Elisabeth R. Mathiesen

The natural course of microalbuminuria in insulin-dependent diabetes : a 10-year prospective study

The purpose of this study was to describe the clinical course in patients followed right from the onset of microalbuminuria to the development of diabetic nephropathy. A 10‐year prospective follow‐up of 209 consecutive normotensive insulin‐dependent diabetic patients with normal urinary albumin excretion (UAE <30 mg 24 h−1), age 34 (18–50) years and duration of diabetes 17 (10–30) years was performed. Twenty‐four‐hour urinary albumin excretion was measured every 4 months, glycated haemoglobin and supine blood pressure was measured annually. Two‐hundred (96%) patients completed 10 (range 5–10) years follow‐up. Twenty‐nine (15%) patients developed persistent microalbuminuria (UAE 30–300 mg 24 h−1). Eight of these have progressed to nephropathy and one had died of diabetic nephropathy. Multiple stepwise logistic regression analysis demonstrated baseline urinary albumin excretion (p = 0.0016) and glycated haemoglobin (p = 0.0014) but not blood pressure as predictors of development of microalbuminuria within the following 10 years. The median annual increase in urinary albumin excretion was 27 (range 17–65)% in the 29 patients developing microalbuminuria. The median duration from onset of microalbuminuria to development of nephropathy was 7 years. The prevalence of patients receiving antihypertensive treatment (BP > 140/90 mmHg) increased from 10% at onset of microalbuminuria to 45% 4 years after onset of microalbuminuria. The prevalence of patients with proliferative retinopathy increased from 7% at onset of microalbuminuria to 28% 4 years after onset of microalbuminuria. The incidence of persistent microalbuminuria in normotensive insulin‐dependent diabetic patients is 2% per year, and development of persistent microalbuminuria is a strong predictor of overt nephropathy. Development of hypertension is frequent in the early course of microalbuminuria and treatment modalities for normotensive patients with microalbuminuria are urgently needed.

Effective Antihypertensive Treatment Postpones Renal Insufficiency in Diabetic Nephropathy

The effect of long-term, aggressive, antihypertensive treatment on kidney function in diabetic nephropathy was studied prospectively in 11 insulin-dependent diabetic patients (mean age, 30 years). Renal function was assessed every 4 months by measurement of glomerular filtration rate (GFR) (single-bolus 51Cr-EDTA technique) and by albuminuria (radial immunodiffusion). During the median pretreatment period of 2.4 years (range, 1.9 to 5.5 years), the GFR decreased significantly and albuminuria and the arterial blood pressure increased significantly. During the 9.7-year (range, 2.8 to 10.4 year) period of antihypertensive treatment with metoprolol, hydralazine, and furosemide, the arterial blood pressure decreased from 143/96 mm Hg to 130/84 mm Hg and albuminuria decreased from 1,038 micrograms/min to 547 micrograms/min. The rate of decline in GFR decreased from 10.7 mL/min/yr (range, 5.3 to 17.5 mL/min/yr) before treatment to 2.5 mL/min/yr (range, 0.5 to 4.8 mL/min/yr) during treatment. The rate of decline in GFR is significantly smaller during the last 6 years compared with the first 3 years in patients who received long-term antihypertensive treatment (> or = 9 years). One patient died from acute myocardial infarction (GFR, 46 mL/min/1.73 m2). Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy.

Pregnancy and progression of diabetic nephropathy.

Abstract.Aims/hypothesis: Pregnancy could damage kidney function in diabetic nephropathy. We investigated the long-term impact of pregnancy on the progression of diabetic nephropathy. Methods: Our observational follow-up study included all women patients with Type I (insulin-dependent) diabetes mellitus who developed diabetic nephropathy between 1970 and 1989 at Steno Diabetes Center (n = 93). Follow-up lasted 16 years (range 3–28) from the onset of diabetic nephropathy until death or the year 2000. A total of 26 women became pregnant after the onset of diabetic nephropathy (group A). The remaining 67 served as control subjects (group B). All patients received aggressive antihypertensive treatment (blood pressure goal < 140/90 mmHg). Results: The two groups were comparable at onset of diabetic nephropathy regarding blood pressure, albuminuria, s-cholesterol, smoking, retinopathy and s-creatinine (mean 79(SD 23) μmol/l). The slopes of 1/s-creatinine (1000 · l ·μmol–1· year–1) during the whole observation period were –0.39(0.40) compared with –0.41(0.70) (group A vs B – NS). The slopes of 1/s-creatinine before and after pregnancy were similar. Decline in creatinine clearance (ml/min/yr) was 3.2 (3.4) compared with 3.2 (5.1) (group A vs B -NS). At the end of follow-up, 35 % (95 %-CI:17–53) of the pregnant women had died and 19 % (7–39) had reached end stage renal disease compared to 34 % (23–45) and 24 %(14–34) of the control subjects, respectively(NS). Group A and B had similar blood pressure levels during the whole observation period: 136(13)/83(7) vs 139 (14)/85(7) mmHg (NS). Conclusion/interpretation: Pregnancy has no adverse long-term impact on kidney function and survival in Type I diabetic patients with well-preserved kidney function (normal serum creatinine) suffering from diabetic nephropathy. [Diabetologia (2002) 45: 36–41]

Possible effect of angiotensin-converting enzyme inhibition on glomerular charge selectivity

Angiotensin-converting enzyme (ACE) inhibitors are known to reduce urinary albumin excretion (UAE) in diabetic patients. Animal studies have shown that, besides diminishing the glomerular capillary pressure, ACE inhibitors might reduce albuminuria by influencing glomerular charge selectivity through glomerular preservation of heparan sulphate proteoglycan. In humans, an indirect measurement of glomerular charge selectivity can be obtained by calculating the glomerular charge selectivity index (SI), a clearance ratio of IgG/IgG4, two identically sized but differently charged molecules. The aim of the present study was to evaluate the effect of ACE inhibition on charge selectivity by comparing SI in type I (insulin-dependent) diabetic patients with microalbuminuria after 6 years of treatment either with or without captopril. Thirty-five of 45 patients participating in a prospective randomized study evaluating the effect of captopril in preventing the development of diabetic nephropathy were included in the present study, 17 being treated with captopril, 18 left as untreated controls. The selectivity index was calculated after measuring s-IgG, u-IgG, s-IgG4, and u-IgG4. The results demonstrated a higher selectivity index in the captopril-treated group [1.21 (0.51-1.94) median (range)] compared to the control group [0.94 (0.31-1.87)], however, the difference was not statistically significant (p = 0.16). A negative correlation between the selectivity index and UAE was demonstrated in the captopril-treated group (r = -0.77; p = 0.0004), whereas the correlation in the control group did not reach statistical significance (r = -0.3; p = 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention and treatment of diabetic nephropathy with blood pressure lowering drugs

Summary: Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 h), a relentless decline in glomerular filtration rate (GFR), and raised arterial blood pressure. the prevalence of abnormal elevated albumin excretion rate (>30 mg/24 h) is approximately 40% in insulin‐dependent (IDDM) and non‐insulin‐dependent (NIDDM) patients. Diabetes has become the leading cause of end‐stage renal failure in the United States of America and Japan and it remains the second leading cause in Europe. Patients suffering from diabetic nephropathy have an enormous increase in morbidity and mortality from cardiovascular disease in addition to renal death. Elevated blood pressure is an early and frequent phenomenon and furthermore accelerates the course of diabetic nephropathy. Studies in humans suggest that angiotensin‐converting enzyme (ACE) inhibitors postpone and may even prevent progression to clinical overt diabetic nephropathy in normotensive IDDM and NIDDM patients with persistent microalbuminuria. Conventional antihypertensive therapy and ACE inhibition usually combined with a diuretic reduces albuminuria and postpones renal insufficiency in hypertensive IDDM patients with overt nephropathy. A more beneficial effect on the rate of decline in glomerular filtration rate has been demonstrated by ACE inhibitors compared to conventional antihypertensive treatment in IDDM patients with diabetic nephropathy and reduced kidney function (serum creatinine >133 mmol/L). These findings suggest that ACE inhibition causes renal protection (i.e. a beneficial effect on kidney function [structure] above and beyond what would be expected from blood pressure lowering effect alone). Finally, it should be stressed that ACE inhibition and conventional antihypertensive treatment postpone end‐stage renal failure and improve survival in diabetic nephropathy.

Acute Modulation of Renal Function in Microalbuminuric and Macroalbuminuric Insulin-Dependent Diabetic Patients

Recently, the impact on kidney function of hemodynamic factors (e.g., blood pressure), metabolic variables (e.g., blood glucose), vasoactive hormones (e.g., prostaglandins, angiotensin II), and protein loading or restriction has been elucidated in diabetic animals and man. This chapter reviews the influence of blood pressure, prostaglandins, and angiotensin II on urinary albumin excretion and glomerular filtration rate (GFR) in insulin-dependent diabetes mellitus (IDDM) patients with incipient and overt diabetic nephropathy.