Terri J Allen

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.

Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat

Aims/hypothesisDiabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension.MethodStreptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2xa0mg/l), the AGE formation inhibitor, aminoguanidine (1xa0g/l) and a combination of both agents and were followed for 32 weeks.ResultsDiabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFβ1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine.Conclusion/interpretationThese findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury.

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.

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.

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.

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.

Natural history of early diabetic nephropathy: What are the effects of therapeutic intervention?

Several studies have shown that lowering of blood pressure slows the rate of progression of diabetic renal disease. Some placebo-controlled studies have also shown that angiotensin-converting enzyme (ACE) inhibitors decrease or stabilize albuminuria in incipient nephropathy and slow the rate of progression of advanced nephropathy. However, it is not yet clear if prolonged treatment with ACE inhibitors or with other agents exerts a specific renoprotective effect in incipient diabetic nephropathy. It is proposed that such an effect should be independent from changes in systemic blood pressure and should be characterized by amelioration of the rate of rise of albumin excretion rate (AER) and the rate of fall of glomerular filtration rate (GFR) and independence from changes in other parameters known to influence AER (glycemic control, protein intake, sodium intake). In addition, there should be evidence that the potentially reversible effects of therapeutic intervention on AER and GFR are translated to long-term changes in renal function and structure. This paper reviews the evidence on which the concept of renoprotection is based, with particular reference to choice of end points, heterogeneity of study groups, and complexities of the disease process, and relates this evidence to the natural history of nephropathy in type I and type II diabetes. Based on the above, an assessment is made of the comparative effects of ACE inhibitors and other antihypertensive agents on AER and GFR. It is suggested that longitudinal intra-individual analysis of both variables may be necessary in order to determine whether ACE inhibitors exert greater renoprotection than calcium channel blockers or other antihypertensive agents.