Glomerular morphology by light microscopy in non-insulin-dependent diabetes mellitus. Lack of glomerular hypertrophy.

We quantitated glomerular structure by light microscopy in 19 subjects with non-insulin-dependent diabetes mellitus (NIDDM) and studied the possible connection between morphology and urinary albumin concentration. Autopsy material was collected retrospectively from diabetic subjects in whom urinary albumin concentration had been measured within 1.5 yr. Nineteen consecutive sex- and age-matched nondiabetic subjects were controls. A quantitative study of a random sample of glomeruli was performed blindly on periodic acid-Schiff (PAS)-stained sections. The main parameters obtained were 1) mean volume of open glomeruli, 2) frequency of glomerular occlusion, and 3) volume fraction of red-stained material (PAS-positive substance) in open glomeruli [Vv(R/G)]. There was no increase in glomerular volume in these NIDDM subjects, contrary to the glomerular hypertrophy found early as well as late in insulin-dependent diabetes mellitus. An increase in Vv(R/G) was found in diabetic subjects, demonstrating the presence of glomerulopathy as it is diagnosed by light microscopy. The frequency of glomerular occlusion was not significantly different between the groups. A high urinary albumin concentration did not necessarily reflect more advanced glomerulopathy.

Irreversibility of glomerular basement membrane accumulation despite reversibility of renal hypertrophy with islet transplantation in early experimental diabetes.

A quantitative morphologic study of the glomeruli in rats after 4 wk of streptozotocin-induced diabetes showed a number of glomerular changes, as previously described. Of particular interest was the increase in the total amount of glomerular basement membrane material [from 0.94 +/- 0.13 (SD) mm3 to 1.26 +/- 0.14 mm3 per kidney]. This parameter did not change after 4 wk of normoglycemia following islet cell transplantation (1.19 +/- 0.17 mm3), nor was the total glomerular volume normalized. The contralateral kidney was weighed and used for estimating the total amounts of protein, RNA, and DNA. Four weeks of diabetes expectedly resulted in a 50% increase in kidney weight, and islet cell transplantation diminished this to 15% in excess of normal. The average cell size (protein/DNA ratio) paralleled the kidney size after diabetes and following transplantation. The average amount of RNA per cell (RNA/DNA) increased significantly after induction of diabetes and was totally normalized after transplantation. Kidney protein concentration (mg protein/mg kidney) remained constant throughout the experiment. Considering that a few weeks of diabetes provokes a large increase in basement membrane material, it is especially noteworthy that 1 mo of normoglycemia is quite insufficient to reverse the accumulation.

Quantitative changes of cerebral neocortical structure in insulin-treated long-term streptozocin-induced diabetes in rats.

The brains of rats with streptozocin-induced diabetes treated with a low-dose insulin regimen (1 IU/day) were studied with morphometric techniques. After 1 yr of diabetes, brain weight decreased slightly (1350 +/- 71 vs. 1521 +/- 55 mg, 2P less than .01) as did the volume of the neocortex (498 +/- 36 vs. 567 +/- 40 mm3, 2P less than .05). A significant loss of neocortical neurons occurred (38 +/- 2 X 10(6) vs. 46 +/- 3 X 10(6), 2P less than .01), and the length of the capillary network in the neocortical tissue shortened disproportionately (405 +/- 102 vs. 631 +/- 47 m, 2P less than .01), leading to increased diffusion distance. The mechanisms underlying cerebral loss in this model are unknown, but abnormalities of the vascular supply with prolongation of the route of diffusion might play a role.

Advanced diabetic glomerulopathy. Quantitative structural characterization of nonoccluded glomeruli.

Quantitative ultrastructural data were obtained from kidney biopsy material of 12 long-term insulin-dependent diabetics. All patients had overt diabetic nephropathy with increased urinary albumin excretion and reduced glomerular filtration rate. Renal clearance of 51Cr-EDTA was in the range of 16-50 ml X min-1 X 1.73 m-2. All patients received antihypertensive treatment. A combined light- and electron-microscope study was performed. A significant proportion of the glomeruli was totally occluded (mean 36%, range 24-67%). Structural data presented relate only to the open, still-functioning glomeruli. Comparison with data previously obtained showed that the thickness of the peripheral basement membrane [647 nm, coefficient of variation (C.V.) 0.22] was more than twice the normal value (310 nm, C.V. 0.08); the width of epithelial foot processes (352 nm, C.V. 0.07) was significantly greater than in normal biopsies (224 nm, C.V. 0.06); and the mean volume of the open glomeruli was markedly increased compared with normal and clearly exceeded that in the early diabetic hypertrophy. Total mesangial volume and total basement membrane material per open glomerulus were increased by 277 and 614%, respectively. However, capillary length and surface per open glomerulus were similar to those observed in early diabetic hypertrophy. These findings suggest that a late glomerular hypertrophy with preservation of capillary surface occurs as a compensatory phenomenon, prolonging renal survival for diabetic nephropathy patients.

Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients.

Diabetic nephropathy leading to kidney failure is a major complication of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus, and glomerular structural lesions (especially expansion of the mesangium) may constitute the principal cause of decline in kidney function experienced by a significant fraction of diabetic patients. Although the biochemical bases of these mesangial abnormalities remain unknown, an understanding of the natural history of diabetic nephropathy from a combined structural and functional approach can lead to greater pathophysiological insight. Work in animals has supported the concept that the metabolic disturbances of diabetes mellitus cause diabetic nephropathy, with structural and functional lesions prevented or reversed with improved or normalized glycemic control. Additional research must address this fundamental issue in humans, especially the response of advancing mesangial lesions to improved glycemic control. Factors not directly related to the metabolic perturbations of diabetes may serve to accelerate or diminish the pathophysiological processes of diabetic nephropathy. The elucidation and management of these factors, when coupled with improved glycemic control, may moderate the development or progression of diabetic kidney lesions in humans.

Glomerular structure and function in diabetic nephropathy. Early to advanced stages.

Kidney biopsies from 14 insulin-dependent diabetes mellitus patients with persistent albuminuria were studied by light and electron microscopy. In terms of kidney function, the patients spanned stages from early to advanced nephropathy. The clinical parameters were (ranges, with medians in parentheses) urinary albumin excretion (UAE) 158-5494 micrograms/min (1153 micrograms/min), glomerular filtration rate (GFR) 30-128 ml.min-1 x 1.73 m-2 (90 ml.min-1 x 1.73 m-2) and mean arterial blood pressure (BP) 87-122 mmHg (109 mmHg). The severity of clinical nephropathy (UAE, GFR, and BP together) correlated with an index of the structural lesions (basement membrane [BM] thickness, mesangial expansion, and glomerular occlusion together; r = 0.62, 2P less than 0.05). GFR compared with remnant surface of glomerular capillaries (filtration surface; FS) gave values of r = 0.72 and 2P = 0.004, and UAE compared with the percentage of the peripheral BM surface carrying fluffy loose intrinsic fine structure gave r = 0.62 and 2P = 0.02. BP per se did not correlate with structural parameters. The area of FS per open glomerulus did not decrease with increasing mesangial volume fraction, which indicates compensatory changes of the capillaries in early and advanced stages of glomerulopathy. In 7 patients with less than 10% occluded glomeruli, correlations between glomerular volume and the parameters of diabetic glomerulopathy (i.e., BM thickness and volume fractions of mesangium and mesangial matrix) failed to reach statistical significance. The actual glomerular volume, however, is a product of the individual's original glomerular volume, probably the early diabetic hypertrophy and modifying changes consequent to the development of glomerulopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetic glomerulopathy. Structural characteristics of the early and advanced stages.

Studies of the glomerular structure in diabetes mellitus have helped to elucidate the basis for some functional abnormalities. The decline in glomerular filtration occurring in many long-term diabetics is a functional disorder of great clinical importance. Quantitative structural studies of the glomeruli in diabetics at different stages of disease are necessary to learn about the development of structural changes leading to the end-stage kidney disease. Preliminary results of a study of glomeruli from long-term diabetics with clinical nephropathy are compared with those obtained in control subjects and in diabetics within the first 5 yr of disease. In the long-term diabetics the peripheral basement membrane thickness was doubled. On the average, mesangial regions occupied nearly 60% of the total tuft volume as compared with 33% in the early stages. A marked accumulation of basement membrane material in the mesengial regions had taken place so that 85% of the total basement membrane material of the tufts (i.e., peripheral basement membrane in the capillary walls plus mesangial basement membrane-like material) was localized within the mesangial regions. In the early stages equal amounts were found at these two different sites. The distribution of the lesions within the kidney is under investigation in a light microscopic study of autopsy material from long-term diabetics with varying degrees of glomerulopathy. The severity of the diabetic glomerulopathy was quantitated separately within the superficial and the deep cortical zones. The results showed that there was no tendency toward increased severity in the deep glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure elevation versus abnormal albuminuria in the genesis and prediction of renal disease in diabetes.

A number of risk factors associated with the development of diabetic nephropathy has been described, such as elevated blood pressure, poor metabolic control, hyperlipidemia, and smoking. Abnormal albuminuria also is associated with progression of renal disease, but has until recently been considered principally a marker of disease activity rather than a risk factor. This article discusses the role of elevated blood pressure versus abnormal albuminuria in a genesis and prediction of renal disease in diabetes. Controversy exists regarding parental disposition to hypertension and early blood pressure elevation in the course of diabetes, but all studies agree that elevated blood pressure--in the presence of abnormal albuminuria--constitutes a risk factor. Because abnormal albuminuria is associated with progression disease, it may itself be a risk factor because increased macromolecular traffic over the glomerular membrane may produce glomerulopathy. Problems related to blood pressure measurement are important, and 24-h recordings of blood pressure may be recommended in some situations. Regarding renal structure, preliminary results suggest that structural lesions precede blood pressure elevation. The solid end point for evaluation of renal disease progression is the fall rate of GFR, with abnormal albuminuria as an intermediate end point, also in drug trials. Abnormal albuminuria may constitute a new indication for antihypertensive treatment, being, as it is, a clear indicator of organ damage, whereas elevated blood pressure with normal AER may not increase risk substantially.

Influence of insertion/deletion polymorphism in the ACE-I gene on the progression of diabetic glomerulopathy in type 1 diabetic patients with microalbuminuria.

OBJECTIVE: To investigate the influence of the insertion/deletion polymorphism of the ACE gene on the progression of early diabetic glomerulopathy in patients with and without antihypertensive treatment (AHT). RESEARCH DESIGN AND METHODS: There were 30 microalbuminuric patients with >5 years of type 1 diabetes who had renal biopsies taken at baseline and after 26-48 months of follow-up. Of the 30 patients, 13 (4 with II genotype and 9 with ID and DD genotypes) were randomized to AHT (enalapril or metoprolol) during the study. The ACE genotype was determined by a polymerase chain reaction. Glomerular structural changes were measured by stereological methods. RESULTS: Of the patients, 8 had the II genotype, 19 had ID genotype, and 3 had DD genotype. During the study, basement membrane thickness, matrix star volume, and the overall diabetic glomerulopathy index were increased in patients with ID and DD genotypes only (P < 0.001, P = 0.01, P < 0.001, respectively). Among those with ID and DD genotypes, progression of basement membrane thickening and diabetic glomerulopathy index were increased in those without AHT, as compared with the antihypertensive treated patients (P < 0.001, P = 0.02, respectively). In multivariate analysis, the ACE genotype had an independent influence on the progression of basement membrane thickening (P = 0.01), when AHT (P < 0.001) and the mean HbAlc during the study (P < 0.001) were also taken into account. ACE genotype tended to be independently associated with the diabetic glomerulopathy index (P = 0.05). CONCLUSIONS: Microalbuminuric type 1 diabetic patients carrying the D-allele have an increased progression of diabetic glomerulopathy. Presence of this allele and no AHT seems to enhance this process. Larger studies are needed to confirm the clinical significance of our findings.

Predictors of renal morphological changes in the early stage of microalbuminuria in adolescents with IDDM.

OBJECTIVE: To evaluate the impact of glycemic control, blood pressure, lipid levels, glomerular filtration rate (GFR), age, and duration of IDDM on the degree of structural glomerular changes in the transitional stage of microalbuminuria. RESEARCH DESIGN AND METHODS: Fifteen adolescents (seven boys and eight girls) with > 5 years of duration of IDDM and with low-grade microalbuminuria (15-30 micrograms/min) participated. Seventeen living kidney donors served as healthy control subjects. Five-year mean HbA1c; 5-year mean systolic and diastolic blood pressure; GFR, cholesterol, and triglycerides 2-5 years before renal biopsy; age; and duration of IDDM were investigated and related to basement membrane thickness (BMT), mesangial and matrix volume fractions, and the overall glomerulopathy index [(BMT/10 + mat/glom, %) + matrix star volume]. RESULTS: BMT and the overall diabetic glomerulopathy were increased in diabetic patients as compared with control subjects (P < 0.001), whereas matrix volume fraction, but not mesangial volume fraction, tended to be increased (P = 0.11). In multivariate analysis, BMT was predicted by 5-year mean HbA1c, diabetes duration, and previous GFR (R2 = 0.71, P = 0.003). With matrix volume fraction as the dependent variable, BMT and diabetes duration were the only significant determinants (R2 = 0.63, P = 0.003). Diabetes duration, 5-year mean HbA1c, and GFR were the variables with an independent influence on the overall diabetic glomerulopathy index (R2 = 0.72, P = 0.003). Preceding blood pressure and lipid levels or age had no significant independent influence on these morphometric measures. CONCLUSIONS: In the very early stage of microalbuminuria in IDDM adolescents, a high percentage of the variation in BMT and overall severity of glomerulopathy is explained by prolonged hyperglycemia and diabetes duration. Previous glomerular hyperfiltration may also add to the prediction of these morphological changes.

Severity of glomerulopathy predicts long-term urinary albumin excretion rate in patients with type 1 diabetes and microalbuminuria.

OBJECTIVE: To investigate whether the degree of glomerular structural lesions in young patients with type 1 diabetes and microalbuminuria was associated with urinary albumin excretion rate (AER) 6 years later and whether the AER level was influenced by blood glucose control, blood pressure, or glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: There were 17 young adults with type 1 diabetes and microalbuminuria, 8 men and 9 women with mean age 20 years (95% CI: 18-22) and duration of diabetes of 11 years (10-13), who participated in a 6-year prospective study. Kidney biopsies (measurements of basement membrane thickness [BMT] and mesangial and matrix volume fractions) and GFR were performed at baseline. AER and HbA1c were measured at least three times a year and blood pressure once a year. RESULTS: In a multivariate analysis, baseline BMT and mean 6-year HbA1c contributed significantly to AER at the end of the study (R2 = 0.69, P < 0.01). When mesangial volume fraction replaced BMT as the independent variable, this parameter and AER at baseline predicted the AER at 6 years (R2 = 0.55, P < 0.55). Mesangial volume fraction and BMT (in separate analysis) contributed significantly to change in AER during the study. During the study, neither AER (30 micrograms/min [19-40] to 16 micrograms/min [7-90]) nor blood pressure (96 mmHg [92-102] to 95 mmHg [91-98]) changed significantly in the group. However, HbA1c was reduced from 10.3 (9.6-11.0) to 8.4% (7.8-9.1) (P < 0.01). CONCLUSIONS: In young patients with microalbuminuria, the long-term urinary AER was predicted by the degree of glomerular structural changes and associated with blood glucose control, but not with blood pressure or GFR.

Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study.

OBJECTIVE: To evaluate kidney function 7 years after the end of treatment with cyclosporine A (CsA) (initial dosage of 9.3 tapered off to 7.0 mg.kg-1.day-1) in young patients (mean age 20 years) with newly diagnosed type 1 diabetes participating in a randomized, double-blind, placebo-controlled CsA trial. RESEARCH DESIGN AND METHODS: In this study, 21 patients received CsA for 12.5 +/- 4.0 months (mean +/- SD) and 19 patients received placebo for 14.4 +/- 3.8 months. The two groups were similar with regard to mean arterial blood pressure (BP), urinary albumin excretion rate (UAER), serum creatinine, and estimated glomerular filtration rate (GFR [Cockcroft and Gault]) at initiation of CsA treatment (baseline). HbA1c (mean +/- SEM) during 7 years of follow-up was also the same: 8.7 +/- 0.4 vs. 8.3 +/- 0.4% in the CsA and placebo groups, respectively. RESULTS: During the 7 years after cessation of study medication, two CsA group patients and one control patient were lost to follow-up. One placebo-treated patient developed IgA nephropathy (biopsy proven) and was excluded. Four CsA-treated patients developed persistently elevated UAER > 30 mg/24 h (n = 3 with microalbuminuria), whereas all the 17 placebo-treated patients had normal UAER (< 30 mg/24 h) after 7 years of follow-up. At the end of follow-up, the CsA group had a more pronounced rise in UAER: 2.5-fold (95% CI 1.4-4.5) higher than baseline value vs. 1.1-fold (0.7-1.7) in the placebo-treated group (P < 0.05). Estimated GFR (ml.min-1.1.73 m-2) declined from baseline to end of follow-up (1994) by 6.3 +/- 6.0 in the former CsA group, whereas it rose by 7.4 +/- 5.0 in the placebo group (P = 0.05). In 1994, 24-h blood pressure was nearly the same: 131/77 +/- 4/2 vs. 127/75 +/- 2/2 mmHg (NS) in the CsA and placebo groups, respectively. Five randomly selected CsA-treated patients had a kidney biopsy performed shortly after the CsA treatment was stopped. Interstitial fibrosis/tubular atrophy and/or arteriolopathy were present in two subjects who both subsequently developed persistent microalbuminuria. CONCLUSIONS: The results of our 7-year follow-up study suggested that short-lasting CsA treatment in young, newly diagnosed type 1 diabetic patients accelerated the rate of progression in UAER and tended to induce a loss in kidney function. Longer term follow-up is mandatory to clarify whether CsA-treated patients are at increased risk of developing clinical nephropathy.

Effect of the calcium channel blocker nitrendipine in normotensive and spontaneously hypertensive, diabetic rats on kidney morphology and urinary albumin excretion.

OBJECTIVE: To investigate the effect of nitrendipine on the development of renal changes in experimental diabetes. DESIGN: Streptozotocin (STZ)-induced diabetic normotensive Wistar rats (WIS) and spontaneously hypertensive rats (SHR) were randomly allocated to nitrendipine treatment (250 mg/kg fodder) or placebo treatment for 6 months. METHODS: Blood pressure was assessed by the tail-cuff method, urinary albumin excretion (UAE) was determined, and glomerular basement membrane (GBM) thickness, mesangial volume, and mean glomerular volume (MGV) were estimated by morphometric measurements. RESULTS: In diabetic WIS, nitrendipine significantly reduced UAE after 2 months of treatment (P< 0.05), while no effect was was seen after 4-6 months. In diabetic SHR, no effect on UAE was seen at any time. Nitrendipine was unable to inhibit the renal and glomerular enlargement in diabetic WIS and SHR. Diabetes plus hypertension was associated with significant increase in GBM thickness, while diabetes or hypertension alone showed no significant increase in GBM. Nitrendipine treatment was unable to prevent increased GBM in diabetic SHR. CONCLUSION: Nitrendipine inhibits an early increase in UAE in normotensive, diabetic rats, but fails to sustain this effect in long-term diabetes. No effect of nitrendipine was observed in SHR.

Effect of nitrendipine and nisoldipine on renal structure and function in long-term experimental diabetes in rats.

This study investigates the efficacy of late intervention with the calcium channel blockers (CCBs) nitrendipine and nisoldipine in preventing development of albuminuria and glomerular hypertrophy in experimental diabetes. Streptozotocin (STZ)-induced diabetic rats were treated with nitrendipine or nisoldipine for 6 weeks after 3 or 6 months of untreated diabetes. The CCBs were administered in the fodder in a concentration of 250 mg/kg. After 3 months of untreated diabetes, nitrendipine treatment for 6 weeks significantly reduced urinary albumin excretion (UAE; P < 0.05) and glomerular hypertrophy. Nitrendipine also prevented an increase in systemic blood pressure compared with untreated diabetes. Nisoldipine showed no significant effect on UAE or glomerular hypertrophy despite systemic blood pressures similar to those of the diabetic nitrendipine-treated group. After 6 months of untreated diabetes, treatment with nitrendipine or nisoldipine for 6 weeks did not show effects on UAE, glomerular hypertrophy, or systemic blood pressure. No effect was found on renal growth in the treatment groups, and neither nitrendipine nor nisoldipine had any effect on body weight, blood glucose level, or food intake.

Glomerular structure in lithium-induced chronic renal failure in rats.

The effects of long-term lithium administration on glomerular structure and intervention with angiotensin converting enzyme inhibitor (ACEI) were studied in rats. Male Wistar rats were fed a lithium-containing diet (Li) or control diet (C) for 16 weeks postnatally. Li-treated rats developed renal failure, hypertension and proteinuria. During the subsequent 24 weeks, subgroups were treated with ACEI. The kidneys were fixed by perfusion, and tissue blocks were serially cut for estimation of glomerular volume and glomerular characteristics by light microscopy. Mesangial and mesangial matrix volume fractions, surface density of capillary walls, basement membrane thickness and foot process width (FPW) were measured by electron microscopy. Glomerular volume was decreased in Li-rats, with increased intra-individual variation. In all Li-rats, some glomeruli (mean 27%) were abnormal, with severe changes in only three rats. Ultrastructural parameters obtained by systematic sampling of three glomeruli in each rat showed no differences among groups. Among Li-treated animals there was a significant correlation between FPW and albumin excretion per unit filtration surface, and between filtration surface per glomerulus and inulin clearance. In conclusion, long-term lithium administration to newborn rats caused marked changes in glomerular volume which were not associated with measurable changes in structural parameters. No effect of ACEI-treatment was detectable.

Renal structural changes in insulin-dependent diabetic patients with albuminuria. Comparison of cases with onset of albuminuria after short or long duration.

The large interindividual variation in diabetes duration until the onset of nephropathy is partly unexplained. This study was performed to compare renal structure in insulin-dependent (IDDM) patients who had developed signs of nephropathy after a short or long duration of diabetes. Renal biopsies were obtained from 17 IDDM patients, with albumin excretion rate 20-300 microg/min and normal blood pressure. Six patients had <25 years duration ("short-term", early onset of microalbuminuria) and eight patients had duration >30 years ("long-term", late onset of microalbuminuria). Biopsies were obtained 18 months after entry into a study testing the effect of low-dose antihypertensives. Parameters characterizing diabetic glomerulopathy were significantly increased in IDDM patients compared with those in 17 living donors: Basement membrane thickness, mean and (CV): 591 nm (0.17) vs 320 nm (0.12), mesangial volume fraction per glomerulus 0.27 (0.19) vs 0.19 (0.10), matrix volume fraction per glomerulus 0.16 (0.20) vs 0.097 (0.22), matrix star volume 38.5 microm3 (0.43) vs 13.9 microm3 (0.31), (p<10(-4) for each). Comparison of short vs long-term patients showed no significant differences in glomerulopathy parameters, glomerular volume or extracellular material per glomerulus, whereas the fraction of occluded glomeruli was significantly increased in long-term patients. A close correlation obtained between fraction of occluded glomeruli and glomerular filtration rate (r=0.72, p= 0.001). Glomerular occlusion occurred unrelated to the severity of diabetic glomerulopathy. It is suggested that diabetic macroangiopathy and arteriolar hyalinization may play an important role in the renal function of patients with slow development of nephropathy.

Long-term studies of the juxtaglomerular apparatus in young microalbuminuric type 1 diabetic patients.

AIM: To determine the long-term changes of the juxtaglomerular apparatus in incipient diabetic nephropathy. METHODS: Three renal needle biopsies were performed on 15 young type I diabetic patients with microalbuminuria; at baseline and after an average of 2.4 and 8.2 years. Using light microscopy, 1 microm serial sections of the plastic-embedded biopsies were investigated and volumes of the juxtaglomerular apparatus and glomerulus and areas of the macula densa and lumina of the afferent and efferent arterioles were measured. RESULTS: From baseline to second follow-up there was a significant decrease in JGA relative to glomerular volume. There was an increase in luminal area of the efferent arteriole which was paralleled by (non-significant) changes in the afferent arteriole. CONCLUSION: Over a period of 8.2 years JGA size remained stable, but decreased relative to glomerular size. Also, an increase in luminal area was noted in efferent arterioles. This may be due to increased single nephron blood flow secondary to nephron loss.

Renal structures in type 2 diabetic patients with elevated albumin excretion rate.

Renal biopsies were obtained from type 2 diabetic patients with elevated albumin excretion. The aim was to obtain quantitative structural data to correlate with clinical findings. Biopsies from 27 diabetic patients and 12 non-diabetic cases were analysed. Stereological methods were applied by light- and electron microscopy. Diabetic patients showed quantitatively markedly expressed diabetic glomerulopathy, but also an increase in glomerular volume, in prevalence of new-vessel formation at the vascular pole, prevalence of glomerular occlusion and in interstitial volume fraction. A significant correlation was not observed between the degree of interstitial and glomerular involvement. The glomerular hypertrophy is interpreted as a compensatory phenomenon, leading to preservation of filtration surface in the open glomeruli. Close correlation was seen between glomerulopathy and glomerular function, and also with the stage of retinopathy. New vessel formation at the vascular pole was most frequent in patients with proliferative retinopathy. Signs of non-diabetic glomerulopathy were not observed, but various atypical ultrastructural changes accompanying the advanced stages are illustrated. Our present findings correspond to data from type I diabetic patients. It is emphasised that all compartments of the kidney are affected by the diabetic state. It is suggested that the interstitial and glomerular lesions are influenced by different factors.

Renal arterioles in patients with type I diabetes and microalbuminuria before and after treatment with antihypertensive drugs.

Antihypertensive drugs can slow or even reverse the progression of diabetic nephropathy at the microalbuminuric stage. This study was performed to obtain quantitative data on changes in the renal arterioles in a follow-up study. Twelve patients with type I diabetes and with microalbuminuria were allocated to treatment for 3 years with either an ACE inhibitor (group I, 6 patients) or a beta blocker (group II, 6 patients). Baseline and follow-up renal needle biopsy specimens were taken and serially sectioned at 1 microm for light microscopy, enabling identification of arterioles as afferent or efferent. Thin sections for electron microscopy were made at 50-microm intervals, and micrographs were taken of arteriolar profiles. Matrix volume fraction of the media and a calculated matrix thickness were obtained. At baseline, structural parameters were higher than normal values. At follow-up all patients were normoalbuminuric. Both groups showed only minor changes in arteriolar structures over 3 years. In the afferent arterioles in group II there was a significant increase in the matrix volume fraction of the media, and there was a tendency to an increase in matrix thickness in both groups. In the efferent arterioles there were no significant changes in parameters. There were no differences between the two groups in arteriolar structural changes from baseline to follow-up. Thus, this study shows a slight but significant matrix accumulation in the afferent arterioles during treatment with antihypertensive drugs. This may have implications for the progression to overt nephropathy, which indicates a need for more long-term studies of treatment with antihypertensive drugs in incipient nephropathy in type I diabetes.

Enlargement of the juxtaglomerular apparatus in insulin-dependent diabetes mellitus patients with microalbuminuria.

Kidney biopsies from 15 insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria were investigated to obtain quantitative data on the juxtaglomerular apparatus. The IDDM patients were young and normotensive with a mean duration of microalbuminuria of 2 years. Eight healthy kidney donors served as controls. Measurements taken by light microscopy, using 1-microm serial sections of epon blocks, included volumes of the juxtaglomerular apparatus and of glomeruli, areas of the macula densa and luminal area of the juxtaglomerular (afferent and efferent) arterioles at the level of the glomerular vascular pole. The volume of the juxtaglomerular apparatus was significantly larger in the IDDM group than in controls [6.08 (2.96-18.8) 10(4) microm3 vs 3.48 (1.84-5.21) 10(4) microm3, P=0.003, median and (range)], as was the volume of the juxtaglomerular apparatus relative to glomerular volume [1.89(1.28-4.21)% vs 1.48 (1.13-1.71)%, P=0.004]. The area of the macula densa was also larger in the IDDM patients (1370 microm2 vs 937 microm2, P=0.03). Luminal areas of the afferent and efferent arterioles and the ratio between them did not differ significantly between the two groups. In conclusion, the juxtaglomerular apparatus is enlarged more than would be expected from the glomerular hypertrophy in IDDM patients with microalbuminuria.