versus 24-hour urinary albumin excretion as predictors of microvascular disease in type II diabetics (abstract). Am J Hypertens 4:83, 1991. 2. Jerums G, Allen TJ, Tsalamandris C, Akdenir A, Sinha A, Gilbert R, Cooper ME: Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in type II and type I diabetic patients. Diabetologia (in press) 1991. 3. Gilbert RE, Tsalamandris C, Bach LA, Panagiotopoulos S, O'Brien RC, Allen TJ,Goodall I, Young V, Seeman E, Murray RML. Cooper ME, Jerums G. Long-term glycemic control and the rate of progression of early diabetic kidney disease. Kidney Int (in press) 1993. 4. Mauer SM, Steffes MW. Ellis EN et al.: Structural-functional relationships in diabetic nephropathy. J Clin Invest 74:11431155,1984. 5. Bennett PH: Microalbuminuria and diabetes: A critique -assessment of urinary albumin excretion and its role in screening for diabetic nephropathy. Amer J Kid Dis 13:29-34, 1989. 6. Lane PH, Steffes MW, Mauer SM. Glomerular structure in IDDM women with Iow glomerular filtration rate and normal urinary albumin excretion. Diabetes 41 :581-586, 1992. 7. Forsblom CM, Groop PH, Ekstrand A, Groop LC: Predictive value of microalbuminuria in patients with insulin-dependent diabetes of long duration. BMJ 305:1 051 -1053, 1992. 8. Hasslacher C, Ritz E, Terpstra J, Gallasch G, Kunowski G, Rall C: Natural history of nephropathy in type I diabetes. Relationship to metabolic control and blood pressure. Hypertens 7:1174-1178, 1985. 9. Reichard P, Nilsson BY, Rosenqvist U: The effect of Iong-term intensified insulin treatment on the development of micro cular complications of diabetes mellitus. New Engl J Med 329: 304-309, 1993. 10. Diabetes Control and Complications Trial. New Engl J Med 1993 (in press). 11. Yki-Jarvinen H, Kauppila M, Kujansuu E et al.: Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. New Engl J Med 327:1426-1431, 1992. 12. Myers BD, Meyer TW: Angiotensin-converting enzyme inhihitors in the prevention of experimental diabetic glomerulopathy. Am J Kidney Dis 13:20-24, 1989. 1 3 . Jyothirmayi GN, Reddi AS: Effect of diltiazem on glomerular heparan sulfate and albuminuria in diabetic rats. Hypertens 21:795-802, 1993. 14. Marre M, Chatellier G, Leblanc H, Guyene TT, Menard T, Passa P: Prevention of diahetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ 297: 1092-1 095, 1988. 1 5. Stornello M, Valvo EV, Scapellato L: Angiotensin converting enzyme inhibition in normotensive type II diabetics with persistent mild proteinuria.J Hyperten (suppl.7):S464-466, 1988. 16. Rudherg S, Aperia A, Freyschuss U, Persson B: Enalapril reduces microalbuminuria in young normotensive type I (insulindependent) diabetic patients irrespective of its hypotensive effect. Diabetologia 33:470-476, 1990. 17. Mathiesen EK, Hommel E, Giese J Parving HH: Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ 303:81-87, 1991. 18. Melbourne Diabetic Nephropathy Study Group: Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. Brit Med J 302:21 O-21 6, 1991. 19. Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. The 1984 report of the joint national committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med 144.1045. 1047, 1984 20. Mogensen CE, Hansen KW, Pedersen MM, Christensen CK: Renal factors influencing blood pressure threshold and choice of treatment for hypertension in IDDM. Diabetes Care l4(suppl 4):1 3-26, 1991. 134 NEFROPATIA DIABETICA PRECOZ 21. Jerums C, Allen TJ, Tsalamandris C, Cooper ME for the Melbourne Diabetic Nephropathy Study Group: Angiotensin converting enryme inhibition and calcium channel blockade in incipient diabetic nephropathy. Kidney Int 41 :904-91 1, 1992. 22. Mogensen CE: Angiotensin converting enryme inhibitors and diabetic nephropathy. BMJ 304:327-328, 1992. 23. Bakis CL: Angiotensin-converting enryme inhibitors and progression of diabetic nephropathy. Editorial. Annals Int Med 11 8:643-644, 1993. 24. Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M: Longterm stabilizing effect of angiotensin-converting enryme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Annals of Int Med 1 18:577-581, 1993. 25. Parving HH, Hommel E, Damkjaer NM, Giese J: Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ 299:533. 536, 1989. 26. Parving HH, Andersen AR, Smidt VM, Hommel E, Mathiesen ER, Svendsen PA: Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J 294:14431447, 1987. 27. Slataper R, Vicknair N, Sadler R, Bakris CL: Comparative ef- fects of different antihypertensive treatment on progression o f diabetic renal disease. Arch Intern Med 153:973-980, 1993. 28. Kasiske BL Kalil RSN, Ma JZ, Liao M, Keane WF: Effect of antihypertensive therapy on the kidney in patients with diabetes: A meta-regression analysis. Annals Int Med 118:129-1 38, 1993. 29. Borch-Johnsen K, Kreiner S. Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetic mellitus. BMJ 294:1651-1 654, 1987. 3 0 . Mulec H, J o h n s o n SA, Bjorck S: Relationship between serum cholesterol and diabetic nephropathy. Lancet 1 :1537-1 538, 1990. 31. Winocour PH, Durrington PN, Ishola M, Anderson DC, Cohen H: Influence of proteinuria on vascular disease, blood pressure, and lipoproteins in insulin dependent diabetes mellitus. Brit Med J 294:1648-1651, 1987. 3 2 . Keilani T, Schlueter A, Levin ML. Batlle DC: Improvement of lipid abnormalities associated with proteinuria using fosinopril. an angiotensin-converting enryme inhibitor. Annals Int Med 118:246-254, 1993. 33. Appel LJ, Stason WB: Ambulatory blood pressure monitoring and blood pressure self-measurement in the diagnosis and management of hypertension. Annals Int Med 118:867-882, 1993. 135

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