Intra- and extrarenal vascular changes in the acute renal failure of the rat caused by mercury chloride

Summary Histologic evidence of intrarenal vasomotor changes were observed in the rat in the course of acute renal failure caused by the injection of HgCl₂. Male Wistar rats injected s.c. with 2.5 or 4.7 mg HgCl₂ per kg b.wt. developed fibrinoid damage in the media segments of preglomerular renal vessels, mostly in the arcuate and interlobular arteries. The lesions were patchy and irregularly scattered throughout the kidneys. 24 h post-injection the lesions were very rare and of only mild degree, whereas they were fully developed and regularly seen 48 h post-injection. A high percentage of similar changes was found in certain extrarenal vascular areas especially in the mesentery and pancreas. The damaged vascular segments were usually dilated. The results of various trichrome stains and histochemical reactions suggested edema of vascular smooth muscle cells and imbibition of the media by blood plasma substances, sometimes reaching the degree of fibrinoid necrosis. These findings were confirmed by electron microscopy. The imbibition of the smooth muscle cells by blood plasma material was clearly evidenced by the demonstration of intracellular fibrin precipitations. In connection with the degeneration of smooth muscle cells, accumulations of crystal-like fibrin formations could often be shown. Subendothelial fibrin formations were not observed. 96 h after the 2.5 mg injection the changes were already regressing, but edema of the vascular wall and signs of disturbed vasotonia persisted for several days. The maximum of the vascular changes usually coincided with the maximum of azotemia and the formation of debris cylinders in the renal tubules. However, no clear relationship was recognizable in individual cases between vascular damage, extent of tubular necrosis and renal function. The pathogenesis of the vascular changes is obscure, but neurogenic factors, increased release of catecholamines and/or vasoactive agents of renal origin in connection with other factors might play a decisive role. Arterial hypertension was absent. It is assumed that the structural damage of the vascular media is mainly brought about by prolonged or recurring vasospasms, or by alternating spasm and vasodilatation with local ischemia and increased tension of the vascular wall in the dilated segments. The altered function and structure of the vascular wall might, to a certain extent, contribute to renal insufficiency.Part of this work has been communicated at the 59, meeting of the German Society of Pathology, Kiel, May 20–24, 1975 (Verh. Dtsch. Ges. Path. 59, 454 (1975)) and at the Hacettepe University of Ankara (Turkey), June 22, 1976     

Effects of unilateral nephrectomy on erythrocytosis and arteriosclerosis induced in rats by intrarenal injection of nickel subsulfide

Summary Administration of Ni₃S₂ to rats by unilateral inrarenal (ir) injection (5 mg/rat) caused erythrocytosis, arteriosclerosis, and abnormal plasma concentrations of asparagine, glycine, histidine, and lysine. Resection of the ipsilateral (Ni₃S₂-treated) kidney on the fourth day after the ir injection prevented erythrocytosis, amino acid disturbances, and severe arteriosclerotic lesions (fibrous intimal plaques and focal medial necrosis), but did not prevent early arteriosclerotic lesions (subintimal oedema with splitting of elastica). The early arteriosclerotic lesions appear to be initiated by vascular dissemination of Ni₃S₂ particles immediately post-injection, whereas the erythrocytosis, amino acid disturbances, and advanced arteriosclerotic lesions depend upon continued presence of the Ni₃S₂-injected kidney. Resection of the contralateral (non-injected) kidney has no effect upon Ni₃S₂-induced erythrocytosis, arteriosclerosis, or amino acid disturbances. Glomerulomegaly and mesangial hyperplasia developed in control rats following unilateral nephrectomy, owing to compensatory renal hypertrophy. Glomerulomegaly was more pronounced in Ni₃S₂-treated rats following contralateral nephrectomy than following ipsilateral nephrectomy, suggesting that erythrocytosis and compensatory renal hypertrophy act synergistically to enhance glomerulomegaly.Supported by grants from the U.S. Department of Energy (EV-03140) and the National Institute of Environmental Health Sciences (ES-01337)     

Hypertrophy of Actin Bundles in Tubular Cells in Acute Renal Failure

Small bundles of actin filaments are normally present in the basal part of proximal and distal renal tubular cells and are attached to the basal cell membrane. Their functional significance is unknown, but by contracting they may have a function as a modulator of the intratubular pressure. Increased thickness and number of such actin bundles have been thought to occur in various pathologic conditions, including acute renal failure (ARF), but no quantitative data have been provided. In 19 cases of ARF of the ischemic type (“acute tubular necrosis”), the volume of these bundles was determined by morphometry and expressed per unit area underlying basement membrane (BM). It was found that in ARF there is a significant twofold to fourfold increase in actin bundles in proximal and distal tubular cells compared with findings in nine controls.     

ON THE MORPHOGENESIS OF MASSIVE CEREBRAL HEMORRHAGE IN EXPERIMENTAL HYPERTENSIVE RATS

The morphogenesis of massive cerebral hemorrhagic lesions was studied in 6 experimental hypertensive rats. Hemorrhage due to rupture of arteries caused by hypertensive arterial lesions (plasmatic arterionecrosis) was found in the middle cerebral arteries in the subarachnoid space and immediately after their penetrating into the cerebral parenchyma. This primary hemorrhage induced, through circulatory disturbances, secondary bleedings of small vessels and veins, which were all combined to give rise to a massive hemorrhagic lesion. The hypertensive arterial lesions, which were the direct cause of the cerebral hemorrhage, were constituted by necrosis and disappearance of smooth muscle cells and blood plasma infiltration in the media, blood plasma infiltration, especially deposition of fibrin, having periodic cross striation of about 200 Å (fibrinoid degeneration) in the intima, and dissolution and disappearance of the internal elastic lamina.     

Dynamics of glomerular ultrafiltration in Amphiuma means

To study renal function inAmphiuma means, the hydrostatic pressures in vascular and tubular structures and the glomerular filtration rate were determined at different arterial blood pressures. In the arterial blood pressure range studied no evidence of autoregulation of the glomerular capillary pressure or of the hydrostatic pressure gradient over the capillary membrane was found. The glomerular filtration ceases at an arterial blood pressure below 12 cm H₂O. No significant difference between tubular free flow pressure and peritubular capillary pressure was noted. Furthermore, it was found that the glomerular capillary pressure could be estimated by measuring the intratubular stop-flow pressure and arterial colloid osmotic pressure at an arterial pressure above 15 cm H₂O. It was also found possible to measure the glomerular capillary pressure at the very end of the afferent arteriole. The protein concentrations in afferent and efferent arteriolar blood were determined and the colloid osmotic pressures were calculated according to a new formula derived forAmphiuma plasma. The dynamics of glomerular ultrafiltration was evaluated. A filtration equilibrium across the glomerular membrane was reached, since the efferent colloid osmotic pressure was not significantly different from the hydrostatic pressure gradient across the glomerular capillary membrane.     

Current concepts on the pathophysiology of acute renal failure.

In the pase decade, several experimental models of acute renal failure (ARF) have been evaluated with micropuncture and hemodynamic techniques. Five of these models have been most extensively studied: glycerol injection, renal artery clamping, intrarenal norepinephrine infusion, uranyl nitrate, and mercuric chloride administration. In the first three models, renal ischemia is the initiating insult, whereas in the two nephrotoxic models a direct effect of the agent on cellular integrity is also seemingly operative. In all of these models, renal blood flow 24--48 h after the initial insult either spontaneously returns to normal or can be elevated to this level with volume expansion but without restoration of the glomerular filtration rate. Therefore, the maintenance of ARF in these various models is due to other factors, which include tubular obstruction, leakage of filtrate across damaged tubular epithelium, and a decrease in the glomerular capillary ultrafiltration coefficient. In a given model, one or all three of these alterations may be present. Although these various models may not be completely analogous to the clinical setting, they have provided powerful tools for the study of ARF and their use has greatly increased our knowledge in this field.     

Cis-diamminedichloroplatinum (II)-induced acute renal failure in the rat. Correlation of structural and functional alterations

Studies were undertaken to examine the relationship between renal morphologic and functional alterations during the development of cis-diamminedichloroplatinum (II) (CDDP)-induced acute renal failure (ARF). Control and CDDP-treated rats (10 mg/kg, intraperitoneally) were housed in metabolic cages for the purpose of renal function determinations. Renal morphology was studied by light and electron microscopy at 6, 24, 48, 72, and 96 hours following treatment. Six hours following CDDP administration, morphologic alterations consisting of nucleolar segregation, ribosome dispersion, and the formation of aggregates of smooth endoplasmic reticulum were observed throughout the P3 portion of the proximal tubule located in the outer stripe of the outer medulla and medullary rays. These changes became more frequently observed throughout P3 during the course of the study. At 24 and 48 hours, focal changes were also observed involving the P1 and P2 segments of the proximal tubule which make up the pars convoluta. ARF, indicated by a reduced creatinine clearance, was first apparent 48 hours following CDDP administration. The development of ARF was associated with focal, primarily sublethal, cell injury throughout the proximal tubule. By 72 and 96 hours necrosis primarily affecting P3 became widespread, and renal function progressively worsened. The establishment of ARF prior to the development of tubular necrosis suggests that the processes of tubular obstruction and/or tubular fluid backleak are not involved in the initiation of ARF in this model. Instead, the alterations involving P1 and P2 appear to be most important during the early stages of CDDP-induced ARF. The severity of the convoluted tubular injury at 48 hours showed a significant correlation with the degree of renal function impairment. The tubular injury affecting P3 did not correlate with the loss of renal function at any of the time points studied. However, tubular injury in P3 did appear responsible for some degree of renal function impairment at 72 and 96 hours, probably as a result of tubular obstruction and/or tubular fluid backleak.     

Cellular mechanism of ischemic acute renal failure: Role of Ca2+ and calcium entry blockers

Summary This presentation briefly reviews the cellular mechanism of ischemic acute renal failure (ARF) with particular emphasis on the role of Ca²⁺ and calcium entry blockers (CEB). Vascular consequences of an ischemic renal insult including vasoconstriction, diminished glomerular permeability, loss of autoregulation, and hypersensitivity to renal nerve stimulation may relate to increased cellular Ca²⁺ concentration in the renal afferent arteriole and glomerular mesangial cells. Evidence is also presented that the ischemic injury to tubular plasma membranes is associated with increased Ca²⁺ uptake. With an ischemic insult of a short duration, the renal mitochondria are able to buffer the increased cellular Ca²⁺. However, after an ischemic insult of long duration, the Ca²⁺ overloaded mitochondria deteriorate, adenosine triphosphate (ATP) synthesis decreases, and cell death follows. If a sufficient number of renal tubular cells undergo this cell death, tubular obstruction, i.e. the maintenance phase of ARF, occurs.     

Plasma protein extravasation and vascular endothelial growth factor expression with endothelial nitric oxide synthase induction in gentamicin-induced acute renal failure in rats

Microvascular hyperpermeability to plasma proteins via vascular endothelial growth factor (VEGF) with endothelial nitric oxide synthase (eNOS) induction may contribute to wound healing through matrix remodeling. However, vascular hyperpermeability is not examined in acute renal failure (ARF), a unique form of wound healing. Subcutaneous injection of gentamicin (400 mg/kg per day for 2 days in divided doses every 8 h) in rats increased serum creatinine levels and induced tubular damage, which peaked at day 6, after the last gentamicin injection. Ki67-positive regenerating proximal tubules (PTs) peaked in number at day 6 and almost covered the bare tubular basement membrane (TBM) by day 10. Staining of fibrinogen and plasma fibronectin began to increase in the peritubular regions as early as day 0, steadily increased in TBM and tubular lumen until day 6 and then decreased. Hyperpermeable peritubular capillaries were identified by extravasation of perfused-fluoresceinated dextran (both 70 kDa and 250 kDa) into peritubular regions as early as day 0 and prominently into TBM and tubular lumen at day 6. Electron microscopy further suggested the intraendothelial pathway of dextran. Immunoreactive VEGF increased in the damaged and regenerating PTs. Immunoreactive VEGF receptors-1 and -2 did not change, but immunoreactive eNOS increased in the peritubular capillaries after induction of ARF. Western blotting for VEGF and eNOS supported the immunostaining findings. In addition, we assessed the effects of NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) on vascular hyperpermeability during the recovery phase of this model. Treatment with l-NAME (s.c. at a dose of 100 mg/kg/day from day 3 to day 6) decreased extravasation of perfused-250-kDa dextran and significantly inhibited the regenerative repair of PTs at day 6 when compared with vehicle-treated rats. In conclusion, plasma protein extravasation occurred, leading to matrix remodeling, such as the process of wound healing during the tubular repair in gentamicin-induced ARF. Since VEGF-induced vascular hyperpermeability may depend on NO production, VEGF/VEGF receptor system with eNOS induction might be responsible for this process.     

Precipitable tissue proteins can cause experimental acute renal failure

A previous investigation demonstrated that intravenous infusion of a saline-liver extract into rats causes acute renal failure (ARF), manifested by severe azotemia, extensive cast formation, and patchy tubular necrosis. The purpose of the present study was to explore its pathogenesis. Histologic assessments of rat kidneys made 1.5 hours after liver extract infusion demonstrated eosinophilic material within glomerular capillaries, Bowman's space, and proximal tubular lumina, distal nephron cast formation, and tubular dilation without evidence of tubular necrosis. Renal blood flow at this time was normal but the rats were anuric. Assessments made 24 hours after liver extract infusion demonstrated persisting ARF (blood urea nitrogen, 132 +/- 8; creatinine, 2.54 +/- 0.19 mg/dl), profound cast deposition almost exclusively in the inner medulla/papilla, and the appearance of patchy proximal tubular necrosis. Sephacryl S200 fractionation and 10% polyacrylamide gel electrophoresis of liver extract showed high and low molecular weight proteins (less than 30,000). Proteins in both regions demonstrated prominent acid precipitability (pH 4.5) and autoaggregation (at 37 degrees C). Trace amounts of spontaneously precipitated protein recovered from urine during liver extract infusion demonstrated a predominance of low molecular weight proteins by polyacrylamide gel electrophoresis. Infusing rats with filterable low molecular weight proteins (cytochrome c, ribonuclease, myoglobin) without autoaggregation/acid precipitation characteristics or liver extract made devoid of precipitable proteins failed to induce ARF. However, infusing a kidney extract containing acid precipitating/autoaggregating proteins caused inner medullary/papillary cast formation and ARF. Conclusion: normal parenchymal tissues contain proteins which can undergo glomerular filtration and which can spontaneously aggregate under conditions which exist in the distal nephron. If released into the circulation, or if shed from tubular cells into lumina after nephrotoxic or ischemic renal injury, they could help to induce intratubular obstruction and ARF.     

Plasma renin activity in folic acid induced acute renal failure

Summary Peripheral plasma renin activity in acute renal failure induced in rats by a single i.v. injection of folic acid (250 mg/kg b. w., dissolved in 0.3 M NaHCO₃) remained normal during the first 6 hours and fell to low levels 24 hours and 4 days following the injection. Bleeding, however, induced a considerable increase of plasma renin activity on the 4th day after folate injection. There was no evidence of a participation of renin in the development of the functional and morphological renal disturbances produced by folic acid.Supported by Deutsche Forschungsgemeinschaft.     

Acute arterial fibrinoid deposition and ischaemic parenchymal damage of the kidney. Pathogenic factors in the development of malignant hypertension

The development and evolution of hypertensive vascular lesions affecting the arterial supply of (a) the kidney and (b) organs other than the kidney were studied in rats developing either malignant (MHY) or benign (BHY) hypertension 3, 6, 9 and 12 days after aortic ligation between the renal arteries. Vascular disease evolved into two distinct patterns which suggested acute renal damage to be the determinant for the development of either the malignant or benign form of hypertension. Three days after aortic ligation MHY and BHY animals showed widespread fibrinoid deposition in vascular territories above the aortic ligature. However, in MHYs these lesions were much more severe and, in the kidney, they were accompanied by the development of focal parenchymal atrophy, microinfarcts and hyalin droplet degeneration of cells of the Bowman capsule. The degree of renal damage correlated with elevations in blood urea nitrogen (BUN) and plasma creatinine; however, there was no correlation with rises in blood pressure, plasma renin activity (PRA), aldosterone or corticosterone which were similarly elevated in 3-day MHY and 3-day BHY animals. Between 6 and 12 days a marked clearance of fibrinoid took place in all organ beds of BHYs, but in the non-renal vasculature of MHY animals fibrinoid remained prominent and served as the central core for necrotising arterial lesions. In the kidney of MHYs some reduction in the fibrinoid content was observed, but the parenchymal damage perpetuating from the earlier stages had exacerbated leading to collagen deposition and a marked increase in the collagen concentration of the renal cortex. These features were accompanied by further elevations in PRA and corticosteroids and a progressive deterioration of renal function. By contrast, in 12-day BHY animals, despite sustained hypertension, PRA and corticosteroids were falling from their previously higher levels and normal renal function was maintained. These studies warrant inference that extensive parenchymal damage of the kidney due in part to severe arterial fibrinoid deposition is one of the initial events in the development of malignant hypertension.     

Morphology of infectious-toxic shock in salmonellosis

Clinico-morphological data on a severe course of salmonellosis (Stenley Salmonella) with the development of the infectious-toxic shock are presented. The shock was manifested by changes of the microcirculatory bed with the development of disseminated intra vascular blood coagulation (DIBC), brain and lung oedema as well as degenerative and necrobiotic lesions of the inner organs (acute tubular renal necrosis, necrobiosis and necrosis of the gastrointestinal tract epithelium, necrobiotic processes in the adrenal parenchyma, neuronal lysis etc.) as a consequence of circulatory disturbances determining the severity of the course and outcome of the disease. The possibility of a protracted course of the DIBS-syndrome as the main component of the infectious-toxic shock is shown and pathogenetically grounded.     

Morphogenesis of plasmatic arterionecrosis as the cause of hypertensive intracerebral hemorrhage

Summary The morphogenesis of the vascular lesions, which were considered to be the immediate cause of hypertensive intracerebral hemorrhage, was morphologically studied in autopsy cases. The direct cause of the hemorrhage was the rupture of the intracerebral microaneuysms resulted from the plasmatic arterionecrosis. The arterionecrosis was predominantly present in the intracerebral arteries of approximately 150 µ diameter, especially in the external branches of the arteriae corporis striati mediae in the putamen, and characterized by medial smooth muscle cell loss, blood plasma insudation in the intima, histolysis of the internal elastic lamina and intimal collagenous fibers, fibrin deposition (fibrinoid degeneration) in the intima, and luminal dilatation. The morphogenesis of the arterionecrosis was the development of histolysis as well as fibrinoid degeneration caused by blood plasma insudation in the wall of the intracerebral arteries with preceding necrosis and loss of medial smooth muscle cells and subsequent fibrous intimal thickening with dilated lumina. Intracerebral microaneurysms were also formed by the plasmatic arterionecrosis in a narrow sense, in which histolysis due to blood plasma insudation had occurred, but fibrin (fibrinoid substance) deposition in the intima had not yet arisen.     

Acute diffuse interstitial fibrosing pneumonitis and bilateral renal cortical necrosis

An autopsy case of a 69-year-old male with acute diffuse interstitial fibrosing pneumonitis complicated by bilateral renal cortical necrosis was presented. Autopsy revealed acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis, non-bacterial thrombotic endocarditis, involving the aortic and mitral valves, and some interesting vascular lesions, dissemination of fibrinoid change of arterioles and fibrin thrombus of small vessels in various organs; accumulation of polymorphonuclear leukocytes in the lumen of the smaller interlobular arteries and arterioles of the kidney with cellular infiltration and disintegration of the wall; severe disorganization of the wall with intraluminar and intramural fibrinous exudation in smaller branches of the hepatic artery; diminution and disarrangment of muscle fibers and patchy hyalinization in the media of the renal and interlobar arteries. The inter-relationship between acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis which may be regarded as a 'hallmark' of the generalized Shwartzman reaction, and disseminated intravascular coagulation was discussed.     

ACUTE DIFFUSE INTERSTITIAL FIBROSING PNEUMONITIS AND BILATERAL RENAL CORTICAL NECROSIS

An autopsy case of a 69-year-old male with acute diffuse interstitial fibrosing pneumonitis complicated by bilateral renal cortical necrosis was presented. Autopsy revealed acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis, non-bacterial thrombotic endocarditis, involving the aortic and mitral valves, and some interesting vascular lesions, dissemination of fibrinoid change of arterioles and fibrin thrombus of small vessels in various organs; accumulation of polymorphonuclear leukocytes in the lumen of the smaller interlobular arteries and arterioles of the kidney with cellular infiltration and disintegration of the wall; severe disorganization of the wall with intraluminar and intramural fibrinous exudation in smaller branches of the hepatic artery; diminution and disarrangment of muscle fibers and patchy hyalinization in the media of the renal and interlobar arteries. The inter-relationship between acute diffuse interstitial fibrosing pneumonitis, bilateral renal cortical necrosis which may be regarded as a 'hallmark' of the generalized Shwartzman reaction, and disseminated intravascular coagulation was discussed.     

In vivo and in vitro models demonstrate a role for caveolin-1 in the pathogenesis of ischaemic acute renal failure

Caveolae and their proteins, the caveolins, transport macromolecules; compartmentalize signalling molecules; and are involved in various repair processes. There is little information regarding their role in the pathogenesis of significant renal syndromes such as acute renal failure (ARF). In this study, an in vivo rat model of 30 min bilateral renal ischaemia followed by reperfusion times from 4 h to 1 week was used to map the temporal and spatial association between caveolin-1 and tubular epithelial damage (desquamation, apoptosis, necrosis). An in vitro model of ischaemic ARF was also studied, where cultured renal tubular epithelial cells or arterial endothelial cells were subjected to injury initiators modelled on ischaemia-reperfusion (hypoxia, serum deprivation, free radical damage or hypoxia-hyperoxia). Expression of caveolin proteins was investigated using immunohistochemistry, immunoelectron microscopy, and immunoblots of whole cell, membrane or cytosol protein extracts. In vivo, healthy kidney had abundant caveolin-1 in vascular endothelial cells and also some expression in membrane surfaces of distal tubular epithelium. In the kidneys of ARF animals, punctate cytoplasmic localization of caveolin-1 was identified, with high intensity expression in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, 24 h to 4 days after ischaemia-reperfusion. Western immunoblots indicated a marked increase in caveolin-1 expression in the cortex where some proximal tubular injury was located. In vitro, the main treatment-induced change in both cell types was translocation of caveolin-1 from the original plasma membrane site into membrane-associated sites in the cytoplasm. Overall, expression levels did not alter for whole cell extracts and the protein remained membrane-bound, as indicated by cell fractionation analyses. Caveolin-1 was also found to localize intensely within apoptotic cells. The results are indicative of a role for caveolin-1 in ARF-induced renal injury. Whether it functions for cell repair or death remains to be elucidated.     

樟柳碱、东莨菪碱、山莨菪碱对急性肾功能衰竭大鼠的治疗作用

本文采用直接从左肾动脉注射油酸的方法制备大鼠急性肾功能衰竭(ARF)模型,从改善微循环的角度寻求ARF的防治措施。结果表明,樟柳碱、东莨菪碱、山莨菪碱均可不同程度减轻肾内微血管损伤及肾组织水肿,改善肾内脉动血管的功能,提高肾组织血液灌流量,提高血液中前列环素(PGI_2)的浓度,减轻肾组织缺血及肾小管损伤。樟柳碱的效果优于东莨菪碱及山莨菪碱。这些结果证明,莨菪类药对油酸致大鼠ARF有治疗作用。     

Acute renal failure in Tupaia belangeri and rats.

Acute renal failure in man can best be simulated in model experiments by using either temporary occlusion of the renal artery or perfusions of noradrenaline into the renal artery. The kidney of the Tupaia belangeri, a primitive primate, is more resistant to temporary occlusion of the renal artery than of the rat. In Tupaia as in rats, anuria developing 48 hours after temporary ischemia is brought about by intratubular proteinaceous casts blocking the flow of urinary filtrate, most likely at Henle's loop. As proof that the proteinaceous casts block the tubular lumina, we found that when two micropipettes are inserted into the same nephron and that nephron perfused, the intratubular pressures rise, approaching systolic pressures.     

Development of renal structural lesions in type-1 diabetic patients with microalbuminuria

Kidney biopsies were obtained in 18 type-1 diabetic patients with microalbuminuria and again 8 years later. Over the first 30 months, a treatment protocol (conventional versus intensified treatment) was followed. The biopsies were embedded into plastic and sectioned serially. The volume of individual glomeruli and the vascular pole area was determined. The number of glomeruli showing capsular drops, fibrinoid lesions, adhesions, extra efferent arterioles and corpuscles totally occluded were counted and expressed as a percentage of the total number of corpuscles. Cortical interstitium and degenerated tubules were estimated by point counting. From baseline to the 8-year biopsy, the group of patients showed significant increase in interstitial volume fraction, mean glomerular volume and vascular pole area. The frequency of glomerular occlusion, fibrinoid lesions, adherences and extra efferent arterioles increased, whereas the frequency of capsular drops did not change, and degenerated tubular profiles showed a non-significant increase. No correlation was seen between these light microscopic observations and the concomitant development of diabetic glomerulopathy. Increase in albumin excretion rate was associated with increase in glomerular volume and vascular pole area. No correlation was seen with the glomerular filtration rate, blood pressure or metabolic control. The increase in structural parameters illustrates the slowly ongoing alteration of renal structures in type-1 diabetic patients with microalbuminuria.