J. Sandahl Christiansen

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.

Increased kidney size, glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics.

SummaryGlomerular filtration rate (GFR), renal plasma flow (RPF) and kidney volume were measured in thirteen male subjects (mean age 30 years) with short-term insulin-dependent diabetes (mean duration of disease 2.4 years) and fourteen normal male subjects (mean age 29 years). GFR and RPF were measured by constant infusion technique using I125-iothalamate and 131I-hippuran. Kidney size was determined by means of ultrasound. GFR, RPF and kidney volume were increased in the diabetic patients compared to the normal controls, 144 versus 113 ml/ min×1.73m2 (p<0.0005), 627 versus 523 ml/ min×1.73 m2 (p<0.0025) and 278 versus 224 ml/ 1.73 m2 (p<0.0005) respectively. Combining results from diabetic patients and controls revealed a positive correlation between kidney size and GFR (r= 0.70, p<0.001) and between kidney size and RPF (r=0.61, p<0.001). Within the groups kidney size and RPF correlated significantly in the diabetics (p< 0.01) and the same was found for kidney size and GFR (0.025< p<0.05), while no correlations were found in the normal group. GFR and RPF correlated in the diabetics when evaluated separately (r=0.81, p<0.001) and in the controls (r=0.73, p<0.001). The previous and present data suggest that the mechanisms of the elevated GFR in insulin-dependent diabetics are enhanced RPF, increased transglomerular hydrostatic pressure gradient and increased glomerular ultrafiltration coefficient. The increased kidney size is probably the main cause of the above alterations in the GFR determinants.

Renal function in streptozotocin-diabetic rats

SummaryRenal function was examined with micropuncture methods in the insulin-treated streptozotocin-diabetic rat. Kidney glomerular filtration rate was significantly higher in the diabetic rats (1.21 ml/min) than in the control group (0.84 ml/min) Nephron glomerular filtration rate increased in proportion to the rise in kidney glomerular filtration rate (diabetic rats: 37.0 nl/min; control rats: 27.9 nl/min). Likewise renal plasma flow was significantly higher in the diabetic rats (4.1 ml/min) than in the control group (3.0 ml/min). Glomerular capillary pressure was identical in both groups (56.0 and 56.0 mmHg, respectively). The proximal intratubular pressure was significantly reduced in the diabetic rats (10.4 mmHg; control value: 12.5 mmHg). The effective glomerular ultrafiltration coefficient was slightly but not significantly higher in the diabetic rats (0.027 nl s-1mmHg-1) than in the control group (0.023 nl s-1mmHg-1). Kidney weight was significantly higher in the diabetic rats (1.15 g; control rats: 0.96 g) while body weight was similar in both groups (diabetic rats: 232 g; control rats: 238 g). Calculations indicate that the increases in transglomerular hydraulic pressure, renal plasma flow and ultrafiltration co-efficient of the glomerular membrane contribute about equally to the rise in glomerular filtration rate. The increases in the values of the determinants of glomerular filtration rate may be the result of renal hypertrophy. These studies suggest that this model provides a useful method for investigating kidney function in diabetes, which may have relevance for our understanding of the kidney abnormalities in human diabetes.

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.

Prevalence of diabetic autonomic neuropathy measured by simple bedside tests

SummaryTo investigate the prevalence of diabetic autonomic neuropathy, five simple bedside tests, beat-to-beat variation during quiet respiration, beatto-beat variation during forced respiration, heart rate and blood pressure response to standing, heart rate response to exercise, and heart rate response to Valsalvas manoeuvre were applied to 75 male insulindependent diabetics, mean age 40 years, (range 30–49 years). The subjects were subdivided into three groups according to duration of diabetes, which was between 0 and 40 years. Twenty-eight healthy age-matched male controls were also studied. The prevalence of diabetic autonomic neuropathy in the whole diabetic population indicated by abnormal response in beat-to-beat variation during forced respiration was 27%. Diabetic autonomic neuropathy increased in frequency with duration of disease. Patients with nephropathy or proliferative retinopathy had a significantly higher prevalence of diabetic autonomic neuropathy as indicated by abnormal beat-to-beat variation during forced respirations (p<0.01) than patients without these complications.

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.

Effect of intravenous glucose infusion on renal function in normal man and in insulin-dependent diabetics

SummaryThe effect of intravenous glucose infusion on glomerular filtration rate and renal plasma flow (constant infusion technique using 125I-iothalamate and 131I-hippuran) and on urinary excretion of albumin and β-2-microglobulin were studied in ten normal subjects and seven metabolically well-controlled insulin-dependent diabetics. Following glucose infusion in normal subjects (n = 10) blood glucose increased from 4.7±0.1 to 10.9±0.4 mmol/1 (SEM) (p ⩽ 0.01). Glomerular filtration rate increased from 116±2 to 123±3ml/min x 1.73 m2 (p ⩽ 0,01), while no change in renal plasma flow was seen 552±11 versus 553±18 ml/min × 1.73 m2. Volume expansion with intravenous saline infusion in six of the normal subjects induced no changes in blood glucose or kidney function. In seven strictly controlled insulin-dependent diabetics, blood glucose values were raised from 4.6±0.4 to 16.0±0.6 mmol/1 and clamped by means of an ‘artificial beta cell’. Glomerular filtration rate increased in all patients, from 133 ±5 to 140±6 ml/min × 1.73 m2 (p ⩽ 0.02), as did renal plasma flow from 576±26 to 623±38 ml/ min × 1.73 m2 (p ⩽ 0.02). Urinary albumin excretion remained unchanged in both normal subjects and diabetics. β-2-microglobulin excretion rate increased significantly in the diabetics following glucose infusion, while no significant change was seen in the normal subjects. Our results show that hyperglycaemia per se contributes to the increased glomerular filtration rate and renal plasma flow in insulin-dependent diabetes.

The effect of intravenous insulin infusion on kidney function in insulin-dependent diabetes mellitus.

SummaryGlomerular filtration rate, renal plasma flow, urinary excretion of β-2-microglobulin and albumin, heart rate and blood pressure were studied in eight young male insulin-dependent diabetics. Measurements were performed before and during insulin infusion at 2 mU/kg/min. No patient had discernible insulin antibodies. Two studies were performed at random in each patient. In series A blood glucose concentration was allowed to decline, while in series B it was maintained at a constant level. Ten 20 min clearance periods were performed, four before and six during insulin infusion. Results are given as mean±SEM of values from the first four (control) and last four (test) clearance periods. Blood glucose declined in series A experiments from 10.8±0.8 mmol/l in the control period to 5.8±0.5 mmol/l during the test period, but remained constant during experiment B (9.8±1.1 and 9.5±1.1 mmol/l). Plasma insulin levels were comparable in the two series. Glomerular filtration rate fell from 141±7 ml/ min X 1.73m2 to 132±7ml/min X 1.73m2 (p< 0.01) in series A but did not change significantly during series B. Similarily renal plasma flow declined with declining glucose but remained constant when glucose was maintained at a constant level. In series A the magnitude of decrease in renal plasma flow was correlated with the magnitude of decrease in glomerular filtration rate (r=0.95, p< 0.001). β-2-microglobulin excretion decreased significantly (p < 0.05) in both series (A: 89±17 to 60±13 ng/min, B: 117±46 to 62±17ng/min). Albumin excretion increased in five out of six patients with normal control values (not significant) in series A and in four out of six in series B. No significant changes in heart rate or blood pressure were observed. Thus insulin infusion reduced renal plasma flow and glomerular filtration rate, but this effect could be completely abolished by keeping blood glucose constant. This suggests that it is not the lack of insulin but the associated hyperglycaemia which contributes to the elevated renal plasma flow and glomerular filtration rate in insulin-dependent diabetics.

Kidney function and size in type 1 (insulin-dependent) diabetic patients before and during growth hormone administration for one week

SummaryKidney function and size were studied in seven well-controlled male Type 1 (insulin-dependent) diabetic patients before and after administration of highly purified human growth hormone for one week. Glomerular filtration rate, renal plasma flow (steady state infusion technique with urinary collections using 125I-iothalamate and 131I-hippuran), kidney size (ultrasonic scanning) and urinary excretion rates of albumin and β-2-microglobulin were measured. Highly purified growth hormone was injected subcutaneously, 2 IU in the morning and 4 IU in the evening. The growth hormone dosage applied induced an elevation in plasma growth hormone concentration from the normal level seen in these very well controlled diabetics to levels within the range previously demonstrated in normally controlled Type 1 diabetic patients. During the week of growth hormone administration, glycaemic control was maintained unchanged by increasing the insulin dose by 79 ±9% (mean ± SEM). Glomerular filtration rate increased from 122±3 to 131±3 ml/min × 1.73 m2 (p <0.05) and renal plasma flow increased from 535±10 to 569±22 ml/min × 1.73 m2 (p<0.05). Kidney size changed from 128±5 to 133±5 ml/1.73 m2 (NS). Urinary excretion rates of albumin and β-2-microglobulin were unchanged. The present findings suggest that the growth hormone elevation typically found in Type 1 diabetic patients with reasonable clinical control, contributes to the enhanced glomerular filtration rate and renal plasma flow present in that disease.

Acute and long-term renal effects of angiotensin converting enzyme inhibition in normotensive, normoalbuminuric insulin-dependent diabetic patients.

Glomerular filtration rate (GFR) (thalamate clearance), renal plasma flow (RPF) (hippuran clearance), and urinary albumin excretion rate (AER) were measured in 10 normoalbuminuric, normotensive insulin‐dependent diabetic patients and 8 normal subjects before and during acute angiotensin converting enzyme (ACE) inhibition by means of enalapril (10 mg IV). The effect of placebo versus enalapril (30 mg day−1) was also studied for 3‐month treatment periods in the insulin‐dependent diabetic patients.