It is well recognized that persons with non. Microalbuminuria, Blood Pressure, Metabolic Control, and Renal Involvement

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1 AJH 1997;10:189S 197S Microalbuminuria, Blood Pressure, Metabolic Control, and Renal Involvement Longitudinal Studies in White Non Insulin-Dependent Diabetic Patients Anita Schmitz In the present paper, longitudinal studies in non insulin-dependent diabetes mellitus (NIDDM) dealing with risk factors, especially microalbuminuria, blood pressure, and glycemic control, and the course of the kidney function are addressed. The definition of microalbuminuria, limits for abnormal albuminuria, and possible causes of microalbuminuria in NIDDM are discussed. Microalbuminuria is a major independent risk marker for early mortality, and new studies indicate that even high normoalbuminuria carries a risk. Furthermore, risk markers agreed on among various studies include apart from abnormal albuminuria, age and preexisting cardiovascular disease, whereas there is some inconsistency concerning glycemic control, lipoproteins, and even hypertension. People with microalbuminuria, NIDDM patients as well as nondiabetics, share an increased prevalence of atherosclerosis and its risk factors as well as an It is well recognized that persons with non insulin-dependent diabetes mellitus (NIDDM) are jeopardized not only by diabetes-specific microvascular complications, but also, and foremost, by macrovascular diseases and a considerably increased mortality. During recent years a From the Medical Department (Diabetes & Endocrinology), Aarhus Kommunehospital and Medical Department, Horsens Sygehus, Denmark. Address correspondence and reprint requests to Anita Schmitz, MD, Medical Department, Horsens Sygehus, Sundvej 30, DK-8700 Horsens, Denmark. increased TER alb. Albuminuria in NIDDM may thus have two different causes: general vascular disease and diabetic glomerulopathy. The clinical course of renal function is with large interindividual variation in both patients with or without overt proteinuria. Systolic blood pressure, glycemic control, and level of albuminuria appear to determine the deterioration in kidney function and progression of albuminuria, and to influence the overall prognosis, thus being obvious items for intervention. Long-term intervention studies demonstrating improved survival are, however, still awaited. Am J Hypertens 1997;10:189S 197S 1997 American Journal of Hypertension, Ltd. KEY WORDS: normal albumin excretion, microalbuminuria, risk factors, renal function, non insulin-dependent diabetes mellitus, nondiabetics. number of studies have been conducted to identify risk factors with the purpose of eventually improving the prognosis. Microalbuminuria has emerged as a key parameter in diabetes and has recently been brought into focus also as a marker of cardiovascular disease and probably early mortality also in the nondiabetic population. The mechanism behind this association has, however, not been clarified. In NIDDM several intervention studies against probable risk factors are ongoing. So far, though, almost only short-term results have been reported, and no advancement with respect to survival has hitherto been documented by the American Journal of Hypertension, Ltd /97/$17.00 Published by Elsevier Science, Inc. PII S (97)

2 190S SCHMITZ AJH-SEPTEMBER 1997-VOL. 10, NO. 9, PART 2 TABLE 1. SIGNIFICANT PROGNOSTIC VARIABLES, THE WAY THEY WERE PRESENTED IN THE COX REGRESSION ANALYSES, AND HAZARD RATIOS Risk Factor Regression Coefficient P Value Relative Risk Age (years) Diabetes duration 10 years Serum creatinine 115 mol/l UAC UAC ( ) (2.41) UAC, urinary albumin concentration. 15 g/ml was chosen as the upper limit of a normal UAE and 200 g/ml as the upper limit of microalbuminuria. The patients were divided in three categories accordingly. The hazard ratios in the groups with elevated UAC relative to those with UAC 15 g/ml were 1.65 (P.003) and 2.41 (P ) respectively. Reproduced from Schmitz and Væth. 9 MICROALBUMINURIA A CARDINAL RISK MARKER Microalbuminuria was defined in 1985 by a consensus conference 1 as a urinary albumin excretion rate (UAE) during 24 h collections of 20 to 200 g/min (30 to 300 mg/24 h). The upper limit corresponds approximately to a total urinary protein concentration of 0.5 g/l, the former indicator of diabetic nephropathy. The urinary albumin excretion is 25% lower during overnight collections (15 to 150 g/min). 2 Previously in three different cohorts 3 6 of patients with insulin-dependent diabetes mellitus (IDDM) it had been documented that a raised UAE (below the level of overt proteinuria) predicts the ensuing development of diabetic nephropathy with a high probability. These studies, however, used different limits for abnormal albuminuria and various methods for urine collection, necessitating this standardization for the future comparison of studies from different centers. The recognition of the ability of microalbuminuria to predict the development of overt diabetic nephropathy led to the definition of a new stage: incipient diabetic nephropathy equal to persisting microalbuminuria. The concepts of microalbuminuria and incipient nephropathy have, during the last decade, been directly transferred to apply also to patients with NIDDM, although longitudinal studies to verify this are sparse. The first reports that microalbuminuria is associated with an increased mortality in persons with NIDDM was in 1984 by Mogensen 7 and Jarrett et al. 8 We further examined the impact of abnormal albuminuria also as compared with other potential clinical risk factors. 9 An outpatient cohort comprising a total of 416 NIDDM patients, age 50 to 75 years, with an average urinary albumin excretion 200 g/ml during measurements in early morning urine samples (EMU) during 1 year, were followed up for 10 years. Thereafter 219 had died. The potential prognostic influence of clinical variables and UAC stratified in three categories (UAC 15 g/ml, UAC 15 and 40 g/ml, and UAC 40 g/ml) were evaluated by Cox regression analyses. The significant independent risk markers and the hazard ratios are given in Table 1. The survival curves by level of urinary albumin excretion corrected for the influence of the other independent risk markers are shown in Figure 1. From this it is clear that even a minor increase in albumin excretion is associated with a poor prognosis. The causes of death were mainly associated with cardiovascular diseases, whereas only a minor fraction died from or with uremia. Subsequently a number of longitudinal studies have been conducted, further documenting the predictive power of microalbuminuria, summarized in Table 2. From these studies it can be concluded that abnormal albuminuria, age and preexisting cardiovascular disease are all major risk factors, whereas there is some incongruence when it comes to factors such as glycemic control, lipoproteins, and, perhaps surprisingly, hypertension. It is also evident from Table 2 that renal disease mortality is relatively rare in white patients with NIDDM, apparently a paradox considering the very high prevalence of microalbuminuria and proteinuria in NIDDM: 20% to 40% and 5% to 15%, respectively. 9,16 19 Two further items are presented in the table: in two recent studies 14,15 it was shown that high normoalbuminuria carries a risk. Gall et al 14 divided the normoalbuminuric (urinary albumin excretion rate 30 mg/24 h) patients into those with a UAE FIGURE 1. Survival curves for the three albuminuria categories after correction for the influence of the other significant independent risk markers: age, known diabetes duration and serum creatinine. Reproduced with permission from Kluwer Academic Publishers. 58

3 AJH-SEPTEMBER 1997-VOL. 10, NO. 9, PART 2 MICROALBUMINURIA AND OTHER RISK FACTORS IN NIDDM 191S TABLE 2. LONG-TERM FOLLOW-UP STUDIES ON THE IMPACT OF MICROALBUMINURIA AND OTHER RISK MARKERS ON MORTALITY IN PERSONS WITH NIDDM AND IN HEALTHY SUBJECTS Author/Study N (included/died) Follow-Up (years) Age Definition of Microalbuminuria/ Discriminating Value Independent Risk Markers for All- Cause Mortality Independent Risk Markers for Cardiovascular Mortality Renal Disease Mortality n (%) Normoalbuminurics Schmitz, / UAC g/ml Mattock, / UAE g/ min Damsgaard, / UAE median of 17.4 g/min Neil, / UAC g/ml Uusitupa, / AER g/ml Gall, / AER mg/ 24 h MacLeod, / AER g/min Nondiabetics Yudkin, /9* AER 20 g/ min Damsgaard, / UAE median of 7.52 g/min UAC, serum creatinine, known duration, age microalbuminuria (serum cholesterol) 5 (2.3) 0 UAE, prevalent IHD? UAC, retinopathy lens opacity, age Prevalent CHD AER, HbA 1c, age AER, age prevalent IHD 2% among 149 normo-albuminuric subjects, 33% of 18 microalbuminuric subjects died Hypertension, male sex, UAE Smoking, AGE, Ischaemic ECG, BG, LDL triglyceride (AER) Prevalent CHD, macroalbuminuria, HbA 1c, systolic BP 2 (2)? 3 (6) n 191. AER median: 8 mg/24 h; relative mortality risk (0.7) Borderline: AER g/min; OR 2.27** UAC, urinary albumin concentration (mean of all values (EMU) during 1 year); UAE, urinary albumin excretion rate (overnight); One hour excretion rate; Random spot urine; AER, albumin excretion rate (24 h); AER during a glucose tolerance test. * : 13 newly diagnosed diabetic subjects, 171 nondiabetics. ** : 43 cases dying compared to 29 control subjects (AER 10.5 g/min). IHD, ischemic heart disease; CHD, coronary heart disease; BP, blood pressure; BG, blood glucose; OR, odds ratio.

4 192S SCHMITZ AJH-SEPTEMBER 1997-VOL. 10, NO. 9, PART 2 above or below the median of 8 mg/24 h and found that the risk for all-cause mortality was increased by a factor of 2.7 in the former during 5 years of observation. MacLeod et al 15 had chosen an interval for albumin excretion of 10.6 to 29.9 g/min, assigned the term borderline albuminuria. Subjects of this category as well had an increased risk for mortality over an 8-year period. Two studies in nondiabetic persons have shown that, also in this group, a raised albumin excretion is associated with a reduced life expectancy. 11,20 In a Danish study 11 the median UAE in 216 elderly nondiabetic persons was 7.52 g/min, (25 to 75 interpercentile range 4.77 to 14.84). The 8 to 9 year mortality was significantly increased in subjects with a higher UAE: of 109 with UAE above the median, 26 died as compared with 15 of 107 with the lower values. These latter findings apparently indicate that the current definition of microalbuminuria may not apply in NIDDM, and that the limits for abnormal albuminuria need to be revised. The UAE in nondiabetic individuals is quite below the limit of 20 g/min in most cases. 18,21 25 In a general population based epidemiological study 21 comprising 2,613 apparently healthy persons 30 to 70 years of age, without renal or urinary tract diseases, the upper decile of UAE in overnight urine samples was 7.0, median 2.8 g/min. Likewise, in a number of other population surveys, albeit embracing different age-groups and collection methods the median value during daytime was rather comparable: 3.8 to 6.4 g/min, 90th percentiles though being up to approximately 20 g/min. 22 In elderly (54 to 68 years), healthy (by history, clinical examination, a blood screen, and ECG) subjects participating as controls in clinical studies, the UAE in 24 h urine samples averaged 5.5 g/min (maximum 11.5 g/min). 23 One problem in defining a normal albumin excretion and hence microalbuminuria is to define healthiness. Also the question of whether abnormal albuminuria is a marker or a predictor of disease needs consideration. Persons with microalbuminuria, NIDDM patients as well as nondiabetic subjects, share an increased prevalence of atherosclerosis, raised blood pressure, dyslipidemia, and increased trancapillary escape rate of albumin (TER alb ), Figure 2. 20,23 26 The coexistence of increased TER alb and raised urinary albumin excretion may express a general vascular leakiness promoting the atherosclerotic process. This could explain the relations seen between microalbuminuria, cardiovascular disease, and its risk factors. Furthermore, the insulin resistance syndrome might, with its cluster of risk factors, underlie both atherosclerotic heart disease and NIDDM. 27 Increased prevalence of cardiovascular risk factors was found in subjects, who later developed NIDDM. Microalbuminuria has been shown also to predict the development of NIDDM, although not after adjustment for plasma glucose and insulin levels at baseline. 28,29 At any rate, known risk factors do not FIGURE 2. Two different causes of microalbuminuria in NIDDM. One is shared by nondiabetics with microalbuminuria and may be associated with general vascular leakiness and atherosclerosis. The other is the diabetes specific glomerulopathy that in turn may aggravate the former. explain the high mortality seen in diabetes. In addition, in NIDDM comes the diabetes-specific renal involvement, giving rise also to elevations in albumin excretion. If indeed the case, two different mechanisms causing microalbuminuria, distinguishing in NIDDM what is what would be inconceivable, unless renal biopsies are performed or future investigations reveal differences in the urinary components. This could also possibly explain why the course of diabetic renal disease seems to differ between the two types of diabetes, and the apparent paradox of very frequent abnormal albuminuria and relative rareness of renal failure. Furthermore the term incipient nephropathy is not synonymous with microalbuminuria in NIDDM. RENAL STRUCTURE AND FUNCTION IN NIDDM In NIDDM there are some controversies among various studies as to whether glomerular filtration rate (GFR) is increased in patients without overt nephropathy. 30 In most studies however, in elderly whites, hyperfiltration is not a hallmark of the disease as it is in IDDM. Also on cross-section GFR is not different between patients with normo- or microalbuminuria. 31 Prospectively we studied a cohort of such nonproteinuric patients during 5.5 years, 32 (with interim report after 3.4 years 33 ) with the purpose of evaluating the rate of decline in renal function as measured by the

5 AJH-SEPTEMBER 1997-VOL. 10, NO. 9, PART 2 MICROALBUMINURIA AND OTHER RISK FACTORS IN NIDDM 193S plasma clearance of 51 -chrome-edta as well as the possible relationship to some potential risk factors. The rate of decline in renal function was, on average, similar in patients with normo- or microalbuminuria, and showed no enhancement as compared with the age-dependent decline. However, a rather large interindividual variation was seen, and data after 3.4 years showed the rate of decline in GFR to depend on systolic blood pressure (r 0.47), but at further follow-up after 5.5 years this influence could not be verified. Poor glycemic control was associated with the rate of decline in patients not receiving antihypertensive medication. This discrepancy may be caused by the fact that the patients completing the study were in rather good blood pressure control. Furthermore, the selective mortality and disability hamper clinical follow-up studies of these kinds of patients. Nevertheless, the present results at least point to blood pressure and glycemic control as items for intervention. In patients with proteinuria the scene is not less complicated. GFR in patients with proteinuria is scattered across a broad range, and also the rate of decline in GFR show variety (Figure 3). 34 Systolic blood pressure, also, in these patients followed for 5.2 years, determined the rate of decline (r 0.71) in GFR. We studied the glomerular morphology in 20 such patients, who had a biopsy performed. 35 The severity of the diabetic glomerulopathy was estimated and compared with previous data from patients with IDDM FIGURE 3. Glomerular filtration rate and the course during an average of 5.2 years of follow-up in 26 NIDDM patients with proteinuria. Reproduced with permission from Springer-Verlag from Gall et al. 34 and renal transplant donors. From these data it appeared that NIDDM patients demonstrated a noticeable dispersal in the severity of glomerulopathy and might even reveal a normal structure, at least as regards the structural parameters characterizing diabetic glomerulopathy. Yet, when retinopathy was taken into account, all patients with this complication had diabetic glomerulopathy (Figure 4). It can be deduced from this that proteinuria as well as microalbuminuria have causes other than diabetic glomerulopathy. Interesting also in this respect was the differences between GFR in elderly NIDDM patients as compared with IDDM patients with the same degree of proteinuria (Table 3), a more preserved renal function apparently in NIDDM. In this and also previous studies on glomerular morphology in NIDDM patients with various degrees of albuminuria, rather weak correlations between level of albuminuria and degree of structural lesions has been demonstrated. 36 Supplementary to this finding is the poor relationship between albuminuria and retinopathy in NIDDM. Indeed in three different studies, 9,17,18 as much as approximately 60% of patients with proteinuria had no retinopathy. The associates of abnormal albuminuria in fact differed in an outpatient cross-sectional cohort with complications shifted towards preponderance of macrovascular rather than microvascular complications in NIDDM as compared with IDDM (Table 4). 18

6 194S SCHMITZ AJH-SEPTEMBER 1997-VOL. 10, NO. 9, PART 2 TABLE 4. ASSOCIATES OF ABNORMAL ALBUMINURIA IN AN OUTPATIENT COHORT IDDM (%) NIDDM (%) FIGURE 4. Glomerulopathy index (an expression of the sum of changes in the peripheral basement membrane and mesangium) in nondiabetic subjects ND, and NIDDM patients without O, with background B, and with proliferative P retinopathy. Reproduced with permission from Springer Verlag from Østerby et al. 35 BLOOD PRESSURE Identification of risk factors is certainly complex in NIDDM as evidenced by discrepant results between studies, both those including microalbuminuria (Table 2) and also in previous studies, when primarily more conventional risk factors were included The impact of hypertension on mortality showed dissimilar results, as is the case also in the more recent studies. Overall, however, it appears that relatively often the systolic blood pressure has significant impact on outcome. There are some noticeable differences concerning blood pressure between IDDM (Table 5) 43 and NIDDM (Table 6) 9,12,17,18,44,45 : in the former, blood pressures are normal in patients with normal urinary albumin excretion and only start to increase along with the development of incipient nephropathy. A rather marked increase is seen in both the systolic as well as the diastolic TABLE 3. COMPARISON OF CLINICAL PARAMETERS IN 20 NIDDM AND 22 IDDM PATIENTS WITH PROTEINURIA, MEAN (RANGE) NIDDM IDDM Age (years) 54 (37 67) 35 (24 47) Known duration (years) 7 (1 19) 21 (12 31) UAE (g/24 h) 1.2 ( ) 1.5 ( ) GFR ml/min/1.73 m 2 93 (24 146) 51 (16 104) Adapted from Osterby et al. 35 Albuminuria ( 10.5 g/min) Retinopathy Peripheral vascular disease Ischemic heart disease Peripheral neuropathy Treated hypertension Adapted from Marshall et al. 18 pressure. In NIDDM, hypertension may either precede or follow overt diabetes and the difference is obvious between patients with or without diabetes, being, however, much less apparent between those with normal albumin excretion and those with microalbuminuria. The difference is most pronounced concerning the systolic, rather that the diastolic, blood pressure, pointing to atherosclerosis as the main cause of blood pressure elevation (and microalbuminuria), rather than nephropathy. Several short-term studies have demonstrated that microalbuminuria, as well as overt proteinuria, can be reduced by antihypertensive treatment Ravid et al, 50 during his 7 year prospective study, demonstrated treatment with an ACE inhibitor to stabilize albuminuria and renal function (estimated by the inverse of serum creatinine) in relatively young normotensive NIDDM patients with microalbuminuria. GLYCEMIC CONTROL Obviously, the problem of diabetes is a problem involving glucose metabolism. For some reason, however, it has been difficult to prove that poor glycemic control is involved in the pathogenesis of diabetic complications. Several epidemiological studies have indicated that poor control is associated with the development of diabetic microvascular complications in both types of diabetes. 51,52 The DCCT 53 study finally showed that improvement of glycemic control is advantageous in IDDM with respect to complications, but regarding NIDDM, results from long-term studies are still awaited. The relation between poor glycemic control and the development of macrovascular complications has been a matter of debate for some time. There are indications from follow-up studies 13,28 that glycemic control has an impact on cardiovascular disease and death (Figure 5) but, again, intervention studies are still anticipated. PROGRESSION OF ALBUMINURIA With the purpose of estimating the rate of progression of albuminuria, yearly average urinary albu-

7 AJH-SEPTEMBER 1997-VOL. 10, NO. 9, PART 2 MICROALBUMINURIA AND OTHER RISK FACTORS IN NIDDM 195S TABLE 5. BLOOD PRESSURES IN RELATION TO ALBUMINURIA IN IDDM PATIENTS, AND CONTROLS Controls (n 40) Normoalbuminuria (n 74) Incipient Nephropathy (n 39) Overt Nephropathy (n 28) Systolic BP Diastolic BP Adapted from Christensen. 43 BP, blood pressure (mm Hg). TABLE 6. BLOOD PRESSURES (SYSTOLIC/DIASTOLIC MM HG) IN RELATION TO ALBUMINURIA IN NIDDM Study/Year/Reference Normo- Micro- Macro- Schmitz n /91 163/92 170/90 Marshall n /82 157/85 162/85 Gall MA n 344 (untreated) 145/80 157/83 161/83 Neil n /87 166/90 177/95 Schmitz n /87 158/87 171/92 Normo-, normal albumin excretion; Micro-, microalbuminuria; Macro-, macroalbuminuria. During 24 h measurements blood pressures were 130/77 in 10 healthy controls v 144/81 in untreated NIDDM patients with normo or microalbuminuria. 45 min concentration in early morning urines, and factors influencing this increase, we prospectively followed for 6 years a cohort of 278 NIDDM patients. 44 The average annual relative increase in albuminuria was 17%, but with a considerable interindividual variation. By multiple regression analysis, systolic blood pressure influenced this increase as did the level of albuminuria. Only a modest fraction (R ) of the variation between subjects was, however, explained by these factors. As the interindividual variation in rate of progression was substantial, a group of progressors that is, those who exhibited an increase in the category of albumin excretion, for example normo- to microalbuminuria as well as an increase of more than 20% was defined. Compared with their nonprogressing counterparts these patients had a higher systolic blood pressure, poorer glycemic control, and a higher level of albuminuria at baseline (Table 7). It should be mentioned, however, that some of the normoalbuminuric progressors had a very low initial value of albumin concentration, 1 g/ml, at baseline. This underlines the fact that periodic measurements are necessary to identify all patients at risk. A very recent interim report 54 from an ongoing study on the effect of intensive treatment of NIDDM patients with microalbuminuria showed that, during improvement of glycemic control, reduction of blood pressure, and elimination of smoking, in some albuminuria was reduced as compared with a similar group receiving conventional treatment in general practice. Whether this intensified regimen will improve survival and significantly reduce the number of serious cardiovascular events is not yet known, after 2 years of observation. CONCLUSIONS In NIDDM, microalbuminuria is a major independent risk marker for early mortality, the major causes of death being related to cardiovascular disease. New data indicate that high normoalbuminuria carries a risk. This means that the limits for abnormal albuminuria may have to be revised. Elevated albuminuria in NIDDM may, to a large extent, reflect a general vascular leakiness and thus may be a marker of atherosclerosis as well as of diabetic glomerulopathy. This could explain the apparently divergent course of diabetic renal disease seen in NIDDM as compared with IDDM. Studies so far point to elevated (systolic) blood pressure and poor glycemic control as factors worsening progression of albuminuria, decline in kidney function, and development of macrovascular disease. These factors are probable items for intervention, as supported by short-term studies. However long-term data, as well FIGURE 5. The 3.5 year incidence of CHD deaths and all CHD events (death or nonfatal MI) with respect to tertiles of GHbA 1c (low 6.0%; middle 6.0% to 7.9%; high 7.9%; *P.05, **P.01 compared with the lowest tertile. Reproduced with permission from the American Diabetes Association Inc. from Kuusisto et al. 28

8 196S SCHMITZ AJH-SEPTEMBER 1997-VOL. 10, NO. 9, PART 2 TABLE 7. DIFFERENCES IN POTENTIAL CLINICAL RISK FACTORS BETWEEN PROGRESSORS AND NONPROGRESSORS AMONG NIDDM PATIENTS WITH NORMO- OR MICROALBUMINURIA Progressors (n 46) as data that will demonstrate improvement in survival, are still anticipated REFERENCES Nonprogressors (n 124) HbA 1c % P.05 BPs (mm Hg) P.01 BPd (mm Hg) NS UAC ( g/ml) P.001 BPs/BPd, blood pressure (systolic/diastolic); UAC, urinary albumin concentration. In normoalbuminuric progressors UAC was 7.1 g/ml v 3.8 (P.0001). In microalbuminuric progressors UAC was 47.3 g/ml v 31.8 (P NS). Data from Schmitz et al Mogensen CE, Chachati A, Christensen CK, et al: Microalbuminuria: an early marker of renal involvement in diabetes. Uremia Invest ;9: Eshøj O, Feldt-Rasmussen B, Larsen ML, Mogensen EF: Comparison of overnight, morning and 24-hour urine collections in the assessment of diabetic microalbuminuria. 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