Plasma immunadsorption treatment in patients with primary focal and segmental glomerulosclerosis

BACKGROUND: In primary focal and segmental glomerulosclerosis (FSGS) renal prognosis is poor if no remission of proteinuria can be obtained by treatment. In some patients a permeability factor, responsible for damaging the glomerular epithelial cell and detectable by an in vitro test (GVV-test), seems to be present in the serum. METHOD: We determined the effects of an immunadsorption treatment (IAT) on proteinuria and glomerular permselectivity (using a neutral dextran and dextransulfate-sieving technique to assess glomerular size and charge selectivity) in five patients with FSGS in the native kidneys and three patients with recurrence of FSGS after kidney transplantation. Furthermore, we performed the GVV-test using sera obtained from the patients before and after therapy. RESULTS: IAT reduced proteinuria by more than 50% in four patients, all of whom had an improvement in glomerular-size selectivity. Charge selectivity was better preserved after therapy in three out of these four subjects. The GVV-test prior to IAT was positive in two patients who also responded clinically to therapy. After IAT the GVV-test was negative in all patients, indicating an elimination of the proteinuric factor in the two previously positive patients. CONCLUSION: We conclude that a positive GVV-test before treatment makes a favourable response of IAT on proteinuria likely in patients with FSGS. If a reduction of proteinuria can be obtained by IAT this is due to an improvement in glomerular size and/or charge selectivity.     

Study of the in vitro effect on glomerular albumin permselectivity of serum before and after renal transplantation in focal segmental glomerulosclerosis

BACKGROUND: The selective proteinuria observed in patients with focal segmental glomerulosclerosis (FSGS) suggests an abnormal loss of fixed anionic charges on the glomerular capillary wall. METHODS: In this article, we have studied the putative presence of such factor(s) by using a new in vitro assay to assess glomerular permselectivity by measuring glomerular volume variation (GVV) in isolated glomeruli after hypotonic stress. We randomly tested the serum GVV activity of 10 healthy donors and 143 patients before transplantation. Of the patients, 80 had FSGS, 26 membranous glomerulonephritis, 19 polycystic kidney disease, and 18 malformative uropathies. Moreover, we tested the pre- and posttransplantation serum of 14 patients with recurrence and 14 without recurrence. RESULTS: Serum GVV was significantly higher in patients with FSGS than in those with the other end-stage renal diseases studied (P<0.01) or in healthy donors (P<0.01). However, a wide distribution of serum GVV activity in patients with and without FSGS was observed. Statistically, pregraft GVV values were not predictive of the recurrence of FSGS after transplantation. Moreover, we observed a significant decrease in serum GVV activity after transplantation in patients without recurrence (P<0.01) compared to those who underwent a recurrence. CONCLUSIONS: These results reinforce the hypothesis of a circulating factor that alters glomerular albumin permselectivity in FSGS patients. However, the presence of this factor before transplantation did not appear to predict relapse of the disease after transplantation, as recently supported, although its activity seems to be down-regulated after transplantation in patients who do not experience recurrence of the disease.     

Age and ethnicity affect the risk and outcome of focal segmental glomerulosclerosis

In patients with proteinuria, African-American (AA) ethnicity is reported to be a risk factor for focal segmental glomerulosclereosis (FSGS) and its progression to end-stage renal disease (ESRD). We reviewed our single-center experience to determine the probability of FSGS and its progression to ESRD based on ethnicity and age at presentation in children with proteinuria with or without nephrotic syndrome. Proteinuria without systemic disease or acute glomerulonephritis was the presenting feature in 17% (236/1,403) of children in the renal patient database of Texas Children's Hospital, Baylor College of Medicine. Histopathological diagnoses were established in 107 of 236 patients (45%). FSGS was identified in 65 patients, accounting for 28% of all patients with proteinuria and 61% of patients who underwent renal biopsy. FSGS was more prevalent in AA (45%) than in non-AA patients (22%) (P=0.001), and AA patients with FSGS were older at presentation (12.7+/-4.4 years) than non-AA patients (5.6+/-4.6 years) (P<0.001). Among patients who underwent renal biopsy, increasing age at presentation increased the probability of having FSGS in AA but not non-AA patients (P=0.04). Five-year actuarial renal survival of FSGS was worse in AA (8%) than in non-AA patients (31%) (P=0.01). These data suggest an increased risk and worse outcome of FSGS in AA compared with non-AA children.     

Cyclosporine protects glomeruli from FSGS factor via an increase in glomerular cAMP

Cyclosporine (CsA) administration to patients with recurrent focal segmental glomerulosclerosis (FSGS) after transplantation results in remission of proteinuria. We have shown that sera from patients with recurrent FSGS can increase the glomerular albumin permeability (Palbumin) and that increase in glomerular cAMP levels can alter the permeability characteristics of glomeruli in vitro. The purpose of this study was to determine if the increased glomerular levels of cAMP were related to the protective effects of CsA on an increase in Palbumin by FSGS sera. Glomeruli from Sprague-Dawley rats following intraperitoneal administration of CsA (25 mg/kg/day), cremophore (25 mg/kg/day), or saline for 5 days were incubated with 1:50 dilution of serum from three FSGS patients or with pooled normal human serum prior to calculation of Palbumin. Glomerular cAMP was measured by radioimmunoassay. Glomerular ultrastructural changes were assessed by transmission electron microscopy (TEM). Serum from three FSGS patients markedly increased Palbumin of glomeruli from saline or cremophore treated rats (saline, 0.68+/-0.08; 0.72+/-0.07; 0.70+/-0.07; and cremophore, 0.79+/-0.05; 0.81+/-0.02; 0.79+/-0.01; n=25 glomeruli in each group). In contrast Palbumin of glomeruli from CsA treated rats was not increased by any of the three FSGS sera tested (0.03+/-0.02; 0.04+/-0.05; 0.02+/-0.07, n=25 glomeruli in each group). Glomerular cAMP (pmol/mg of protein) increased 5 fold in CsA treated rats (328+/-26; 5 rats) compared with cremophore or saline treated rats (87+/-24 and 65+/-23, P<0.01; 5 rats in each group). The glomerular basement membrane appeared to be thickened and the lamina densa had an irregular appearance after treatment with CsA. No ultrastructural changes of glomerular epithelial or endothelial cells were evident. We conclude that CsA may have a direct protective effect on the glomerular filtration barrier in FSGS. We postulate that increased levels of glomerular cAMP by CsA may play an important role in protecting the glomerular Palbumin effect of the FSGS factor and may contribute to remission of proteinuria in FSGS patients.     

Secondary collapsing glomerulopathy associated with Loa loa filariasis

This is the first case of nonprimary collapsing focal segmental glomerulosclerosis (FSGS) associated with Loa loa filariasis. Loa loa micofilariae were detected on a blood smear after a patient presented with nephrotic syndrome (NS), microhematuria, and renal failure. The renal biopsy showed a collapsing glomerulopathy variant of FSGS. Microfilariae also were identified in renal microvasculature, including the afferent arterioles and the glomerular and peritubular capillaries.     

Therapy of focal and segmental glomerulosclerosis with methylprednisolone, cyclosporine A, and prednisone

Patients with steroid-resistant focal and segmental glomerulosclerosis (FSGS) have a poor prognosis but may benefit from high-dose methylprednisolone or cyclosporine A therapy. Ten patients were treated with a protocol of methylprednisolone infusions for 8 weeks followed by a combination of cyclosporine A and alternate-day prednisone for maintenance of remission for 2 weeks. Eight of ten patients remitted the nephrotic syndrome within 8 weeks of beginning treatment. One patient remitted edema but remained proteinuric, and one did not respond. After observation for 12-24 months, seven patients maintained remission with normal glomerular filtration rate. One non-responder had renal insufficiency and one patient had secondary non-response and end-stage renal disease. No patients developed hypertension. One patient had the diagnosis of Hodgkin disease made after 10 months of therapy. Follow-up renal biopsy in four patients showed no evidence of progressive interstitial disease. There were no other major side effects. Steroid-resistant FSGS may be successfully treated with the described protocol. Additional studies will be needed to determine if this approach prevents progression of renal disease.     

Clinical and morphological predictors of renal outcome in adult patients with focal and segmental glomerulosclerosis (FSGS)

In this retrospective study, we examined 35 adult patients with biopsy-proven, primary focal and segmental glomerulosclerosis (FSGS) and nephrotic syndrome to determine whether any of the clinical and morphological features of FSGS were associated with a higher risk of a poor renal outcome. Clinical factors assessed were the age, sex, amount of urinary protein, and presence of microscopic hematuria, hypertension and renal dysfunction at onset in each patient. Morphological parameters included the number of segmental sclerosis and global sclerosis, sclerosis score, location of segmental sclerosis, mean glomerular diameter, grade of tubulo-interstitial changes, and presence of vascular lesions. Twenty-three patients (66%) were in complete or incomplete (partial) remission, and 12 (34%) were non-responders at the end of follow-up. On univariate analysis, the age at onset, sclerosis score, mean glomerular diameter, and grade of tubulo-interstitial changes in no response were significantly greater than those parameters in remission. Multivariate logistic regression analysis revealed that the degree of tubulo-interstitial changes and mean glomerular diameter were independent risk factors for a poor renal outcome. These findings suggest that the estimation of these latter two parameters allows the nephrologist to predict the probable course and prognosis of an adult with FSGS. Intensive and prolonged therapy is recommended for patients without these two morphological features.     

Enhancement effect of an ethanol/Panasate 800 binary vehicle on anti-inflammatory drug permeation across excised hairless mouse skin

A total of 65 adult cases (53 males, 12 females) with biopsy-proven focal segmental glomerulosclerosis (FSGS) were studied. Hypertension, ascites and haematuria were seen in 13, 12 and 24 cases, respectively. Decreased creatinine clearance at presentation was found in 9 cases. Mean proteinuria per day, serum cholesterol and total protein were 7.5 +/- 4.3 g, 388.95 +/- 213.4 mg% (10.11 +/- 5.55 mmol/l) and 5.27 +/- 1.1 g% (0.527 +/- 0.11 milligram), respectively. Mesangial proliferation was seen in 13 cases and hilar sclerosis in 5. Fifty percent showed positive immunofluorescence; IgM in 10, C3 in 8, and IgG in 2. Forty-two cases could be followed (mean 32 months), out of which 38 had nephrotic syndrome and were treated with prednisolone; 58% showed response (31% complete remission and 27% partial remission). One patient in each group of responders and nonresponders had renal failure at the end of follow-up. Hypertension, degree of proteinuria, mesangial proliferation, degree of tubular atrophy and immunofluorescence findings did not significantly affect the response to steroids. We conclude that a group of patients with idiopathic adult FSGS has a favourable response to steroids, which cannot be predicted clinically.     

Identification of nitric oxide synthases in isolated bovine brain vessels

Initial reports on antiproteinuric effect of pefloxacine in small groups of patients with minimal-change nephropathy (MCN) and focal and segmental glomerulosclerosis (FSGS) have not been confirmed in other papers. To assess its antiproteinuric effect in experimental animals we administered pefloxacine to rats with adriamycin nephropathy showing morphological changes resembling human minimal-change disease or focal segmental glomerulosclerosis, and clinically with full-blown nephrotic syndrome. Pefloxacine treatment was at least partially effective in preventing further increase of proteinuria in rats with adriamycin nephropathy. The mechanism of this effect remains unclear and deserves further studies concentrating on the glomerular cytokine network and glomerular production of reactive oxygen species.     

Glomerular morphology in nephrotic heroin addicts

Renal biopsies of 23 heroin addicts who presented with the nephrotic syndrome were examined by light and electron microscopy. The majority of patients (14) showed focal segmental glomerular sclerosis on light microscopy, four patients showed "minimal change", and two were classified as "focal global sclerosis." In one case focal mesangial proliferation was the outstanding feature; one patient had diabetic glomerulosclerosis; and one had mesangiocapillary glomerulonephritis and dysproteinemia. Visceral epithelial swelling and proliferation were present in 14 patients on light on light microscopy. Electron microscopy showed distinct podocyte changes consisting of loss of foot processes, vacuolization, and cytoplasmic degeneration; focal separation of podocytes from basement membranes was found in 11 of 18 cases. In some instances a few electron-dense deposits were present in the mesangium. Membranous nephropathy was not encountered, although it occurs in 30 to 40% of unselected adult nephrotic individuals. Of 15 patients followed for 2 months to 5 years, one died of heroin overdose, eight went into renal failure, two improved, and four continued to have proteinuria. It is concluded that nephrotic syndrome of heroin addicts is most often associated with focal segmental glomerular sclerosis and occasionally with minimal change disease or focal global sclerosis. Conceivably these three conditions represent different phases of one disease process, although different reactions to heroin or its various vehicles and contaminants cannot be excluded. The morphologic resemblance to experimental aminonucleoside and N,N'-diacetylbenzidine-induced nephrosis suggests a possible toxic origin.     

De novo collapsing glomerulopathy in renal allografts

BACKGROUND: Collapsing glomerulopathy is a recently described form of glomerular injury characterized by capillary collapse and visceral epithelial hypercellularity associated with nephrotic range proteinuria and a rapid, progressive decline in renal function. The lesion has rarely been described in allografts. METHODS: We reviewed 892 allograft biopsies from a population of 1079 recipients who received renal transplants between 1978 and 1996. RESULTS: Five cases of de novo collapsing glomerulopathy were identified (0.6% of biopsies; 3.2% since 1993). None occurred before 1993. The patients were 31 to 66 years of age and they presented 6 to 25 months after transplantation. The 24-hr urinary protein ranged from 1.8 to 11.8 g. All patients and donors were negative for the human immunodeficiency virus and had no risk factors for human immunodeficiency virus infection. Diffuse or focal, global or segmental collapse of glomerular capillaries, swelling and hypercellularity of the visceral epithelium, hyaline arteriolosclerosis, and interstitial fibrosis were characteristic histologic features. Two cases had concomitant glomerular immune complex deposits. Progressive decline in allograft function occurred within 2-24 months after diagnosis, culminating in return to dialysis in all patients. CONCLUSION: Collapsing glomerulopathy can arise in renal allografts as a de novo disease. Although its pathogenesis remains to be clarified, it is important to distinguish this lesion in allografts as it can be associated with rapidly progressive graft failure.     

Value of fluorescence in situ hybridization for detecting the bcr/abl gene fusion in interphase cells of routine bone marrow specimens

A patient presented with a severe nephrotic syndrome and a renal biopsy consistent with early focal segmental glomerulosclerosis (FSGS). After a year of intensive immunosuppressive therapy proteinuria was unabated and renal function began to deteriorate. Treatment with weekly plasmapheresis combined with moderate doses of prednisone and azathioprine produced a dramatic decrease in proteinuria and serum creatinine. A marked fall in the B-cell population occurred during treatment, as well as an increase both in T-lymphocytes of the mature CD4+ helper/suppressor phenotype and in the immature/cytotoxic CD8+ phenotype. Activation of the immune system during treatment was demonstrated by an increase in the rate of spontaneous proliferation of peripheral blood mononuclear cells and an increase in T-cell expression of the interleukin-2 receptor.     

Charge and size selectivity of proteinuria in children with idiopathic nephrotic syndrome

Experimental studies have pointed to charge selectivity as an important determinant of glomerular permeability to macromolecules. Loss of glomerular basement membrane (GBM) polyanion has been proposed as a cause of the selective proteinuria in minimal change nephrotic syndrome (MCNS). However, the presence of less-anionic albumin in urine than plasma from MCNS and focal and segmental glomerulosclerosis (FSGS) patients has been interpreted both as evidence for partial maintenance of charge selectivity and for involvement of other pathogenic mechanisms. The exact role of charge selectivity in the pathogenesis of nephrotic proteinuria remains controversial. We have examined the clearance of endogenous proteins of differing size and charge in children with idiopathic nephrotic syndrome (NS). Chromatofocusing was used to determine the isoelectric points (pIs) of albumins in paired plasma and urine samples from patients with FSGS (n = 6) and MCNS (n = 6). Charge selectivity was assessed by comparing the pIs of the fractions with the highest albumin concentration (model pI) in plasma and urine. The difference between the modal pIs was defined as the delta modal pI. Charge selectivity was also assessed from the albumin/transferrin and IgG4/IgG1 clearance ratios; size selectivity from the IgG1/albumin and IgG1/transferrin as well as the IgG4/albumin and IgG4/transferrin clearances. In children with FSGS, the mean (+/-SD) delta modal pI was -0.05 +/- 0.16, and in MCNS -0.05 +/- 0.11. Neither value differed significantly from zero. The albumin/transferrin clearance ratio showed no significant difference between FSGS and MCNS, but the IgG4/IgG1 clearance ratio was significantly higher in MCNS (P < 0.05). Size selectivity was significantly reduced in FSGS compared with MCNS (for IgG1/transferrin P < 0.01 and for IgG1/albumin P < 0.05). For IgG4/transferrin and IgG4/albumin, P was < 0.05. In conclusion, there was no evidence for residual charge selectivity in idiopathic NS associated with either MCNS or FSGS during nephrotic-range proteinuria. There was a significant loss of GBM size selectivity in children with FSGS with heavy proteinuria compared with children with MCNS with heavy proteinuria.     

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.     

Clinicopathological analysis and therapy in hepatitis C virus-associated nephropathy

The authors evaluated, using computer image analysis system, 15 renal biopsy specimens from patients with MCD and 15 from patients with FSGS. As a control group 5 biopsy and 10 autopsy renal specimens were used. These studies revealed, that in MCD glomeruli showed proliferative changes unrecognizable by light microscopy. In FSGS glomeruli without sclerotic changes were larger than in controls and showed glomerular cells proliferation (per unit of glomerular area) similar to MCD. FSGS in comparison with MCD showed larger glomeruli and prominent interstitial fibrosis. These observations appeared to be helpful in distinguishing MCD and recent forms of FSGS. There were no correlations between relative interstitial volume and glomerular changes in MCD as well as in FSGS. The authors concluded, that histomorphometry can't be used instead of morphological examinations of renal biopsy specimens, but it gives objective informations about progression of the illness and may be useful in differential diagnosis of selected cases of MCD and FSGS.     

Glomerular tip lesions--a newly described glomerular change

Glomerular tip lesion is a newly described histopathological lesion characterized by a focal and segmental widening of the mesangial matrix without hypercellularity together with capillary dilatation, hyaline exudation on the inside of capillary walls and occurrence of vacuolized cells, localized to the peripheral segments of the glomerular tuft. Clinically, these patients have a pronounced nephrotic syndrome with slightly reduced renal function, but terminal renal failure is seldom seen, even after many years of disorder. Two characteristic case histories are presented. The classification of this lesion among the glomerular disorders is at present uncertain. It may represent a transitional form between minor lesion nephritis and focal segmental sclerosis, a separate disorder, or a functional lesion associated with high proteinuria.     

Feasibility of an emergency department-based, risk-targeted voluntary HIV screening program

Renal biopsies from 19 boys and 11 girls, most with moderate or severe forms of hemolytic uremic syndrome (HUS) of the classic diarrhea-associated type, were analyzed as part of their long-term follow-up. Patients were biopsied because of late or persistent proteinuria, hypertension, and prolonged renal failure. The median length of follow-up was 11.2 years (range 0.9-22.0 years). Four histological groups were identified: focal segmental glomerulosclerosis and hyalinosis (FSGSH) (17 patients), diffuse mesangial proliferative glomerulonephritis (DMPGN) (9 patients), diffuse glomerulosclerosis (2 patients), and minimal glomerular changes (2 patients). The median interval between the onset of disease and renal biopsy was significantly shorter in DMPGN than in FSGSH (P < 0.001). The pathological findings may be the expression of two different stages of the same dynamic process: a regular sequence of glomerular lesions consisting of early DMPGN, followed by FSGSH. This lesion would ultimately lead to the final stage of global glomerulosclerosis. At the last examination, only a quarter of the patients had normal renal function. These observations also confirm that prolonged oligoanuria during the acute stage of HUS frequently results in an unfavorable long-term prognosis.     

Comparative clinical and biochemical analyses of two methods of pancreatic cannulation in pigs

Over the last 16 years the evolution of 24 pregnancies in 17 women with biopsy-proven glomerular disease was analyzed. The underlying renal histology was IgA nephropathy in 8 cases, lupus nephritis in 7, mesangiocapillary glomerulonephritis type I in 1, and focal segmental glomerulosclerosis in 1. All but 2 had normal renal function before conception and 3 were hypertensive. Fetal survival rate was 75%. There were 6 preterm deliveries (33.3%), 3 newborns small for gestational age (17%), 1 stillbirth, and 5 therapeutic abortions. The perinatal mortality was 5.5%. De novo hypertension occurred in 8 pregnancies (33.3%). In 11 pregnancies (46%) increased proteinuria was diagnosed and in 6 (25%) a decline in maternal renal function was recorded. Permanent impairment of renal function was seen in 2 women with renal insufficiency before conception. Maternal hypertension and renal function impairment were associated more frequently with obstetric complications. In conclusion, pregnancy is safe for normotensive mothers with glomerular diseases and normal renal function. Hypertension and impaired renal function at conception seem to carry increased risk for mothers and fetuses. Low-dose immunosuppressive treatment during pregnancy is not harmful for the fetus.     

Primary Sj?gren's syndrome and glomerulonephritis

HISTORY AND CLINICAL FINDINGS: An 82-year-old woman with hypertension for 20 years developed a nephrotic syndrome with severe oedema followed by acute oliguric renal failure after a bout of bronchitis and a gastrointestinal infection. She also complained of xerostomia and dry eyes of recent onset. INVESTIGATIONS: Biochemical tests showed a serum creatinine level of 6.1 mg/dl, a 1:5120 antinuclear antibody (ANA) titre, and positive values for Ro(SS-A) and La(SS-B) antibodies. HLA-DR typing demonstrated HLA-DR3 (HLA-DRB1*0301) and DR13 (HLA-DRB1*13) antigens. Renal biopsy revealed minimal glomerular lesions with focal and segmental glomerulo-sclerosis as well as (hypertension-induced) benign nephrosclerosis and focal tubular atrophy with interstitial fibrosis. TREATMENT AND COURSE: After two hemofiltrations and concomitant administration of 100 mg prednisone renal function quickly improved and the proteinuria fell to 1 g/dl. At the same time the xerostomia improved. The nephrotic syndrome recurred 7 months later after the prednisone dose had been reduced to 10 mg/d, but after the dose had been raised to 50 mg/d and cyclosporin A (150 mg/d) had been added a lasting remission occurred and renal function became stable though impaired. CONCLUSION: The relatively rare association of glomerular disease (here focal segmental glomerulosclerosis) with Sj?gren's syndrome can, as in this case, be triggered by a viral infection. A genetic predisposition for Sj?gren's syndrome is suggested by the demonstration of HLA-DR3 alleles. Administration of steroids is indicated for the treatment of the nephrotic syndrome and, in case of recurrence, can be combined with cyclosporin A. Both drugs also influence the symptoms of Sj?gren's syndrome.     

Primary focal segmental glomerulosclerosis: clinical course and response to therapy

Primary focal segmental glomerulosclerosis (FSGS) is a lesion associated with a poor prognosis and results in end-stage renal disease after 5 to 10 years. Based on past experience, many nephrologists have considered primary FSGS a lesion that is steroid resistant and therefore are reluctant to offer steroids as treatment. Recent data, however, have demonstrated that patients with primary FSGS have a response to steroid therapy that is considerably better than had been described. Thus, it may be that nephrologists have been more "steroid reluctant" than the lesion is steroid resistant. To better understand this issue we review the clinical course and response to therapy in patients with primary FSGS.