Diabetic Nephropathy Future avenue GIANCARLO VIBERTI, MD JEANNIE YIP-MESSENT, MB ANNA MOROCUTTI, MD

Diabetes mellitus has become the leading cause of ESRF in the United States. Patients with diabetic nephropathy suffer high cardiovascular morbidity and mortality. Because only 40% of diabetic patients eventually develop diabetic kidney disease, it may be possible to devise primary prevention measures targeted at the subset of patients at risk. Recently, a predisposition to hypertension, a family history of diabetic nephropathy, and a family history of CVD disease each have been associated independently with the development of diabetic renal complication in IDDM. Risk factors for macrovascular damage, including raised arterial BP, dyslipidemia, and insulin resistance, can be detected early in the course of progression to diabetic nephropathy. These risk indicators recently have been shown to be already present at the stage of normoalbuminuria in those patients who eventually will progress to microalbuminuria. Treatment of established renal disease can only delay the onset of ESRF, and lowering of microalbuminuria has been shown to retard the onset of persistent proteinuria. However, no study to date has demonstrated prevention of renal disease in these patients. The ultimate aim should, therefore, be the prevention of the transition from normoalbuminuria to microalbuminuria in individuals who are at higher risk of diabetic renal disease and CVD.

frequency (4-6), whereas the highest cumulative incidence of —50-60% after 20 yr of diabetes has been reported among the Pima Indians and the Japanese (7,8). The vast majority of IDDM patients with proteinuria eventually will progress to ESRF or die prematurely from cardiovascular complications. Without any medical intervention, GFR falls at an average of 1 ml • min" 1 • mo" 1 , even though a large fivefold variation exists between individuals, leading to ESRF in a mean period of 7 yr (9,10). In addition, this group of proteinuric patients displays a 20- to 40-fold increased risk of cardiovascular mortality compared with age, sex, and duration of disease-matched diabetic patients without proteinuria (11). CVD is the most common cause of mortality in European NIDDM patients with proteinuria (12), whereas in populations such as the Japanese, with low incidence of CVD, ESRF predominates (13).

Once overt persistent proteinuria is established, no known strategy exists that can stop or reverse the progression to ESRF. Effective treatment of hypertension and LPD both have been reported to benefit in retarding the rate of decline of GFR in some, but not all, patients with idney disease of diabetes mellitus is betic ESRF has approached $2 billion in impaired renal function. Whether such becoming the most common cause 1990 (2). Diabetic nephropathy develops interventions prolong life expectancy is of ESRF in the western world. In in —35% of patients with IDDM (3) and unresolved. Retrospective cohort studies the U.S., where —33% of all patients between 15-60% of NIDDM patients, seem to lend support to the efficacy of entering renal replacement therapy are depending on their ethnic origin. Euro- antihypertensive therapy to reduce renal diabetic (1), the cost of caring for dia- pean patients tend to have the lowest and possibly cardiovascular mortality in proteinuric IDDM patients significantly (14). Preventive measures before the onof clinical proteinuria clearly are reset FROM THE UNIT FOR METABOLIC MEDICINE, UNITED MEDICAL AND DENTAL SCHOOLS, GUY'S HOSPITAL, quired. LONDON, UNITED KINGDOM.

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ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO J. YIP-MESSENT, MB, UNIT FOR METABOLIC MEDICINE, 4TH FLOOR, HUNT'S HOUSE, GUY'S HOSPITAL, ST. THOMAS ST., LONDON SE1 9RT, U K

ESRF, END-STAGE RENAL FAILURE; IDDM, INSULIN-DEPENDENT DIABETES MELLITUS; CVD, CARDIOVASCULAR DISEASE; BP, BLOOD PRESSURE; NIDDM, NON-INSULIN-DEPENDENT DIABETES MELLITUS; GFR, GLOMERULAR FILTRATION RATE; A E R , ALBUMIN EXCRETION RATE; C S I I , CONTINUOUS SUBCUTANEOUS INSULIN INFUSION; CIT, CONVENTIONAL INSULIN THERAPY; ACE, ANGIOTENSIN-CONVERTING ENZYME; A C E I , ANGIOTENSIN-CONVERTING ENZYME INHIBITOR; S M C , SMOOTH MUSCLE CELL; L P D , LOW-PROTEIN DIET; VPD, VEGETABLE PROTEIN DIET; PGE, PROSTAGLANDIN; N A - L I CT, SODIUM-LITHIUM COUNTERTRANSPORT; RBC, RED BLOOD CELL; CV, COEFFICIENT OF VARIATION; BMT, BASEMENT MEMBRANE THICKNESS; E I P A , ETHYLISOPROPYLAMILORIDE.

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MICROALBUMINURIA— Approximately 20% of IDDM and 25% of NIDDM patients with urine negative to Albustix test excrete higher than normal amounts of albumin in their urine ( 1 5 17). This subclinical elevation of urinary AER has been termed microalbuminuria and is defined conventionally as AER between 30-300 mg/24 h. The signifi-

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ASSOCIATIONS OF MICROALBUMINURIA— Several

543210

NIDDM

IDDM

with microalbuminuria

Figure 1—Relative risk of cardiovascular mortality in microalbuminuric NIDDM and IDDM patients.

cance of microalbuminuria was first described in a 14-yr follow-up study of 63 IDDM patients in which those patients with microalbuminuria were —20 times more likely to develop clinical proteinuria than patients with normoalbuminuria (18). This observation was confirmed later by three other medium-term (6-10 yr) longitudinal studies (19-21). When all studies were combined involving 200 patients, for 1876 patient-yr of observation, microalbumiuria had a predictive power of >80%. Recently, in a reanalysis of our original cohort after a 23-yr follow-up, microalbuminuria emerged as a significant predictor of premature cardiovascular mortality, conferring a relative risk of 2.9 (22). In NIDDM, retrospective and prospective studies have shown that microalbuminuria is not only a predictor for proteinuria (23), but also a prognostic indicator of early mortality, mostly from CVD (23-25). Figure 1 summarizes the relative risk for cardiovascular mortality in both NIDDM and IDDM patients with microalbuminuria. Moreover, microalbuminuria has been predictive of cardiovascular mortality in middle-aged and elderly nondiabetic subjects (2628). Preliminary cross-sectional data suggest that the association between microalbuminuria and risk factors for CVD is also true for patients with essential hypertension (28,29).

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studies have described positive associations between microalbuminuria and risk factors for renal and atherosclerotic disease. Dyslipidemia, in the past considered primarily a consequence of advanced renal disease, has been described increasingly in both IDDM and NIDDM patients with microalbuminuria. Elevated levels of total and very-low-density lipoprotein triglycerides, total and lowdensity lipoprotein-cholesterol, apolipoprotein B, and reduced levels of highdensity lipoprotein 2 cholesterol have been found (30). More recently, lipoprotein (a), which is believed to be an independent risk factor for atherosclerosis in the general population, has been shown to be elevated in microalbuminuric IDDM patients by some researchers (31). In addition, an increased level of plasma fibrinogen, another independent risk factor for macrovascular disease, also has been documented in this group of patients. Such atherogenic lipid profiles may be important contributors to the excess cardiovascular mortality described in patients with microalbuminuria. In IDDM patients with microalbuminuria, an increase in whole-body transcapillary escape of albumin has been described (32). In studies in diabetic animals, the increased albumin leakage has been associated with an enhanced intravascular permeation of protein (33). This hyperpermeability of both small and large vessels may favor penetration into the arterial wall of other substances, such as lipoproteins. Therefore, binding to specific apolipoprotein receptors on macrophages, SMCs, and fibroblasts may result in acceleration of the proliferative process, leading to accelerated formation of atherosclerotic plaque. A consistent association has been reported by several researchers between microalbuminuria and higher levels of arterial pressure. The rise in arterial pressure often still falls within the accepted normal range, but, on average, microalbuminuric patients display BP values

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that are about 10 mmHg above that of age-, sex-, and duration-matched IDDM patients with normoalbuminuria (34). The relation to BP is independent of other variables, such as blood glucose control. Furthermore, changes in BP have been shown to be correlated positively with changes in AER in a 2-yr prospective study (35). Poorer blood glucose control is another independent association of microalbuminuria (34). Preliminary studies in both NIDDM (L. Groop et al., unpublished observations, 1991) and IDDM patients 0- Messent et al., unpublished observations, 1992) with microalbuminuria suggest that the metabolic basis for this phenomenon is a reduced sensitivity to insulin. Renal biopsy studies in microalbuminuric IDDM patients have revealed that significant glomerular abnormalities are already discernible at this stage, although the vast majority of patients still enjoy a normal, or even supranormal GFR (36). Thickening of glomerular basement membrane, expansion of mesangial volume, and increased mesangial matrix volume fraction all have been reported (39) (Table 1). The more marked lesions tend to occur in those microalbuminuric patients with elevated BP and modest reduction in creatinine clearance (39). Microalbuminuria is extremely uncommon in the first 5 yr (40) after diabetes onset and in children < 15 yr of age, supporting the view that microalbuminuria is an early indicator of glomerular disease rather than a marker of susceptibility to it. INTERVENTION STRATEGIES — Aggregation of risk factors for renal disease and CVD occurs early in the course of diabetes in a subset of patients and predates the onset of established nephropathy. Microalbuminuria appears to be responsive to treatment and, in recent years, many studies have been conducted on the effectiveness of postprimary intervention measures in arresting or delaying the progression from

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nephropathy

Table 1—Structural abnormalities normoalbuminuria PATIENTS (N) MiCROALBUMINURIC (6) NORMOALBUMINURIC (10)

in IDDM patients

BMT

(NM)

571 (CV0.12)* 442 (CV 0.25)*

with microalbuminuria and

Vv MES/GLOM

Vv MAT/GLOM

0.31 (0.20)** 0.22 (0.14)**

0.17(0.25)** 0.11(0.24)**

Vv mes/glom, volume of mesangium as a fraction of glomerular volume; Vv mat/glom, volume of mesangial matrix as a fraction of glomerular volume. *P < 0.05. **P< 0.01.

microalbuminuria to established nephropathy. BLOOD GLUCOSE CONTROL — Blood glucose control definitely is a determinant of diabetic renal disease, but once overt nephropathy has developed, the restoration of near-normoglycemia does not appear to retard progression to renal failure (41). More encouraging results have come from studies of strict metabolic control in IDDM patients with microalbuminuria. Both short-term (42) and medium-term controlled studies (43) demonstrated that tight glucose control using CS1I therapy was effective in reducing AER in microalbuminuric IDDM patients compared with patients on CIT. The beneficial effect of strict glucose control was confirmed by longer term studies (35), which showed an arrested progression of microalbuminuria in patients receiving intensified insulin therapy. In one study, 28% of microalbuminuric patients treated with CIT progressed to overt clinical proteinuria over 2 yr. By contrast, overt nephropathy did not develop in any of the patients receiving CSI1. When these patients were restudied after 6 yr, this difference in progression still persisted (28 vs. 6%), despite the fact that over the last 3 yr of observation, blood glucose control was similar between the two groups (CSII vs. CIT: HbAlc 8.2 ± 1.2 vs. 8.7 ± 1.3%), as was BP (42). Patients with AER < 70 (xg/min showed no progression to clinical proteinuria independent of their treatment allocations. Intensified insulin

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therapy with CSII was accompanied by a reduction of GFR within the normal range, more hypoglycemic episodes, and an increased risk of ketoacidosis. These results suggest that strict blood glucose control may have a renal protective effect, but also highlight some of the risks of this type of intervention approach. BP CONTROL— In IDDM patients with established nephropathy, reduction of elevated BP has been demonstrated in several studies to slow the rate of loss of GFR and check the increasing albuminuria (45-47). A variety of antihypertensive agents were used in these trials, including ACEI. This class of drugs has received special attention because of its supposedly specific renal protective effect (48-50) and has been used extensively to treat microalbuminuric patients. In a placebo-controlled, 1-yr study, microalbuminuric IDDM patients receiving enalapril showed significantly lower BP and a lower rate of progression of AER (51). These results were confirmed by a 4-yr randomized placebo-controlled trial in which captopril was shown to be effective in reducing AER and postponing the development of clinical proteinuria in normotensive microalbuminuric IDDM patients, independently of a reduction in systemic BP (52). The findings of this study appear to support the evidence from animal models of diabetic renal disease that ACE inhibition may lower intraglomerular pressure, independently of systemic pressure changes (48). However, in another study comparing

perindopril to nifedipine treatment in microalbuminuric IDDM patients with and without hypertension, only the patients with hypertension showed a significant improvement in AER, which was associated with a reduction in BP whatever the mode of antihypertensive treatment (53). In normotensive patients, the effect was less clear, with mean BP falling by only 5 mmHg and a nonsignificant reduction in AER. However, on withdrawal of antihypertensive medication, be it with ACEIs or calcium channel blockers, both the normotensive and hypertensive patients displayed a significant rise in AER. Some evidence shows that in addition to lowering intraglomerular pressure, ACEI may improve glomerular selectivity properties. Studies using different experimental designs have demonstrated that treatment of proteinuric diabetic patients with ACEI significantly reduces the augmented clearance of large-sized neutral dextrans without any measurable change of renal hemodynamics and independently of systemic BP changes (49,54). ACEIs may possess other properties that make them particularly suitable for the treatment and prevention of diabetic renal disease. These specifically concern their influence on insulin metabolism and cell growth. In both IDDM and NIDDM patients, ACEIs have been suggested to improve insulin sensitivity (55). The changes are, however, small, and considerable controversy still surrounds this topic, with conflicting results reported by various groups of researchers (56). Angiotensin II has been shown to stimulate DNA and protein synthesis in cardiovascular tissue and induce hypertrophy in cultured rat and human aortic SMCs in the presence of serum in vitro (57,58). ACE inhibition was effective in preventing increases in aortic SMC content and medial SMC weight in the spontaneous hypertensive rat; and in decreasing wall-to-lumen ratio, myocardial wall hypertrophy, and cross-sectional wall area of aortas and arterioles in both the hypertensive and

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normotensive rats (59,60). Moreover in the spontaneous hypertensive rat, nonantihypertensive doses of lisinopril have been shown to repair the myocardial fibrosis that occurs in this model (61). In IDDM patients with microalbuminuria, treatment with ACEI reportedly has reduced left ventricular hypertrophy (62). In the kidney, administration of ACEIs in rats from an early stage of life resulted in a marked attenuation of maturational growth of glomerular structure and function, without interference of somatic growth (63). Chronic administration of ACEIs in subtotally nephrectomized animals, on the other hand, not only ameliorates the development of sclerosis, but also the marked hypertrophy that precedes sclerosis (64).

LPDS OR VPDS— In IDDM patients with clinical proteinuria, reduction of animal protein in the diet to —0.6 g/kg body wt/day significantly slowed the rate of GFR decline over an average follow-up period of 3 and 5 yr (65,66). The effects of the LPD were independent of BP, but the response was heterogenous, with some patients showing no improvements in the rate of disease progression. In microalbuminuric IDDM patients, restriction of dietary protein by the same amount has lowered AER over the short term (67). Whether it actually delays the onset of clinical proteinuria remains to be investigated. This degree of dietary protein restriction seems to have no long-term detrimental effects on nutritional status. Because compliance with LPD often proves difficult, substituting vegetable for animal protein is receiving much attention. In one study involving healthy, nondiabetic control subjects, a VPD with a normal protein content (~ 1 g/kg body wt/day) induced similar renal hemodynamic changes, like those obtained by LPD (68). If the ongoing studies in micro- and macroalbuminuric patients confirm the efficacy of VPD, it would be possible in the future to design diets that, while maintaining a normal

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total protein content, might prove more acceptable to patients. The mechanism of action of LPD and VPD in ameliorating renal function is not understood fully, but appears to implicate the intrarenal synthesis of PGEs (69,70) and kinin (71), and possibly an indirect effect of these mediators on insulin sensitivity (72). TRANSITION FROM NORMOALBUMINURIA TO MICROALBUMINURIA— Although results from postprimary intervention studies are encouraging, no evidence to date measures which devices are successful in reducing microalbuminuria and will lead to an amelioration of the abnormal glomerular morphology already detectable in these patients and prevent ESRF. It is, therefore, important to understand the factors involved in the transition from normoalbuminuria to microalbuminuria so that effective primary preventive strategies can be implemented. In a U.K. multicenter trial, 148 normoalbuminuric, nonhypertensive IDDM patients with an average diabetes duration of 14 yr were recruited between 1984-86 and followed-up in a prospective study (73). After 4 yr, 11 patients developed persistent microalbuminuria (AER > 30 |xg/min), giving a cumulative frequency of 9%. One hundred and three remained persistently normoalbuminuric, and 23 exhibited intermittent microalbuminuria. The three groups of patients were similar in age, duration of diabetes, and body mass index. The progressors already displayed significantly higher baseline systolic and diastolic BP, AER, and poorer metabolic control than those patients who remained persistently normoalbuminuric. Among the progressors, a significantly higher proportion smoked than in the nonprogressors. In a multiple regression analysis, initial mean blood pressure, AER, and a positive history of smoking emerged as significant determinants of persistent microalbuminuria. These results suggest that against a

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background of poor glucose control, which may initially increase AER, smoking and an early rise of arterial pressure are implicated in the transition from normoalbuminuria to microalbuminuria in IDDM patients. Furthermore, elevated arterial pressure and AER appear to develop in parallel in these subjects at risk for diabetic renal disease. However, it remains to be resolved whether patients who progress to persistent microalbuminuria started off with an initial AER in the upper distribution of the normal range or simply were individuals who advanced at a much faster rate because of a predisposition to higher BP. The possibility of a vascular hyperpermeable trait in the groups of progressors remains to be investigated by long-term, follow-up studies of short-term IDDM patients. Cigarette smoking has been demonstrated previously in cross-sectional studies to be associated with microalbuminuria (74), but the mechanisms of the relationship between smoking and microalbuminuria remain to be elucidated. Mathiesen et al. (75) reported, in a 5-yr follow-up study of 205 normoalbuminuric IDDM patients, progression to microalbuminuria in 15 patients. Poor blood glucose control was the most significant predictor of subsequent development of persistent microalbuminuria, and the rise in AER preceded the increase in systemic BP by at least 2 yr in the progressors. The discrepancies between the U.K. and the Danish studies may lie in the study design. In the U.K. study, all measurements were collected every 6 mo, with BP measured by a standardized technique to the nearest 2 mmHg by a research registrar in each participating center. In the Danish study, urinary AERs were collected more frequently and at different times than GHb and BP readings. Furthermore, BP was measured by different clinic doctors only once a year and recorded to the nearest 5 mmHg, thus potentially introducing important observer variation and lack of precision. Small, albeit significant,

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changes in BP could have been overlooked. GLOMERULAR HYPERFILTRATION— Another factor that has been suggested as a prognostic indicator of diabetic renal disease preceding the development of microalbuminuria is glomerular hyperfiltration (76). Animal studies suggest that hemodynamic determinants of glomerular hyperfiltration may contribute significantly to glomerulopathy in diabetes (77,78). The role of glomerular hyperfiltration in the pathogenesis of human diabetic nephropathy remains controversial. In an 18-yr follow-up study of 29 IDDM patients, no association between increased AER and initial glomerular hyperfiltration was demonstrated (79). In another study, the effect of long-standing glomerular hyperfiltration was investigated in 29 subjects, including three IDDM patients with single kidneys (80). The authors concluded that long-standing pronounced hyperfiltration had no detectable harmful effects on kidney function. In an ongoing British casecontrolled study of nonhypertensive, nonproteinuric IDDM patients, after 8 yr, subjects with initial glomerular hyperfiltration did not exhibit higher mean AER, BP, or lower GFR than the normofiltering control subjects (81). On the contrary, in a 13-yr retrospective study of a smaller, selected group of proteinuric IDDM patients (76) and in an 8-yr prospective study of nonproteinuric Swedish adolescent IDDM patients, initial glomerular hyperfiltration was associated significantly with the development of micro- or macroalbuminuria. Hyperfiltration is related to the degree of blood glucose control, and intensified insulin treatment reduces GFR toward normal levels (83-85). Improvement in metabolic control has been reported by some, but not all, researchers to be effective also in decreasing renal size over a medium-term period ( 8 5 87). Excess renal production of PGEs and kinins has been proposed as an im-

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portant mediator of glomerular hyperfiltration (70,88). Administration of PGE inhibitors has been shown by some, but not all, authors to reduce GFR in hyperfiltering IDDM patients (89,90). In the animal model, treatment with a kallikrein inhibitor also lowers the GFR. A similar effect on glomerular hyperfiltration is obtained by a short course of LPD in diabetic patients (91). In conclusion, the predictive value of glomerular hyperfiltration remains to be established, and whether a reduction of supranormal GFR by whatever means confers any longterm renal benefit is unknown.

LIPID DISTURBANCES— Dyslip idemia is documented early in the course of diabetic renal disease, but whether it actually plays a role in its pathogenesis is unknown. In the obese Zucker rat, hypertriglyceridemia precedes the development of proteinuria and glomerular injury, and the levels of lipids increase in parallel with the rise in urinary albumin excretion (92). Lowering of the lipid levels has been found to protect against renal sclerosis without affecting renal hemodynamics in these animals (92). Cholesterol feeding resulted in an increased in serum cholesterol and urinary albumin excretion in both the spontaneous hypertensive and the Wistar-Kyoto rats (93). In humans, however, hyperlipidemia per se is not associated with glomerular disease in the general population, and its role in the pathogenesis of diabetic kidney disease remains unknown (94). Dyslipidemia may be implicated indirectly in the development of diabetic renal disease by causing a disturbance of intrarenal eicosanoid production and thus an imbalance between vasoconstrictive and vasodilatory PGEs. DETECTION OF SUSCEPTIBILITY TO DIABETIC NEPHROPATHY— An aggregation of risk factors for the development of diabetic renal disease and CVD is already apparent at the stage of microalbuminuria and may even predate its onset. Patients with microalbu-

minuria already have significantly more severe degrees of morphological damage than their normoalbuminuric counterparts. Although the results of postprimary intervention measures are encouraging, the long-term benefits remain to be proven. This argues for an improvement in our ability to predict the subset of patients at risk for diabetic renal disease and CVD at onset of diabetes mellitus. FAMILY HISTORY OF HYPERTENSION AND CVD — Clustering of diabetic nephropathy in the family was first reported by Seaquist et al. (95) and later confirmed by BorchJohnsen et al. (96). In IDDM, 82% of diabetic siblings of probands with diabetic nephropathy have evidence of nephropathy, compared with only 17% of diabetic siblings of probands without nephropathy—a significant fivefold difference (95). A familial influence in the development of nephropathy has been described similarly in Pima Indians with NIDDM (97). These findings are consistent with the postulate that inherited factors play an important role in determining susceptibility to diabetic nephropathy, but do not provide insight into the nature of these factors. Viberti et al. (98), and later Krolewski et al. (99), both reported higher levels of arterial pressure in parents of IDDM patients with elevated AER. More recently, in a case-control study, Barzily et al. (100) showed that patients with established nephropathy not only had a greater prevalence of positive history of parental hypertension, but also higher mean arterial pressure during adolescence. Follow-up data in this study suggested a relative risk of developing overt nephropathy of 3.8, if one or both parents were hypertensive. Together, these studies strongly suggest that a family history of hypertension confers an increased susceptibility to the development of proteinuria in some groups of diabetic patients. A relationship between parental and offspring BP was not found by Jensen et al. (101),

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Studies of a cell membrane sodium transport system, the Na-Li CT, the activity of which is largely determined genetically recently have contributed to further defining some of the potentially inherited susceptibility to diabetic renal disease and CVD. Elevated Na-Li CT activity, a recognized marker of essential hypertension (104) and its associated cardiovascular complications, has been described in IDDM patients with microalbuminuria and clinical proteinuria DN CVD HT (99,101,105,106). The hereditary nature of this phenomenon has been confirmed Figure 2—Risk of developing diabetic by some, although not all, family studies nephropathy in IDDM patients with a positive showing a higher Na-Li CT activity in family history of diabetic nephropathy in the parents of proteinuric diabetic patients siblings (DN), cardiovascular disease (CVD), or compared with parents of diabetic pahypertension in parents (HT). tients without proteinuria (101,107), and by a study that demonstrated a close but this was most likely attributed to the correlation between the Na-Li CT rates of selection of probands and the control identical twins discordant for IDDM (108). group (100). Hypertension is one of the major In a cross-sectional investigation risk factors of the excess CVD observed of IDDM patients by Lopes de Faria et al. in IDDM patients with proteinuria. (107), the rates of Na-Li CT were found Whether familial aggregation of CVD oc- to be associated with AER and arterial curs in diabetic patients with nephrop- BP. The activity of this membrane transathy was explored recently in a study of port system emerged as the strongest deparental cardiovascular morbidity and terminant of proteinuria, followed by armortality of IDDM patients with and terial pressure, duration of diabetes, and without proteinuria (103). The preva- blood glucose control. A raised Na-Li CT lence of CVD was significantly greater in activity (>0.41 mM RBC/h) conferred a parents of proteinuric patients (31 vs. fourfold increased risk of developing 14%, P < 0.01). CVD as a direct cause of proteinuria. A significant interaction bedeath was significantly higher in parents tween rates of Na-Li CT and blood gluof patients with nephropathy (40 vs. cose control as determinants of protein22%, P < 0.03). Among the diabetic pa- uria was found; the highest frequency of tients with nephropathy, a positive fam- proteinuria occurred in those patients ily history of CVD was significantly more with GHb above the median and with a prevalent in those who had suffered a Na-Li CT activity above the normal range cardiovascular event (odds ratio 6.2, (