Mark E. Cooper

Progressive Decline in Renal Function in Diabetic Patients With and Without Albuminuria

This study describes patterns of progression of albuminuria and renal function in a subgroup of 40 patients from a total cohort of 211 diabetic patients (118 type I, 93 type II) followed over a period of 8–14 years. Forty patients (18 with type I diabetes, 22 with type II diabetes) showed progressive increases in albumin excretion rate (AER) and/or decreases in creatinine clearance (CC) during the study period. Of these, AER alone increased in 15 patients, AER increased and CC decreased in 13 patients, and CC alone decreased in 12 patients, with a similar distribution of type I and type II diabetic patients in each group. Of the 28 patients who showed an increase in albuminuria, AER increased at an annual rate of 30–40%, resulting in a 4- to 8-fold increase in AER to > 20 μg/min during the study. Of the 25 patients who showed a decrease in renal function, CC decreased at an annual rate of 4–5 ml/min, resulting in an approximate halving of CC to < 90 ml/min during the study. The rate of fall in CC was not related to the presence or absence of concomitant increases in albuminuria. However, a significant preponderance of women in the group showed a decline in CC alone. The decline in CC was associated with an increase in plasma creatinine as well as a progressive decrease in urinary creatinine excretion, but the underlying mechanisms remain unexplained. These data support the concept that a subgroup of diabetic patients may show a decline in renal function in the absence of significant increases in AER. Additional functional and structural data will be needed to determine if these patients have diabetic nephropathy. However, this study does suggest that albuminuria alone may not predict renal functional changes in all diabetic patients.

Enalapril retards glomerular basement membrane thickening and albuminuria in the diabetic rat

SummaryThis study has evaluated the effects of the angiotensin converting enzyme inhibitor Enalapril on glomerular ultrastructure and albuminuria in normotensive and hypertensive diabetic rats. Streptozotocin-diabetes was induced in Wistar Kyoto and spontaneously hypertensive rats. Enalapril was administered in drinking water in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Enalapril therapy prevented an increase in glomerular basement membrane thickness in diabetic normotensive, control hypertensive and diabetic hypertensive rats without any significant effect on fractional mesangial volume. Enalapril decreased albuminuria in diabetic normotensive, control hypertensive and diabetic hypertensive rats. Thus, enalapril retards the development of glomerular basement membrane thickening and albuminuria in the rat, in the presence or absence of hypertension.

Adrenomedullin and calcitonin gene-related peptide in the rat isolated kidney and in the anaesthetised rat: in vitro and in vivo effects.

The effects of adrenomedullin and calcitonin gene-related peptide (CGRP) were compared in the rat isolated perfused kidney and in the anaesthetised rat. Adrenomedullin and CGRP both elicited concentration-dependent vasodilator responses from perfused kidneys (adrenomedullin was less potent than CGRP). These responses were blocked by CGRP-(8-37) (1 microM). Adrenomedullin and CGRP elicited dose-dependent hypotension in anaesthetised rats (adrenomedullin was less potent than CGRP). The hypotensive responses to CGRP, but not those to adrenomedullin, were antagonized by CGRP-(8-37) (12 nmol/kg/min). These studies indicate that the in vivo response to adrenomedullin may be mediated through CGRP-(8-37) insensitive receptors.

Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in Type 2 (non-insulin-dependent) and Type 1 (insulin-dependent) diabetic patients

SummaryThis study has explored the temporal relationship between apoprotein(a), blood pressure and albuminuria over a mean interval of 11 years in a cohort of 107 diabetic patients of whom 26 (14 Type 2 (non-insulin-dependent), 12 Type 1 (insulin-dependent) had progressively increasing albuminuria (‘progressors’). In Type 2 diabetic patients, no significant differences were noted for HbA1, blood pressure, creatinine clearance or serum lipids between progressors and non-progressors. In Type 1 diabetic patients, final systolic and diastolic blood pressures were higher in progressors compared with non-progressors and progressors showed impairment of renal function in association with a rise in blood pressure at the macroalbuminuric stage. Initial apoprotein(a) levels were similar in progressors and non-progressors of either diabetes type. Apoprotein(a) levels increased exponentially with time in 12 of 14 Type 2 progressors but only in 5 of 12 Type 1 progressors (p<0.01). In Type 2 diabetic patients, the annual increase in apoprotein(a) levels was 9.1±2.4%, which was significantly greater than in non-progressors, 2.0±1.2% (p<0.01) and also exceeded the rates of increase of apoprotein(a) in progressors with Type 1 diabetes, 4.0±1.4%, (p<0.05). Apoprotein(a) levels correlated significantly with albuminuria in 8 of 14 Type 2 progressors but only in 3 of 12 Type 1 progressors (p<0.05). The rate of increase of apoprotein(a) levels was not related to mean HbA1, creatinine or creatinine clearance levels, or to albuminuria. The rate of rise of apoprotein(a) was not influenced by initial apoprotein(a) levels, suggesting that specific apoprotein(a) isoforms do not influence albuminuria-related increases in apoprotein(a). The data are consistent with the hypothesis that apoprotein(a) levels increase in response to albuminuria and may be part of a self-perpetuating process. This study also suggests that increases in apoprotein(a) levels commence during the microalbuminuria stage in diabetic patients, which is earlier than has been documented in non-diabetic proteinuria.

Complementary Effects of Pravastatin and Nicotinic Acid in the Treatment of Combined Hyperlipidaemia in Diabetic and Non-Diabetic Patients

Background: Given that treatment with a single drug is frequently unsuccessful in patients with combined hyperlipidaemia, there is a rationale for the study of regimens using drugs that have complementary therapeutic profiles. We therefore set out to compare the efficacy of a combined pravastatin and nicotinic acid regimen with higher dose monotherapy using either drug in patients with non-insulin-dependent diabetes and in non-diabetic patients with combined hyperlipidaemia. Methods: Forty-four patients with total-cholesterol levels of 6.5 mmol/l or higher and triglyceride levels of 2.5 mmol/l or above were randomly assigned to receive either pravastatin alone (40 mg/day) or nicotinic acid alone (1500 mg/day) for 12 weeks. At the end of this period, the participants received a combination of pravastatin (20 mg/day) and nicotinic acid (1000 mg/day) for a further 12 weeks. The lipid parameters measured included levels of total cholesterol, triglycerides, low-density-lipoprotein (LDL) cholesterol and high-density-lipoprotein (HDL) cholesterol. Results: Thirty-three patients (22 without and 11 with diabetes) completed the protocol. Monotherapy with pravastatin was more effective than that with nicotinic acid in reducing levels of total cholesterol (−24.9 versus −9.8%, P <0.001) and LDL cholesterol (−32.1 versus −16.9%, P <0.01), similar in reducing levels of triglyceride (−28.0 versus −31.8%, NS) and tended to be less effective in elevating levels of HDL cholesterol (+16.4 versus +30.8%, P = 0.06). Combination therapy was more effective than pravastatin monotherapy in reducing levels of triglyceride (−39.3 versus −28.0%, P <0.05) and elevating those of HDL cholesterol (+35.6 versus +16.4%, P <0.001) and was equally effective in reducing total-cholesterol (−22.3 versus −24.9%, NS) and LDL-cholesterol (−27.1 versus −32.1%, NS) levels. Combination therapy was more effective than nicotinic acid monotherapy in reducing levels of total cholesterol (−23.8 versus −9.8%, P < 0.001), triglyceride (−39.4 versus −31.8%, P <0.05) and LDL cholesterol (−35.7 versus −16.9%, P <0.05) and equally effective in elevating HDL-cholesterol levels (+33.6 versus +30.8%, NS). Diabetic and non-diabetic participants responded similarly to combination therapy. Eleven patients (25%) were withdrawn from the study: Nine as a result of nicotinic acid intolerance (flushing and nausea) and one through pravastatin intolerance (nausea); one patient died of a myocardial infarction. Combination therapy elevated glycosylated haemoglobin A1c levels in non-diabetic patients (5.5 to 5.8%, P <0.001); in diabetic patients, however, the observed rise (7.4 to 7.9%) was not statistically significant. Fasting plasma glucose levels, liver function tests and levels of creatine kinase or uric acid were unaffected by either monotherapy or by combination therapy, with the exception of an elevation of the glucose level in diabetic patients receiving nicotinic acid monotherapy. Conclusion: Pravastatin and nicotinic acid in a lower-dose combination are more effective than pravastatin alone in reducing levels of triglyceride and elevating those of HDL cholesterol and are more effective than nicotinic acid alone in reducing total-cholesterol, triglyceride and LDL-cholesterol levels. Combination therapy is equally effective in type-II diabetic and non-diabetic people. The complementary effects of the combination therapy on lipid levels suggest that this regimen should be considered as a therapeutic option in patients with combined hyperlipidaemia who tolerate the side effects of nicotinic acid.

Triphasic changes in selectivity with increasing proteinuria in type 1 and type 2 diabetes

Two indices of the selectivity of proteinuria, the immunoglobulin G (IgG)/albumin and the IgG/transferrin clearance ratios, were studied cross‐sectionally and serially over 7 years in a cohort of 52 Type 1 and 60 Type 2 diabetic patients without established diabetic nephropathy. In Type 1 and Type 2 diabetic patients with albuminuria <30 μg min−1, both protein clearance ratios were significantly higher than in 27 control subjects. As albuminuria increased, there was a decrease in both protein clearance ratios. However, at albumin clearances above 90 nl s−1 equivalent to albumin excretion rates of >250 μg min−1, a positive correlation was found in Type 2 diabetic patients between protein clearance ratios and albuminuria. In individual Type 1 and Type 2 diabetic patients with progressively increasing proteinuria, serial measurements of selectivity showed a decline in both protein clearance ratios with the onset of microalbuminuria. Episodes of transient microalbuminuria were also associated with a fall in the IgG/albumin clearance ratio. The results suggest that the selectivity of proteinuria undergoes a triphasic change with the development of diabetic nephropathy. In the first phase, proteinuria is non‐selective with IgG clearance equal to or exceeding transferrin or albumin clearance. As microalbuminuria develops, there is a progressive increase in selectivity reflecting the preferential excretion of transferrin and albumin compared with IgG. In later stages of nephropathy, as shown in Type 2 diabetic patients with macroalbuminuria, there is a return to non‐selective proteinuria.

Extracellular matrix and its interactions in the diabetic kidney: a molecular biological approach.

Increased extracellular matrix (ECM) is the ultrastructural hallmark of diabetic microangiopathy. Its accumulation within the kidney is directly linked to the clinical manifestations of diabetic nephropathy, namely proteinuria and declining renal function. The pathogenesis of ECM changes in diabetes is not well understood, but is likely to involve interaction between cells, growth factors, structural proteins, and cell receptors for these molecules. Molecular biological techniques may offer the necessary tools for gaining insight into the pathogenetic processes that eventually lead to renal failure in diabetes.

Lack of effect of gliclazide on early diabetic nephropathy and retinopathy: a two-year controlled study

This study has attempted to document a specific haemovascular action of gliclazide on the reversal of early diabetic microangiopathy. A prospective double-blind controlled study was performed over 2 years, comparing gliclazide versus placebo in insulin-treated and gliclazide versus glibenclamide in non-insulin-treated diabetic subjects, after a 1-year run-in period. Glycaemic control was not significantly different in gliclazide- and non-gliclazide-treated subjects before or after the commencement of active therapy. Following treatment with gliclazide in 17/32 insulin-treated and 8/17 non-insulin-treated subjects with Albustix-negative proteinuria, there was no difference in retinopathy score, total proteinuria or the renal clearance of creatinine, albumin, transferrin and immunoglobulin G. In the insulin-treated group, progression of retinopathy was observed in approximately one-third of subjects, but no parameter of proteinuria progressed over 2 years. Thus, this study did not detect a reversal of the parameters measured and does not support an action of gliclazide on diabetic microangiopathy, independent of its hypoglycaemic action.

Prediction of persistent microalbuminuria in patients with diabetes mellitus.

Persistent microalbuminuria [albumin excretion rate (AER): 30-300 micrograms/min] is predictive of clinical nephropathy in patients with insulin-dependent diabetes mellitus (IDDM) and cardiovascular mortality in addition to nephropathy in patients with non-insulin-dependent diabetes. The clinical significance of intermittent microalbuminuria, however, is unknown. We performed serial measurements of urinary albumin excretion at intervals of approximately 6 months in 139 diabetic patients who at entry did not have persistent microalbuminuria to determine whether intermittent microalbuminuria occurs more frequently in those patients who subsequently develop persistent microalbuminuria. The relative risk for the development of persistent microalbuminuria in diabetic patients with a greater proportion than 3 out of 20 determinations in the microalbuminuric range was 17.4 (95% confidence interval, 3.92-77.2) in those with IDDM and 2.78 (0.99-7.8) in those with non-insulin-dependent diabetes when compared with matched diabetic patients with fewer elevated measurements. These data suggest that frequent intermittent microalbuminuria predicts the future development of persistent microalbuminuria particularly in IDDM patients and that AER should be assessed by serial rather than single measurements.

Effects of aromatase inhibition with aminoglutethimide in men with benign prostatic hypertrophy [Poster 28]

Abstract Fourteen men with benign prostatic hypertrophy were treated with the aromatase inhibitor aminoglutethimide for periods of up to 3 months. LH, FSH and testosterone levels rose within one week and remained elevated, while estradiol levels decreased. Despite significant changes in these hormones there was no change in urine flow rates or prostatic size over the study period.