Harolo v. Gise

Significance of Tubulointerstitial Changes in the Renal Cortex for the Excretory Function and Concentration Ability of the Kidney: A Morphometric Contribution

This is an editorial review of investigations into the correlation of structure and function of the kidney in various inflammatory and noninflammatory glomerular diseases and in focal and diffuse interstitial nephritis. In detail these investigations produced the following results: (1) The excretory function of the glomeruli for substances usually eliminated with the urine is, in the case of inflammatory and noninflammatory glomerular diseases, detrimentally affected by tubulointerstitial changes, i.e. by processes accompanied by interstitial fibrosis and tubular atrophy. Likewise primary interstitial renal diseases when accompanied by interstitial fibrosis and tubular atrophy may lead to reduction in GFR. (2) Inflammatory and noninflammatory glomerular diseases, even when very severe, are not accompanied by a measurable reduction in GFR when the renal cortex interstitium shows no changes and the tubules exhibit no pathological findings. (3) The concentration ability of the kidney, too, depends primarily on tubulointerstitial changes and not primarily on a reduction of the glomerular filtration surface area. As interstitial fibrosis and tubular atrophy increase, the maximum concentration ability of the kidney decreases, even when the glomerular structure is preserved. (4) The decrease in GFR in the case of processes in the renal cortex accompanied by severe interstitial fibrosis is the result of the reduction of the number and of the area of the postglomerular vessels, i.e. the result of an impeded outflow from the glomeruli and of a concomitant slower circulation through the glomeruli. (5) In the case of inflammatory and noninflammatory glomerular and extraglomerular renal diseases accompanied by slight interstitial fibrosis and tubular atrophy, the GFR is detrimentally affected via a hormonally controlled self-regulating mechanism (Thurau-mechanism) in the form as modified by Baumbach and Skott and Leyssac. The glomerular function thereby adapts to an insufficient tubular function, without there necessarily being any structural changes in the glomeruli.

The obliteration of the postglomerular capillaries and its influence upon the function of both glomeruli and tubuli

SummaryOur study in a group of patients (heterogeneous in terms of glomerular lesions), supplementing and confirming earlier findings, indicated that1.An increase of the relative cortical interstitial volume and the serum creatinine concentration at the time ob biopsy is accompanied by a statistically significant reduction in the number of intertubular capillaries and a decrease in capillary area per area unit.2.The length of diffusion between the intertubular capillaries and tubuli increases and the tubular epithelium becomes atrophic as relative cortical interstitial volume increases.3.The glomerular capillaries and the Bowmans capsule are significantly larger in moderately severe mesangioproliferative or grades I to III membraneous GN with elevated serum creatinine concentrations than in equally severe renal diseases with normal serum creatinine concentrations.4.The glomerulus in moderately severe mesangioproliferative GN progressively increases as the serum creatinine concentration rises. On the basis of these findings, it was concluded that the increase of the cortical interstitial volume results in an increase in resistance of the postglomerular capillary network with impairment of the glomerular flow. This impairment leads to a functional or, to be more precise, a chronic rise in hydrostatic pressure and also to a reduction in the glomerular blood flow and therefore a rise in serum creatinine concentration. The chronic rise in hydrostatic pressure also results in an increase in the size of the glomerulus. The increase of the cortical interstitium additionally leads to an increase in the length of diffusion between the tubules and the intertubular and peritubular capillaries. This increase in the length of diffusion subsequently results in atrophy of the tubules, reduction of reabsorption, and therefore impairment of the effective filtration pressure.ZusammenfassungVorliegende Untersuchungen führen in Ergänzung und Bestätigung früherer Untersuchungsergebnisse an einem im Hinblick auf die glomerulären Läsionen heterogenen Untersuchungsgut zu folgenden Resultaten:1.Eine Zunahme des relativen Nierenrindeninterstitiumvolumens bzw. der Serumkreatininkonzentration zur Zeit der Biopsie geht mit einer statistisch signifikanten Abnahme der Anzahl der intertubulären Kapillaren und der Kapillarfläche pro Flächeneinheit einher.2.Mit der Zunahme des relativen Nierenrindeninterstitiumvolumens nimmt die Diffusionsstrecke zwischen intertubulären Kapillaren und Tubuli zu und die Tubulusepithelien werden atrophisch.3.Bei mittelschwerer mesangioproliferativer Glomerulonephritis bzw. membranösen Glomerulonephritiden Schweregrad I–III ist das glomeruläre Kapillarkonvolut und die Bowmansche Kapsel bei erhöhter Serumkreatininkonzentration signifikant größer als bei gleich schweren Erkrankungen mit normaler Serumkreatininkonzentration.4.Bei mittelschwerer mesangioproliferativer Glomerulonephritis nimmt das glomeruläre Kapillarkonvolut mit steigender Serumkreatininkonzentration zu. Aus diesen Befunden wird gefolgert, daß es durch die Verbreiterung des Nierenrindeninterstitiums zu einer Erhöhung des Widerstandes in der postglomerulären Kapillarstrecke kommen muß mit Beeinträchtigung des Abflusses aus den Glomerula. Diese Abflußbehinderung führt funktionell zwar zu einer chronischen Steigerung des hydrostatischen Druckes in den Glomerulumkapillaren, jedoch auch zu einer Reduktion der Glomerulumdurchblutung und damit zum Kreatininanstieg. Bedingt durch die chronische Steigerung des hydrostatischen Druckes kommt es ferner zu einer Zunahme des Kapillarkonvolutes (Erweiterung der Kapillaren, vermehrter Einbau von Kollagen, u.a. in die Kapillarwände). Ferner führt die Verbreiterung des Nierenrindeninterstitiums zu einer Zunahme der Diffusionsstrecke zwischen inter- bzw. peritubulären Kapillaren und Harnkanälchen mit konsekutiver Atrophie der Kanälchen und einer Reduktion der Rückresorption und einer dadurch bedingten Beeinträchtigung des effektiven Filtrations-druckes durch Anstieg des hydrostatischen Druckes im Bowmanschen Kapselraum.

Investigations on the cause of the nephrotic syndrome in renal amyloidosis

Systematic electron microscopic investigation of glomeruli of 35 patients with renal amyloidosis (grade I–III), among them 26 with the nephrotic syndrome, reveals the following: 1. The extent of the area of basement membrane denuded of its epithelial covering is correlated significantly with the reduction of plasma protein concentration at the time of renal biopsy. 2. In amyloid free regions of the glomerular capillary loops, the foot processes of the epithelial cells remain intact despite the presence of the nephrotic syndrome. From these findings we conclude that the high glomerular protein losses in amyloidosis occur in areas of the basement membrane which are penetrated by amyloid and denuded of their epithelial covering. With increasing number of these lesions per unit area, the permeability of the capillary network for protein increases to a degree which is significantly correlated with the reduced plasma protein concentration at the time of biopsy. The extent of the area of basement membrane denuded of its epithelial covering is correlated significantly with the reduction of plasma protein concentration at the time of renal biopsy. In amyloid free regions of the glomerular capillary loops, the foot processes of the epithelial cells remain intact despite the presence of the nephrotic syndrome. From these findings we conclude that the high glomerular protein losses in amyloidosis occur in areas of the basement membrane which are penetrated by amyloid and denuded of their epithelial covering. With increasing number of these lesions per unit area, the permeability of the capillary network for protein increases to a degree which is significantly correlated with the reduced plasma protein concentration at the time of biopsy.

Nephrotic syndrome and renal insufficiency in association with amyloidosis: A correlation between structure and function

SummaryThe following results were obtained by correlating light and electron microscopic findings from 85 cases of glomerular renal amyloidosis with clinical parameters:1. Amyloid masses deposited in the glomeruli do not represent an effective filtration barrier, i.e., the formation of primary urine is not significantly influenced even by extensive amyloid masses in the glomeruli; protein retention is first observed when the glomerular capillaries are almost totally obliterated.2. Once the nephrotic syndrome has developed in association with glomerular renal amyloidosis, it shows no tendency for remittance, despite progressing renal insufficiency.3. The reason for this persistance of the nephrotic syndrome, despite increasing renal insufficiency, is a progressive reduction in the capacity of the tubules for protein reabsorption in the presence of increasing interstitial fibrosis of the kidney.4. Interstitial fibrosis of the kidney cortex leads to increasing impairment in the oxygen and energy supply to the tubule cells together with considerable functional deterioration which, in addition to other metabolic disturbances, also results in a reduced capacity for protein reabsorption.ZusammenfassungDie Korrelation von licht- und elektronenmikroskopischen Befunden mit klinischen Parametern von 85 Fällen glomerulärer Nierenamyloidose führte zu folgenden Ergebnissen:1. Glomerulär abgelagerte Amyloidmassen stellen keine wesentliche Filtrationsbarriere dar, d.h. die Primärharnbildung wird selbst durch ausgedehnte Amyloidablagerungen im glomerulären Kapillarkonvolut nicht signifikant beeinflußt und eine Proteinretention kann erst beobachtet werden, wenn die glomerulären Kapillaren fast vollständig obliteriert sind.2. Wenn sich bei der Nierenamyloidose erst einmal ein nephrotisches Syndrom entwickelt hat, so zeigt es trotz zunehmender Niereninsuffizienz keine Tendenz zur Rückbildung.3. Der Grund für das Fortbestehen des nephrotischen Syndroms trotz zunehmender Niereninsuffizienz ist eine zunehmende Abnahme der Rückresorptionskapazität für Proteine durch die Tubuluszellen bei zunehmender interstitieller Fibrose der Nierenrinde.4. Die interstitielle Fibrose der Nierenrinde führt zu einer progressiven Verschlechterung in der Sauerstoff-und Energieversorgung der Tubuluszellen, was neben anderen metabolischen Störungen zu einer abnehmenden Rückresorptionskapazität für Proteine führt.

Morphologic contribution on gross hematuria in mild mesangioproliferative glomerulonephritis without crescents.

SummaryIn order to clarify the pathogenesis of gross hematuria in mild forms of mesangioproliferative glomerulonephritis without crescents, systematic light microscopic, immunohistologic, electron microscopic, and some scanning electron microscopic investigations were carried out on 17 cases of this disease, in part on serial sections. The investigations produced the following results:1.In gross hematuria, erythrocytes pass into Bowmans space in the area of basement membrane ruptures.2.The basement membrane ruptures occur at sites where the basement membrane is infiltrated in its entire width by aggregated immune complexes. This occurs when these immune complexes are detached from the basement membrane by lysosomal digestion.3.As a working hypothesis, it is furthermore considered possible that in diseases accompanied by increased IgA production, circulating IgA is deposited at a higher rate in the glomerular filtration barrier and it is there degraded by an excessive reaction of local cells before morphologically identifiable immune complexes appear. In this process the basement membrane undergoes local destruction.4.It is also assumed that in gross hematuria, immune complexes other than IgA or hitherto unknown substances enter the basement membrane during the filtration process and trigger frustrane phagocytosis at the basement membrane by their presence, with consecutive basement membrane destruction.5.It is pointed out that gross hematuria occurs most often in mild forms of mesangioproliferative glomerulonephritis with IgA and C3 deposits in the mesangium and sometimes also in the capillary periphery.6.It could be shown that in mild forms of mesangioproliferative glomerulonephritis, hematuria occurs more often in the male sex.7.In 12 biopsy specimens from the kidneys of healthy patients who exhibited no erythrocytes in the urine at the time of biopsy, isolated incomplete basement membrane defects, but no basement membrane ruptures, were observed.

Acute renal failure — An integrative discussion of morphologic and functional findings

SummaryThe ultrastructural alterations at the nephron established in animal experiments, were also confirmed, by means of an electron-microscopic examination, in eight cases of human acute renal failure (ARF). Special consideration was given in this study to single cell alterations, particularly in proximal tubular cells, with emphasis being placed on alterations due to single cell damage in the region of the renal fluid compartments. The ultrastructural alterations of the tubular cells in ARF, suggest serious impairment of the cellular capacity for electrolyte transport and metabolic processes. The shunt paths between the tubular fluid compartment and the functional interstitium, arising from necrosis of the tubular cells or dissolution of the gap or tight junctions, were discussed in terms of their significance for the directional, active transport processes of the tubular cells for sodium chloride and the passive water flow. The morphologic findings were reviewed in light of recent findings on cellular membrane processes and electrolyte transport. A reinterpretation of the morphologic and functional findings in ARF is suggested. This takes into consideration single cell function and the integrity of the renal fluid compartments.ZusammenfassungDurch elektronenmikroskopische Untersuchungen an 8 Fällen menschlicher akuter Nierenversagen konnten die aus tierexperimentellen Beobachtungen bekannten ultrastrukturellen Veränderungen am Nephron auch für das menschliche akute Nierenversagen bestätigt werden. Die Untersuchungen erfolgten unter besonderer Berücksichtigung der Einzelzellveränderungen, insbesondere der proximalen Tubuluszellen. Herausgestellt wurden die aus der Einzelzellschädigung resultierenden Veränderungen im Bereich der renalen Flüssigkeitskompartimente. Die ultrastrukturellen Veränderungen der Tubuluszellen beim akuten Nierenversagen deuten auf eine gravierende Beeinträchtigung der zellulären Transportkapazität für Elektrolyte und metabolischer Prozesse hin.Die durch Tubuluszellnekrosen oder durch Lösung von Gap- bzw. Tight-Junctions entstehenden Shunt-Wege zwischen tubulärem Flüssigkeitskompartiment und funktionellem Interstitium werden in ihrer Bedeutung für die gerichteten aktiven Transportvorgänge der Tubuluszellen für Natriumchlorid und den passiven Wasserstrom diskutiert.Die morphologischen Befunde werden unter besonderer Berücksichtigung neuer Ergebnisse der zellulären Membranprozesse und des Elektrolyttransportes besprochen. Eine Reinterpretation morphologischer und funktioneller Befunde beim akuten Nierenversagen unter besonderer Berücksichtigung der Einzelzellfunktion und der Integrität der renalen Flüssigkeitskompartimente wird vorgeschlagen.

Clinical and morphological aspects of nephrotic syndrome in perimembranous, focally sclerosing and membrano-proliferative glomerulonephritis

SummaryThe following data was obtained by morphometric and photometric microscopic studies of renal biopsies from 140 patients with idiopathic perimembranous glomerulonephritis, 108 patients with focally sclerosing glomeruloncphritis and 50 patients with membranoproliferative glomerulonephritis and correlation of the results obtained with available clinical data:1.In all three diseases proteinuria and serum protein concentration show no tendency to stabilization in spite of increasing renal insufficiency.2.With increasing renal insufficiency the proximal tubular cells become increasingly atrophic.3.Protein resorption through the proximal tubulus cells becomes increasingly diminished with advancing renal insufficiency. It is concluded from the present data that proteinuria, which is primarily glomerular caused, is increased by increasingly diminished resorption of proteins in the tubulus system with increasing renal insufficiency. In this way, even under conditions of advanced renal insufficiency with reduced GFR, large amounts of proteins can be excreted and a nephrotic syndrome can persist to a stage of renal insufficiency.