Focal Segmental Sclerosis Research Articles

Renal Biopsy in Patients 65 Years of Age or Older An Analysis of the Results of 334 Biopsies

We studied the clinical and pathological data for 334 patients age 65 or more who underwent renal biopsy for acute renal failure (ARF, n = 55), subacute renal failure (SRF, n = 72), chronic renal failure (CRF, n = 57), proteinuria (n = 137), and hematuria (n = 13). Tissue diagnoses were glomerulopathy (n = 252, 75.4%), acute tubular lesions (n = 18), interstitial nephritis (n = 23), vascular diseases (n = 36, including 14 with cholesterol emboli), and five miscellaneous diagnoses. Of the 55 patients with ARF, 23 had a glomerular lesion, 15 had acute tubular necrosis, and 8 had acute interstitial nephritis. Of 72 patients with SRF, 49 had a glomerulopathy, 12 had a vascular disorder, and six had acute interstitial nephritis. Hence, patients with ARF or SRF exhibited a high potential for reversible lesions. Only 11.3% of patients with CRF had potentially reversible causes. The most common causes of proteinuria were membranous glomerulopathy (34.3%), minimal change disease (14.6%), focal segmental sclerosis (11.7%), and amyloidosis (8.8%). Of the 25 patients with advanced nephrosclerosis, 24 had renal failure, 20 were hypertensive, and 13 had cholesterol emboli. Of 33 patients with diabetes mellitus, 66.7% were found to have lesions not related to diabetes. We conclude that renal biopsy is most useful in older patients with ARF or SRF because of potentially reversible renal disease. Old age alone is not a contraindication to performing a renal biopsy.

Cyclosporin A in the treatment of childhood glomerulonephritis.

Seven children with steroid resistant nephrotic syndrome (focal segmental sclerosis in six, mesangial proliferation in one) were treated with Cyclosporin A for 12 weeks. Five of these children were also resistant to cyclophosphamide. All patients had normal renal function. Cyclosporin was started at 8 mg/kg/day then increased until a trough blood level of 100-300 ng/ml (HPLC) was achieved. Three of the seven patients achieved complete remission, and the other four had a significant reduction in their proteinuria (p less than 0.05). In the three patients who achieved complete remission, relapse of proteinuria occurred within six weeks of ceasing Cyclosporin. All patients experienced some impairment in renal function with mean creatinine clearance decreasing from 129 +/- 19 to 91 +/- 13 ml/min/1.73m2 (p less than 0.05). One child was subsequently treated with Cyclosporin for 12 months. He remains in remission with a repeat renal biopsy showing no evidence of nephrotoxicity. One other child with steroid sensitive minimal change nephrotic syndrome who had severe steroid toxicity was treated with a lower dose (5 mg/kg/day) for 12 months. She remained in remission off steroids, but relapsed 16 weeks after Cyclosporin was ceased. A renal biopsy after 12 months showed no nephrotoxicity. Cyclosporin should be considered in steroid resistant nephrotic syndrome, and in children with minimal change disease who show signs of steroid toxicity and short remission period after cyclophosphamide. Serial renal biopsies are recommended with prolonged therapy.

Glomerular diseases in children. "The Iranian experience".

A total of 411 children, aged from 0.3 to 18 years, suffering from glomerular diseases, were studied by renal biopsy between 1976 and 1985. The clinical presentation included nephrotic syndrome (79% of cases), renal failure (43%), and arterial hypertension (38%). In all, 177 cases presented with primary nephrotic syndrome; all had complicated courses and most were either corticosteroid-dependent or -resistant. Only 26.6% had minimal change disease on renal biopsy; 56.5% had focal-segmental sclerosis; and immunofluorescent deposits were observed in half of the group. Acute poststreptococcal (36 cases), mesangiocapillary (80 cases), and lupus (34 cases) glomerulonephritis occurred frequently; IgA glomerulopathy (10 cases) and haemolytic uraemic syndrome (6 cases) were uncommon. Glomerular crescents were observed in 71 cases. These observations illustrate the types of glomerular diseases seen in Iranian children.

The effect of the elastase on aminonucleoside nephrosis

In this paper, we studied the effect of elastase on aminonucleoside (AN) nephrosis which is considered a model of focal glomerular sclerosis (FGS). Elastase is an enzyme which disintegrates elastin, discovered by Balo, and used in the treatment of arteriosclerosis and hyperlipidemia. It has also been known to improve metabolism of acid mucopolysaccharides, so, this study focused on metabolic improvement. Three groups of male Sprague-Dawley rats were studied and observed at regular intervals; 30, 60, 90 days. The ANE group (AN + elastase) was administered one shot of AN (10 mg/100 g B.W.) during the test interval, while elastase (5 mg/kg B.W.) was injected 5 days/week for the entire test interval. The AN group was administered one shot of AN only. The third group was a control (C). The following results were observed: (1) Focal segmental hyalinosis and sclerosis (FSHS); ANE group was weaker than AN group. (2) Other significant qualifying glomerular changes (vacuolar change and hyaline droplets of the epithelial cells, adhesion, and foam cells); ANE group was weaker than AN group. (3) Anion loss in GBM was shown by a lack of colloidal iron staining under light microscopy, and by a lack of PEI particles under electron microscopy; there was significantly less anion loss with ANE group, than with AN group. The findings suggest that elastase has an affect on the metabolism of acid mucopolysaccharide and collagen in sclerotic lesion, and may restrain the progress of amino-nucleoside nephrosis.

IgM nephropathy: morphological study related to clinical findings.

This study describes 10 cases of IgM nephropathy in whom the main morphological findings consisted of diffuse mesangial deposition of IgM and varying degrees of mesangial cell proliferation. In addition, focal segmental sclerosis was present in 1 patient and global sclerosis in another. An ill-defined electron-dense deposit was seen within the mesangial area in 1 case. Except for 1 patient, who had hematuria only, all suffered from nephrotic syndrome without deterioration of renal function. In view of the constant and characteristic finding of a diffuse mesangial IgM deposition, it is suggested that this form of nephropathy constitutes an entity separate from focal glomerulosclerosis or minimal change disease.

1568 PREDICTION OF PROTEINURIA BY RANDOM AND 24 HOUR URINE PROTEIN CREATININE RATIOS (U P/Cr) IN NEPHROTIC CHILDREN

The feasibility of using the U P/Cr to predict dally protein excretion in nephrotic patients was tested in 125, 24 hour urine collections from 47 children with nephrotic syndrome (aged 19 mos - 16 years). Six patients were steroid non-responsive and had focal segmental sclerosis by biopsy; all others were considered to have minimal change disease either by biopsy or Prednisone responsiveness. Urine protein was measured by the Coomassle blue binding technique (Bio-Rad Lab) and creatinine by the spectre-photometric Pierce Test Kit. Total protein excretion (TP) ranged from 2 mg to 32 g/m2/day. U P/Cr ranged from .002 to 33 in 24 hour urine samples. The correlation between daily protein excretion and U P/Cr was highly significant (n = 125, r = 0.57, p < 0.001). However, the scattergram of all data suggested non-linearity when proteinuria was minimal (< 100 mg/m2/d) or excessive (> 1 g/m2/d). Logarithmic conversion improved the correlation of data at both extremes of TP:Logarithmic conversion of all data enabled accurate prediction of TP from U P/Cr [n = 125, r = .97, Log TP = 0.9 (Log U P/Cr) -0.5], Random U P/Cr from 9 specimens collected on the day following a 24 hour urine were also predictive of TP (r = 0.96, p < .001). These data support the concept that U P/Cr can accurately predict proteinuria although non-linearity outside moderate ranges requires logarithmic conversion.

A clinicopathologic study of forty-eight infants with nephrotic syndrome

The clinical and histopathologic features of 48 children presenting with the nephrotic syndrome during the first year of life were analyzed. Proteinuria was discovered soon after birth to 3 months of age in 39 infants (congenital nephrotic syndrome), and nine infants had an infantile onset presenting between 4 and 12 months of age. Neither histologic parameters--microglomeruli, epithelial, or mesangial proliferation, focal segmental or global sclerosis, fibrinoid necrosis, or tubular microcysts--nor histologic classification--microcystic disease, mesangial proliferative glomerulonephritis, focal segmental glomerular sclerosis/hyalinosis-predicted the outcome. Rather, age at presentation was found to predict outcome: One of 39 infants with a congenital onset and seven of nine infants with an infantile onset underwent a complete remission (P less than 0.0001).

Efficacy of cyclophosphamide in steroid-sensitive childhood nephrotic syndrome with different morphological lesions.

We have reviewed the efficacy of cyclophosphamide in 39 steroid-sensitive frequently relapsing nephrotic children. Cyclophosphamide was used because of heavy steroid dependence and steroid toxicity. A percutaneous renal biopsy done prior to administration of cyclophosphamide showed the lesion to be minimal change in 7 children, IgM nephropathy in 17 children, and evolving from minimal change nephrotic syndrome to focal segmental sclerosis (FSGS) in 15 children. 100% of patients with minimal change nephrotic syndrome responded to cyclophosphamide, but only 58% of IgM patients responded (p less than 0.05). Only 1 of 15 FSGS patients responded (p less than 0.001 vs. minimal change nephrotic syndrome and p less than 0.01 vs. IgM). In view of the failure of cyclophosphamide to produce a remission in FSGS and its potential for long-term impairment of suppressor T cell function, we suggest that it should not be used in patients whose disease has evolved from minimal change to FSGS.

HIGH RATE OF MORPHOLOGICAL TRANSITION IN CHILDREN WITH STEROID SENSITIVE MINIMAL CHANGE NEPHROTIC SYNDROME (M.C.N.S.)

We reviewed the clinical course and morphology of 48 children with biopsy proven M.C.N.S. with a minimum follow-up of at least 5 years. Mean age at onset was 4.1 yrs (11 mo-16 yrs). Mean follow-up was 11.2 yrs (5-18). 33 of 48 children (66%) underwent a second biopsy at a mean time of 4.5 yrs after the first biopsy because of frequent relapses or steroid dependence. 15 (45%) converted to focal segmental sclerosis (F.S.G.S.). 9 (27%) evolved into IgM nephropathy and only 9 (27%) retained the original morphology of M.C.N.S. 6 of these 9 patients with M.C.N.S. had a 3rd biopsy. Only one showed persistent M.C.N.S., and he converted to IgM nephropathy on 4th biopsy.Overall, among patients undergoing repeat renal biopsies, only 12% continued to show a persistent M.C.N.S. lesion, the rest evolving into IgM nephropathy or F.S.G S. Analysis of age at onset, frequency of hematuria, hypertension or elevated creatinine at onset did not distinguish the children with morphological transition from the remaining ones.At the end of the study, 25% of these children are dead of renal causes, on dialysis, transplanted or in chronic renal failure with a creatinine clearance less than 20 ml/min.Our study concludes that a very high frequency of morphological transition is present in M.C.N.S. patients who have a relapsing or steroid dependent course and that the prognosis ir these cases is guarded.

Evolution of Renal Segmental Atrophy (Ask-Upmark Kidney) in Children With Vesicoureteric Reflux: Radiographic and Morphologic Studies

A radiographic and morphologic study of nine patients with renal segmental “hypoplasia,” whose kidneys were radiographically normal when first examined, showed the lesion to be a form of localized, progressive renal atrophy. The renal abnormality bears a strong relationship to vesicoureteric reflux, which could be demonstrated in every patient. No evidence of renal scarring or atrophy was observed in initial roentgenographic examinations at a mean age of 2.9 years (range 0.1 to 10 years); however, serial studies during five to 14 years after discovery of vesicoureteral reflux demonstrated both a lack of renal growth and a progressive loss of substance irrespective of infection. Radiographic lengths of scarred kidneys, as measures of renal growth, correlated poorly with the radiographic surface areas of the renal parenchymal outlines. The mean time from discovery of vesicoureteric reflux to appearance of a renal scar was 6.1 years, and to onset of hypertension in six patients was 7.8 years. The renal abnormality consisted of lobar with variable tubular atrophy and glomerular sclerosis and with parenchymal destruction that in some specimens had proceeded to a complete loss of nephronic elements. The occasional presence of relatively well-preserved glomeruli and tubules and of focal segmental sclerosis within persisting glomeruli was taken as evidence of a progressive renal abnormality, as opposed to a static developmental hypoplasia. These observations indicate that renal scarring, the injury presumably having been initiated by vesicoureteric reflux, can progress despite correction of the reflux and despite prevention of urinary tract infection.

Evolution of renal segmental atrophy (Ask-Upmark kidney) in children with vesicoureteric reflux: Radiographic and morphologic studies

A radiographic and morphologic study of nine patients with renal segmental "hypoplasia," whose kidneys were radiographically normal when first examined, showed the lesion to be a form of localized, progressive renal atrophy. The renal abnormality bears a strong relationship to vesicoureteric reflux, which could be demonstrated in every patient. No evidence of renal scarring or atrophy was observed in initial roentgenographic examinations at a mean age of 2.9 years (range 0.1 to 10 years); however, serial studies during five to 14 years after discovery of vesicoureteral reflux demonstrated both a lack of renal growth and a progressive loss of substance irrespective of infection. Radiographic lengths of scarred kidneys, as measures of renal growth, correlated poorly with the radiographic surface areas of the renal parenchymal outlines. The mean time from discovery of vesicoureteric reflux to appearance of a renal scar was 6.1 years, and to onset of hypertension in six patients was 7.8 years. The renal abnormality consisted of lobar atrophy with variable tubular atrophy and glomerular sclerosis and with parenchymal destruction that in some specimens had proceeded to a complete loss of nephronic elements. The occasional presence of relatively well-preserved glomeruli and tubules and of focal segmental sclerosis within persisting glomeruli was taken as evidence of a progressive renal abnormality, as opposed to a static developmental hypoplasia. These observations indicate that renal scarring, the injury presumably having been initiated by vesicoureteric reflux, can progress despite correction of the reflux and despite prevention of urinary tract infection.

A lymphocytotoxic factor(s) in plasma of patients with minimal change nephrotic syndrome: Partial characterization

The incidence, relationship to clinical disease, and physical characteristics of a plasma cytotoxic factor(s) were studied in steroid-responsive minimal change nephrotic syndrome (MCNS) and other renal diseases. Plasma activity was found in 76% of 67 children with MCNS and in 67% of 9 children with focal segmental sclerosis (FSS). Of 31 normal adults and children and 7 adults with membranous glomerulonephritis, only 1 individual had toxic plasma. In MCNS, degree of plasma activity was not related to clinical disease, prednisone dosage, or serum levels of IgG or α-2-macroglobulin. The active factor(s) was found more frequently in plasma than in serum, was heat stable and nondialyzable by selected filtration, and was approximately 100,000 to 300,000 molecular weight. By DEAE column chromatography, activity coincided with fractions containing IgA and IgM but not IgG. While the nature of the plasma factor(s) has not been identified, these data indicate that MCNS plasma may adversely affect lymphocyte viability by a slow process of cytotoxicity requiring 24 or more hr, and that such plasma activity occurs frequently in children with MCNS and also with the more severe FSS.

Primary nephrosis in childhood associated with focal glomerular sclerosis: Is long-term prognosis that severe?

In our study, 32 nephrotic children with focal glomerular sclerosis were observed for an average period of 8 years (ranging 1-19 years of age). Of the 32, 25 children showed histological lesions of focal segmental sclerosis (FSG) and 7 of focal global glomerulosclerosis (FGG). All patients were reevaluated in 1979, creating the most recent status as follows: for children with FSG, 6 (24%) are in remission, 10 (40%) have a relatively normal renal function but exhibit either a persisting proteinuria (PP) or a recurrent nephrotic syndrome (NS), 1 (4%) is in chronic renal failure, 5 (20%) required dialysis and transplantation, and 3 (12%) died from non-renal causes. For children with FGG, 4 (57%) are in remission, 2 (29%) have a good renal function but display either PP or NS, and 1 patient (14%) is in chronic renal failure. The long-term observation of our study shows a more favorable prognosis than the one reported in researched literature. We believe that such results reflect a difference in the type of population encountered in our institution. Our population of patients represents less a highly referred population than the one of the centers who reported similar long-term studies, and we believe therefore that our study may represent a wider spectrum of the natural history of the disease. Moreover, the group of patients with PP or NS does not show a progressive decrease of glomerular filtration rate with time, which suggests that the disease may progress in a stepladder fashion.

Vibrio cholerae meningitis in a neonate

the delays before renal failure developed showed wide variations, and ranged from two to 16 years. 12, 13 In the present family, the two youngest patients died from nonrenal causes, so that the course of the renal disease remains unknown. Two siblings reported by Moncrieff et al ~' developed a NS at 11 months and had normal renal function 22 and 13 years later. Steroid-resistant familial nephrosis may have a protracted course, and an early pessimistic prognosis must be given with caution. The two older patients of this family had a steroidresistant NS which did not differ from sporadic steroidresistant nephrosis with minimal changes, and further development of focal segmental hyalinosis or sclerosis. Although environmental factors accounting for the familial incidence cannot be excluded, it is more likely that the disease of the three children was hereditary. This favors the hypothesis that steroid-resistant nephrosis may be caused by several primary mechanisms and is not a single entity?~, 13

1545 PRIMARY HEMATURIA (PH): PREDICTIVE VALUE OF PERIPHERAL LYMPHOCYTE MARKERS, SERUM IMMUNOGLOBULINS AND RENAL HISTOPATHOLOGY

P.H. has been reported as having a good prognosis except in some cases of IgA mesangial deposition (MGN-A) with focal segmental sclerosis and proliferation (FSS) which may progress to ESRD. HLA, lymphocytes bearing surface IgA (SIgA), serum immunoglobulins (Ig) and renal histopathology were evaluated in patients with P.H. persisting > 6 months. HLA-A, B and C were determined in 49 patients (29 MGN-A and 20 MGN-non A) and in 524 controls. In P.H. patients the frequency of Bw35 was 43% (similar in MGN-A and MGN-non A) and 23% in controls (p<0.01). Dr7 was present in 8/22 MGN-A (36%) but only in 19/109 (17%) control subjects. SIgA was elevated in 41/42 (98%) patients but only in 3/52 (6%) controls (p <0.001). Mean serum IgA and IgM levels were higher in P.H. patients compared to controls. Of 10 Bw35 patients with MGN-A, 9 had FSS (3 of the 9 evolving to ESRD) compared to 8/19 withoug Bw35 (p <0.01). It is concluded that 1) HLA-Bw35 is present and SIgA elevated more frequently in patients than in controls, and may be useful in separating P.H. from other hematurias, 2) a positive correlation of these findings with FSS and/or progression to ESRD exists only in MGN-A patients, 3) Dr7 seems increased in MGN-A patients, and 4) some P.H. patients require renal biopsy for better assessment of prognosis.

IgM associated primary diffuse mesangial proliferative glomerulonephritis.

Twenty-three cases of IgM associated primary diffuse mesangial proliferative glomerulonephritis are presented. In 18, IgM was the sole localising host immunoglobulin, and it was the predominant globulin in five; C3 was also present in 18. Light microscopy revealed variable diffuse and global mesangial proliferation in all cases, with additional focal global sclerosis in 16, focal segmental sclerosis in 15, and small capsular crescents in seven. Material for electron microscopy was available from 19 patients; in 13, occasional intramesangial electron dense deposits were identified, and in 18 there were irregular, rather ill defined areas of increased electron density in mesangial regions. Clinically, 14 patients presented with the nephrotic syndrome, and nine had asymptomatic proteinuria. During follow-up, only 10 patients showed no change in renal function or improved; the remainder showed increasing hypertension and/or renal function deterioration and four developed end stage renal failure. It is suggested that IgM associated mesangial proliferative glomerulonephritis should be considered as a distinct clinicoimmunopathological entity.

Familial Hyperuricemia and Renal Disease

Information on a familial syndrome of hyperuricemia and renal disease with or without gout was obtained on 33 of 41 blood relatives: Nine had renal disease; abnormalities of the urinary sediments were minimal; serum uric acid levels were elevated in seven and were not measured in two. Hyperuricemia was noted in three additional family members without evidence of renal disease. Goulty arthritis (three patients) did not precede renal disease. One individual had hyperuricosuria. The following erythrocyte purine enzyme levels were normal: adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, phosphoribosylpyrophosphate, synthetase, adenosine deaminiase, and purine nucleoside phosphorylase. Renal biopsy specimens showed focal global and segmental sclerosis of glomeruli, occasional hypercellularity, foci of atrophic tubules, chronic interstitial inflammation, and folding and wrinkling of glomerular basement membrane without electron-dense deposits. There were no immunofluorescent abnormalities.

Microscopic hematuria in schoolchildren: Epidemiology and clinicopathologic evaluation

An unselected population of 8,954 children, age 8 to 15 years, was screened for hematuria. Four urine specimens from each were examined; microscopic hematuria was found in one or more specimens in 4.1%, and in two or more specimens in 1.1% of the children. The prevalence was not age or sex dependent. Those with two or more positive samples were re-examined twice during a half-year period: 33 had hematuria of 6 or more RBC/0.9 mm3, or more than 100,000 RBC/hour, on both occasions; renal biopsy performed on 28 of them revealed two cases of IgA-IgG nephropathy, one of focal segmental sclerosis, one of extracapillary glomerulonephritis, and one of possible hereditary nephritis. In 12 patients the biopsy was entirely normal; the rest showed equivocal changes. Co-existing proteinuria and the degree of hematuria correlated well with the severity of the morphologic alterations. Pathologic findings in microscopic hematuria seem to be less frequent than in hematuria in general; in most such patients, renal biopsy is probably not indicated. In some children the low-grade hematuria may merely represent the upper end of physiologic variation.

IgA localisation in glomerular diseases.

The structural changes found on light and electron microscopy study of 25 renal biopsy specimens that showed significant glomerular IgA deposition on immunofluorescence were correlated with relevant clinical data. The morphology of a wide range of glomerulopathies seeen included mesangial proliferative (60%), membranous (12%), rapidly progressive proliferative (8%), mesangio-capillary (8%), and no light microscope change (8%). Four of the 15 cases (60%) of mesangial proliferative glomerulonephritis were associated with focal segmental sclerosis and 10 with focal segmental and focal global sclerosis. In addition, 7 of the 15 cases showed capsular crescents. The clinicopathological correlations indicated that the prognosis in this group is unfavourable when focal global sclerosis and capsular crescents are present, particularly when both occur in the same biopsy specimen.

The significance of focal glomerular sclerosis in children who have nephrotic syndrome.

This study was undertaken to learn the significance of focal glomerular sclerosis in children who have nephrotic syndrome. Tissue obtained by percutaneous renal biopsy 10-15 years previously was re-examined. Initially, two of the 29 biopsy specimens contained focal segmental hyalinosis or sclerosis and five of the 29 had focal glomerular obsolescence. The paraffin blocks were serially sectioned and examined. Following this procedure, seven of the 29 biopsies had focal segmented hyalinosis and 16 of the 29 had focal glomerular obsolescence. The percentages of focal segmental hyalinosis and focal glomerular obsolescence were recorded. Only those patients whose focal segmental hyalinosis exceeded 2% progressed to renal failure. Age-matched autopsy material from patients dying without renal dysfunction was used as a control. Focal glomerular sclerosis was seen in 75.8% of the control specimens, although few glomeruli within each specimen were involved. Focal glomerular sclerosis may be found normally; it may be found in nephrotic children who do not develop renal failure. The quantification of sclerotic lesions may be of prognostic significance in childhood nephrosis.