A. R. Andersen

Diabetic nephropathy in type 1 (insulin-dependent) diabetes: An epidemiological study

SummaryA follow-up of 1475 Type 1 (insulin-dependent) diabetic patients diagnosed before 1953 (815 males, 660 females) and before the age of 31 years was conducted. All patients were seen at the Steno Memorial Hospital and were referred from all parts of Denmark; 91 (6%) could not be traced. The rest (94%) were followed until death or for at least 25 years; 249 (17%) were followed for >40 years. Clinical diabetic nephropathy developed in 531 (41%) of the 1303 patients in whom sufficient information was available regarding proteinuria. Other causes of proteinuria were found in 3%, and 57% did not develop persistent proteinuria. The prevalence of diabetic nephropathy was 21% after 20–25 years of diabetes duration followed by a decline to 10% after 40 years. Two incidence peaks of the onset of proteinuria were seen, one after 16 and another after 32 years duration of diabetes. Incidence increased steeply 10 years after onset of diabetes and was low after 35 years duration. The cumulative incidence was 45% after 40 years of diabetes. A male preponderance was seen among patients with nephropathy. A significant difference in the pattern of annual incidence rates of diabetic nephropathy was seen, when groups with onset of diabetes before 1933, between 1933–1942, and 1943–1952, respectively, were compared. An association between daily insulin requirement and nephropathy incidence was found. Patients with nephropathy had a much poorer survival than those without proteinuria; 40 years after onset of diabetes, only 10% of patients who developed nephropathy were alive, whereas >70% of patients who did not develop nephropathy survived. Uraemia was the cause of death in 66% of the patients with nephropathy; 7 years after the onset of persistent proteinuria, 49% of the patients had died. It is concluded that diabetic nephropathy is the major life threatening complication in Type I diabetes of juvenile onset.

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.

A prospective study of glomerular filtration rate and arterial blood pressure in insulin-dependent diabetics with diabetic nephropathy

SummaryGlomerular filtration rate (GFR, single bolus 51Cr-EDTA technique), serum creatinine, proteinuria and arterial blood pressure have been measured prospectively in 14 young onset insulin-dependent diabetics selected by of persistent proteinuria (> 0.5 g/day) secondary to diabetic nephropathy. Twelve of the 14 patients had normal serum creatinine levels. None of the patients received antihypertensive treatment. During the mean observation period of 26 months (range 23 to 33 months) GFR decreased from 107 to 87 ml/min/1.73 m2 (p< 0.001), serum creatinine remained unchanged: 107 and 112/gmmol/l (NS), proteinuria increased from 1.8 to 3.3 g/day (p<0.001) and arterial blood pressure rose from 132/88 to 153/101 mmHg (p<0.001). Glomerular filtration rate decreased linearly with time (slope=−0.75, r=0.99, p<0.001) by a mean of 0.75 ml/min/month (range 0.1 to 1.5 ml/ min/month). The decrease in GFR did not correlate with sex, age at onset, duration of diabetes, arterial blood pressure, proteinuria, insulin requirement, postprandial blood glucose or the initial GFR, but numbers were small. The decline in GFR in each individual was constant, but varied considerably between patients. Increase in arterial blood pressure to a hypertensive level is an early feature of diabetic nephropathy in young insulin-dependent diabetics.

Diabetic nephropathy and arterial hypertension.

SummaryThe relationship between arterial blood pressure and diabetic nephropathy was examined in 61 Type 1 (insulin-dependent) diabetic patients (22 females and 39 males). All patients fulfilled the following criteria: persistent proteinuria (>0.5g/day), onset of diabetes before 31 years of age, age <42 years, serum creatinine <130 μmol/l, and no antihypertensive treatment. Thirty Type 1 diabetic patients without persistent proteinuria but matched for sex, age, ideal body weight and duration of diabetes, and 30 healthy subjects matched for sex, age and ideal body weight were also studied as controls. The diabetic patients with persistent proteinuria had elevated blood pressures (146/96±17/10 mmHg, mean±SD) compared with 123/75±11/8 mmHg in diabetic patients without persistent proteinuria, and normal subjects (120/77±6/6 mmHg; p<0.001 for each). Diastolic blood pressure ⩾95 mmHg was found in 51% of the group with persistent proteinuria. Elevated arterial blood pressure is frequently present in young Type 1 diabetic patients with diabetic nephropathy and normal serum creatinine.

Impaired autoregulation of glomerular filtration rate in Type 1 (insulin-dependent) diabetic patients with nephropathy

SummaryThe effect of acute lowering of arterial blood pressure upon kidney function in nephropathy was studied in 13 patients with long-term Type 1 (insulin-dependent) diabetes. Ten normal subjects (six normotensive and four hypertensive) and five short-term Type 1 diabetic patients without nephropathy served as controls. Renal function was assessed by glomerular filtration rate (single bolus 51Cr-EDTA technique) and urinary albumin excretion rate (radial immunodiffusion). The study was performed twice within 2 weeks, with the subjects receiving an intravenous injection of either clonidine (225 μg) or saline (0.154 mmol/l). The arterial blood pressure was similar in the diabetic patients with nephropathy (mean 136±11 mmHg) and in the non-diabetic control subjects 88±5 (mean 140±25 mmHg). The clonidine injection induced sim- 92±15 ilar reductions in mean arterial blood pressure in all three groups (16–18 mmHg). While glomerular filtration rate and urinary albumin excretion rate remained unchanged in both control groups after clonidine injection, glomerular filtration rate dimished from 78 to 71 ml/min per 1.73 m2 (p<0.01), and urinary albumin excretion declined from 1707 to 938 μg/min (p<0.01) in the patients with diabetic nephropathy. Our results suggest that an intrinsic vascular (arteriolar) mechanism underlying the normal autoregulation of glomerular filtration rate, i. e. the relative constancy of glomerular filtration rate that occurs in response to rather wide variations in perfusion pressure, is defective in diabetic nephropathy.

Diabetic Nephropathy and Arterial Hypertension: The Effect of Antihypertensive Treatment

Our longitudinal study of urinary albumin excretion rate in long-term insulin-dependent diabetics without proteinuria (negative albustix) suggests that early detection of patients at high and low risk of developing persistent proteinuria, i.e., diabetic nephropathy, is possible by using a sensitive method for albumin determination. Our prospective studies in young insulin-dependent diabetics with diabetic nephropathy show that the rate of decline in giomerular filtration rate (GFR) varies considerably, with a mean of 0.75 ml/min/mo and a range from 0.1 to 1.50 ml/min/mo, and that an increase in arterial blood pressure to a hypertensive level is an early feature; 43% of the patients had diastolic blood pressure >100 mm Hg. Early and aggressive antihypertensive treatment reduces both albuminuria and the rate of decline in GFR in young patients with diabetic nephropathy.

Renal changes in long-term type 1 (insulin-dependent) diabetic patients with and without clinical nephropathy: a light microscopic, morphometric study of autopsy material.

SummaryThe relationship between clinical diabetic nephropathy and morphological renal changes was studied in autopsy material from 34 long-term Type 1 (insulin-dependent) diabetic patients of juvenile onset. Seventeen had no clinical signs of nephropathy (defined by persistent proteinuria, hypertension, and elevated serum creatinine) while a further 17 age-matched diabetic patients with a similar duration of diabetes had severe clinical nephropathy. The renal tissue was examined by morphometric light microscopy, using a point counting technique and the results compared with renal tissue from subjects who died without diabetes. In the diabetic patients without clinical nephropathy, arteriolohyalinosis was much more pronounced compared with non-diabetic subjects (2p< 0.001) and within the glomeruli the amount of subcapsular fibrosis and glomerular mesangium was increased (2p < 0.05 and < 0.001, respectively). The area of open capillaries was decreased compared with non-diabetic subjects (2p < 0.025), and the percentage of occluded glomeruli was significantly increased (2p< 0.05). The diabetic patients with clinical nephropathy had significantly more interstitial tissue and glomerular mesangium (2p < 0.001) and less open glomerular capillaries (2p < 0.001) than diabetic subjects without clinical nephropathy, but severe glomerulosclerosis could be seen in the diabetic patients without any sign of clinical nephropathy. Serum creatinine correlated with the mesangial area (r = 0.792, 2α < 0.001). No difference was observed between the two diabetic groups regarding the degree of arteriolohyalinosis, the number of Kimmelstiel-Wilson lesions or exudative lesions. A significant negative correlation existed between the relative area of open capillaries and the relative area of mesangium (r =-0.86, 2α <0.001). Remarkable mesangial enhancement was present in most of the diabetic patients with, but also in several diabetic subjects without, clinical nephropathy. On the other hand, the area of open capillaries was within the normal range in most of the patients who did not show any clinical sign of nephropathy. Thus, preservation of a normal area of open capillaries in renal tissue from long-term diabetic patients with glomerulosclerosis seems to be a good light microscopic indicator of absence of clinical nephropathy.

Monitoring Progression of Diabetic Nephropathy

Glomerular filtration rate (GFR, single bolus 51Cr-EDTA technique), serum creatinine and serum beta 2-microglobulin concentrations were measured simultaneously in 49 insulin-dependent diabetics with diabetic nephropathy. GFR ranged from 148 to 23 ml/min/1.73 m2. Inverse serum concentrations of creatinine and beta 2-microglobulin showed a significant correlation with GFR over the whole range of values, r = 0.87 and r = 0.90, respectively (p less than 0.001). In the 31 patients with a GFR less than 80 ml/min/1.73 m2, serum concentration of creatinine and beta 2-microglobulin were within the normal range in 12 and 9 patients, respectively. With GFR below 60 ml/min/1.73 m2, all patients had elevated serum beta 2-microglobulin concentrations, while 24% of the patients still had normal creatinine concentration. Linear regression analysis between log GFR and log serum beta 2-microglobulin showed a better relationship than between log GFR and log serum creatinine, slope -0.90 and -0.57, respectively, p less than 0.01. A prospective study for up to 70 months was performed in 18 of the patients. The study showed a closer relationship between the individual rate of decline in log GFR and log serum beta 2-microglobulin compared to log GFR versus log serum creatinine, p less than 0.01. Neither serum creatinine nor serum beta 2-microglobulin can be used as methods for screening of early impairment of renal function (GFR less than 80 ml/min/1.73 m2 in diabetic nephropathy. Our study suggests that serum beta 2-microglobulin is more ideal endogenous marker for GFR estimation than serum creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)