Focal glomerulosclerosis and maximal glomerular hypertrophy in human nephronopenia.

This study examines the relationship of the degree of glomerular hypertrophy in nephronopenia to the development of focal segmental glomerulosclerosis (FGS) in humans. To this end, group mean glomerular diameters in a variety of acquired and congenital nephronopenic states in native kidneys and long-surviving renal allografts with and without FGS were analyzed and compared. The results indicate that all groups of native nephronopenic kidneys without FGS develop significant and equivalent glomerular hypertrophy. By contrast, long-surviving renal allografts without FGS do not undergo glomerular hypertrophy. For groups with FGS, long-surviving renal homografts had a significantly smaller mean glomerular diameter when compared with any other group of native nephronopenic kidneys. There was no significant difference among group mean glomerular diameters of native nephronopenic kidneys with FGS. Pairwise comparisons in each category of nephronopenia indicated that, except in the groups with uninephrectomy, the mean glomerular diameters were significantly larger in those with FGS than without. These observations are interpreted to indicate that nephronopenic individuals with native kidneys, by undergoing glomerular hypertrophy, consume much or all their capacity for glomerular enlargement. This brings them closer to their maximal diameters at which FGS develops. Finally, long-surviving renal allografts without nephronopenic FGS do not undergo glomerular hypertrophy. However, when FGS develops in long-surviving allografts, it does so at glomerular diameters significantly smaller than in native nephronopenic kidneys, reflecting their decreased capacity to undergo glomerular hypertrophy, acquiring maximal diameters at a smaller dimension than native nephronopenic kidneys.

Glomerular size and the association of focal glomerulosclerosis in long-surviving human renal allografts.

This biopsy study exploits the unique opportunity offered by long-surviving human renal allografts to analyze the effects of nephronopenia-induced glomerular hypertrophy on the association of focal glomerulosclerosis. Methods include glomerular morphometry and analysis of variance. Only allografts with focal glomerulosclerosis detected after 3 yr posttransplantation (Group TxFGS > 2 yr) have a group mean glomerular diameter (203.1 microns +/- SE (mean) 10.36) significantly larger (P < 0.05) than that of allografts biopsied beyond 2 yr posttransplantation but without focal glomerulosclerosis (Group No TxFGS > 2 yr; 158.3 microns +/- SE (mean) 8.32), allografts biopsied within 2 yr of transplantation with (Group TxFGS < 2 yr; 165.3 microns +/- SE (mean) 5.35) or without (Group NoTxFGS < 2 yr; 155.8 microns +/- SE (mean) 5.53) focal glomerulosclerosis, or allograft diameters at transplantation (Group CTx; 148.3 microns +/- SE (mean) 5.66). However, the increase is approximately 37% over that at transplantation, significantly less than the increase of approximately 70% attained by congenitally nephronopenic native kidneys (P < 0.50) with focal glomerulosclerosis (Group CNP; 264.4 microns +/- SE (mean) 11.01) over their controls (Group CN; 154.8 microns +/- SE (mean) 4.46). This observation suggests that the nephronopenic allograft has a curtailed ability for glomerular hypertrophy when compared with congenitally nephronopenic native kidneys and may explain the association of focal glomerulosclerosis in long-surviving renal homografts at a significantly smaller glomerular diameter. Although smaller, this appears to be the maximal glomerular dimension attained by long-surviving nephronopenic homografts in the absence of intrinsic glomerular disease (excluding focal glomerulosclerosis). Thus, these results are in accord with and offer further support for the general hypothesis that focal glomerulosclerosis develops in maximally hypertrophied glomeruli.

The glomerulopathy of homozygous sickle hemoglobin (SS) disease: morphology and pathogenesis.

This morphologic and morphometric study of native-kidney biopsies of six homozygous sickle hemoglobin (SS) nephrotics defines a distinctive glomerulopathy of focal sclerosis developing in maximally hypertrophied glomeruli. In each biopsy, two patterns of segmental glomerulosclerosis were observed: a "collapsing" pattern and an "expansive" pattern. Morphologic analysis comparing group mean glomerular (Bowman's capsular) diameters indicates that glomeruli in SS are routinely markedly enlarged whether nephrotic (group SSN, 233.6 mu +/- SE of 25.3 [N = 6]) or not (control group SSC, 243.5 mu +/- SE of 12.5 [N = 5]). These values are significantly larger when compared with those of matched normal controls (group NC, 158.0 mu +/- SE of 12.7 [N = 6]) or to matched patients with idiopathic focal glomerulosclerosis (group IFS, 188.2 mu +/- SE of 17.9 [N = 6]). Furthermore, based on a previous study, it is most likely that glomerular enlargement in SS represents the maximal hypertrophy attainable in humans. Correlating observations of renal homografts in two sickle hemoglobin patients that developed segmental sclerosis of only the collapsing pattern soon after transplantation, it is proposed that in homozygous sickle hemoglobin nephrotics the collapsing pattern of segmental glomerulosclerosis represents an initial but progressive obliteration of the glomerular capillary bed by red blood cell sickling which cannot be compensated by further glomerular hypertrophy. Hemodynamic glomerular injury then supervenes from the sustained or increasing hyperfiltration in a diminishing capillary bed, manifesting morphologically as the expansive pattern of sclerosis.

Morphologic and immunohistochemical observations in granulomatous glomerulonephritis.

Eight renal biopsies of Wegener's granulomatosis and other vasculitic syndromes with periglomerular granulomatous reactions (granulomatous glomerulonephritis) are studied. Controls consist of 57 biopsies of crescentic and focal necrotizing glomerulonephritis (of various diseases, excluding systemic lupus erythematosus). Both groups have in common the morphologic alterations of inflammatory tuft necrosis, fibrin exudation into the urinary space, crescent formation, and breaks of Bowman's capsule. In the study group, the unique feature of glomeruli with surrounding granulomatous reactions was the presence, within the urinary space, of an exudate of fibrin mixed with immune reactants (immunoglobulins and usually complement) in association with gaps of Bowman's capsule. This contrasts with an exudate of fibrin alone in glomeruli of the control group and other glomeruli of the study group. The study group also had a significantly greater incidence of immune deposits in Bowman's capsule (P less than 0.001). Giant cells may result from the interaction of macrophages of the granuloma with Bowman's capsule that is permeated with immune reactants.

Focal sclerosis of hypertrophied glomeruli in solitary functioning kidneys of humans.

Morphometric data on glomerular size are presented on three patients with solitary functioning kidneys and one with bilateral oligomeganephronic hypoplasia. Renal biopsy of each of two patients with a congenitally absent kidney (unilateral renal agenesis) and a patient with oligomeganephronie, all with proteinuria and renal insufficiency, reveal increases of mean glomerular diameters of at least 1.75X and mean glomerular volumes greater than 5X. These dimensions, which are in the range of maximal increases recorded for man, are associated in all three biopsies with focal sclerosis of the hypertrophied glomeruli. By contrast, the functionally fully-compensated solitary kidney of a patient who lost function of the contralateral kidney from acquired disease, is characterized by the absence of focal glomerulosclerosis and by glomerular enlargement of significantly lesser degree (increased mean diameter 1.24X and mean volume less than 2X). These observations correlate glomerular injury with glomerular size and suggest that in the setting of reduced nephron numbers, nephron destruction via focal glomerulosclerosis may be initiated when compensatory glomerular hypertrophy has reached its limits.

Iga nephropathy: presentation, clinical course, and prognosis in children and adults.

Eighty-two patients, 56 male and 26 female, biopsied since 1972 had IgA nephropathy. At the time of kidney biopsy, 24 patients were children and 58 were adults. In both groups the clinical course was documented in sufficient detail to allow prediction of disease outcome. Twenty-six (45%) of the adult patients had chronic renal insufficiency either at first evaluation or subsequently. Fourteen eventually required chronic hemodialysis. Hypertension as the initial sign of disease was seen more frequently in patients with chronic renal insufficiency. Adult males were more likely to have chronic renal insufficiency. The life table method was used to predict age at initiation of dialysis and kidney survival from date of onset of clinically apparent disease. Thirty-five percent of the male patients were predicted to require dialysis by age 40. Kidney death was predicted at 10 years from onset for 33% of male and 22% of all patients biopsied as adults. While all patients with progressive disease had over 2.0 g/24 h urinary protein excretion at least once, many individuals with serum creatinine concentration below 1.5 mg/dL showed marked fluctuation in degree of proteinuria, often exceeding 2.0 g/24 h. Thus, in some cases, degree of proteinuria was not a reliable predictor of outcome.

Clinical trial of chlorozotocin, DTIC, and dactinomycin in metastatic malignant melanoma.

Thirty evaluable patients with metastatic malignant melanoma were treated with a combination of chlorozotocin, DTIC, and dactinomycin. One complete and four partial responses were achieved, for an overall response rate of 17%. Cumulative myelotoxicity was noted, as well as universal gastrointestinal intolerance. One patient developed probable drug-related nephrotoxicity. A survival advantage was noted for responding patients. We conclude that the addition of chlorozotocin did not improve response rate or response duration and that further trials with this drug combination cannot be recommended.

Noninflammatory renal microangiopathy of systemic lupus erythematosus ('lupus vasculitis').

5 (group 1) of 9 patients with systemic lupus erythematosus (SLE) who underwent a kidney biopsy during a 1-year period had a noninflammatory renal microangiopathy which significantly narrowed or occluded the lumens of arterioles and terminal segments of interlobular arteries. Though these lesions resemble those of malignant hypertension and the thrombotic microangiopathies, their distinctive features, revealed by light, immunofluorescence and electron microscopy, differentiate them from the others. 4 of these 5 (group 1) patients developed hypertension; in 3 the microangiopathy predated the hypertension. None of the remaining 4 (group 2) patients without these lesions has become hypertensive. One group-1 patient with extensive lesions involving 40% of intrarenal arterioles at biopsy developed renal failure shortly thereafter with increasing arteriolar involvement but unchanged glomerular histology.

Focal and segmental glomerular sclerosis in reflux nephropathy.

Reflux nephropathy was diagnosed in 23 patients (14 per cent of all the patients who received transplants) between 1973 and 1977, and nephrectomy was performed in all. Histology and immunofluorescence revealed a glomerular sclerosis associated with the idiopathic nephrotic syndrome. No focal and segmental glomerular sclerosis was seen in kidneys removed from patients with nonglomerular renal disease. Twenty-four hour urinary protein excretion in grams was 3.1 +/- 0.3 (mean +/- SEM) and was greater than that in our patients with end-stage nonglomerular renal disease. Thirty-one renal transplants were performed in these 23 patients; thereafter, maximum protein excretion was 1.4 g. Focal and segmental glomerular sclerosis was seen in only one (chronic rejection, protein excretion less than 0.5) of the 20 kidneys available for histologic study. Thus, focal and segmental glomerular sclerosis is extremely common in reflux nephropathy, accounts for "glomerular" proteinuria and may contribute importantly to progressive renal failure but, unlike that associated with the idiopathic nephrotic syndrome, rarely recurs after renal transplantation.

Evaluation of a new method for treating segmental renal disease.

Experimental segmental renal artery embolization was performed to evaluate the feasibility of therapeutic segmental renal embolization. In group 1, a two kidney dog model, segmental embolization of the right kidney was performed in ten dogs using Gelfoam, Silastic elastomer and barium sulfate. In group 2, a one kidney dog model, segmental embolization of left kidney was performed using Gelfoam and Silastic elastomer. In the remaining three dogs of group 2, embolization was not done for control. Sequential blood pressure measurements, plasma renin activities and renal arteriograms were obtained. Three dogs in group 2 died following unintentional complete renal embolization. Seventeen of the 18 dogs of the entire study remained normotensive after embolization. One dog had persistent hypertension develop which was controlled by a second, total renal embolization. The results suggest that therapeutic segmental renal embolization is a feasible method for treating segmental renal disease.

Hydronephrosis with ureteral valve: diagnosis by ultrasonography and antegrade pyelography.

A case of massive hydronephrosis secondary to a ureteral valve was discovered upon evaluation of mild trauma. The orderly diagnostic studies, including ultrasonography and antegrade pyelography, led to the correct diagnosis and appropriate therapy. Ultrasonography as a diagnostic tool in urology is discussed and characteristics of the 18 cases of ureteral valves reported to date are reviewed.

The effects of amphotericin B therapy on the intrarenal vasculature and renal tubules in man. A study of biopsies by light, electron and immunofluorescence microscopy.

Renal morphology was studied by light and electron microscopy in 10 patients after 25 mg/kg body weight of amphotericin B as part of a controlled study designed to evaluate the possible protective effects of mannitol against the nephrotoxicity of amphotericin B. Five patients received amphotericin B 1 mg/kg body weight every other day and five received amphotericin B and mannitol 1 g/kg body weight in the infusion. Small arterial and arteriolar changes were present in all biopsies and were characterized by focal vacuolization of medial smooth muscle cells. Electron microscopy suggested formation of these vacuoles by fusion of dilated endoplasmic reticulum. A few small vacuoles were also seen in renal biopsies of age matched patients who did not receive amphotericin B. Vacuoles in biopsies of the amphotericin treated patients were considerably larger (P less than 0.001) and much more numerous (P less than 0.001) than in controls. It is hypothesized that the vacuoles in the amphotericin B treated group represent the morphologic effect of intrarenal vasoconstriction caused by amphotericin B therapy. Nephrocalcinosis was observed in all biopsies and appeared to originate by precipitation of calcium salts in tubular casts.

A possible relationship between Henoch-Schonlein syndrome and IgA nephropathy (Berger's disease). An illustrative case.

A 29-year-old white male with the Henoch-Schonlein syndrome and rapidly progressive glomerulonephritis received a kidney transplant. Postransplant, a glomerulonephritis histologically and immunologically indistinguishable from IgA nephropathy (Berger's disease) developed in the absence of any extrarenal manifestations of the Henoch-Schonlein syndrome. A possible pathogenetic interrelationship between these two diseases is discussed.