A. Bohle

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 pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis.

Investigation of renal biopsy specimens from 488 patients with diabetic glomerulosclerosis (DGS) of varying severity revealed the following: 1) The severity of DGS increases with the duration of the diabetes. 2) As the severity of DGS increases, it is complicated with increasing frequency by exudative changes, which correspond in detail to hyperperfusion lesions described in the literature. 3) As the severity of DGS increases, the severity of arteriolosclerosis and the incidence of nephrotic syndrome increase significantly. 4) The 5- and 10-year renal survival rates are highest for those diabetic patients in whom the tubules and renal cortical interstitium are of normal appearance. These survival rates are diminished if any of the following are present at the time of biopsy: a) interstitial fibrosis; b) hyperperfusion lesions; c) nephrotic syndrome; d) elevation of the serum creatinine concentration to more than 1.3 mg%. 5) No significant correlation was found between renal survival rate and age, sex, or type of diabetes. 6) The inflammation of the renal interstitium seen in diabetes does not differ from that seen in chronic glomerulonephritis. Monocytes, macrophages, T lymphocytes, fibroblasts and fibrocytes play the major role in this inflammation. This inflammatory process is considered to represent not pyelonephritis, but rather an auto-immune process. In other words, it is proposed that the diabetic kidney fails not only as a result of non-specific glomerular lesions (hyperperfusion lesions) but also because of non-specific tubulointerstitial changes, whereas diabetic glomerulosclerosis alone does not lead to chronic renal failure.

Structure and Function of the Kidney in Diabetic Glomerulosclerosis: Correlations between Morphological and Functional Parameters

Histological and clinical findings in 103 middle-aged patients suffering from diabetic glomerulosclerosis (gs) (biopsy material) are reported. In diabetic gs (as in other inflammatory and non-inflammatory glomerular disease) a statistically highly significant positive correlation exists between the grade of fibrosis of the renal cortical interstitium and the serum creatinine concentration at the time of biopsy. Rank correlations exist between vessel index and relative cortical interstitial volume on the one hand as well as serum creatinine concentration on the other. Significant differences are also shown to exist between the mean values of the cortical interstitium as well as the serum creatinine concentration and the vessel index in the four grades of diabetic gs. Severe glomerular lesions may be accompanied by a normal serum creatinine concentration, only if the interstitium shows no fibrotic changes. Mild glomerular lesions, when accompanied by an interstitial fibrosis, always have elevated serum creatinine concentrations. The incidence of hypertension, proteinuria, the nephrotic syndrome and hematuria in diabetic gs appears to vary greatly. From the highly significant correlation between the cortical interstitium and the serum creatinine concentration we presume the following: Alterations of the postglomerular vessels by interstitial fibrotic changes result in an increased resistance to renal cortical blood flow with a subsequent reduction of glomerular perfusion. This reduction of the glomerular perfusion may result in a rise of the serum creatinine concentration, independently of the severity of the glomerulosclerosis. It is also conceivable that glomerular function is affected by the malfunctioning atrophic tubules in areas of interstitial fibrosis.

Significance of Postglomerular Capillaries in the Pathogenesis of Chronic Renal Failure

Correlations between the relative volume of the intertubular capillaries in the renal cortex and the serum creatinine concentration in primary glomerulopathies, renal vasculopathies, and chronic interstitial nephritides are reported. In the mesangioproliferative glomerulonephritides, there are significant negative correlations between the number and area of the intertubular capillaries in the cortex and the serum creatinine concentration. In diabetic glomerulosclerosis, renal glomerular amyloidosis, decompensated benign nephrosclerosis, secondary malignant nephrosclerosis, and chronic interstitial nephritis, there is a significant negative correlation between the relative area of the intertubular capillaries and the serum creatinine concentration. Thus, in these diseases, there is progressive narrowing/ obliteration of the postglomerular capillaries which leads to a progressive decrease in glomerular filtration rate and thus to a rise in serum creatinine concentration.

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.

IgA Nephritis: On the Importance of Morphological and Clinical Parameters in the Long-Term Prognosis of 239 Patients

This study is concerned with the correlation between tubulointerstitial changes (interstitial fibrosis, acute renal failure, and interstitial fibrosis with acute renal failure), glomerular changes (focal and segmental lesions, hyperperfusion lesions), vascular changes, clinical data at the time of biopsy (serum creatinine concentration, creatinine clearance, hematuria, proteinuria, and hypertension) and first symptoms (hematuria, proteinuria and hypertension) and the kidney survival rate in 239 patients with IgA nephritis without nephrotic syndrome. The morphological and clinical parameters were subjected to multivariate analysis in order to examine their significance with regard to the prognosis. The interstitial fibrosis was proven to be the most important morphological parameter, and the most important clinical parameters were the serum creatinine concentration and the creatinine clearance.

The Consequences of Tubulo-Interstitial Changes for Renal Function in Glomerulopathies: A Morphometric and Cytological Analysis

Morphometric investigation of the structures of the cortex in kidneys exhibiting various types of glomerulopathy revealed the following: 1. In various types of glomerulonephritis, diabetic glomerulosclerosis, and glomerular amyloidosis there are significant correlations between the severity of fibrosis of the renal cortical interstitium and tubular atrophy resulting from chronic interstitial inflammation, and the serum creatinine concentration, creatinine clearance, inulin clearance and PAH clearance. 2. As illustrated with the example of membranoproliferative glomerulonephritis type I, if glomerulopathy alone is present, there is no elevation of the serum creatinine concentration, even if the glomerular inflammatory changes are severe; neither are severe renal amyloidosis that is confined to the glomeruli and severe isolated diabetic glomerulosclerosis associated with elevation of the serum creatinine concentration. 3. There is a significant negative correlation between the severity of interstitial fibrosis resulting from chronic inflammation and the total number and cross-sectional area of the intertubular capillaries; i.e., the total cross-sectional area and number of capillaries per unit area decrease as the fibrosis of the cortical interstitium increases. 4. Cases of glomerulonephritis in which there is accompanying fibrosis of the renal cortical interstitium have a significantly worse long-term prognosis than those in which there is only severe glomerulitis. 5. Obliteration of the post-glomerular capillaries leads to an increase in the cross-sectional area of the glomerular capillary convolution, the morphological equivalent of an increase in intraglomerular pressure. 6. The cause of the disease of the renal cortical interstitium that may accompany the various types of glomerulonephritis is not known. It is considered possible, as a working hypothesis, that this inflammation represents a T-cell stimulated autoimmune process in which fibroblast proliferation occurs, leading to an increase in numbers of fibrocytes in the renal cortical interstitium and thus to increased production of collagen.

The Consequences of Tubulo-Interstitial Changes for Renal Function in Glomerulopathies

In recent years it has become recognized to an increasing extent that a wide range of inflammatory and non-inflammatory glomerular diseases may be complicated with varying frequency by disease in the region of the post-glomerular intertubular capillaries. Thus we found additional disease of the tubulo-interstitial system in 4.0 – 69.5% of patients with the diseases listed in Table 1. Amongst these diseases, accompanying inflammation of the renal cortical interstitium occurs least often in endocapillary glomerulonephritis and most often in diabetic glomerulosclerosis. Amongst the glomerulonephritides, interstitial inflammation leading to fibrosis is observed most frequently in rapidly progressive glomerulonephritis and membranoproliferative glomerulonephritis. Interstitial inflammation is found relatively often in glomerular amyloidosis. As a result of investigations we have undertaken in the last three years, it has been possible to demonstrate that the character of the inflammatory interstitial changes that accompany glomerular diseases is always the same, no matter what the glomerulopathy may be. The cells most predominantly involved in the inflammatory process are T lymphocytes, macrophages, fibroblasts and fibrocytes. Thus dense foci of T lymphocytes and macrophages are seen not only in Table 1 Survey of the incidence of intertubular inflammation associated with interstitial fibrosis in various glomerulopathies. Various Glomerulopathies And The Occurrence Of Interstitial Inflammation And Interstitial Fibrosis Total Number Of Casas Cases With Interstitial Fibrosis (%) 1) Endocapillary GN 137 4.0 2) Minimal Changes With NS 470 8.5 3) Focal Sclerosing GN 469 34.1 4) Mesangioproliferative GN 805 23.0 a) Immunologically Negative GN 238 13.9 b) IgA Nephritis 369 23.3 c) Non-lgA Nephritis 198 33.3 5) Chronic Idiopathic Membranous GN 642 23.8 6) Membranoproliferative GN Type I 259 41.0 7) Rapidly Progressive GN 208 56.7 8) Perireticular Amyloidosis 443 48.0 9) Diabetic Glomerulosclerosis 406 69.5 mesangioproliferative glomerulonephritis, but also in the interstitial inflammation that complicates renal amyloidosis. The tubulo-interstitial inflammation of diabetic glomerulosclerosis is also characterized by T lymphocytes, macrophages, fibroblasts and fibrocytes.

The long-term prognosis of the primary glomerulonephritides. A morphological and clinical analysis of 1747 cases.

Long-term studies of all types of primary glomerulonephritis (GN) taking into consideration the major morphological and clinical findings revealed the following: 1) Endocapillary GN, post-streptococcal type has a very good prognosis when only glomerulitis is present. The prognosis is significantly worse if either interstitial inflammation with fibrosis or nephrotic syndrome (NS) is present at the time of the biopsy. 2) The prognosis of the various types of mesangioproliferative GN (IgA nephritis, non-IgA nephritis, and immunohistologically negative GN) is very good if there is only glomerulitis. The prognosis is worse for all three types when the renal cortical interstitium exhibits inflammation with fibrosis at the time of the biopsy, and is worst of all when both interstitial fibrosis (IF) and the signs of acute renal failure (ARF) are present. Of this group, the type in which there are negative immunohistological findings exhibits the best prognosis. No difference in prognosis is found between IgA nephritis and non-IgA nephritis. 3) Minimal changes GN with NS has a very good prognosis when the interstitium is not involved. The presence of interstitial inflammation and fibrosis worsens the prognosis significantly. 4) Focal sclerosing GN has a much poorer prognosis than minimal changes GN with NS, even when there is glomerulitis only (5- and 10-year renal survival rates (RSRs) of 90% and 67%, respectively). If interstitial inflammation and fibrosis are present, the prognosis is significantly worse (5- and 10-year RSRs of 84% and 55%, respectively). The prognosis is worst when both ARF and IF are present at the time of the biopsy (5- and 10-year RSRs of 56% and 46%, respectively). From the clinical side, the prognosis is significantly worse if, at the time of the biopsy, NS is present or the serum creatinine concentration is elevated to more than 1.3 mg%. 5) Chronic membranous GN has a better prognosis than focal sclerosing GN if glomerulitis only is present (5-year RSR, 88%; 10-year RSR, 77%). If the renal cortical interstitium is also involved (in the form of IF), the prognosis is significantly worse (5-year RSR, 65%; 10-year RSR, 38%). The prognosis in this disease, too, is worst when both ARF and IF are present at the time of the biopsy (5-year RSR, 38%; 10-year RSR, 25%). 6) Membranoproliferative GN has a worse prognosis than any of the types of GN so far mentioned (5-year RSR, 51%; 10-year RSR, 32%).(ABSTRACT TRUNCATED AT 400 WORDS)

Correlations between renal interstitium and level of serum creatinine

Morphometric investigations in 40 patients suffering from perimembranous glomerulonephritis at different stages showed that there is no certain relationship between the severity of glomerular lesions and the serum creatinine level. In 19 cases in stages I–III, with serum creatinine level less than 1.2 mg/100 ml on biopsy, the renal interstitium was less enlarged than in 21 cases in the same stages, but with serum creatinine level higher than 2 mg/100 ml. There is a significant positive correlation between the relative interstitial volume and the level of serum creatinine. The best congruence was demonstrated in the lin/log-plotting indicating that our values correlate best with an exponential function. We therefore conclude that in perimembranous glomerulonephritis, generally considered to be a glomerular disease, functional impairment cannot be explained by the glomerular lesions alone; interstitial changes have also to be taken into account as a cause of renal insufficiency. The following hypothesis is proposed; that the increase in renal interstitium and possible shrinking of collagen fibres may lead to a narrowing of intertubular capillaries. This may result in slowing of glomerular blood flow and may lead to renal insufficiency.