Complete remission of nephrotic syndrome in an infant with focal segmental glomerulosclerosis: is it renin–angiotensin blockade?

Nephrotic syndrome presenting in the first year of life is often challenging, with substantial risk of progression to end-stage renal disease (ESRD). Focal segmental glomerulosclerosis (FSGS) comprises up to 20% of biopsy-proven glomerular disease in children and adults. We report on a 9-month-old infant who presented with nephrotic syndrome, hypertension and progressive deterioration of renal function due to FSGS. As immunosuppressive agents are often unsuccessful in treating this condition, we adopted renoprotection as the mainstay treatment for this patient, through rigorous control of blood pressure and proteinuria with a multi-drug regimen including renin-angiotensin axis blockade. Initially, there was partial improvement, with a gradual decline in proteinuria and a concomitant rise in the glomerular filtration rate, before the disease eventually passed into complete clinical and laboratory remission. We speculate that infants with steroid-resistant nephrotic syndrome due to FSGS may benefit from tight control of hypertension, mainly though early blockade of the renin-angiotensin axis. We believe that its renoprotecive mechanism counteracts the deleterious effects of both hypertension and proteinuria, thereby not only preventing progressive renal disease, but even paving the way for a remission, as in our patient. To the best of our knowledge, this is the first report of an infant with nephrotic syndrome (NS) due to FSGS that passed into complete remission while the patient was on renoprotective measures including the use of angiotensin-converting enzyme inhibitors (ACEis).     

Focal and segmental glomerulosclerosis: definition and relevance of a partial remission

Focal and segmental glomerulosclerosis (FSGS) is one of the most common primary glomerular diseases to terminate in ESRD. A complete remission (CR) confers an excellent long-term prognosis, but the quantitative benefits of partial remissions (PR) have not been defined. This study evaluated the rate of renal function decline (slope of creatinine clearance) and renal survival in nephrotic FSGS patients with CR, PR, or no remission. It also examined relapse rate from remission and its impact on outcome. Multivariate analysis included clinical and laboratory data at presentation and over follow-up, BP control, the agents used, and immunosuppressive therapy. The study cohort was 281 nephrotic FSGS patients who had a minimum of 12 mo of observation and were identified from the Toronto Glomerulonephritis Registry. Over a median follow-up of 65 mo, 55 experienced a CR, 117 had a PR, and 109 had no remission. A PR was independently predictive of slope and survival from renal failure by multivariate analysis (adjusted time-dependent hazard ratio, 0.48; 95% confidence interval, 0.24 to 0.96; P = 0.04). Immunosuppression with high-dose prednisone was associated with a higher rate of PR and CR. Relapse from PR was frequent (56%) and associated with a more rapid rate of renal function decline and worse renal survival compared with relapse-free partial remitters. Only female gender and the nadir of proteinuria during remission were associated with a sustained remission. A PR in proteinuria and its maintenance are important therapeutic targets in FSGS, with implications for both slowing progression rate and improving renal survival.     

Glomerular tip lesion: a distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum

BACKGROUND: The glomerular tip lesion (GTL) is a distinctive but controversial histopathologic lesion occurring in patients with idiopathic nephrotic syndrome. The relationship of GTL to minimal change disease (MCD) and idiopathic focal segmental glomerulosclerosis (FSGS) has been disputed. METHODS: In order to define the clinical features and natural history of GTL, we retrospectively reviewed the presenting clinical features, biopsy findings and outcome of 47 cases. Presenting clinical features of GTL were compared to those of controls with MCD (N= 61) or idiopathic FSGS (N= 50). RESULTS: The cohort of GTL consisted of 45 adults and two children (mean age 47.5 years; range 12 to 79 years), including 76.6% Caucasians and 53% males. At presentation, 93.6% of patients had edema, 89.1% had nephrotic syndrome (mean urine protein 8.31 g, mean serum albumin 2.27 g/dL, and mean cholesterol 340.6 mg/dL), and 34.8% had renal insufficiency. Mean time from onset of renal disease to biopsy was 2.4 months. At biopsy, glomerular segmental lesions included GTL alone in 26%, GTL and peripheral lesions in 6%, GTL and indeterminate lesions in 36%, and GTL with peripheral and indeterminate lesions in 32%. No initial biopsy contained perihilar sclerosis and most (81%) segmental lesions were cellular. Follow-up data were available in 29 patients, of whom 21 received steroids alone and eight received sequential therapy with steroids and a cytotoxic agent. At a mean follow-up of 21.5 months, 58.6% of patients achieved complete remission of nephrotic syndrome, 13.8% had partial remission, and 27.6% had persistent nephrotic proteinuria. Only one patient progressed to end-stage renal disease (ESRD). Predictors of nonremission included severity of proteinuria at presentation and % peripheral lesions. When compared to controls with MCD and idiopathic FSGS, GTL more closely resembled MCD with respect to high incidence of nephrotic syndrome (P < 0.001), severity of proteinuria (P < 0.05), short duration from onset to biopsy (P < 0.001), and absence of chronic tubulointerstitial disease (P < 0.0054). CONCLUSION: Within the MCD/FSGS spectrum, GTL is a distinctive and prognostically favorable clinical-pathologic entity whose presenting features and outcome more closely approximate those of MCD.     

Asymptomatic haematuria and proteinuria: Renal pathology and clinical outcome in 54 children

In a mass screening programme, 54 children with haematuria and proteinuria were detected and evaluated by clinical findings and renal histology. IgA glomerulonephritis (GN) occurred in 29 patients, diffuse mesangial proliferative GN (DPGN) in 16, membranous GN (MGN) in 4, membranoproliferative GN (MPGN) in 3, and focal segmental glomerular sclerosis (FSGS) was seen in 2. Of the 35 children with proteinuria less than or equal to 1 g/m² per day, 21 with IgA GN and 14 with DPGN had only mild to moderate glomerular changes. None of these children had developed renal impairment after a mean period of 6.5 years (range 5–10 years). On the other hand, 8 children with IgA GN, 2 with DPGN, 4 with MGN, 3 with MPGN, and 2 with FSGS had proteinuria that exceeded 1 g/m² per day. The biopsy specimens from these children showed moderate to severe glomerular changes, and 7 of these children had hypertension or renal impairment during the period of evaluation. This study suggests that a poor outcome correlates with the level of proteinuria and the severity of renal pathology in children with haematuria and proteinuria.     

Association of single measurements of dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year incidence of end-stage renal disease in the multiple risk factor intervention trial

The incidence of ESRD is increasing rapidly. Limited information exists regarding early markers for the development of ESRD. This study aimed to determine over 25 yr the risk for ESRD associated with proteinuria, estimated GFR (eGFR), and hematocrit in men who did not have identified kidney disease and were randomly assigned into the Multiple Risk Factor Intervention Study (MRFIT). A total of 12,866 men who were at high risk for heart disease were enrolled (1973 to 1975) and followed through 1999. Renal replacement therapy was ascertained by matching identifiers with the United States Renal Data System's data; vital status was from the National Death Index. Men who initiated renal replacement therapy or died as a result of kidney disease were deemed to have developed ESRD. Dipstick urine for proteinuria, eGFR, and hematocrit were related to development of ESRD. During 25 yr, 213 (1.7%) men developed ESRD. Predictors of ESRD were dipstick proteinuria of 1+ or > or =2+ (hazard ratio [HR] 3.1 [95% confidence interval (CI) 1.8 to 5.4] and 15.7 [95% CI 10.3 to 23.9] respectively) and an eGFR of <60 ml/min per 1.73 m(2) (HR 2.4; 95% CI 1.5 to 3.8). Correlation between eGFR and serum creatinine was 0.9; the risk for ESRD with a 1-SD difference of each was identical (HR 1.21). Bivariate analysis demonstrated a 41-fold increase in ESRD risk in those with an eGFR <60 ml/min per 1.73 m(2) and > or =2+ proteinuria (95% CI 15.2 to 71.1). There was no association between hematocrit and ESRD. Other baseline measures that independently predicted ESRD included age, cigarette smoking, BP, low HDL cholesterol, and fasting glucose. Among middle-aged men who were at high risk for cardiovascular disease but had no clinical evidence of cardiovascular disease or significant kidney disease, dipstick proteinuria and an eGFR value <60 ml/min per 1.73 m(2) were strong predictors of long-term development of ESRD. It remains unknown whether intervention for proteinuria or early identification of those with chronic kidney disease reduces the risk for ESRD.     

C1q nephropathy: a variant of focal segmental glomerulosclerosis

BACKGROUND: C1q nephropathy is a poorly understood and controversial entity with distinctive immunopathologic features. In order to better define the clinical-pathologic spectrum, we report the largest single-center series. METHODS: Nineteen biopsies with C1q nephropathy were identified from among 8909 native kidney biopsies received from 1994 to 2002 (0.21%). Defining criteria included (1). dominant or co-dominant immunofluorescence staining for C1q, (2). mesangial electron dense deposits, and (3). no clinical or serologic evidence of systemic lupus erythematosus (SLE). RESULTS: The 19 patients were predominantly African American (73.7%), female (73.7%), young adults and children (range, 3 to 42 years; mean, 24.2 years). Presentation included nephrotic range proteinuria (78.9%), nephrotic syndrome (50%), renal insufficiency (27.8%), and hematuria (22.2%). No patient had hypocomplementemia or evidence of underlying autoimmune or infectious disease. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 17 (including six collapsing and two cellular) and minimal-change disease (MCD) in two. All biopsies displayed co-deposits of immunoglobulin G (IgG), with more variable IgM (84.2%), IgA (31.6%), and C3 (52.6%). Foot process effacement varied from 20% to 100% (mean, 51%). Twelve of 16 patients with available follow-up received immunosuppressive therapy. One patient had complete remission of proteinuria and six had partial remission. Four patients with FSGS pattern had progressive renal insufficiency, including two who reached end-stage renal disease (ESRD). Median time from biopsy to ESRD was 81 months. On multivariate analysis, the best correlate of renal insufficiency at biopsy and at follow-up was the degree of tubular atrophy and interstitial fibrosis (P = 0.0495 and 0.0341, respectively). CONCLUSION: C1q nephropathy falls within the clinical-pathologic spectrum of MCD/FSGS. Although further studies are needed to determine the pathomechanism of C1q deposition, we hypothesize that it may be a non-specific marker of increased mesangial trafficking in the setting of glomerular proteinuria.     

Individualized scheme of immunoadsorption for the recurrence of idiopathic focal segmental glomerulosclerosis in the graft: a single center experience

Abstract

Objectives: To explore the role of immunoadsorption (IA) for the treatment of idiopathic focal segmental glomerulosclerosis (FSGS) recurrence in the renal allograft, if applied in a personalized manner. Methods: We studied patients with end-stage renal disease (ESRD) due to idiopathic FSGS, transplanted between 2001 and 2010. Patients with FSGS recurrence were treated with daily sessions of IA for the first week, followed by an every other day scheme and then individualized tapering until discontinuation. Complete remission was defined as a reduction of 24-h proteinuria to ≤0.5?g/day and partial remission as a reduction of 24-h proteinuria to 50% or more from baseline. Results: Of the 18 renal transplant recipients with ESRD due to idiopathic FSGS, 12 (66.7%) experienced disease recurrence in a mean time of 0.75 months post-transplantation (KTx), with a mean proteinuria of 8.9?g/day at the time of recurrence. The mean recipient age was 30.8 years; the mean donor age was 47.4 years, while living related donors provided the allograft in seven cases. Four of the patients received therapy with rituximab in addition to IA. During a mean time of follow-up of 48.3 months, seven patients (58.3%) achieved complete remission, and five (41.7%) partial remission. At the end of follow-up, eight patients (66.7%) had functioning grafts, being in sustained remission, in contrast to four patients (33.3%), who ended up in ESRD because of FSGS recurrence. Conclusions: IA was shown efficacious in a small series of patients with recurrent FSGS in the graft. Renal function remained stable in eight of the 12 patients with FSGS recurrence.     

Rituximab in idiopathic membranous nephropathy

Selective depletion of B cells with the mAb rituximab may benefit the autoimmune glomerular disease idiopathic membranous nephropathy (IMN). Here, we describe our experience treating 100 consecutive IMN patients with persistent nephrotic syndrome with rituximab. We defined complete remission as persistent proteinuria <0.3 g/24 h and partial remission as persistent proteinuria <3 g/24 h, each also having >50% reduction in proteinuria from baseline. During a median follow-up of 29 months after rituximab administration, 65 patients achieved complete or partial remission. The median time to remission was 7.1 months. All 24 patients who had at least 4 years of follow-up achieved complete or partial remission. Rates of remission were similar between patients with or without previous immunosuppressive treatment. Four patients died and four progressed to ESRD. Measured GFR increased by a mean 13.2 (SD 19.6) ml/min per 1.73 m(2) among those who achieved complete remission. Serum albumin significantly increased and albumin fractional clearance decreased among those achieving complete or partial remission. Proteinuria at baseline and the follow-up duration each independently predicted the decline of proteinuria. Furthermore, the magnitude of proteinuria reduction significantly correlated with slower GFR decline (P=0.0001). No treatment-related serious adverse events occurred. In summary, rituximab achieved disease remission and stabilized or improved renal function in a large cohort of high-risk patients with IMN.     

Effect of organic solvent exposure on chronic kidney disease progression: the GN-PROGRESS cohort study

It has been suggested that solvent exposure may have a role in the progression of glomerulonephritis (GN) to ESRD, but this has never been tested with an appropriate cohort study design. A total of 338 non-ESRD patients with a first biopsy for primary GN between 1994 and 2001 were included: 194 IgA nephropathies (IgAN), 75 membranous nephropathies (MN), and 69 FSGS. ESRD, defined as an estimated GFR <15 ml/min per 1.73 m2 or dialysis, was registered during a mean follow-up period of 5 yr. Patients' lifelong solvent exposures before and after diagnosis were recorded by interview and assessed by industrial hygienist experts. Cox models were used to estimate adjusted hazard ratios (HR) of ESRD related to exposures. Overall, 15 and 14% of the patients had been exposed at a low and a high level before diagnosis, respectively. Forty-two with IgAN, 12 with MN, and 22 with FSGS reached ESRD. A graded relationship was observed for MN (age- and gender-adjusted HR [95% confidence interval] for low exposure versus none was 3.1 [0.5 to 18.2] and for high exposure versus none was 8.2 [1.9 to 34.7]) and for IgAN (1.6 [0.7 to 3.9] and 2.2 [1.0 to 4.8]) but not for FSGS. Solvent risk was mediated only partly by baseline proteinuria: Adjusted HR for high exposure versus none was 5.5 (1.3 to 23.9) for MN and 1.8 (0.8 to 3.9) for IgAN. In patients with IgAN, there was a trend in increasing HR with exposure duration before and its persistence after diagnosis. These findings support the hypothesized association of solvent exposure with the progression of GN to ESRD. They should prompt clinicians to give greater attention to patients' occupational exposures and possibly to consider professional reclassification.     

Hypertension after kidney donation: Incidence,predictors, and correlates

Incidence of postdonation hypertension, risk factors associated with its development, and impact of type of treatment received on renal outcomes were determined in 3700 kidney donors. Using Cox proportional hazard model, adjusted hazard ratios (HRs) for cardiovascular disease (CVD); estimated glomerular filtration rate (eGFR) <60, <45, <30 mL/min/1.73m²; end stage renal disease (ESRD); and death in hypertensive donors were determined. After a mean (standard deviation [SD]) of 16.6 (11.9) years of follow‐up, 1126 (26.8%) donors developed hypertension and 894 with known antihypertensive medications. Hypertension developed in 4%, 10%, and 51% at 5, 10, and 40 years, respectively, and was associated with proteinuria, eGFR < 30, 45, and 60 mL/min/1.73m², CVD, and death. Blood pressure was <140/90 mm Hg at last follow‐up in 75% of hypertensive donors. Use of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers (compared to other antihypertensive agents) was associated with a lower risk for eGFR <45 mL/min/1.73m², HR 0.64 (95% confidence interval [CI] 0.45‐0.9), P = .01, and also less ESRD; HR 0.03 (95% CI 0.001‐0.20), P = .004. In this predominantly Caucasian cohort, hypertension is common after donation, well controlled in most donors, and factors associated with its development are similar to those in the general population.     

One-center experience with cyclosporine in refractory nephrotic syndrome in children

 Uncontrolled or refractory nephrotic syndrome (NS), seen in a variety of glomerular disorders, leads to end-stage renal disease (ESRD). This study describes the use and efficacy of cyclosporine (CSA) for the treatment of refractory NS in 83 children seen over a 10-year period. The histological diagnosis leading to the NS was focal segmental glomerulosclerosis (FSGS) in 51% (n=42), IgM nephropathy in 20% (n=17), membranoproliferative glomerulonephritis in 10% (n=8), lupus nephritis in 6% (n=5), human immunodeficiency virus (HIV) nephropathy in 5% (n=4), minimal change disease in 7% (n=6), and membranous nephropathy in 1% (n=1) of patients. During CSA therapy the mean proteinuria of the study population decreased from 5.14 g/24 h (4.80 g/m² per 24 h) to 1.23 g/24 h (0.92 g/m² per 24 h) (P<0.001), the mean serum albumin increased from 2.13 g/dl to 3.53 g/dl (P<0.001), the mean serum cholesterol decreased from 364 mg/dl to 223 mg/dl (P<0.001), and the mean serum creatinine increased from 0.77 mg/dl to 1.2 mg/dl (P<0.01). When analyzed by histological diagnosis, similar significant trends of reduction in proteinuria were seen in all but the lupus group. There was a rise in serum creatinine following the use of CSA in patients with FSGS, lupus nephritis, and HIV nephropathy; however the elevated serum creatinine was only significant in patients with FSGS. At the end of the study period, 20 patients had reached ESRD, of which 11 had FSGS, 5 had lupus nephritis, and 4 were patients with HIV nephropathy. Fifty-four patients were in remission at the end of the study period (48 with proteinuria <100 mg/24 h and 6 with proteinuria <500 mg/24 h). In conclusion, among children with refractory NS, CSA induced a remission in a large proportion. However toxicity, as noted by the rise in serum creatinine, was observed in several patients. Since this toxicity may be drug induced or a natural progression of the disease, careful monitoring and close follow-up are essential. Received: 21 October 1997 / Revised: 30 April 1998 / Accepted: 29 May 1998     

Angiotensin-converting enzyme gene polymorphism and the progression rate of focal segmental glomerulosclerosis in Iranian children

Aim: Focal segmental glomerulosclerosis (FSGS) is one of the most common forms of glomerulonephritis leading to end-stage renal disease (ESRD). A few clinical and paraclinical factors are considered as contributing factors in progression rate. However, there are controversial reports on the relationship between ACE gene polymorphism and rapidity of progression of FSGS to ESRD in different populations. To elucidate this issue, we investigated the relationship between the insertion (I) and deletion (D) ACE gene polymorphism and rapidity of progression of FSGS to ESRD in Iranian children. Methods: Forty-one children aged 1–18 years admitted to St AlZahra Hospital, Isfahan, and St Ali Asghar Hospital, Tehran, Iran, with idiopathic FSGS were enrolled. Renal death was defined as a glomerular filtration rate (GFR) of less than 50 mL/min per 1.73 m² or a decreased GFR to less than 50% compare to baseline. Reaching renal death in less or more than 2 years were labelled as rapid progressors (RP) or slow progressors (SP), respectively. Intron 16 of the ACE gene was amplified by the polymerase chain reaction technique. Results: Twenty-eight patients were male and 13 were female. In 15 RP patients, the genotype distribution was 26.6% DD, 6.7% II and 66.7% ID. In 26 SP patients, the genotype was similar (38.6% DD, 7.6% II and 53.8% ID, P > 0.05). There were no statistically significant differences for ACE I/D gene polymorphism between the two groups of patients (P > 0.05). Conclusion: Our study revealed no correlation between ACE I/D gene polymorphism and rapidity of progression of FSGS to ESRD in Iranian children.     

Long-term plasmapheresis and protein A column treatment of recurrent FSGS

Transient or intermittent plasmapheresis with concurrent immunosuppressive therapy is thought to be beneficial in the treatment of recurrent focal segmental glomerulosclerosis (FSGS) in the early post-transplant period. The results of long-term (6-year) plasmapheresis therapy, in a 9-year-old female with an immediate recurrence of FSGS [urinary protein/urinary creatinine (UP/UC)=17.7] after cadaveric renal transplant, are presented. A 4-week plasmapheresis course induced a decline in the proteinuria, but a relapse occurred after cessation of plasmapheresis. Addition of protein A column therapy led to a further decrease in the proteinuria, to a non-nephrotic range. Long-term control of the nephrotic syndrome was established using a chronic treatment regimen consisting of a single-volume plasmapheresis, followed by a protein A column treatment, performed on sequential days every 3–4 weeks. Mean UP/UC values decreased to 1.15±0.9. A course of cyclophosphamide was successfully used to control a worsening of proteinuria 4 years post transplant. Although sequential renal biopsies demonstrated progressive glomerular sclerosis, the patient’s mean calculated creatinine clearance only modestly declined from 78.3 ml/min per 1.73 m², at the time of transplantation, to 62.7 ml/min per 1.73 m², 6 years later. This patient demonstrated dependence on plasmapheresis/protein A column therapy to maintain a clinical remission of her FSGS recurrence. While long-term plasmapheresis and protein A column therapy in combination with immunosuppressive therapy reversed the effects of uncontrolled nephrosis and possibly facilitated long-term renal allograft survival, the glomerular sclerosis continued to progress. Received: 4 April 2001 / Revised: 15 June 2001 / Accepted: 15 June 2001     

Long-term outcome of heavy proteinuria in patients under 2 years of age

From January 1985 to July 2000, a retrospective study of 53 patients in Taiwan was performed in order to evaluate the underlying diseases causing heavy proteinuria and the clinical outcome in children under 2 years of age (33 boys and 20 girls). Renal biopsy or autopsy was performed in 26 of the children. Renal pathology revealed 2 patients with congenital nephrosis (CNS) (7.7%), 4 with diffuse mesangial sclerosis (DMS) (15.4%), 4 with minimal change nephrotic syndrome (MCNS) (15.4%), 5 with focal segmental glomerulosclerosis (FSGS) (19.2%), 9 with IgM nephropathy in (34.6%), and 2 with hepatitis B virus-associated membranous glomerulonephritis (7.7%). Based on available histology and family history of heavy proteinuria progressing to end-stage renal disease (ESRD), patients were divided into two groups. Group I comprised 10 patients, including CNS (2 cases), DMS (4 cases), and 4 children with a familial history of heavy proteinuria progressing to ESRD. All patients in group I were initially steroid resistant. After methylprednisolone pulse therapy plus cyclosporin A treatment, no patients with CNS or DMS responded, but the other 4 patients experienced a remission. Group II comprised 43 patients; 19 patients (44.2%) were initially steroid resistant. Of these steroid-resistant patients, all experienced remission after methylprednisolone pulse therapy plus cyclosporin A, except 3 children with FSGS. One experienced a thromboembolic event during his clinical course. In conclusion, steroid-resistant nephrotic syndrome (NS) was more common than steroid-sensitive NS in Chinese patients under 2 years of age. Patients with CNS, DMS, or a family history of heavy proteinuria progressing to ESRD had a poor prognosis. Methylprednisolone pulse therapy plus cyclosporin A treatment achieved remission in some children who were initially steroid resistant. This study indicates that children with conditions associated with poor steroid responsiveness (e.g., CNS, DMS) do not respond to immunosuppressive therapy, but other children under 2 years of age, including those with a family history of progression to ESRD, may benefit from aggressive immunosuppressive therapy.     

Role of remission clinics in the longitudinal treatment of CKD

Heavy proteinuria is a major determinant of progression to ESRD for patients with chronic nephropathies and reducing proteinuria should be a key target for renoprotective therapy. In the Remission Clinic, we applied a multimodal intervention to target urinary proteins in 56 consecutive patients who had >3 g proteinuria/d despite angiotensin-converting enzyme inhibitor therapy. We compared the rate of GFR decline and incidence of ESRD in this cohort with 56 matched historical reference subjects who had received conventional therapy titrated to a target BP. During a median follow-up of 4 yr, the monthly rate of GFR decline was significantly lower in the Remission Clinic cohort (median -0.17 versus -0.56 ml/min per 1.73 m2; P < 0.0001), and ESRD events were significantly reduced (3.6 versus 30.4% reached ESRD). Follow-up BP, cholesterol, and proteinuria were lower in Remission Clinic patients than in reference subjects, such that disease remission or regression was achieved in up to 50% of patients who would have been otherwise expected to progress rapidly to ESRD on conventional therapy. Proteinuria reduction independently predicted a slower rate of GFR decline and ESRD incidence, but response to treatment differed depending on the underlying disease. Regarding safety, no patient was with drawn because of hyperkalemia. In summary, multidrug treatment titrated to urinary protein level can be safely and effectively applied to normalize proteinuria and to slow the loss of renal function significantly,especially among patients without type 2 diabetes and with otherwise rapidly progressing chronic nephropathies.     

Plasmapheresis for recurrent posttransplant focal segmental glomerulosclerosis

The high recurrence rate of focal segmental glomerulosclerosis (FSGS) in kidney transplant recipients suggests that such patients have a circulating factor that alters glomerular capillary permeability. Serum from patients with FSGS increases glomerular permeability to albumin. This permeability factor has been partially identified as a protein. The removal of this protein by plasmapheresis (PP) decreases proteinuria. In this study we report data on the therapeutic effects of PP in FSGS children with recurrence in the transplanted kidney. Three hundred pediatric (age <19 years) renal transplants were performed, including 21 patients (24 transplants) with FSGS as a cause of renal failure. Fourteen (58.3%) subjects experienced disease recurrence (proteinuria >1 g/m(2) per day) within 1 month after transplantation. Mean age patient was 12 +/- 4.3 years, including 83.3% Caucasians and 70.2% recipients of living donor grafts. Nine were treated with 10 cycles of PP (3 cycles/weekly), initiated immediately after recurrence (<48 hours). Immunosuppression included high doses of cyclosporine (C(2) levels of 1700-1800 ng/mL), mycophenolate sodium or mofetil, and prednisone. Thirteen patients were induced with anti-IL2 receptor monoclonal antibody (daclizumab/basiliximab). Among the patients who underwent PP, five (55.5%) achieved a complete remission and one (12%), a partial remission (1 g/24 hours). There were no cases of remission among the five patients who were not treated with PP. Those who achieved remission after PP experienced no recurrences during the 2.6 +/- 1.4 years follow-up. PP appears to be effective to treat recurrent FSGS following kidney transplantation. It should be started as soon as possible.     

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. Received February 4, 1998; received in revised form March 30, 1998; accepted April 20, 1998     

Circulating suPAR in Two Cohorts of Primary FSGS

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America–based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.FSGS is an important cause of ESRD in children and adults.^1–3 It can occur as a primary disorder, consequent to genetic mutations in specific podocyte proteins, secondary to a wide range of medical problems, or as a consequence of adaptive changes to reduced kidney mass.^4,5 Intensive research for >50 years has focused mainly on genetic, immunologic, and systemic causes of FSGS but the cause of primary disease remains elusive.In recent years, there has been a great deal of investigation into the role of permeability factors in the pathogenesis of proteinuria and the development of primary FSGS. Proposed candidate molecules include hemopexin, vascular endothelial growth factor, and cardiotrophin-like cytokine-1.^6–8 However, the detection of increased levels of most circulating permeability factors is generally not specific for a given glomerular disorder, and the activity or expression of these factors may be increased in patients with FSGS and minimal change nephrotic syndrome, two disorders with markedly disparate responses to therapy and long-term prognosis.⁹Soluble urokinase receptor (suPAR), the soluble form of urokinase plasminogen-type activator receptor, has been reported to be elevated in a number of diseases including cancer and infection in a nonspecific manner. However, its underlying mechanism of action in these conditions and its clinical value either in diagnosis or prognosis is still far from clear.¹⁰ Recently, Wei et al. reported the molecular identity of a putative permeability factor in FSGS.¹¹ Approximately two-thirds of patients with primary FSGS had increased suPAR. Moreover, the circulating suPAR concentration was mostly normal in other forms of primary glomerular diseases including minimal change nephrotic syndrome, idiopathic membranous nephropathy, or preeclampsia.¹¹ The investigators related the abnormal suPAR level to the pathogenesis of FSGS based on both in vitro and in vivo studies, which demonstrated suPAR binding to and, more importantly, activation of β3 integrin on podocytes. This interaction led to alterations in the morphology (foot process effacement) and function of podocytes, which resulted in proteinuria and initiation of FSGS.¹¹The prevalence of elevated circulating suPAR levels in patients with primary FSGS has not been systematically evaluated in any other large patient cohort. In addition, it is unclear if the circulating suPAR is modulated by immunosuppressive therapy. Therefore, in this report, we detail suPAR levels in two discrete well described cohorts of children and young adults with biopsy-proven primary FSGS—the North America–based FSGS clinical trial (CT), and the Europe-based consortium for study of steroid-resistant nephrotic syndrome (PodoNet).     

Focal segmental glomerulosclerosis: prognostic implications of the cellular lesion.

The cellular lesion (CELL), seen in some patients with primary focal segmental glomerulosclerosis (FSGS), comprises proliferation, hypertrophy, and pathologic changes in the cells overlying the glomerular scar. The prognosis of the cellular lesion was retrospectively studied in 100 patients with FSGS (43 had FSGS-CELL and 57 had FSGS without the cellular lesion (classic segmental scar [CS]). Patients with the FSGS-CELL lesion were more often black and severely proteinuric and developed more end-stage renal disease (ESRD). Nephrotic patients with FSGS-CELL (n = 39) were more proteinuric at presentation than patients with FSGS-CS (n = 36). ESRD developed more frequently in patients with the FSGS-CELL (17 of 39, 44% versus 5 of 36, 14%, P = 0.005), and patients with extensive FSGS-CELL (> or = 20% glomeruli) were mainly black (94%), severely nephrotic (67%, >10 g/d), and had a poor response to treatment (23% remission). In nephrotic patients, initial serum creatinine, interstitial expansion > or = 20%, and CELL independently predicted ESRD. However, the rates of remission in treated nephrotic patients with FSGS-CELL and FSGS-CS were the same (9 of 17, 53% versus 17 of 39, 52%), and patients in both groups who achieved a remission had a 5-yr survival of 100%. Steroid treatment was the only variable that predicted remission. Patients with the FSGS-CELL have an increased prevalence of ESRD, but the improved prognosis associated with remission is so significant that a therapeutic trial is warranted in all nephrotic FSGS patients, regardless of the presence of the cellular lesion.     

Urinary low-molecular-weight protein excretion in pediatric idiopathic nephrotic syndrome

Background

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of idiopathic nephrotic syndrome (INS). We have evaluated the reliability of urinary neutrophil-gelatinase-associated lipocalin (uNGAL), urinary alpha1-microglobulin (uα1M) and urinary N-acetyl-beta-D-glucosaminidase (uβNAG) as markers for differentiating MCD from FSGS. We have also evaluated whether these proteins are associated to INS relapses or to glomerular filtration rate (GFR).

Methods

The patient cohort comprised 35 children with MCD and nine with FSGS; 19 healthy age-matched children were included in the study as controls. Of the 35 patients, 28 were in remission (21 MCD, 7 FSGS) and 16 were in relapse (14 MCD, 2 FSGS). The prognostic accuracies of these proteins were assessed by receiver operating characteristic (ROC) curve analyses.

Results

The level of uNGAL, indexed or not to urinary creatinine (uCreat), was significantly different between children with INS and healthy children (p?=?0.02), between healthy children and those with FSGS (p?=?0.007) and between children with MCD and those with FSGS (p?=?0.01). It was not significantly correlated to proteinuria or GFR levels. The ROC curve analysis showed that a cut-off value of 17 ng/mg for the uNGAL/uCreat ratio could be used to distinguish MCD from FSGS with a sensitivity of 0.77 and specificity of 0.78. uβNAG was not significantly different in patients with MCD and those with FSGS (p?=?0.86). Only uα1M, indexed or not to uCreat, was significantly (p?<?0.001) higher for patients in relapse compared to those in remission.

Conclusions

Our results indicate that in our patient cohort uNGAL was a reliable biomarker for differentiating MCD from FSGS independently of proteinuria or GFR levels.