Eva Hommel

Effect of antihypertensive treatment on kidney function in diabetic nephropathy.

The effect of long term, aggressive antihypertensive treatment on kidney function in diabetic nephropathy was studied prospectively in 11 insulin dependent diabetics (mean age 30). During the mean pretreatment period of 32 (range 23-66) months the glomerular filtration rate decreased significantly and albuminuria and the arterial blood pressure increased significantly. During the 72 (range 32-91) month period of antihypertensive treatment the average arterial blood pressure fell from 143/96 mm Hg to 129/84 mm Hg and albuminuria decreased from 1038 micrograms/min to 504 micrograms/min. The rate of decline in the glomerular filtration rate decreased from 0.89 (range 0.44-1.46) ml/min/month before treatment to 0.22 (range 0.01-0.40) ml/min/month during treatment. The rate of decline in the glomerular filtration rate was significantly smaller during the second three years compared with the first three years in patients who received long term antihypertensive treatment (greater than or equal to 6 years). One patient died from acute myocardial infarction (glomerular filtration rate 46 ml/min/1.74 m2). Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy.

Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy.

STUDY OBJECTIVE--To assess whether long term inhibition of angiotensin converting enzyme with captopril and frusemide or bendrofluazide protects kidney function in diabetic nephropathy. DESIGN--Non-randomised controlled before-after trial of matched hypertensive insulin dependent diabetics with nephropathy treated with captopril and frusemide or bendrofluazide. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--Treatment group of 18 hypertensive insulin dependent diabetics with nephropathy (mean age 33), who had not been treated previously. Control group of 13 patients (mean age 32) fulfilling the same entry criteria from a prospective study. INTERVENTIONS--Treatment group was given daily captopril 37.5-100.0 mg and frusemide (mean) 98 mg (10 patients) or bendrofluazide (mean) 4 mg (seven). Treatment was continued for about two and a half years. Controls were not treated. END POINT--Measurement of arterial blood pressure, albuminuria, and glomerular filtration. MEASUREMENTS AND MAIN RESULTS--Baseline values were identical in treated and untreated groups respectively: mean blood pressure 146/93 (SE 3/1) mm Hg v 137/95 (2/1) mm Hg; geometric mean albuminuria 982 (antilog SE 1.2) micrograms/min v 936 (1.2) micrograms/min; and mean glomerular filtration rate 98 (SE 5) ml/min/1.73 m2 v 96 (6) ml/min/1.73 m2. Mean arterial blood pressure fell by 8.7 (1.3) mm Hg with captopril and rose by 6.6 (1.5) mm Hg in controls, (p less than 0.001); Albumin excretion decreased to 390 (1.1) micrograms/min with captopril and rose to 1367 (1.3) micrograms/min in controls (p less than 0.001). The rate of decrease in glomerular filtration rate was lower with captopril (5.8 (0.7) ml/year v 10.0 (1.3) ml/year) (p less than 0.01). Rate of fall in glomerular filtration rate and mean arterial blood pressure were significantly correlated (n = 31, r = 0.37, p less than 0.05). CONCLUSIONS--Captopril is a valuable new drug for treating hypertension in insulin dependent diabetics with nephropathy.

Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment.

SummaryDiabetic nephropathy is the main cause of increased mortality and morbidity in IDDM patients. The effect of antihypertensive treatment on the progression of the nephropathy is highly variable. The aim of this study was to evaluate putative predictors of the progression in diabetic nephropathy during long-term antihypertensive treatment. Eighteen hypertensive IDDM patients with diabetic nephropathy, who had not been treated previously, were followed during 3 years of treatment with captopril and frusemide or bendrofluazide. Glomerular filtration rate, arterial blood pressure, albuminuria and adjusted albuminuria were used as putative predictors of rate of decline in glomerular filtration. Fall rate in glomerular filtration rate was 4.6 (4.0) mlmhr-1 year-1 (mean (SD)) during treatment. Relative change in albuminuria (ratio of first year of treatment/baseline) and albuminuria during first year of treatment were significantly correlated to fall rate in glomerular filtration rate during 3 years of treatment (r = 0.73, p > 0.001) and (r = 0.60, p > 0.01), respectively. Arterial blood pressure and glomerular filtration rate measured at baseline, during first year of treatment or relative changes in these variables did not correlate with fall rate in glomerular filtration rate during 3 years of treatment. Haemoglobin Alc, serum-cholesterol, protein intake and sodium excretion remained unchanged during treatment, and were not correlated with loss of kidney function. Reduction in albuminuria during captopril treatment predicts an attenuated rate of decline in glomerular filtration rate in early diabetic nephropathy (glomerular filtration rate <70 ml· mirr-1 · 1.73 nr-2). The finding suggests a clinical application in monitoring the efficacy of antihypertensive treatment in early diabetic nephropathy.

Glomerular Structure and Function in Diabetic Nephropathy: Early to Advanced Stages

Kidney biopsies from 14 insulin-dependent diabetes mellitus patients with persistent albuminuria were studied by light and electron microscopy. In terms of kidney function, the patients spanned stages from early to advanced nephropathy. The clinical parameters were (ranges, with medians in parentheses) urinary albumin excretion (UAE) 158–5494 μg/min (1153 μg/min), glomerular filtration rate (GFR) 30–128 ml · min −1 · 1.73 m−2 (90 mh ml · min−1 · 1.73 m−2) and mean arterial blood pressure () 87–122 mmHg (109 mmHg). The severity of clinical nephropathy (UAE, GFR, and BP together) correlated with an index of the structural lesions (basement membrane [BM] thickness, mesangial expansion, and glomerular occlusion together; r = 0.62, 2P < 0.05). GFR compared with remnant surface of glomerular capillaries (filtration surface; FS) gave values of r = 0.72 and 2P = 0.004, and UAE compared with the percentage of the peripheral BM surface carrying fluffy loose intrinsic fine structure gave r = 0.62 and 2P = 0.02. BP per se did not correlate with structural parameters. The area of FS per open glomerulus did not decrease with increasing mesangial volume fraction, which indicates compensatory changes of the capillaries in early and advanced stages of glomerulopathy. In 7 patients with <10% occluded glomeruli, correlations between glomerular volume and the parameters of diabetic glomerulopathy (i.e., BM thickness and volume fractions of mesangium and mesangial matrix) failed to reach statistical significance. The actual glomerular volume, however, is a product of the individuals original glomerular volume, probably the early diabetic hypertrophy and modifying changes consequent to the development of glomerulopathy. Our study shows a correlation between the parameters of glomerular structural lesions and those of the functional abnormalities in diabetic nephropathy.

Impact of Arterial Blood Pressure and Albuminuria on the Progression of Diabetic Nephropathy in IDDM Patients

To evaluate the impact of systemic blood pressure and albuminuria on the progression of diabetic nephropathy, we followed 41 IDDM patients with persistent albuminuria (> 300 mg/24 h) by measuring glomerular filtration rate (51Cr-EDTA technique), blood pressure, and albuminuria. None of the patients were taking drugs other than insulin. Arterial blood pressure, albuminuria, and blood glucose were measured four to eight times/yr, whereas glomerular filtration rate was determined twice yearly. During the median investigation period of 36 (15–66) mo, glomerular filtration rate decreased from 102 ± 23 to 83 ± 27 ml · min−1 · 1.73 m−2 (P < 0.001), albuminuria increased from 633 to 1435 μg/min (P < 0.001), and blood pressure rose from 133/85 ± 10/9 to 149/93 ± 8/11 mmHg (P < 0.001). Univariate analysis revealed a significant correlation between the rates of decline in glomerular filtration rate and diastolic blood pressure (r = 0.52, P < 0.01) and glomerular filtration rate and albuminuria (r = 0.34, P < 0.02). But stepwise multiple linear regression analysis only showed a significant correlation between the rate of decline in glomerular filtration rate and diastolic blood pressure (P < 0.01). In patients with diastolic blood pressure below the mean value of 89 mmHg, stepwise multiple regression analysis showed that albuminuria and not blood pressure was correlated significantly with rate of decline in glomerular filtration rate. Patients were stratified by average value of diastolic blood pressure measured during the investigation period. Patients in the lowest fertile had a rate of decline in glomerular filtration rate of 4.3 ± 4 ml · min−1 · yr−1 compared with the middle and the highest tertiles of 7.7 ± 5 and 10.1 ± 5 ml · min−1 · yr−1, respectively (P < 0.01). The average diastolic blood pressure in the three groups was 81, 89, and 98 mmHg, respectively. This study suggests that systemic blood pressure elevation and albuminuria accelerate the progression of diabetic nephropathy. The latter progression promoter seems only to play a role in patients with normotension (diastolic blood pressure <89 mmHg).

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.

A strong correlation between glomerular filtration rate and filtration surface in diabetic nephropathy.

SummaryQuantitative structural studies were performed in kidney biopsy specimens from 24 long-term Type 1 (insulin-dependent) diabetic patients with persistent albuminuria due to diabetic glomerulopathy. Ten patients were receiving antihypertensive treatment, and among the remaining patients the mean blood pressure was 142/91 mmHg (SD = 11/9). The urinary albumin excretion rate showed a range from 100 to 5494 μg/min (geometric mean 688 μg/min.) Glomerular filtration rate also showed a wide range, from supranormal to markedly decreased values (128 to 28 ml·min−1· (1.73 m2)−1, mean 75). The filtration surface (interface between capillary and urinary space) per total number of nephrons (open+occluded) was estimated by combined light- and electron microscopy. The percentage occluded glomeruli as well as structural quantities in the open glomeruli were taken into account in this estimate. A highly significant correlation was seen between glomerular filtration rate and filtration surface per nephron (r=0.77, p<10−4). The percentage occluded glomeruli contributed significantly to the variation in glomerular filtration rate (for this relationship tested separately r=-0.78, p<10−5). The volume of open glomeruli was even larger than that seen in early diabetic glomerular hypertrophy and tended to increase with the percentage of glomerular closure, indicating that a compensatory hypertrophy might have taken place. In the open glomeruli the filtration surface constituted a smaller percent of total capillary surface (the remaining part facing the mesangial regions) than in early diabetic patients and control subjects.Our study has demonstrated that reduced glomerular filtration surface is closely associated with reduced glomerular filtration rate in Type 1 diabetic patients with diabetic nephropathy.

Increased blood pressure and erythrocyte sodium/lithium countertransport activity are not inherited in diabetic nephropathy

SummaryGenetic predisposition to essential hypertension, represented by maximal erythrocyte sodium/lithium countertransport activity, has been suggested as a marker for the risk of developing clinical nephropathy in Type 1 (insulin-dependent) diabetes mellitus. To evaluate this hypothesis we measured arterial blood pressure and maximal sodium/lithium countertransport activity of erythrocytes in 80 parents of 49 Type 1 diabetic patients with clinical nephropathy, 78 parents of 49 normoalbuminuric patients and 17 age-matched non-diabetic individuals. The two diabetic groups were carefully matched. In the two groups of parents blood pressure and cell sodium/lithium countertransport activity showed no significant differences (137/83 vs 133/81 mmHg and 0.33 vs 0.32 mmol/(1 cells x h) respectively). The proportion of parents who had died or received anti-hypertensive drugs was similar in the two groups.The patients with Type 1 diabetes had significantly higher sodium/lithium countertransport compared to the 39 non-diabetic control subjects independently of the presence or absence of nephropathy (p<0.002). However, patients with nephropathy tended to have higher sodium/lithium countertransport activity than normoalbuminuric patients (0.48 vs 0.41 mmol/(1 cells x h), p = 0.06). We conclude that genetic predispositions to essential hypertension and increased maximal erythrocyte sodium/lithium counter-transport activity do not appear to be risk markers for the development of clinical nephropathy in Type 1 diabetic patients.

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]

Angiotensin-converting enzyme inhibition in diabetic nephropathy : ten years' experience

The aim of our prospective study was to evaluate putative progression promoters, kidney function, and prognosis during long-term treatment with angiotensin-converting enzyme inhibition in insulin-dependent diabetes mellitus patients suffering from diabetic nephropathy. Eighteen consecutive hypertensive insulin-dependent diabetes patients with nephropathy (mean age, 33 years) who had not been treated previously were all treated with captopril in combination with frusemide or bendrofluazide. The four patients who were refractory to this regimen also received nifedipine. Treatment was continued for a median of 8.9 years (range, 6.3 to 9.8, years). Renal function was assessed every 6 months by measurement of glomerular filtration rate (GFR) (single-bolus 51Cr-EDTA technique) and albuminuria by radioimmunoassay. Baseline values (+/- SE) were mean arterial blood pressure 146/93 +/- 3/1 mm Hg, albuminuria (geometric mean +/- antilog SE) 982 +/- 1.2 micrograms/min, and GFR 98 +/- 5 mL/min/1.73 m2. Angiotensin-converting enzyme inhibition induced a significant reduction during the whole treatment period of blood pressure (137/85 +/- 3/1 mm Hg; P < 0.01) and albuminuria (392 +/- 1.4 microns/min; P < 0.01), and the rate of decline in GFR was 4.4 +/- 0.7 mL/min/yr, in contrast to previous reports of 10 to 14 mL/min/yr (natural history). Univariate analysis revealed a significant correlation between the rate of decline in GFR and mean arterial blood pressure (r = 0.58, P = 0.01), albuminuria (r = 0.67, P < 0.01), hemoglobin A1c (r = 0.69, P < 0.01), and serum total cholesterol concentration (r = 0.51, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)