Recurrent focal glomerulosclerosis: natural course and treatment with plasma exchange.

BACKGROUND: Focal glomerulosclerosis (FGS) can recur after renal transplantation and prognosis is poor in untreated patients. A circulating plasma factor has been implicated in the pathogenesis of a recurrent FGS and treatment with plasma exchange has proven effective in decreasing proteinuria in some patients. METHODS: We retrospectively studied the course of disease in patients with recurrent FGS, transplanted in our centre. Seven patients transplanted between 1991 and 1997, received treatment with plasma exchange, whereas 10 patients, transplanted between 1973 and 1991, were left untreated and served as historical controls. RESULTS: The time of onset of proteinuria (>3.5 g/day) was comparable in the untreated and treated patients (9 and 10 days respectively), as was the average proteinuria at that time (5.5 and 5.8 g/day respectively). In the untreated patients, proteinuria persisted and eventually all grafts were lost, on average 43 months after the diagnosis of a recurrence. In five cases (50%) the recurrence was the single cause of graft loss. The clinical course was different in the seven patients who were treated with plasma exchange. In five of these patients, the recurrence occurred within 3 weeks after transplantation. Plasma exchange was started 1-14 days after onset of proteinuria in these patients. Two lost their grafts after 0.7 and 1.0 months because of untreatable rejection. In the remaining three patients the plasma exchange resulted in abrupt disappearance of the proteinuria, and the response has been lasting for 2-3.2 years. In these patients the only histological abnormality was foot effacement on electron-microscopy. In two patients the recurrence became manifest at 9 weeks and 5.8 years after transplantation respectively. These two patients relapsed after the initial course of plasma exchange, but responded to repeated session, and are currently being treated once a month. They have been followed for 1. 7 and 1.4 years after the onset of proteinuria and their urinary protein levels are 0.23 and 1.2 g/10 mmol creatinine. CONCLUSIONS: The prognosis of untreated recurrent FGS is poor. Treatment with plasma exchange can lead to complete remission of proteinuria and relapsing patients may respond to repeated sessions. Best results are obtained when plasma exchange is started early, when there are no visible lesions on light-microscopy.     

Poorly differentiated adenocarcinoma of the rectum in a nephrotic patient with focal segmental glomerulosclerosis

We report herein a case of poorly differentiated adenocarcinoma of the rectum occurring in a nephrotic patient with focal segmental glomerulosclerosis. The neoplasm which first appeared to be a submucosal tumor occurred in a 29-year old Japanese man with a neophrotic syndrome for 2 years and 6 months. Autopsy disclosed a large tumor located between the rectum and urinary bladder. Renal specimens showed changes consistent with focal segmental glomerulosclerosis.     

Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade

Steroid-resistant nephrotic syndrome of childhood poses a dilemma in attempting to balance toxicity of medications against long-term prognosis. This report presents our preliminary experience with the novel use of combined mycophenolate mofetil (MMF) and angiotensin blockade (AB) in the treatment of nine children and young adults with focal glomerulosclerosis (FSGS). All patients were steroid resistant and had failed conventional treatment regimens. Prior to the initiation of the MMF-AB protocol, the patients were pre-treated with weekly intravenous methylprednisolone (MP) (15 mg/kg per week) for 4–8 weeks. Angiotensin-converting-enzyme inhibitors and/or angiotensin receptor blockers were begun when intravascular volume was restored. MMF was given at a dose of 250–500 mg/m² per day. Proteinuria, as measured by urine protein/creatinine ratios (Up/c), decreased by 43% following MP (P<0.05). After 6 months of MMF-AB protocol, the Up/c was 72% below baseline (P<0.01). This level was maintained for a minimum of 24 months of observation. Similarly, hyperlipidemia, as measured by total cholesterol and triglycerides, improved significantly with treatment (536±163 to 265±70 mg/dl, 447±168 to 230±92 mg/dl, respectively, P<0.01). Our data support the use of MMF and AB for treatment of steroid-resistant FSGS when other conventional treatments have failed and/or induced toxicity.     

Treatment of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) commonly presents with nephrotic syndrome (NS), and spontaneous remission is rare. NS is a poor prognostic marker for renal survival, and has serious extra-renal complications. Rapid remission using drugs with minimal side effects is desirable. Tacrolimus (Tac) has a more potent immunosuppressive effect and may be less toxic at therapeutic doses than ciclosporin (CsA). Although CsA has a role in the treatment of FSGS, there are limited data regarding the use of Tac monotherapy in this setting, and this is limited to experience in children. METHODS: We prospectively report the outcome for six adult patients with FSGS treated with Tac from first presentation with NS, and for a further five adult patients in remission on CsA converted to Tac in an attempt to arrest a progressive decline in renal function on CsA. RESULTS: All six patients treated with Tac from presentation with NS achieved remission after 6.5 +/- 5.9 months. The serum albumin for the group increased from 26.8 +/- 4.6 to 37.7 +/- 1.9 g/l (P = 0.003), and there was a significant reduction in the mean 24 h urinary protein excretion from 11.0 +/- 4.5 to 2.8 +/- 2.5 g (P = 0.003). All remissions were partial with a mean reduction in 24 h urinary protein of 75.2 +/- 16.8%. There was a non-significant reduction in MDRD GFR from 71.7 +/- 22.4 to 55.9 +/- 9.7 ml/min/1.73 m(2) (P = 0.07), which manifest within the first 3 months of Tac treatment but renal function was subsequently stable. The mean follow-up for the group was 12.8+/-5.5 months. Two of the five patients converted from CsA to Tac maintained complete remission, and the remaining three patients in partial remission had further reductions in proteinuria. There was an improvement in renal function concomitant with conversion to Tac in each case, with an overall improvement in MDRD GFR for the group of +1.9+/-1.1 ml/min/1.73 m(2)/month. CONCLUSIONS: Tac rapidly and effectively induced remission of NS in FSGS. Conversion from CsA to Tac indicates that Tac might be a more potent agent with less nephrotoxicity in this setting.     

A prospective study of collapsing focal segmental glomerulosclerosis

Collapsing focal segmental glomerulosclerosis (cFSGS) is characterized by rapid progression to end-stage renal disease (ESRD). We evaluated the clinicopathological spectrum of cFSGS and compared its clinical behavior to steroid and tacrolimus (TAC)-resistant noncollapsing focal segmental glomerulosclerosis (FSGS). All patients (>14 years) diagnosed with cFSGS were enrolled in the study. Staining for differentiated podocyte markers such as WT 1, PAX and KI67 were performed in all patients. The outcome and histological features of cFSGS was compared with a prospectively followed cohort of steroid and TAC-resistant noncollapsing FSGS. The study included 22 cFSGS patients and 19 cases of steroid and TAC-resistant FSGS. Complete remission, partial remission, steroid resistance, progression to ESRD and death were observed in 13.6%, 4.5%, 27.3%, 36.4% and 18.2% patients, respectively. Patients with cFSGS had higher serum creatinine and more advanced tubulointerstitial changes compared to resistant FSGS. Twenty-six percent of therapy resistant noncollapsing FSGS progressed to ESRD after two years of stopping TAC. However, there was no difference in progression to ESRD between cFSGS and therapy-resistant noncollapsing FSGS at the end of two years. Glomerular collapse in the setting of FSGS is poorly responsive to treatment and has a high rate of progression to ESRD. The long-term prognosis of cFSGS and steroid and TAC-resistant FSGS are similar.     

Single-centre experience with cyclosporin in 106 children with idiopathic focal segmental glomerulosclerosis.

BACKGROUND: Although remission is achieved in most children with nephrotic syndrome by treatment with corticosteroids, a significant proportion of patients experience relapses. Continuous or repeated use of corticosteroids inevitably induces features of steroid side-effects. Cyclosporin (CsA) has been used in the treatment of idiopathic steroid-dependent and -resistant nephrotic syndrome. However, relapse often occurs shortly after the CsA treatment is terminated. Furthermore, long-term clinical outcome of patients treated with CsA is unclear. METHODS: We retrospectively reviewed the data of 106 nephrotic children having primary focal segmental glomerulosclerosis (FSGS) who received CsA between 1993 and 2002. Indications of CsA therapy were steroid resistance (n = 45) and steroid dependence with steroid toxicity (n = 61). Fifty-four patients received cyclophosphamide prior to CsA therapy. CsA starting dose was 6 mg/kg/day to be readjusted to maintain a whole blood trough level of 80-150 ng/ml. The drug was received for 6-48 months (mean: 22.1+/-11 months). The observation period was 5.8+/-3 and 6.1+/-1.9 years before and after CsA treatment, respectively. RESULTS: Complete remission [proteinuria <4 mg/h/m2 body surface area (BSA)], partial remission (proteinuria 4.1-40 mg/h/m2 BSA) and resistance to CsA (proteinuria > or =45 mg/h/m2 BSA) were observed in 71.7, 7.5 and 20.8% of patients, respectively. CsA-sensitive and -resistant patients differed only in the percentage of steroid responsiveness, being 66.7% in the former group and 22.7% in the later (P<0.0001). Logistic regression analysis identified steroid resistance as the only predictor of resistance to CsA (odds ratio: 12.9; P = 0.03). Hypertension, renal impairment (>30% rise of serum creatinine), gingival hyperplasia and hypertrichosis occurred in 12.3, 6.6, 22.6 and 51.9% of patients, respectively. With the exception of hypertrichosis, side effects were significantly more frequent among CsA-resistant children. We were able to stop steroids in 91 patients, of whom 31 patients relapsed. Out of 20 patients for whom CsA was intentionally discontinued while in remission, 16 patients relapsed. Of these, four (25%) were resistant to a second course of CsA. At the last follow-up, one child had developed end-stage renal failure and three had chronic renal insufficiency. CONCLUSIONS: CsA is effective in the treatment of children with idiopathic FSGS, but with a high relapse rate on drug withdrawal. Renal dysfunction and hypertension, which may be drug-induced or natural progression, are the most serious complications; therefore, close monitoring is essential.     

Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children.

This study was conducted to evaluate the safety and efficacy of tacrolimus (TAC) in children with SRNS. The study group comprised of 22 consecutive children with steroid-resistant nephrotic syndrome (SRNS) who were studied prospectively. TAC was initiated with a dose of 0.10 mg/kg/day, and the dose was increased to attain a trough level of 5.0-10.0 g/l. These patients were treated with concomitant prednisone, which was subsequently tapered off and stopped. The primary outcome variable was the number of patients who attained a complete remission (CR) or partial remission (PR). The mean age of onset was 7.33 +/- 5.9 years, and there were 20 boys and 2 girls. Of the 22 children, 9 had minimal change disease, 11 had focal segmental glomerulosclerosis and the other 2 had diffuse mesangial hypercellularity on histopathology. TAC had to be withdrawn in 3 children because of its side effects. Of the remaining 19 children who received adequate therapy and were able to achieve target levels, CR was seen in 16 (84%) children, 2 (10.5%) attained PR and 1 was nonresponsive. The mean time to achieve remission was 63.2 +/- 44 days and the mean dose of TAC was 0.18 +/- 0.07 mg/kg. The mean urine spot protein/creatinine ratios were significantly lower (0.33 +/- 0.58 vs. 13.5 +/- 21.9 mg/mg, p = 0.002) and the mean serum albumin levels were significantly higher (3.92 +/- 0.35 g/dl vs. 2.39 +/- 0.56 g/dl, p = 0.00005), as compared to those prior to starting TAC. The mean glomerular filtration rate values at the end of the study were similar to those prior to starting TAC (97.9 +/- 21.2 ml/min/1.73 m(2) vs. 96.4 +/- 18.4 ml/min/1.73 m(2), p = 0.30). The mean duration of follow-up was 290 +/- 126 days. This is the largest study so far on the safety and efficacy of TAC therapy in SRNS. Our results suggest that TAC is an effective therapeutic modality for SRNS, including the subgroup of children who are nonresponsive to the current therapeutic modalities like cyclophosphamide and cyclosporine.     

Eye involvement in children with primary focal segmental glomerulosclerosis

Distinct eye abnormalities have been described in children with nephrotic syndrome, particularly in diffuse mesangial sclerosis (i.e. Pierson syndrome). The aim of the study was to investigate whether there were any associated ocular anomalies in children with steroid-resistant nephrotic syndrome (SRNS), all of whom had revealed primary focal segmental glomerulosclerosis in biopsy. Thirty-three SRNS patients (16 male, 17 female) with a median age of 10.5 years (range 3–25 years) were enrolled in the study. Twenty steroid-sensitive nephrotic syndrome (SSNS) patients (ten male, ten female) with a median age of 8 years (range 3–15 years) served as controls. All SRNS patients were examined by mutational analysis for mutations in the NPHS2, WT1, and LAMB2 genes. Nine out of 33 SRNS patients (27.2%) showed various eye abnormalities. However, no abnormal ocular findings were detected in any of the SSNS patients. Abnormal eye findings detected in SRNS patients were anisometropic amblyopia (n = 4), Mittendorf’s dots (n = 4), myopic astigmatism (n = 3) and exotropia (n = 1). Macular pigment changes (n = 1), posterior subcapsular opacities (n = 1) and cataract (n = 1) were considered as steroid-induced side effects. In four patients, more than one eye abnormality was found. Mutational analysis for the NPHS2, WT1 and LAMB2 genes revealed disease-causing mutations in 24.2% of patients. Homozygous NPHS2 mutations were detected in five patients (15.1%), all of whom had parental consanguinity. In three patients (9%) from non-consanguineous parents, heterozygous de novo WT1 mutations were detected as disease-causing mutations. No LAMB2 mutation was detected in any patient. While four out of five (80%) patients with homozygous NPHS2 mutations showed at least one abnormal ocular finding (i.e. Mittendorf’s dot or anisometric amblyopia), none of the patients with a WT1 mutation had ocular involvement. In conclusion, ocular involvement may accompany SRNS caused by primary focal segmental glomerulosclerosis (FSGS). Ophthalmologic evaluation at the time of diagnosis might be beneficial to characterize further the spectrum of this possible association.     

Factors influencing the course and the response to treatment in primary focal segmental glomerulosclerosis.

BACKGROUND: The clinical course of primary focal segmental glomerulosclerosis (FSGS) varies and there is considerable controversy as to which factors are of importance in determining prognosis or response to therapy. The aim of this study was to identify clinical, pathological or immunohistochemical features at biopsy that could identify patients with progressive disease who might benefit from treatment, and predict long-term outcome. METHODS: The clinical and pathological findings of 33 adult patients with primary FSGS were retrospectively analysed in order to identify features at biopsy that could be predictive of outcome or response to treatment. For this purpose an immunohistochemical study was also performed, using monoclonal antibodies against intracellular adhesion molecules-1, C5b-9, alpha 3 beta 1 integrin, alpha-smooth-muscle actin (SMA), and TGF-beta1. RESULTS: At biopsy 17 patients (51%) were nephrotic and 16 (49%) non-nephrotic. Of the nephrotic patients, 11 were treated and six received only symptomatic therapy. Initial treatment with prednisolone (Pred) for 6-12 months (average 9 months) resulted in remission in 64% of nephrotic patients. To those with partial or no response, cyclosporin (CsA) or cyclophosphamide was given. At the end of follow-up (mean 57 months) three nephrotic patients (28%) were in complete remission, six (54%) in partial remission, and two (18%) did not respond to the treatment. In the seven treated non-nephrotic patients, Pred induced a complete remission in two (28%), a partial remission in three (44%), while two patients (28%) did not respond. Plasma creatinine remained stable in nephrotic patients who responded and it almost doubled in non-responders. Plasma creatinine also remained unchanged in treated non-nephrotic patients who responded to Pred, while two non-responders reached end-stage renal disease (ESRD). In contrast, 50% of untreated nephrotic patients and 67% of untreated non-nephrotic patients progressed to ESRD. Multivariate analysis showed only age and plasma creatinine at biopsy to have an independent predictive value for renal survival in nephrotic patients. This analysis also demonstrated that only the severity of interstitial fibrosis predicted the response to the treatment. In addition, the tubulointerstitial but not the glomerular expression of C5b-9, alpha 3 beta 1 integrin, alpha-SMA, and TGF-beta1 was significantly more extensive in non-responders and correlated with renal function at biopsy. However, only tubulointerstitial expression of TGF-beta1 independently correlated with the degree of renal function impairment at biopsy, but none of the above markers independently predicted renal survival or response to therapy. CONCLUSIONS: Nephrotic patients with FSGS may benefit from a more prolonged course of Pred. Nephrotic patients responding to treatment have a significantly better renal survival than non-responders. Age and plasma creatinine at biopsy are independent risk factors leading to ESRD. The severity of tubulointerstitial fibrosis is predictive of response to therapy.     

Nephrotic syndrome associated with focal segmental glomerulosclerosis in a patient with systemic lupus erythematosus and membranous glomerulonephritis in remission

Renal involvement is frequent in systemic lupus erythematosus (SLE). This lesion, termed lupus nephritis, has been reported clinically in at least 50% of the patients. It is generally assumed that in patients with SLE, renal abnormalities detected clinically are caused by lupus nephritis, especially lupus glomerulonephritis (GN). Thus, renal biopsy is performed not for diagnostic purposes, but rather for determining the type and extent of renal involvement. However, clinically significant renal abnormalities unrelated to lupus nephritis have rarely been described in patients with SLE. The reported case serves to emphasize this consideration. The patient was a 41-year-old woman who presented 11 years previously with severe hypertension, nephrotic syndrome, and a serum creatinine level of 2.9 mg/dL. Renal biopsy showed membranous GN and ischemic damage. After a prolonged remission induced by steroids and cyclophosphamide, the patient presented with nephrotic syndrome and a serum creatinine level of 2.1 mg/dL. Although she was normotensive at that time, there were features of SLE. Repeated renal biopsy showed focal segmental glomerulosclerosis without the changes of membranous GN or any type lupus GN. This case illustrates two interesting observations, ie, resolution of membranous GN and nonlupus renal lesions in patients with SLE.