No nephropathy in Type 2 diabetic patient with POEMS syndrome with an elevated plasma VEGF.

Vascular endothelial growth factor (VEGF) is considered to have a role in the pathogenesis of diabetic retinopathy. Recent experimental observations that anti-VEGF neutralizing antibody fully abolished the hyperfiltration and the increase in urinary albumin excretion suggested the contribution of VEGF to the development of diabetic nephropathy, as well. Here, we present a case of POEMS (Crow-Fukase) syndrome with Type 2 diabetes, which was associated with elevated plasma VEGF level, but no sign of diabetic nephropathy. The findings obtained from this case did not support the hypothesis that VEGF may enhance the development of diabetic nephropathy.

Structural changes in renal arterioles in Type I diabetic patients.

AIMS/HYPOTHESIS: We aimed to obtain data on arteriolar structure in a follow-up study of microalbuminuric diabetic patients. METHODS: Kidney biopsies were obtained at baseline and after 8 years in 18 Type I (insulin-dependent) diabetic patients. Albumin excretion rate, blood pressure and HbA(1C) were measured regularly, and the glomerular filtration rate (GFR) was measured at the time of the kidney biopsy. The biopsy was embedded into plastic blocks and serially sectioned with 1 microm sections. In levels 25 microm apart, afferent and efferent arteriolar profiles were identified and digitised in the electron microscope. The extra-cellular matrix as volume fraction of the media was measured, and estimates of thickness of matrix, media, endothelium and lumen were obtained. Baseline and follow-up biopsies were studied concomitantly. RESULTS: A large increase was seen in matrix volume fraction in afferent ( p = 0.0001) and in efferent arterioles ( p = 0.0004). Estimated thickness of media and matrix increased, whereas endothelial cell thickness decreased, over the 8 years. There was a correlation between the parameters of diabetic glomerulopathy and arteriolar parameters in the biopsies done at 8 years, basement membrane thickness compared with afferent matrix volume fraction: r = 0.74, p = 0.0005. Also aggravation of glomerulopathy and arteriolar structure over 8 years showed positive correlation. Arteriolar parameters correlated with the albumin excretion rate (AER) and inversely with GFR. CONCLUSION/INTERPRETATION: The arteriolar accumulation of matrix parallels that taking place in glomeruli and shows association with functional parameters over 8 years in Type I diabetic patients with microalbuminuria. These changes are considered an important part of the structural lesions in the diabetic kidney underlying the development of diabetic nephropathy.

Kidney function and glomerulopathy over 8 years in young patients with Type I (insulin-dependent) diabetes mellitus and microalbuminuria.

AIMS/HYPOTHESIS: We aimed to investigate prospectively the interrelation between kidney function and glomerular morphological changes over 8 years in young patients with Type I (insulin-dependent) diabetes mellitus and microalbuminuria. METHODS: Kidney biopsies were taken at baseline and after 8 years in 18 subjects who were 20 years of age (19-29 mean and range), had duration of diabetes for 11 years (7-18), and who had an albumin excretion rate of 45 microg/min (15-194). The glomerular ultrastructural parameters were analysed using stereological methods. RESULTS: At the end of the study three patients had an increased albumin excretion rate of more than 25 % a year, two of whom developed overt nephropathy. Glomerular filtration rate declined 2.3 ml/min x 1.73 m(-2) x yr(-1). Glomerular volume, volume fractions of matrix and mesangium, and basement membrane thickness showed an increase over the 8 years. Multiple regression analysis showed that mean 8-years HbA(1 c), matrix volume fraction(baseline) and basement membrane thickness BMT(baseline) accounted for 70 % of the variation in AER at the end of the study. Mesangial volume fraction(baseline,) glomerular filtration fraction(baseline,) and mean 8-year HbA(1 c) accounted for 73 % of the change in glomerular filtration rate from baseline. Smoking was strongly associated with the glomerular filtration rate at baseline ( r = 0.65). When glomerular filtration rate(baseline) was omitted from the equation, smoking was the only significant parameter linked to the change in glomerular filtration rate from the baseline. CONCLUSION/INTERPRETATION: In patients who had diabetes for 20 years, long-term hyperglycaemia and glomerulopathy found 8 years prior to the study, and possibly smoking, affected renal function (i. e. albumin excretion rate and glomerular filtration rate).

The juxtaglomerular apparatus in young type-1 diabetic patients with microalbuminuria. Effect of antihypertensive treatment.

BACKGROUND: Our goal was to investigate the effect of antihypertensive drugs on the juxtaglomerular apparatus (JGA) in young type-1 diabetic patients with microalbuminuria. METHODS: Twelve patients were allocated to treatment with either an angiotensin-converting enzyme inhibitor (group 1, six subjects) or a beta-receptor blocker (group 2, six subjects). A comparable group of nine patients without antihypertensive treatment provided reference values (group 3, nine subjects). Renal biopsies were taken at baseline and after a median of 40 months (groups 1 and 2) and 30 months (group 3). Using light microscopy with 1microm serial sections of the plastic-embedded biopsies, volumes of the JGA and glomerulus and areas of the macula densa and lumina of the afferent and efferent arterioles were obtained. RESULTS: A significant decrease of the volume of the JGA (P=0.026) and of the volume of the JGA relative to that of its corresponding glomerulus (P=0.0005) was noted in the reference group only. Negative correlations existed between the increase in the luminal area of the afferent arteriole and mean diastolic blood pressure in the study period in group 1 (P=0.024) and group 2 (P=0.032). CONCLUSIONS: Our results showed that a decrease in the size of the JGA is offset by antihypertensives. The negative correlation between the change in the luminal area of the afferent arteriole and mean diastolic blood pressure in groups 1 and 2 suggest that renal protection in antihypertensive treatment may be through a better constriction of the afferent arteriole protecting the glomerulus from systemic blood pressure.

On glomerular structural alterations in type-1 diabetes. Companions of early diabetic glomerulopathy.

Glomerular structural modifications were measured in kidney biopsies from two follow-up studies in type-1 diabetic patients with microalbuminuria and in kidney donors. Stereologic methods were used to obtain data on glomerular composition and absolute quantities per glomerulus to supplement data on diabetic glomerulopathy previously published. Diabetic patients at baseline (n=37) showed significant changes compared with controls (n=11). The volume fraction of tuft/glomerulus was increased, the proportion of capillary surface facing peripheral basement membrane was decreased (0.72+/-0.04 vs 0.77+/-0.03, P=0.0008), the ratio of mesangial surfaces, urinary/capillary, was decreased (0.67+/-0.17 vs 1.11+/-0.28, P<10(-4)), and the average capillary diameter was increased (8.9+/-0.9 microm vs 7.5+/-1.0 microm, P=0.0002). The total volume of mesangial extracellular material per glomerulus was increased (P=0.01), whereas glomerular volume was not significantly different from controls. Follow-up biopsies after antihypertensive treatment with ACE-inhibitor (n=7) or beta-blocker (n=6; 36-48 months) and after intensive insulin treatment (n=7; 24-33 months) showed no change. In a conventionally treated group (n=9), the glomerular volume, the volume of extracellular material/glomerulus, and the capillary length increased. The mean capillary diameter did not correlate with the glomerular volume. In conclusion, the development of diabetic glomerulopathy entails structural modifications of the glomerular tuft. Antihypertensive and intensified insulin treatment seem to slow the progression of ultrastructural changes.

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.

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.

Follow-up study of glomerular dimensions and cortical interstitium in microalbuminuric type 1 diabetic patients with or without antihypertensive treatment.

BACKGROUND: A decrease in urinary albumin excretion is regularly seen with antihypertensive treatment in patients with diabetic nephropathy. Our study concerns structural data obtained by light microscopy in baseline and follow-up biopsies in antihypertensive treated patients and in a reference group. METHODS: Microalbuminuric type 1 diabetic patients with diabetes duration of 6-16 years were studied. Two groups, allocated to treatment with either angiotensin-converting enzyme-inhibitor (group 1, n=6) or beta-blocker (group 2, n=6) after the baseline biopsy, were studied in parallel, whereas the reference group (group 3, n=9), without antihypertensive treatment, was part of a previously completed study. The renal plastic-embedded biopsies were serially sectioned (1 microm), the sections being used for determining glomerular volume, vascular pole area, and interstitial space expressed as fraction of tubular cortex. RESULTS: A significant increase in glomerular volume (P=0.04) was seen in group 3 only. Vascular pole area (VPA) and VPA relative to calculated glomerular surface did not show significant changes in any of the groups, only a tendency to increase in VPA in group 3 (P=0.051). The increase in VPA correlated with systolic blood pressure during the study period (r=0.49, P=0.03). Glomerular volume did not correlate with HbA(1C), current diabetic glomerulopathy, or ensuing worsening of glomerulopathy. In group 3 every case showed an increase in interstitium (P=0.0009), group 2 showed a decrease (P=0.03), and group 1 showed no change. Increase in interstitial fractional volume correlated with diastolic blood pressure during the study (r=0.54, P=0.01). CONCLUSIONS: In early microalbuminuria, type 1 diabetic patients show glomerular growth, probably compensatory to the developing glomerulopathy. The increase in interstitial volume fraction, demonstrable in early nephropathy, is further augmented over a few years, but is arrested by antihypertensive treatment.

Lactational competence and involution of the mouse mammary gland require plasminogen.

Urokinase-type plasminogen activator expression is induced in the mouse mammary gland during development and post-lactational involution. We now show that primiparous plasminogen-deficient (Plg(-/-)) mice have seriously compromised mammary gland development and involution. All mammary glands were underdeveloped and one-quarter of the mice failed to lactate. Although the glands from lactating Plg(-/-) mice were initially smaller, they failed to involute after weaning, and in most cases they failed to support a second litter. Alveolar regression was markedly reduced and a fibrotic stroma accumulated in Plg(-/-) mice. Nevertheless, urokinase and matrix metalloproteinases (MMPs) were upregulated normally in involuting glands of Plg(-/-) mice, and fibrin did not accumulate in the glands. Heterozygous Plg(+/-) mice exhibited haploinsufficiency, with a definite, but less severe mammary phenotype. These data demonstrate a critical, dose-dependent requirement for Plg in lactational differentiation and mammary gland remodeling during involution.

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.

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.

TGF-beta1-induced glomerular disorder is associated with impaired concentrating ability mimicking primary glomerular disease with renal failure in man.

Transforming growth factor-beta1 (TGF-beta1) may play a major role in the pathogenesis of glomerulopathy and end-stage renal disease (ESRD). The aim of this study was to explore the functional consequences of localized overproduction of TGF-beta1 in relation to glomerular ultrastructure and the composition of the extracellular matrix (ECM) in the inner medulla. We used a transgenic mouse with overexpression of TGF-beta1 targeted to the juxtaglomerular apparatus (JGA) by the Ren-1c promoter. The kidney function was evaluated using urine production and metabolite excretion over a 24-hour period, glomerular filtration rate (GFR), and concentrating ability. The glomerular structure was analyzed in terms of volume, ie, the volume of the mesangium per glomerulus (Vv[mes/glom]) and the volume of the matrix per glomerulus (Vv[matrix/glom]), ECM per glomerulus, the area of the filtration surface, and the thickness of the peripheral basement membrane (PBM). Immunohistochemistry or in situ hybridization was used to examine the expression of aquaporin 2 (AQP2), plasminogen activator inhibitor-1 (PAI-1), and the composition of the ECM in the inner medulla. The mice exhibited polyuria, reduced concentrating ability, decreased GFR, and albuminuria paralleled by increased glomerular volume, with increased volume of ECM, decreased filtration surface, and thickening of the PBM being detectable between 1 and 2 months of age. The deposition of glomerular ECM was accompanied by increased levels of PAI-1. As estimated by excretion of Clara cell protein-1 (CC16) and lysozyme, tubular damage occurred only in older mice. Collagen Type I was deposited in the inner medulla in the presence of normal AQP2-expression in the collecting ducts. This study reached the following conclusions: (a) TGF-beta1 reduces the GFR and the glomerular filtration surface, (b) TGF-beta1 induces albuminuria in association with widening of the PBM, (c) expansion of the mesangial volume seems to precede the widening of the PBM, (d) TGF-beta1-induced accumulation of glomerular ECM is partly explained by increased PAI-1 expression, (e) Decreased concentrating ability and polyuria caused by accumulation of ECM in the inner medulla may be an early marker of glomerular diseases associated with increased expression of TGF-beta1 in man.

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.

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.

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.

The calcium channel blocker nitrendipine attenuates renal and glomerular hypertrophy in diabetic rats.

The efficacy of the calcium channel blocker nitrendipine in preventing early renal and glomerular hypertrophy and increased urinary albumin excretion (UAE) was studied in experimental diabetes in rats, starting treatment at the onset of diabetes. Female Wistar rats were randomised into four groups: diabetic and non-diabetic rats were given either placebo or nitrendipine (250 mg/kg) in the diet for 8 weeks. After 8 weeks the kidneys in the diabetic animals had increased significantly compared to the non-diabetic controls. In the diabetic nitrendipine-treated animals renal and glomerular hypertrophy was significantly smaller than in the diabetic placebo-treated group (p < 0.05). After an initial increment within the first week, the UAE remained constant throughout the study period in the diabetic nitrendipine-treated animals, while a steady increase was seen in the diabetic placebo-treated group (p < 0.05). No differences were seen in systemic blood pressure between calcium- channel-blocker-treated groups and placebo-treated groups. In conclusion, administration of nitrendipine to diabetic rats for 8 weeks had a significant inhibitory effect on renal and glomerular hypertrophy, and showed a tendency towards a reduction in UAE (p = 0. 06) without affecting metabolic control or systemic blood pressure.

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.

Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular structural changes in young microalbuminuric patients with Type I (insulin-dependent) diabetes mellitus.

AIMS/HYPOTHESIS: To investigate the influence of angiotensin converting enzyme inhibitors and beta blockers on the progression of early diabetic glomerulopathy. METHODS: Thirteen patients with Type I (insulin-dependent) diabetes mellitus (mean age 18.8 years) with microalbuminuria 31 (19-160) microg/min were randomised to treatment with enalapril (group 1, n = 7) or metoprolol (group 2, n = 6). Renal biopsies were taken before and after 38 (36-48) months of treatment. Albumin excretion rate, blood pressure and HbA1c were measured every third month. A reference group without antihypertensive treatment (group 3, n = 9), with similar age, diabetes duration and degree of microalbuminuria as group 1 and 2, had baseline and follow-up renal biopsies taken previously with an interval of 26-34 months, analysed at the same laboratory. Glomerular structures were measured by stereological methods. RESULTS: Measurements of basement membrane thickness, mesangial and matrix volume fractions were similar among groups at baseline. Structural variables were only increased in group 3 at follow-up. Delta values in basement membrane thickness and diabetic glomerulopathy index per 24 months were lower in group 1 and 2 than in group 3 (p < 0.05). Microalbuminuria returned to normal in group 1 and 2 only. Decreased albumin excretion rate tended to inversely correlate with increased basement membrane thickness (p = 0.08) and diabetic glomerulopathy index (p = 0.05). Mean HbA1c was similar between groups. Mean diastolic blood pressure was lower in group 1 and 2 than in group 3 (p < 0.01). Mean HbA1c and mean diastolic blood pressure correlated to changes in basement membrane thickness, mesangial volume fraction and diabetic glomerulopathy index (p < 0.05). CONCLUSION/INTERPRETATION: Contrary to findings in the group without antihypertensive treatment, no progression of glomerulopathy was seen in those treated with enalapril or metoprolol.

Neovascularization at the vascular pole region in diabetic glomerulopathy.

BACKGROUND: Diabetic nephropathy is associated with renal structural changes involving all of the compartments. Most characteristic is the diabetic glomerulopathy. Studies of the histological changes during the early phases of nephropathy have included the glomerulopathy and also the juxtaglomerular structures. Neovascularization, well-known in diabetic retinopathy, has also been observed in the kidney. The present study concerns estimates of frequency of neovascularization at the vascular pole region in early stages of diabetic nephropathy. METHODS: Extra efferent arterioles at the glomerular vascular pole were detected during measurements of the vascular pole area applying 1-microm serial sections through kidney biopsies. It was observed that more than one efferent arteriole existed occasionally. The present study was carried out with the aim of estimating the frequency of this phenomenon in diabetic patients and in non-diabetic controls, the diabetic patients categorized according to the level of albumin excretion rate. RESULTS: Neovascularization was first observed in IDDM patients with microalbuminuria. Some of the cases presented the phenomenon in all of the glomeruli studied. As the examinations of many kidney biopsies continued the phenomenon was observed also in the non-diabetic control group and in one IDDM patient with normoalbuminuria. However, the frequency was statistically highly significantly increased in patients with elevated albumin-excretion. Within this group a strong correlation between frequency of neovascularization and the severity of diabetic glomerulopathy is seen. CONCLUSIONS: The vascular abnormality localized to the vascular pole region is observed occasionally in the normal kidney, but the frequency is increased in patients with diabetic glomerulopathy. The abnormality may develop as a consequence of a long-standing diabetic glomerulopathy and might lead to less pronounced elevation of albumin excretion.

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.