Acute reduction of arterial blood pressure reduces urinary albumin excretion in Type 1 (insulin-dependent) diabetic patients with incipient nephropathy

Summary The effect of an acute reduction in arterial blood pressure upon kidney function was studied in 12 patients with Type 1 (insulin-dependent) diabetes and incipient nephropathy (persistent microalbuminuria). Renal function was assessed by measurement of the glomerular filtration rate (single bolus ⁵¹Cr-EDTA technique) and by the urinary albumin excretion rate (radioimmunoassay). The study was performed twice within 2 weeks, with the patients receiving a slow intravenous injection of either clonidine (225 g) or saline (154 mmol/l) in random order. Clonidine reduced arterial blood pressure from 125/79±13/8 to 104/68±9/7 mmHg (p < 0.01), urinary albumin excretion rate from 68 (31–369) to 46 (6–200) g/min (median and range) (p<0.01), and fractional clearance of albumin in all patients (median 29%) (p < 0.01). Glomerular filtration rate was 110±11 before and 106±13 ml/min/1.73 m² after clonidine injection. The blood glucose concentration was 15±4mmol/l before and 14±5 mmol/l after clonidine injection. In agreement with findings in animal studies, our results suggest that microalbuminuria is to a large extent pressure-dependent, probably because of glomerular hypertension, and that autoregulation of glomerular filtration rate is normal in most patients with incipient diabetic nephropathy.     

Normoalbuminuria ensures no reduction of renal function in type 1 (insulin-dependent) diabetic patients.

Recent reports have suggested that impaired renal function in type 1 diabetic patients may be present despite normal urinary albumin excretion (UAE). We have studied kidney function by means of a constant-infusion technique in normoalbuminuric type 1 diabetic patients without antihypertensive medication (UAE less than 20 micrograms min-1, n = 134), in microalbuminuric patients (20 greater than or equal to UAE less than 200 micrograms min-1, n = 50) and in 27 non-diabetic control subjects. Mean UAE was 4.5 micrograms min-1 (range 1.0-19.3 micrograms min-1) in normoalbuminuric patients, 53.1 micrograms min-1 (range 20.8-147.5 micrograms min-1) in microalbuminuric patients, and 4.0 micrograms min-1 (range 2.1-17.9 micrograms min-1) in controls. Glycosylated haemoglobin A1c was significantly higher in microalbuminuric patients (8.9%, range 5.9-12.6%) than in normoalbuminuric patients (7.9%, range 5.5-11.5%) (P less than 0.0001). Glomerular filtration rate in normoalbuminuric patients (135 ml min-1, range 97-198 ml min-1) was significantly higher than in controls (118 ml min-1, range 94-139 ml min-1) (P less than 1 x 10(-6), and significantly lower than in microalbuminuric patients (142 ml min-1, range 100-186 ml min-1) (P less than 0.05). Mean arterial blood pressure was lower in normoalbuminuric patients (91 mmHg, range 78-108 mmHg) than in microalbuminuric patients (98 mmHg, range 82-131 mmHg) (P less than 1 x 10(-6), but not significantly different from that of controls (89 mmHg, range 73-103 mmHg). We conclude that normal UAE is a reliable indicator of well-preserved renal function. Glomerular hyperfiltration, elevated blood pressure and poor metabolic control are characteristic features of microalbuminuric patients.     

Relationship of renal size to nephropathy in Type 1 (insulin-dependent) diabetes

Summary Thirty-five patients with Type 1 (insulin-dependent) diabetes mellitus and 90 normal subjects had renal size (renal area index) determined by X-ray and also had examination of renal biopsies by light and electron microscopy. Renal area index of 206±32 cm²/1.73 m² (mean±SD) in the Type 1 diabetic patients exceeded that in the normal subjects (180±25 cm²/1.73 m², p<0.001). In the diabetic patients, the renal area index correlated with creatinine clearance (r=+0.43, p<0.05), but did not correlate with urinary albumin excretion, or the electron microscopic measurements of percentage total mesangium and glomerular basement membrane width. In diabetic patients with clinical nephropathy or severe glomerulopathy on biopsy, the kidneys may remain large. Thus, renal size does not indicate the severity of diabetic renal lesions on biopsy.     

Ketone bodies increase glomerular filtration rate in normal man and in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary The purpose of this study was to investigate whether the administration of acetoacetic and hydrochloric acids in a group of control and Type 1 (insulin-dependent) diabetic patients influenced renal haemodynamics. Renal plasma flow increased from 657±88 to 762±81 ml·min^–1. 1.73 m^–2 in diabetic patients (p<0.01) and from 590±71 to 691±135 in control subjects (p<0.01). Glomerular filtration rate increased from 135±9 to 180±8 ml·min^–1·1.73 m^–2 in diabetic patients (p< 0.001) and from 117±8 to 145±7 in control subjects (p<0.01). Similar effects on renal haemodynamics, even if less pronounced, were observed with low dose acetoacetic but not with hydrochloric acid infusion. Total protein, 2-microglobulin but not albumin excretion rates were increased by acetoacetic acid. We conclude that an acute increase in blood concentration of ketone bodies within the range found in diabetic patients with poor metabolic control (1) increases renal plasma flow and glomerular filtration rate both in control subjects and diabetic patients and (2) causes a tubular proteinuria.     

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

Summary The 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 g) 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 g/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.     

Urinary kallikrein excretion in Type 1 (insulin-dependent) diabetes mellitus

Summary Kidney haemodynamics appear to change after the early phases of diabetic nephropathy: increases in glomerular filtration rate and in renal plasma flow have been widely reported, while kidney size is increased. As the renal kallikrein-kinin system has been demonstrated to regulate kidney blood circulation, we have evaluated the excretion of urinary kallikrein in 87 Type 1 (insulin-dependent) diabetic patients with and without hyperfiltration. Urinary kallikrein excretion was measured in 24-h urine collections. The esterolytic activity was determined by fluorimetric assay. The excretion of urinary kallikreins was significantly higher in hyperfiltering patients (472±125 esterase units/24 h) than in normofiltering (168±77 esterase units/24 h) and control subjects (151±39 esterase units/24 h), p<0.001. Furthermore, we observed a positive correlation between urinary kallikrein excretion and glomerular filtration rate (r=0.785). These data suggest that variations of kallikrein and kinin concentrations may play a role in the alteration of renal haemodynamics in Type 1 diabetes. It is possible that the kinin-kallikrein system, the renin-angiotensin system and the prostaglandins may interact to determine the haemodynamic alterations which are present in the diabetic disease.     

Prevalence of microalbuminuria in children with Type 1 (insulin-dependent) diabetes mellitus

Summary The prevalence of microalbuminuria was determined in children aged 7 to 18 years with Type 1 (insulin-dependent) diabetes of more than 2 years' duration. All patients (n =102) attending 2 diabetes clinics were asked to collect 2 overnight timed urine samples for albumin analysis by radioimmunoassay. Complete urine collection was obtained in 97 patients (95%). Overnight urinary albumin excretion rates were also measured in 36 healthy children matched for age and sex. Nineteen of the 97 patients (20%) had microalbuminuria, i. e. overnight urinary albumin excretion rates above the upper normal level (14 g/min) in both urine collections. Microalbuminuria was only demonstrated in patients aged 15 years, prevalence 37% (19/52 patients). Arterial blood pressure was elevated, mean 122/84±11/9mmHg, in the microalbuminuric group (19 patients) compared to the age-matched normoalbuminuric diabetic group (33 patients), mean 117/74±10/10 mm Hg,p < 0.001. The prevalence of simplex retinopathy was identical in these two groups, i. e. 25%. Glycosylated haemoglobin was slightly higher in the microalbuminuric patients,p < 0.10. Our cross-sectional study reveals a high prevalence (37%) of persistent microalbuminuria, a stage highly predictive of later development of diabetic nephropathy, in Type 1 diabetic children aged 15 years.     

Glycaemia,arterial pressure and micro-albuminuria in Type 1 (insulin-dependent) diabetes mellitus

Summary Plasma glucose control and arterial pressure were assessed in 28 Type 1 (insulin-dependent) diabetic patients with different degrees of micro-albuminuria. They were divided into two groups according to their urinary albumin excretion rate: a low micro-albuminuria group (n= 16) with albumin excretion ranging between 12.1 and 28.9 g/min and a high micro-albuminuria group (n= 12) with albumin excretion between 32.4 and 91.3 g/min. The groups were matched for age, sex and duration of diabetes with the same number of normo-albuminuric (2.0–10.4 g/min) diabetic control subjects. Both the low and high micro-albuminuria groups had significantly higher glycosylated haemoglobin levels and mean plasma glucose concentrations during a 24-h profile than their respective normo-albuminuric control subjects. A correlation between glycosylated haemoglobin level and urinary albumin excretion rate was found in the whole study group (r= 0.48; p< 0.001). Arterial pressure (both systolic and diastolic) was significantly higher in the high micro-albuminuria group than in either the control group or the low microalbuminuria group. A significant correlation was found between arterial pressure and albumin excretion rate in the whole study population (r= 0.49; p< 0.001) as well as in the pooled micro-albuminuria groups (r= 0.43; p< 0.05). Multiple regression analysis showed that glycosylated haemoglobin and arterial pressure levels were independently correlated with albumin excretion rates. Diabetic patients with micro-albuminuria of any degree have worse glycaemic control than normo-albuminuric patients. Higher levels of arterial pressure, though often sub-hypertensive, are associated with levels of micro-albuminuria predictive of later development of clinical proteinuria. Thus high plasma glucose and high arterial pressure, or both, characterise those diabetic patients at increased risk of nephropathy. These indices of risk are potentially reversible.     

Exercise as a provocative test in early renal disease in Type 1 (insulin-dependent) diabetes: albuminuric,systemic and renal haemodynamic responses

Summary The value of exercise as a provocative test for early renal disease in Type 1 (insulin-dependent) diabetes was reevaluated. Three carefully characterized groups of males were studied: 10 non-diabetic controls, 16 diabetic patients (group 1) with normal urinary albumin excretion (< 15 g/min) and 14 Albustix-negative diabetics (group 2) with increased urinary albumin excretion (15–122 g/min). Assignment to a study group was made on the basis of three 24-h urine collections, and the groups were well matched for age, weight, height, and serum creatinine concentration. The two diabetic groups were similar with regard to duration of disease (13±6 versus 16±3 years), metabolic control (HbA_1c: 8.4±1.4 versus 8.7±1.3%) and degree of diabetic complications (beat-to-beat variation and retinopathy). An exercise protocol of 450 and 600 kpm/min workloads was employed. In the resting state group 2 patients had elevated systolic blood pressure compared with the normal subjects (132±13 versus 119±9 mmHg), and their glomerular filtration rate was significantly reduced compared with group 1 (123±19 versus 138±15ml/min per 1.73m², p < 0.05). During exercise the urinary albumin excretion rate increased significantly in all three groups (normal subjects: 6±0.7 to 8±1.3 (g/min); group 1: 6±0.6 to 9±1 g/min and group 2: 48±10 to 113±23 g/min), the relative increase being higher in group 2 (p < 0.01). The changes in systemic haemodynamics were similar in all three groups in spite of a reduced maximum working capacity in group 2 (949±249 versus group 1:1163±200 and normal subjects 1267±264 kpm/min (p < 0.05). The renal haemodynamic changes were qualitatively similar for the three groups, but the filtration fraction during exercise increased in groups 1 and 2 to almost identical values and were significantly higher than in normal subjects (group 1 + group 2: 0.29±0.02 versus normal subjects: 0.26±0.03, p < 0.02). These findings suggest that an elevated transcapillary pressure gradient, as obtained during moderate exercise, will not cause an abnormal increase in albumin excretion per se. A functional glomerular lesion, already recognisable at rest (elevated albumin excretion) must also be present.     

Effects of indomethacin on kidney function in Type 1 (insulin-dependent) diabetic patients with nephropathy

Summary We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and albumimiria in diabetic nephropathy. The urinary excretion of immunoreactive prostaglandin E₂ (253pg/min) was significantly elevated in eight Type 1 (insulin-dependent) diabetic women with nephropathy as compared with nine normoalbuminuric Type 1 diabetic women (95pg/min) and 11 non-diabetic women (132 pg/min), respectively (p<0.01). Glomerular filtration rate (single bolus ⁵¹Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within two weeks in the eight Type 1 diabetic women with nephropathy. All eight patients were on a diabetic diet without sodium restriction. The study was performed as a randomized doubleblind trial, with the patients receiving either indomethacin (150mg/day) or placebo for three days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E₂ excretion (73%, p<0.01), glomerular filtration rate diminished from 120±18 to 106±17ml/min/1.73m² (p<0.05), albuminuria declined from 148 to 69 g/min (median and range) (p<0.05) and fractional clearance of albumin diminished 42% (p<0.05). Blood glucose concentrations were comparable during the placebo and indomethacin treatment, 13.4±4 versus 14.2±3 mmol/l, respectively. Our results suggest that glomerular filtration rate in early diabetic nephropathy is dependent on the enhanced glomerular synthesis of vasodilating prostaglandins.     

Blood pressure and metabolic control as risk factors for nephropathy in Type 1 (insulin-dependent) diabetes

Summary The respective rôles of arterial blood pressure and metabolic control in different stages of diabetic nephropathy were analyzed retrospectively in 52 sequentially-followed Type 1 (insulin-dependent) diabetic patients. A negative correlation was found between median post-prandial blood glucose and median duration of diabetes until onset of persistent proteinuria (p<0.01). Systolic blood pressure was higher in patients who subsequently developed persistent proteinuria than those who did not (140 versus 121 mmHg; p<0.05), but duration of the interval until onset of persistent proteinuria was not related to blood pressure. After onset of persistent proteinuria, hypertensive diabetic patients developed elevated serum creatinine concentrations more frequently than normotensive diabetic patients (67% versus 14%, p<0.05). In these patients, the delay until elevation of serum creatinine concentration was negatively correlated with blood glucose (p<0.01). Once serum creatinine was raised, decay of renal function occurred faster in patients with persistent than intermittent hypertension (p<0.05). No effect of metabolic control was demonstrable at this stage of nephropathy. It is concluded that metabolic control determines the early course of diabetic nephropathy, whereas blood pressure is more important in advanced stages of nephropathy.     

Proximal glomerulo-tubular balance in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary To evaluate the glomerulo-tubular balance of sodium and water in the proximal tubules of diabetic patients with elevated glomerular filtration rate, the renal plasma clearance of lithium and the glomerular filtration rate (⁵¹Cr-EDTA plasma clearance) were determined simultaneously in 11 ambulatory Type 1 (insulin-dependent) diabetic patients (aged 25–35 years) with no evidence of diabetic nephropathy and in 10 age-matched healthy subjects. The renal plasma clearance of lithium, which is a measure of flow from the proximal tubule into the thin descending limb of the loop of Henle, did not differ between diabetic and control subjects (28.9±4.0 versus 28.3±5.1 ml/min per 1.73m² surface area, mean±SD), whereas the glomerular filtration rate in the diabetic patients was significantly higher than in the control sub jects (136±10.2 versus 108±13.6 ml/min per 1.73m², p< 0.001). The same held true for the fractional reabsorption rate in the proximal tubules (78.7±3.2 versus 73.6±4.9%, p< 0.02). The results indicate that the elevation of the glomerular filtration rate in diabetic patients is associated with a parallel increase in the proximal reabsorption rate. This type of glomeralo-tubular balance implies that the flow of water and flux of sodium to the segments distal to the proximal tubule are kept constant during variations in the glomerular filtration rate.     

Blood pressure in children,adolescents and young adults with Type 1 (insulin-dependent) diabetes

Summary Blood pressure has been measured by a single observer using a standardised technique in 163 Type 1 (insulin-dependent) diabetic patients aged 4 to 32 years, 232 of their non-diabetic siblings in the same age range and in 292 of their natural parents. Results for each sex were examined separately by analysis of variance. Systolic pressures were not significantly different overall nor in any single 4-year age band. In contrast, phase IV diastolic pressure was slightly but significantly higher in the diabetic males than in their sibling group overall (increment= +2.8 mmHg; p<0.03), a difference also shown individually within the 16–20 year age band (81.3 versus 76.5 mmHg, p<0.025). There were no significant differences in diastolic pressure between the female groups, and no effect of duration of diabetes on blood pressure was shown in either sex. Eighteen of 97 male diabetic patients (19%) had mean blood pressures above the 90th centile for age, derived from the sibling data, compared with 12 of 137 siblings (9%, p=0.05). The higher blood pressures among the diabetic males could not be explained solely by early nephropathy; familial factors appeared to be important in the determination of elevated blood pressure in this group as well as in the siblings. Alone, these small differences in blood pressure are unlikely to make a major contribution to the incidence of diabetic vascular disease, but the isolated increase in diastolic pressure may indicate altered vascular regulation in Type 1 diabetes.     

Reduced transcapillary escape of albumin during acute blood pressure-lowering in Type 1 (insulin-dependent) diabetic patients with nephropathy

Summary The effect of acute arterial blood pressure lowering upon albumin extravasation was studied in 10 patients with nephropathy and retinopathy due to long-standing Type 1 (insulin-dependent) diabetes. The following variables were measured: transcapillary escape rate of albumin (initial disappearance of intravenously injected ¹²⁵I-labelled human serum albumin), and urinary albumin excretion rate (radial immuno-diffusion). The study was performed twice within 2 weeks, with the patients receiving an intravenous injection of either clonidine (225 g) or saline (0.154 mmol/l). The clonidine injection induced the following changes: arterial blood pressure decreased from 134/87 to 107/73 mmHg (p<0.01), transcapillary escape rate of albumin declined from 8.1 to 6.7% of the intravascular mass of albumin/h (p<0.01), albuminuria diminished from 1434 to 815 g/min (p<0.01), and plasma volume raised slightly from 2916 to 2995ml (p<0.05). Our findings demonstrate that the enhanced albumin passage through the wall of the microvasculature characteristically found in long-term Type 1 diabetic patients with clinical microangiopathy is pressure-dependent to a large extent. This may be due to elevated hydrostatic pressure in the microcirculation.     

Early glomerular hyperfiltration and the development of late nephropathy in Type 1 (insulin-dependent) diabetes mellitus

Summary We performed a follow-up study of the glomerular function in a series of 29 Type 1 (insulin-dependent) diabetic patients who had been studied 18 years previously. Initial median duration of diabetes was 2 years (range 0–9) and at follow-up 21 (17–27) years. At follow-up, 8 diabetic patients exhibited increased urinary albumin excretion rate 515 (32-3234) g/min with glomerular filtration rates significantly lower than 21 diabetic patients with normal urinary albumin excretion (85 vs 126ml/min/1.73 m²; p<0.01). The patients with increased urinary albumin excretion rate also had higher arterial blood pressure (145/90 vs 120/80) mm Hg; p<0.02) and increased frequency of proliferative retinopathy (7 out of 8 vs 2 out of 21; p = 0.0001) as compared to the group with normal urinary albumin excretion. However, we found no association of increased urinary albumin excretion rate (incipient or overt nephropathy) to early glomerular hyperfiltration as median initial glomerular filtration rate was 142 ml/min/1.73 m² in the diabetic patients with increased urinary albumin excretion and 147 ml/min/1.73 m² in the patients with normal excretion rate (p>0.05)     

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

Summary Glomerular 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.     

Prevalence of hypertension in Type 1 (insulin-dependent) diabetes mellitus

Summary The prevalence of hypertension in a representative sample (n=10202) of the Danish general population aged 16–59 years was assessed to 4.4% based on three blood pressure readings. In Type 1 (insulin-dependent) diabetic patients of similar age (n=1703) the prevalence was determined in a similar way to 14.7% (p<0.00001). The excess prevalence in Type 1 diabetic patients was due to hypertension in patients with incipient and clinical nephropathy as the prevalence of hypertension among diabetic patients with normal urinary albumin excretion (essential hypertension) was 3.9%, similar to that observed in the general population. The patients with Type 1 diabetes and essential hypertension had higher systolic (146±19 vs 133±18 mmHg, p<0.00001) and diastolic blood pressure (87±12 vs 79±7mmHg, p<0.00001), but less changes in the eye background than patients with incipient nephropathy (urinary albumin excretion 30–300 mg/24 h) (p<0.03), indicating that the two groups were also different with respect to other microangiopathic lesions. Patients with essential hypertension were defined as having a normal urinary albumin excretion before and during antihypertensive treatment (if any). They were followed-up for a 58 (6–234) month period. We confirmed that hypertension is more common among Type 1 diabetic patients than in the general population and found the prevalence of essential hypertension similar in Type 1 diabetic patients to the non-diabetic population. This supports our hypothesis that hypertension is very unlikely to be the cause of diabetic nephropathy.     

HLA antigens and risk factors for nephropathy in Type 1 (insulin-dependent) diabetes mellitus

Summary This study of risk factors for diabetic nephropathy in juvenile Type 1 (insulin-dependent) diabetes mellitus compares two carefully characterised groups of patients, one with proteinuria (n = 23), the other a control group (n = 24) with no evidence of nephropathy despite more than 25 years of diabetic life. No significant difference was observed between the groups in any HLA-A, -B or -DR antigen or Bf allotype. DR3 was present in 87% of patients with proteinuria and 75% of the diabetic control group; DR4 was present in 48% of patients with proteinuria and 63% of diabetic controls; BfFl was present in 17% of patients with nephropathy and 9% of the diabetic control group. Compared with the control group, patients with proteinuria had significantly higher mean diabetic-clinic blood glucose concentrations before the diagnosis of microvascular disease, a significantly earlier age at diagnosis of diabetes, and had more often been treated with once-daily as opposed to twice-daily insulin regimens. Susceptibility to nephropathy in Type 1 diabetes appears to be determined by the quality of metabolic control and age of onset of diabetes; although the number of subjects studied was relatively small no evidence was found of any influence of HLA or Bf phenotype.     

Natural course of kidney function in Type 2 diabetic patients with diabetic nephropathy.

AIMS: To determine the natural course of kidney function and to evaluate the impact of putative progression promoters in Caucasian Type 2 diabetes mellitus (DM) patients with diabetic nephropathy who had never received any antihypertensive treatment. METHODS: A long-term observational study of 13 normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy. Glomerular filtration rate (GFR) was measured approximately every year (51Cr-EDTA plasma clearance technique). Albuminuria, blood pressure (BP) and haemoglobin A1c (HbA1c) was determined 2-4 times per year and serum cholesterol every second year. RESULTS: The patients (12 males/one female), age 56+/-9 (mean +/- SD) years, with a known duration of diabetes of 10+/-6 years, were followed for 55 (24-105) (median (range)) months. GFR decreased from 104 (50-126) to 80 (39-112) ml x min(-1) x 1.73 m(-2) (P = 0.002) with a median rate of decline of 4.5 (-0.4 to 12) ml x min(-1) x year(-1). During follow-up, albuminuria rose from 494 (301-1868) to 908 (108-2169) mg/24 h (P = 0.25), while BP, HbA1c and serum cholesterol remained essentially unchanged. In univariate analysis the rate of decline in GFR did not correlate significantly with neither baseline nor mean values during follow-up of BP, albuminuria, HbA1c and serum cholesterol. CONCLUSIONS: Our study suggests that normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy have a rather slow decline in kidney function, but we did not unravel the putative progression promoters responsible for the variation in rate of decline in GFR.