Search

Background: The ability of the kidney to maintain constancy of the glomerular filtration rate (GFR) over a wide range of renal perfusion pressures is termed autoregulation. Defective autoregulation of GFR has been demonstrated in diabetic nephropathy. Whether this is also the case in patients with nondiabetic nephropathies is not known. Methods: We investigated the effect of acute lowering of blood pressure (BP) on GFR in 16 (8 males and 8 females) albuminuric subjects suffering from different nondiabetic nephropathies and in 14 (7 males and 7 females) controls matched with respect to sex, age, BP, and baseline GFR. The subjects received in random order an intravenous injection of either clonidine (150 to 225 microg) or saline (0.154 mmol/liter) within two weeks. We measured GFR ([51Cr]-EDTA), albuminuria (enzyme-linked immunosorbent assay; ELISA), and BP (Takeda TM-2420). Results: Clonidine induced similar reductions in mean arterial BP 17 (2) versus 19 (2) mm Hg [mean (SE)] in patients with nephropathy and in controls, respectively. GFR diminished in average from 89 (6) to 82 (5) ml/min/1.73 m2 (P < 0.05), and albuminuria declined from a geometric mean of 1218 (antilog SE 1.3) microg/min to 925 (1.3) in the patients with nondiabetic nephropathies (P < 0.05), whereas these variables remained unchanged in the control group. The mean difference between changes in GFR (95% confidence interval) between the nondiabetic macroalbuminuric and control subjects was 6.1 (-0.03 to 12.21) ml/min/1.73 m2 (P = 0.051). Conclusion: Our study suggests that albuminuric patients with nondiabetic nephropathies frequently suffer from impaired autoregulation of GFR. [ABSTRACT FROM AUTHOR]

Background: Impaired autoregulation of the glomerular filtration rate (GFR) implies disturbances in the downstream transmission of the systemic blood pressure into the glomerulus, leading to capillary hypertension or hypotension dependent of the level of blood pressure. The impact on renal autoregulation of different antihypertensive drugs in animals has been elucidated, whereas information in humans is lacking., Methods: A randomized, double-blind crossover study with candesartan cilexetil 16 mg o.d. and placebo was performed in 17 hypertensive type 2 diabetic patients without nephropathy. Each treatment arm lasted four weeks. On the last day, GFR (single shot [51Cr] EDTA plasma clearance technique for 4 hours) was measured twice between 8 a.m. and 5 p.m., first without clonidine and then after an intravenous injection of clonidine 75 microg. Blood pressure (Takeda TM2420, A&D, Tokyo, Japan) was measured every ten minutes, and the urinary albumin excretion rate (UAER) was measured by ELISA during each GFR determination., Results: Candesartan induced a mean (SE) reduction in mean arterial blood pressure (MABP) of 6 (2) mm Hg (P < 0.02) and had a tendency to reduce UAER (P = 0.07), while GFR remained unchanged (95 vs. 93 mL/min/1.73 m2). Clonidine reduced MABP with 17 (2) versus 16 (1) mm Hg during placebo versus candesartan 16 mg o.d., respectively (NS). GFR diminished in average from 95 (3) to 92 (4) mL/min/1.73 m2 with placebo (NS), and from 93 (3) to 89 (4) mL/min/1.73 m2 during treatment with candesartan (NS). The mean difference (95% CI) in the changes in GFR between the examination with placebo and with candesartan was 0.1 (-5.5 to 5.8) mL/min/1.73 m2 (NS)., Conclusion: Candesartan reduces blood pressure without adversely altering the preserved ability to autoregulate GFR in hypertensive type 2 diabetic patients without nephropathy.

Background: Diabetic nephropathy is a chronic, progressive kidney disease with a mean rate of decline of in glomerular filtration rate (GFR) of 10 to 12 mL/min/year (natural history). The introduction of aggressive antihypertensive treatment has improved the renal prognosis during the last decades. To examine whether remission and regression of diabetic nephropathy are possible in type 1 diabetic patients, we analyzed data from a prospective observational cohort study that was started in 1983., Methods: We measured GFR with a 51Cr-EDTA plasma clearance technique every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 microg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. Blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol were measured every three to four months during the study. In total, 271 patients received antihypertensive treatment, 179 patients predominantly with angiotensin-converting enzyme inhibitors. Remission was defined as albuminuria <200 microg/min sustained for at least one year and a decrease of at least 30% from preremission levels (surrogate endpoint), and regression as a rate of decline in GFR (DeltaGFR) equal to the natural aging process: < or =1 mL/min/year during the entire observation period (principal end point)., Results: The total number of patients who obtained remission was 92 (31%), with a duration of remission of [median (range)] 3.4 (1.0 to 14.1) years, and regression 67 (22%). The patients were stratified in quintiles by the average value of office mean arterial blood pressure (mean +/- SE): 93 +/- 0.5, 99 +/- 0.2, 103 +/- 0.1, 107 +/- 0.2, and 113 +/- 0.4 mm Hg. The prevalence of patients obtaining remission/regression was 58/42, 33/32, 25/11, 20/20, and 17/7% in each quintile, respectively. Spontaneous remission and regression occurred in 10 and 14 patients from the persistent normotensive group (N = 30), none of whom had ever received antihypertensive treatment. In all 301 consecutive patients, the (mean +/- SE) DeltaGFR was 4.0 +/- 0.2 mL/min/year during the investigation period., Conclusions: Our study suggests that aggressive antihypertensive treatment in type 1 diabetic patients can induce remission and regression in a sizable fraction of patients with diabetic nephropathy. Lower arterial blood pressure, reduced albuminuria, and better glycemic control were predictors of regression of diabetic nephropathy.

Background: The purpose of this study was to assess whether long-term (8 years) inhibition of angiotensin-converting enzyme (ACE) protects kidney function in normotensive type 1 diabetic patients with diabetic nephropathy., Methods: We performed an open randomized follow-up study of normotensive type 1 diabetics with nephropathy either treated (N = 15) or not (N = 17) with captopril twice per day (average 74, range 12.5 to 125 mg/day). The main outcome measures were arterial blood pressure, albuminuria, and glomerular filtration rate (GFR; 51Cr-EDTA plasma clearance, twice yearly)., Results: Arterial blood pressure (mm Hg) was kept constant in the captopril group, at baseline (mean, SEM), 128/78 (3/2) and during follow-up 129/77 (4/1) but increased significantly in the control group from 127/79 (2/1) to 137/84 (5/2) (P < 0.01). Furthermore, 8 out of the 17 control subjects required treatment with blood pressure-lowering drugs because they developed hypertension. The fractional albumin clearance (x10-5) remained unchanged in the captopril group: baseline [10.8 (1.25) geometric mean and antilog (SEM)] during the eight years [11.8 (1.47)], while a significant rise occurred in control patients: 13.3 (1.23) to 26.2 (1.42) (P < 0.05). Baseline GFR was nearly identical: 111 (6) and 115 (4) mL/min/1.73 m2 in the captopril and control group, respectively. The median (range) rate of decline in GFR (mL/min/year) was 1.7 (10.7 to -2.0) in the captopril group versus 2.8 (17.7 to -2.6) in the control group (P = NS)., Conclusions: The beneficial effect of captopril in arresting the rise in systemic blood pressure and albuminuria is long lasting. A loss in GFR is minimal in most patients with diabetic nephropathy if normotension is sustained by prospective treatment with ACE inhibitors or restored by implementation of other antihypertensive medications with the development of hypertension.

Background: Diabetic nephropathy is a major cause of renal failure. The decline in glomerular filtration rate (GFR) is highly variable, ranging from 2 to 20, with a median of 12 mL/min/year. The risk factors of losing filtration power (progression promoters) have not been clearly identified. Furthermore, information on optimal arterial blood pressure, glycemic control, and cholesterol levels are lacking., Methods: We measured GFR with (51)Cr-EDTA plasma clearance technique, blood pressure, albuminuria, glycosylated hemoglobin A1c, and serum cholesterol every year for seven years (range 3 to 14 years) in 301 consecutive type 1 diabetic patients with diabetic nephropathy recruited consecutively during 1983 through 1997. Diabetic nephropathy was diagnosed clinically if the following criteria were fulfilled: persistent albuminuria> 200 microg/min, presence of diabetic retinopathy, and no evidence of other kidney or renal tract disease. In total, 271 patients received antihypertensive treatment at the end of the observation period., Results: Mean arterial blood pressure was 102 +/- 0.4 (SE) mm Hg. The average decline in GFR was 4.0 +/- 0.2 mL/min/year and even lower (1.9 +/- 0.5 mL/min/year) in the 30 persistently normotensive patients, none of whom had ever received antihypertensive treatment (P < 0.01). A multiple linear regression analysis revealed a significant positive correlation between the decline in GFR and mean arterial blood pressure, albuminuria, glycosylated hemoglobin A(1c), and serum cholesterol during follow-up (R(adj)(2) = 0.29, P < or = 0.001). No threshold level for blood pressure, glycosylated hemoglobin A(1c), or serum cholesterol was demonstrated. A two-hit model with mean arterial blood pressure and glycosylated hemoglobin A(1c) below and above the median values (102 mm Hg and 9.2%, respectively) revealed a rate of decline in GFR of only 1.5 mL/min/year in the lowest stratum compared with 6.1 mL/min/year in the highest stratum (P < 0.001)., Conclusions: The prognosis of diabetic nephropathy has improved during the past decades, predominantly because of effective antihypertensive treatment. Genuine normotensive patients have a slow progression of nephropathy. Several modifiable variables have been identified as progression promoters.

Background: Impairment of glomerular size selectivity has been demonstrated by the dextran-sieving technique in nephropathic diabetics with heavy, but not mild proteinuria. The purpose of the present study was to determine whether such a barrier defect could be demonstrated with mild proteinuria by substituting Ficoll 70, a polysucrose, for dextran as a probe of the filtration barrier., Methods: Differential solute clearances were performed in 12 individuals with early diabetic nephropathy on two occasions: after 60 days of treatment with losartan 50 mg daily or a placebo. An uncharged preparation of nonreabsorbable Ficoll 70 was infused along with inulin. Fractional clearance (theta) of Ficoll of discrete size was determined after separating molecules in urine and plasma in narrow 2 A fractions over a 20 to 60 A radius interval by size exclusion high-performance liquid chromatography (HPLC). A hydrodynamic theory of hindered ficoll transport through water-filled pores was used to characterize the pore size distribution of the glomerular barrier., Results: The theta for Ficoll molecules with radii> 50 A was selectively enhanced in placebo-treated diabetic nephropathy versus corresponding theta in healthy control subjects (N = 12). Computations revealed a lower distribution of glomerular pores that was unaltered in nephropathic diabetics. However, an upper distribution of large, shunt-like pores was more prominent, exceeding healthy controls by one order of magnitude in diabetic nephropathy (P = 0.01). A trend to lower theta for Ficoll in the 56 to 60 A radius range during losartan therapy is computed to have lowered the fraction of shunted filtrate by 26 to 44%, depending on whether glomerular pressure declined. The corresponding reduction in theta for endogenous albumin, IgG, and IgG4 was by 19 to 23% (P < 0.05)., Conclusion: Our findings suggest that shunt-like defects, partially reversible by angiotensin II blockade, are present early in the course of diabetic nephropathy. We estimate that such defects can account for immunoglobulinuria in this disorder. Additional impairment of either charge- or shape-selectivity must be invoked to explain the observed level of albuminuria, however.

Background: The causes of albuminuria in patients with type 2 diabetes are heterogeneous and are scantily investigated, particularly if the patient has a lack of diabetic retinopathy. Therefore, we evaluated the structural background of albuminuria in a large consecutive group of Caucasian patients with type 2 diabetes without retinopathy., Methods: Three hundred forty-seven consecutive patients with type 2 diabetes with persistent albuminuria (>300 mg/24 h) were recorded. Fundus photo (80%) and ophthalmoscopy were performed. Ninety-three (27%) had no retinopathy, and a kidney biopsy was performed in 52 (56%) of these patients. An insufficient tissue sample was obtained in one patient. The biopsies were evaluated by three masked nephropathologists., Results: The biopsies revealed diabetic glomerulopathy in 69% of the patients (28 males and 7 females), while the remaining 31% (95% CI, 18 to 44) had either nondiabetic glomerulopathies such as glomerulonephritis (N = 7, 6 males and 1 female, 13%) or normal glomerular structure (N = 9, 7 males and 2 females, 18%). No significant differences in sex, age (56 +/- 8 vs. 53 +/- 10 years, mean SD), body mass index (30 +/- 4 vs. 31 +/- 8 kg/m2), known duration of diabetes (6 +/- 6 vs. 4 +/- 3 years), GFR (95 +/- 29 vs. 89 +/- 31 mL/min/1.73 m2), albuminuria (1304 +/- 169 to 4731 vs. 1050 +/- 181 to 5176 mg/24 hours), blood pressure (150/87 +/- 16/9 vs. 145/89 +/- 16/9 mm Hg), prevalence of hypertension (89 vs. 100%), hemoglobin A1c (8.2 +/- 1.6% vs. 9.0 +/- 2.5%), and serum total cholesterol (7.1 +/- 2.4 vs. 6.3 +/- 1.6 mmol/L) were found between patients with and without diabetic glomerulopathy., Conclusions: Albuminuric patients with type 2 diabetes without diabetic retinopathy have a prevalence of biopsies with normal glomerular structure or nondiabetic kidney diseases of approximately 30%. A separation between diabetic and nondiabetic glomerular lesions was not possible based on demographic, clinical, or laboratory data. Consequently, such patients may require further evaluation, including a kidney biopsy.

Background: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition., Methods: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo in random order. At the end of each period, albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined., Results: Both doses of losartan and enalapril reduced albuminuria (P < 0.05) and mean arterial blood pressure (MABP; P < 0.05), whereas GFR remained stable. Albuminuria was reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril 20 mg, and MABP fell by 9 +/- 2, 8 +/- 2, 6 +/- 3, and 11 +/- 3 mm Hg (mean +/- SEM), respectively. No significant differences were found between the effects of losartan 100 mg and enalapril 20 mg. HbA1C and sodium intake remained unchanged throughout the study, whereas a significant rise in serum potassium occurred during ACE inhibition., Conclusion: The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.

Background: Initiation of a low-protein diet (LPD) in patients with various nephropathies induces a faster initial and slower subsequent decline in the glomerular filtration rate (GFR). Whether this initial phenomenon is reversible or irreversible remains to be elucidated., Methods: We performed an eight-week prospective, randomized, controlled study comparing the effect of an LPD with a normal-protein diet (NPD) in 29 insulin-dependent diabetic patients with diabetic nephropathy. At baseline, the patients were randomized to either an LPD (0.6 g.kg-1.24 hr-1, LPD group, N = 14) or their NPD (NPD group, N = 15) for four weeks (phase I). Between weeks 4 and 8, all patients received their NPD (phase II, recovery). Dietary protein intake (g.kg-1.24 hr-1), GFR (51Cr-EDTA, ml.min-1.1.73 m-2), albuminuria (enzyme-linked immunoadsorbent assay, mg.24 hr-1), and arterial blood pressure (Hawksley random zero sphygmomanometer, mm Hg) were measured at baseline and after four- and eight-weeks of follow-up. During the investigation, all patients in the LPD group (N = 12) and in the NPD group (N = 14) received their usual antihypertensive treatment., Results: At baseline, the LPD group and the NPD group were comparable regarding dietary protein intake, GFR, albuminuria, and arterial blood pressure. During phase I, a significant decline in dietary protein intake, GFR, and albuminuria (mean, 95% CI) was observed in the LPD group [0.4 (0.3 to 0.5) g.kg-1.24 hr-1, 8.6 (3.2 to 13.9) ml.min-1.1.73 m-2, and 28.7 (14.0 to 40.9)%, respectively] compared with the NPD group [0.0 (-0.1 to 0.2) g.kg-1.24 hr-1 (P < 0.0001 between diets), 2.5 (-1.8 to 6.8) ml.min-1.1.73 m-2 (P = 0.07 between diets), and 0.0 (-20.1 to 23.5)% (P < 0.05 between diets), respectively]. Conversely, during phase II, a significant increase in dietary protein intake, GFR, and albuminuria [mean, 95% CI; 0.3 (0.2 to 0.5) g.kg-1.24 hr-1, 5.9 (0.8 to 11.1) ml.min-1.1.73 m-2, and 25.0 (4.5 to 49.6)%, respectively] took place in the LPD group compared with the NPD group [0.0 (-0.2 to 0.1) g.kg-1.24 hr-1 (P < 0.0001 between diets), -2.9 (-6.4 to 0.6) ml.min-1.1.73 m-2 (P < 0.01 between diets), and 2.9 (-18.3 to 29.7)% (P = 0.16 between diets), respectively]. Arterial blood pressure was comparable in the two groups of patients during phase I and II., Conclusions: Dietary protein restriction for four weeks induces a reversible decline in GFR and albuminuria in insulin-dependent diabetic patients with diabetic nephropathy, whereas systemic blood pressure remains unchanged.

Background: A high plasma total homocysteine (tHcy) concentration is a risk factor for cardiovascular disease in the nondiabetic population and in nondiabetic patients with end-stage renal disease., Methods: We prospectively evaluated the impact of tHcy concentrations on mortality in 211 white non-insulin-dependent diabetic (NIDDM) patients of less than 70 years of age at entry (61 with microalbuminuria and 44 with macroalbuminuria). They were followed for a median of 6.4 (range 0.2 to 7.1) years., Results: At the end of the follow-up period, 49 of 211 (23%) patients had died, 30 (61%) from cardiovascular disease. Univariate Cox survival analysis revealed that baseline tHcy level (1 micromol/liter) was associated with an increased all-cause mortality risk of 1.11 [95% confidence interval (CI) 1.08 to 1.15, P < 0.0001], and a cardiovascular mortality risk of 1.09 (CI 1.03 to 1.16, P < 0.01). The six-year cumulative all-cause mortality hazard was 44%, 14%, and 15% in the high (tHcy >/= 8.2 micromol/liter), the middle (tHcy 6. 2-8.1 micromol/liter), and the low (tHcy

The antiproteinuric effect of angiotensin converting enzyme (ACE) inhibition in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy varies considerably. Therefore, we tested the potential role of an insertion (I)/deletion (D) polymorphism of the ACE gene on this early antiproteinuric responsiveness in an observational follow-up study. Sixty (II, N = 13; ID, N = 26 and DD, N = 21) young hypertensive IDDM patients suffering from diabetic nephropathy were investigated during three months before and for the initial six month period during ACE inhibition [captopril 44 (SD 22) mg/24 hr, no differences in drug dose between groups]. Blood pressure (MABP) and albuminuria (ELISA) were measured three (1 to 6) times before and three (1 to 13) times during ACE inhibition. At baseline the groups (II/ID/DD) had comparable (1) mean arterial blood pressure (MABP mm Hg) of 113 +/- 10/108 +/- 9/114 +/- 8, (2) albuminuria (geometric mean with 95% CI) 1394 (747 to 2608)/1176 (844 to 1797) and 1261 (827 to 2017) mg/24 hr, and (3) serum creatinine (geometric mean with 95% CI), 80 (68 to 93)/85 (76 to 97)/103 (85 to 119) mumol/liter, respectively. Angiotensin converting enzyme inhibition induced a significant reduction in MABP, albuminuria and kidney function in all three groups (II/ID/DD; P < 0.05): (1) MABP (mean +/- SD) 12 +/- 7/5 +/- 7/8 +/- 9 mm Hg (ANOVA, P = 0.02); (2) albuminuria [mean (95% CI)] 61 (34 to 77)/22 (3 to 37)/31 (13 to 46) %, (ANOVA, P < 0.01); and (3) increasing serum creatinine [mean (95% CI)] 8 (4 to 12)/9 (3 to 16)/8 (0 to 16) % (ANOVA, NS), respectively. Adjusting for differences in reduction in MABP did not change the association between decrease in albuminuria and ACE/ID genotypes (P < 0.01). A multiple linear regression analysis revealed that the ACE/ID polymorphism, albuminuria and MABP at baseline independently influenced the decline in albuminuria after initiation of ACE inhibition (R2 = 0.21, P < 0.01). A significant association between changes in MABP and albuminuria was demonstrated (R2 = 0.16, P < 0.01). Our data show that hypertensive albuminuric IDDM patients with the II genotype are particularly susceptible to commonly advocated renoprotective treatment.

We investigated the effect of acute lowering of blood pressure (BP) upon glomerular filtration rate (GFR) in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients, 14 with diabetic nephropathy and 12 with normoalbuminuria. The study was performed twice with the subjects receiving an intravenous injection of either clonidine (150 to 225 micrograms) or saline (0.154 mmol/liter). We assessed GFR, albuminuria, and BP. The two groups were well matched with respect to demographic data, baseline GFR and BP. Clonidine induced similar reductions in mean arterial blood pressure 19 (SE +/- 4) and 21 (SE +/- 3) mm Hg in patients with and without nephropathy, respectively. In the nephropathy group GFR diminished in average from 90 (SE +/- 6) to 81 (SE +/- 7) ml/min/1.73 m2 (P = 0.006), fractional clearance of albumin (x 10(-6)) declined from a geometric mean of 219 (antilog SE /divided by 1.3) to 186 (antilog SE /divided by 1.3) (P = 0.04), and four patients had a complete pressure-passive vasculature, defined as delta GFR% = delta MABP%. A significant correlation between relative reductions in MABP and GFR (r = 0.78, P < 0.001) was demonstrated in albuminuric patients. None of the normoalbuminuric patients had a complete pressure-passive vasculature and there were no significant differences in GFR between the two examinations, but five had abnormal autoregulation of GFR. Mean difference between changes in GFR (95% confidence interval) between the nephropathic and normoalbuminuric group was 5.5 (divided by 2.7 to 13.7) ml/min/1.73 m2 (P = 0.18). Our study suggests that hypertensive NIDDM patients, particularly patients with nephropathy, frequently suffer from impaired or abolished autoregulation of GFR.

The aim of our study was to evaluate the diurnal relationship between arterial blood pressure and albuminuria, and some potential mechanisms responsible for impaired nocturnal blood pressure reduction (non-dippers, groups I and II) in diabetic nephropathy (DN). Twenty-four-hour ambulatory blood pressure, heart rate (HR) variation (autonomic nervous function) and extracellular fluid volume (ECV) were measured, and urine samples were collected three times during the corresponding day- and nighttimes in 47 insulin-dependent diabetic (IDDM) patients with DN. Mean arterial blood pressure (MABP) during the daytime [mm Hg, median (range)] was identical in group I [105 (96-137)], group II [109 (86-124)] and group III [dippers; average blood pressure reduction from day to night > 10%, 107 (93-132), P = NS], while the nighttime MABP differed [group I, 106 (95-144); group II, 100 (78-118); group III, 91 (76-118); P < 0.001]. No significant difference between the groups concerning the daytime or nighttime albuminuria [microgram/min; median (range)] was observed; [Day: group I, 1467 (235-3933); group II, 695 (170-6719); group III, 875 (228-3173). Night: group I, 1079 (279-4665); group II, 572 (113-3807); group III, 659 (81-2493)]. A significant correlation between MABP and albuminuria was demonstrated during day- (rho = 0.50, P < 0.0005) and nighttime (rho = 0.46, P < 0.005), while neither the absolute nor the relative changes in MABP from day to night correlated significantly with absolute or relative changes in albuminuria from day to night. The night/day ratio of HR was higher in group I [0.93 (0.76-1.09), median (range)] compared to group III [0.83 (0.74-1.02), P < 0.005] and a significant correlation between this ratio and the night/day ratio of MABP was found (rho = 0.54, P < 0.0005). ECV was about the same in the three groups. Our study indicated an association between blood pressure and albuminuria, but the mechanisms involved in the reduction of albuminuria from day to night was not unraveled. A relative lack of sympathetic withdrawal during sleep seems to be an important feature of nocturnal hypertension in diabetic nephropathy.

We assessed the prognosis of diabetic nephropathy during long-term antihypertensive treatment as compared to the prognosis during the natural history of this complication in a prospective study of all IDDM patients (N = 45) aged under 50 with onset of diabetes before the age of 31 who developed diabetic nephropathy between 1974 and 1978 at Steno Diabetes Center, and were followed until death or for at least 16 years [median 16 (4 to 21) years]. Antihypertensive treatment was started 3 (0 to 13) years after onset of diabetic nephropathy. Mean arterial blood pressure at start of antihypertensive treatment was 148/96 (sd 12/10) mm Hg and 143/86 (16/6) mm Hg during the whole interval of antihypertensive treatment (P < 0.01). The cumulative death rate was 45% (95% C.I. 38 to 52) 16 years after onset of diabetic nephropathy, in contrast to previous reports 88% and 94% 12 and 16 years after onset of diabetic nephropathy, respectively. The median survival time in our study exceeded 16 years as compared to five and seven years in untreated patients in the past. Uremia was the main cause of death (12 patients; 55%). In 1994 serum creatinine was 116 (74 to 311) mumol/liter in the 23 surviving patients. The preservation of kidney function and the prognosis of diabetic nephropathy has improved during the past two decades mainly because of effective antihypertensive treatment.

Initiation of antihypertensive treatment (AHT) in hypertensive insulin-dependent diabetic (IDDM) patients with diabetic nephropathy (DN) induces a faster initial (0 to 6 months) and a slower subsequent (6 months to end of observation) decline in GFR [delta GFR (ml/min/month) approximately 1.5 vs. 0.35]. Whether this initial phenomenon is reversible (hemodynamic) or irreversible (structural damage) after prolonged AHT is not known. To elucidate these mechanisms we investigated 42 hypertensive IDDM patients (16F/26M, age 40 +/- 7 years, mean +/- SD) with DN receiving AHT (angiotensin converting enzyme inhibition, N = 30) for 6 (2 to 15) years [median (range)]. GFR (ml/min/1.73 m2), arterial blood pressure (BP, mm Hg) and albuminuria (mg/24 hr) were measured the last day on AHT and one month after withdrawal of AHT. The measured variables were all significantly elevated after withdrawal of AHT: GFR [mean(SEM)] from 76(4) to 81(4) (P < 0.0001), BP [mean(SEM)] from 140/82 (2/1) to 151/89 (2/1) (P < 0.0005) and albuminuria [geometric mean (antilog SEM)] from 704 (1.2) to 1122 (1.2) (P < 0.0001). A correlation between relative rise in systolic blood pressure (delta Sys%) and relative change in GFR (delta GFR%) was found (r = 0.44, P < 0.005). Our results render some support of the hypothesis that the faster initial decline in GFR is due to a functional (hemodynamic) effect of AHT, which does not attenuate over time, while the subsequent slower decline reflects the beneficial effect on progression of diabetic nephropathy.

A prospective study of the prevalence and causes of persistent albuminuria (greater than 300 mg/24 hr) was conducted in non-insulin-dependent diabetic (NIDDM) patients, age less than 66 years, attending a diabetic clinic during 1987. All eligible patients (N = 370) were asked to collect at least one 24-hour urine sample for albumin analysis. Urine collection was obtained in 224 males and 139 females (98%). Fifty patients (7 women) suffered from persistent albuminuria (13.8%). The prevalence of albuminuria was significantly higher in males (19%) than in females (5%). A kidney biopsy was performed in 35 patients (70%). The kidney biopsies revealed diffuse and/or nodular diabetic glomerulosclerosis in 27 patients (77%), while the remaining eight patients (23%) had a variety of non-diabetic glomerulopathies, such as minimal lesion and mesangioproliferative glomerulonephritis. Diabetic retinopathy was present in 15 of 27 patients (56%) with diabetic glomerulosclerosis, while none of the eight patients with a non-diabetic glomerulopathy had retinopathy. Our cross sectional study has revealed a high prevalence of albuminuria and of non-diabetic glomerulopathy as a cause of this complication in NIDDM patients. Presence of diabetic retinopathy strongly suggests that a diabetic glomerulopathy is the cause of albuminuria. Albuminuric non-insulin-dependent diabetic patients without retinopathy require further evaluation, that is, kidney biopsy.

For yet unidentified reasons less than 50% of patients with insulin-dependent mellitus develop diabetic nephropathy. Genetic factors have been suggested as risk markers for development of nephropathy in diabetes. To further evaluate this hypothesis we studied the prevalence of nephropathy in diabetic siblings of diabetic patients with and without nephropathy. From a representative sample of 619 patients with insulin-dependent diabetes, we identified 20 patients with and 29 patients without nephropathy having diabetic siblings. Diabetic nephropathy (defined as urinary albumin excretion greater than 300 mg/24 hr) was found in 7 out of 21 siblings to patients with nephropathy and 3 out of 30 siblings to normoalbuminuric patients (P less than 0.04). No significant differences between the two groups of siblings with respect to age, diabetes duration, sex distribution, blood pressure or glycosylated hemoglobin A1c-levels were found. A significant correlation within sib-pair of glycosylated hemoglobin A1c was found (r = 0.47; P less than 0.001). We conclude that familial clustering of diabetic nephropathy does occur. This clustering may either be due to genetic inheritance or to sib-similarities due to shared environment, as indicated by the correlation of glycosylated hemoglobin A1c within sib-pairs.

Genetic predisposition to essential hypertension, as indicated by increased maximal velocity of Na+/Li+ countertransport in red cells, has been suggested as a marker for the risk of developing diabetic nephropathy. To evaluate the validity of this concept in non-insulin-dependent diabetics, we measured the maximal velocity of Na+/Li+ countertransport in red cells in 18 male diabetics suffering from proteinuria due to biopsy proven diabetic glomerulosclerosis (GFR: 51 [range 27 to 146] ml/min/1.73 m2), 17 male diabetics with normoalbuminuria, and in 18 sex-, age-, and body mass index-matched healthy control subjects. Na+/Li+ countertransport was identical in patients with and without diabetic nephropathy, 0.43 (0.24 to 0.92) versus 0.44 (0.20 to 0.83) mmol/(liter cells x hr), but was elevated compared to control subjects, 0.32 (0.09 to 0.73; P less than 0.05). Arterial blood pressure was elevated in patients with nephropathy (162/92 +/- 21/9 mm Hg) compared to normoalbuminuric patients (132/82 +/- 15/7) and control subjects (133/83 +/- 14/7 mm Hg; P less than 0.001). Our study does not support the hypothesis that the risk of diabetic nephropathy in non-insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Diabetes per se seems to enhance Na+/Li+ countertransport activity.

The present study was undertaken to evaluate some pathophysiological mechanisms of edema formation in diabetic nephropathy. Sixty-three subjects were investigated: 9 normal subjects (I), 9 normoalbuminuric Type 1 (insulin-dependent) diabetic patients (II), 15 microalbuminuric Type 1 diabetic patients (III), 16 Type 1 diabetic patients with nephropathy without edema (IV), and 14 Type 1 diabetic patients with nephropathy and edema (V). Plasma volume (125I-albumin), glomerular filtration rate and extracellular fluid volume (51Cr-EDTA) were measured. Colloid osmotic pressure and albumin concentration were measured in plasma and in subcutaneous interstitial fluid (suction blister technique). The ratio between plasma volume and interstitial fluid volume was reduced in patients with edema compared with group 1 (P less than 0.05). The interstitial colloid osmotic pressure (mm Hg) was significantly reduced (P less than 0.05) in group V compared with the other groups (V: 4.3 +/- 1.1, I: 7.9 +/- 1.7, II: 7.5 +/- 1.8, III: 6.6 +/- 1.5, IV: 6.6 +/- 1.1), but the transcapillary colloid osmotic gradient in patients with edema was comparable with the remaining subjects. The ratio between interstitial and plasma albumin concentration was significantly reduced in group V compared with groups I and II (V: 0.31 +/- 0.1, I: 0.43 +/- 0.06, II: 0.44 +/- 0.06; P less than 0.01; III: 0.41 +/- 0.07, IV: 0.41 +/- 0.08). This reduction was mainly due to enhanced lymph flow. The wash-down of subcutaneous interstitial protein indicated increased capillary filtration, but at the same time limited the increase in net filtration pressure and thereby prevented progressive edema formation in diabetic nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Micropuncture studies were made on insulin-treated streptozotocin diabetic rats two weeks after the induction of diabetes and on age-matched control rats. Kidney size, GFR and single nephron GFR were higher in poorly controlled diabetic rats than in normal animals. Single nephron GFR rose as a result of an increase in the hydraulic pressure difference across the glomerular capillary wall caused mainly by a rise in the glomerular capillary pressure due to a diminished ratio of afferent to efferent arteriolar hydraulic resistances. Furthermore, the intratubular pressure was reduced as a result of a decrease in hydraulic resistance in the loop of Henle. Strict metabolic control prevented these changes. In conclusion, the increase in renal function in experimental diabetes is determined by the degree of metabolic control excluding a potential nephrotoxic effect of streptozotocin per se.

GFR, RPF, and kidney size were measured in nine young recently diagnosed insulin-dependent diabetics before (days 0) and 3 and 8 days after the beginning of the initial insulin treatment and in comparable control subjects. Kidney function was measured by a constant infusion technique using I-125-iothalamate and 131-I-hippuran. Kidney size was determined by means of ultrasound. Before insulin treatment elevated values for GFR (+44%, P less than 0.01), RPF (+18%, P less than 0.05), and kidney size (+29%, P less than 0.01) were found. Near-normal metabolic control was achieved in all patients using either multiple subcutaneous injections of insulin or an artificial betacell. GFR decreased from 160 +/- 9 SEM to 141 +/- 6 ml/min X 1.73 m2 (P less than 0.01) and further to 133 +/- 5 ml/min X 1.73 m2 (P less than 0.01, compared to day 0). Renal plasma flow was 601 +/- 33 and 588 +/- 44 ml x 1.73 m2 at days 0 and 3, respectively (NS) and decreased to 558 +/- 35 ml/min x 1.73 m2 at day 0 (P less than 0.01). By contrast no statistically significant changes in kidney volume were observed; the results on day 0, 3 and 8 were 145 +/- 7, 162 +/- 11 and 143 +/- 9 ml/1.73 m2, respectively. The present study demonstrates that kidney size and function are elevated at the onset of insulin-dependent diabetes. Near-normal metabolic control; for 8 days induces a reduction but not a complete normalization in kidney function. From the present observations it is suggested that the rapidly reversible part of the elevation in GFR cannot be explained by concomitant changes in kidney and glomerular size (morphological origin) but is probably due to a reduction in renal plasma flow and to a decreased transglomerular pressure (functional origin).

The glomerular hemodynamics were studied in streptozotocin diabetic rats 3 months after the induction and in age-matched normal animals. Indomethacin infusion failed to cause changes in glomerular hemodynamics in normal rats but produced striking effects in the diabetic rats: The afferent arteriolar hydraulic resistance increased substantially while the efferent resistance rose moderately causing large reductions in single nephron blood flow and in the hydraulic pressure in the glomerular capillaries. Consequently, single nephron glomerular filtration rate (SNGFR) was reduced significantly below normal. The ultrafiltration coefficient of the glomerular membrane was significantly lower in the diabetic than in the normal animals (2.8 versus 5.0 nl min-1 mm Hg-1) and remained unchanged during indomethacin infusion. Our results suggest that the prostaglandin system compensates for the changes in the glomerular hemodynamics induced by diabetes by reducing the arteriolar resistances to increase the glomerular capillary pressure making it possible to maintain normal values of SNGFR and nephron blood flow.