Urinary <Emphasis Type="Italic">N</Emphasis>-acetyl-beta-<Emphasis Type="SmallCaps">D</Emphasis> glucosaminidase (NAG) level in idiopathic nephrotic syndrome

Urinary N-acetyl-beta-D glucosaminidase (NAG) is a sensitive biomarker of renal parenchymal disease. The aim of this study was to investigate variations in the levels of NAG excretion among different sub-groups of nephrotic syndrome (first episode, relapsers, and resistant) and its prediction based on proteinuria. Thirty-five patients with idiopathic nephrotic syndrome, aged 1–12 years, as well as 15 age- and gender-matched normal children (controls) were enrolled in the study. Among the 35 patients, ten were classified with first episode nephrotic syndrome (FENS), 17 with relapsing nephrotic syndrome (RNS), and eight with steroid-resistant nephrotic syndrome (SRNS). Urinary NAG/creatinine levels were significantly increased in SRNS patients as compared to FENS and RNS patients (p < 0.001); the FENS and RNS groups had comparable levels. A urinary NAG/creatinine value of ≤108.9 U/g was found to identify steroid-sensitive patients with a sensitivity, specificity, positive predictive value, and negative predictive value of 78.8, 100, 100 and 77.7%, respectively. Significant correlations were found between experimental and predicted values of urinary NAG/creatinine in steroid sensitive nephrotic syndrome (SSNS) (R ² = 0.9643) and SRNS patients (R ² = 0.9823). Urinary NAG/creatinine values were found to be higher in SRNS than SSNS patients and have moderate predictive value for steroid responsiveness. This level can be obtained based on urinary protein/creatinine ratio or 24 h urinary protein levels.     

High-sensitivity C-reactive protein (hs-CRP) level in children with nephrotic syndrome

The aim of this study was to assess the serum concentration of high-sensitivity C-reactive protein (hs-CRP) in children with nephrotic syndrome (NS) treated with prednisone and cyclosporine A (CyA). Patients were divided into three groups: (I) 20 NS children (aged 4–14 years) in relapse and examined twice, (A) before treatment and (B) after proteinuria regression (a 3–4 week course of prednisone therapy); (II) 20 children with steroid-dependent or steroid-resistant NS, treated with CyA, also examined twice, (D) before treatment with CyA, (E) 6 months after therapy. A control group (C) consisted of 20 healthy children. Serum hs-CRP level was determined by a nephelometric method with a Behring Nephelometer 100 Analyzer, Dade Behring. The results showed that median hs-CRP concentration was the highest in children with relapsing steroid-sensitive NS before treatment (IA). After proteinuria regression (IB), the hs-CRP level had decreased and did not differ from that of healthy controls (C) (P > 0.05). In group II, before CyA administration (IID), the level of hs-CRP was normal, but it had increased after 6 months of treatment (IIE) up to a level six-times higher than that of the control group (P < 0.01). We concluded that, in children with steroid-sensitive nephrotic syndrome in relapse, the serum hs-CRP level is increased but returns to normal after 3–4 weeks of glucocorticoid treatment. In children chronically treated with CyA due to NS, serum hs-CRP level increases significantly during the therapy.     

Recurrence of proteinuria 10 years post-transplant in NPHS2-associated focal segmental glomerulosclerosis after conversion from cyclosporin A to sirolimus

Mutations in the NPHS2 gene, which encodes podocin, are associated with steroid-resistant nephrotic syndrome in childhood. Renal histology frequently presents focal segmental glomerulosclerosis (FSGS). Post-transplant recurrence of proteinuria in patients affected by homozygous or compound heterozygous NPHS2 mutation is encountered rarely (1–2%) compared to 30% recurrence in nonhereditary FSGS. We report on a pediatric kidney transplant recipient with NPHS2-associated nephrotic syndrome and FSGS, who developed biopsy-proven recurrence of FSGS 10 years post-transplant in temporal association with conversion from cyclosporin A (CsA)- to sirolimus (SRL)-based immunosuppression, due to histological evidence of severe CsA-induced nephrotoxicity. Reswitch of the immunosuppressive regimen from SRL to CsA led to a noticeable decrease of proteinuria and to stabilization of graft function. We conclude that patients with hereditary FSGS are not entirely protected from post-transplant recurrence of proteinuria, even in the long term. The close temporal relationship of FSGS recurrence with CsA withdrawal and conversion to SRL suggests that caution should be exercised in the use of CsA-free immunosuppression also in patients with NPHS2-associated FSGS.     

Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome

We performed a multi-centre randomized controlled trial to compare the efficacy of mycophenolate mofetil (MMF) to that of cyclosporine A (CsA) in treating children with frequently relapsing nephrotic syndrome and biopsy-proven minimal change disease. Of the 31 randomized initially selected patients, seven were excluded. The remaining 24 children received either MMF 1200 mg/m² per day (n = 12) or CsA 4–5 mg/kg per day (n = 12) during a 12-month period. Of the 12 patients in the MMF group, two discontinued the study medication. Evaluation of the changes from the baseline glomerular filtration rate showed an overall significant difference in favour of MMF over the treatment period (p = 0.03). Seven of the 12 patients in the MMF group and 11 of the 12 patients in the CsA group remained in complete remission during the entire study period. Relapse rate in the MMF group was 0.83/year compared to 0.08/year in the CsA group (p = 0.08). None of the patients reported diarrhea. Pharmacokinetic profiles of mycophenolic acid were performed in seven patients. The patient with the lowest area under the curve had three relapses within 6 months. In children with frequently relapsing minimal change nephrotic syndrome, MMF has a favourable side effect profile compared to CsA; however, there is a tendency towards a higher relapse risk in patients treated with MMF.     

Association of steroid and cyclosporin resistance in focal segmental glomerulosclerosis

Given the variable response of steroid-resistant nephrotic syndrome (SRNS) to treatment with cyclosporin (CsA), it may be inappropriate to expose all SR patients to additional immunosuppression. How to determine from which patients to withhold CsA is unclear. We tested the hypothesis that in patients with primary focal segmental glomerulosclerosis (FSGS), steroid resistance predicts CsA resistance. We studied 16 children with steroid-dependent (SD) or steroid-resistant (SR) histologically confirmed primary FSGS treated with CsA with no prior exposure to other immunosuppressive medications. All had received at least 4 weeks of daily prednisone, followed by addition of CsA aiming at trough levels of 200 ng/ml. Of the 16 patients, nine (56%) were SR, of whom seven (78%) were CsA resistant and two (22%) were CsA responsive. Seven patients (44%) were SD; all of them (100%) were CsA responsive (P = 0.003, Fisher’s exact test). SR patients had faster deterioration of glomerular filtration rate (GFR) over a median follow-up of 21 months (P = 0.06). These data demonstrate that in primary FSGS, steroid resistance may predict CsA resistance. Genetic testing for known mutations associated with resistance to immunosuppression may be advisable before treatment of SR-FSGS patients with cyclosporin. Prospective studies should be conducted to explore this hypothesis.     

Impact of recurrent nephrotic syndrome after renal transplantation in young patients

Recurrent disease is a frequent complication of patients transplanted for steroid-resistant nephrotic syndrome associated with focal segmental glomerulosclerosis. Its long-term prognosis has rarely been studied. We examined 39 patients aged 4–25 (mean 13.5) years at the time of first transplantation (TX). Twelve of these (30%) developed nephrotic syndrome after the first TX and 2 of 8 after the second TX. The mean observation period from first TX to last observation with a functioning graft or graft loss was 5.4 (0.1–19.3) years. We confirmed that recurrent disease is associated with older age at onset of the primary disease, shorter time from onset to end-stage renal disease, and diffuse mesangial proliferation in the initial kidney biopsy. Remissions occurred in all 3 children undergoing early repeated plasma exchange and in 1 adolescent following introduction of cyclosporin A 7 years after TX. At last observation 42% of relapsing and 48% of non-relapsing patients with a similar follow-up period had a functioning first graft. Median first graft survival was almost identical in the relapsing and the non-relapsing patients (4.3 vs. 4.2 years). Histological lesions of focal glomerulosclerosis were detected in the posttranplant biopsies of only 3 patients. In conclusion, young patients with nephrotic syndrome associated with focal segmental sclerosis have a similar graft survival with and without recurrence of the nephrotic syndrome. Received October 29, 1997; received in revised form February 17, 1998; accepted February 18, 1998     

Nephrotic syndrome preceding psoriasis in children

Nephrotic syndrome is considered to be a late complication of psoriasis, reported usually in adults and characterized by IgA nephropathy or focal segmental glomerulosclerosis. We report on four children in whom steroid-resistant nephrotic syndrome either preceded (n = 3), by 41–120 months, or occurred simultaneously (n = 1) with psoriasis; renal histology showed minimal change disease. Therapy with corticosteroids and cyclosporine resulted in remission of renal and cutaneous symptoms. Minimal change nephrotic syndrome and psoriasis might share similar mechanisms of pathogenesis involving cell-mediated immunity.     

Surgical Management of Leiomyosarcoma of the Inferior Vena Cava

Introduction  Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor for which en bloc resection offers the only chance of cure. Due to its rarity, however, optimal strategies for the management of the primary tumor and subsequent recurrences are not well defined. Methods  We performed a retrospective review of patients who underwent surgical resection of IVC leiomyosarcoma. We evaluated clinical presentations, operative techniques, patterns of recurrence and survival. Results  From 1990 to 2008, nine patients (four females) were identified. Median age was 55 years (40–76). Presentations included abdominal pain (n = 5), back pain (n = 2), leg swelling (n = 4) and abdominal mass (n = 2). Pre-operative imaging studies showed tumor location to be from the right atrium to renal veins (n = 1), retrohepatic (n = 5), and from hepatic veins to the iliac bifurcations (n = 3). En bloc resection included right nephrectomy (n = 5), right adrenalectomy (n = 4), pancreaticoduodenectomy (n = 1), right hepatic trisectionectomy (n = 1) and right hemicolectomy (n = 1). The IVC was ligated in six patients, and a prosthetic graft was used for IVC reconstruction in three patients. Resection margins were negative in seven cases. Median length of stay was 12 days (range, 6–22 days). Major morbidity included renal failure (n = 1) and there was one post-operative mortality. Five patients had leg edema post-operatively, four of whom had IVC ligation. Median survival was 47 months (range, 1–181 months). Four patients had recurrence and the median time to recurrence was 14 months (range, 3–25 months). Two patients underwent successful resection of recurrence. Conclusions  Curative resection of IVC leiomyosarcoma can lead to long-term survival. However, recurrence is common, and effective adjuvant treatments are needed. In selected cases, aggressive surgical treatment of recurrence should be considered. Presented at the Digestive Disease Week 2008, San Diego, CA, USA, May 2008. Grant Support: NIH K12 HD 049109 (T.C.G.).     

Intravenous cyclosporine therapy in recurrent nephrotic syndrome after renal transplantation in children

BACKGROUND: Early recurrence of massive proteinuria after renal transplantation occurs in 20% to 30% of patients with steroid-resistant idiopathic nephrotic syndrome and is responsible for graft failure in approximately half of cases. We report our experience with the use of intravenous (IV) cyclosporine (CsA) in children with recurrent proteinuria after renal transplantation. METHODS: Between March 1991 and August 2001, 36 renal transplantations were performed in 35 patients with steroid-resistant idiopathic nephrotic syndrome in our institution. Recurrence, defined by proteinuria higher than 50 mg/kg per day in the absence of acute rejection or urinary tract infection, was observed in 17 grafts performed in 16 patients. In patients with recurrence, CsA was administered IV, at an initial dose of 3 mg/kg per day, which was afterward adapted to maintain whole-blood levels between 250 and 350 ng/mL. RESULTS: In 14 of 17 cases (82%) with recurrence, proteinuria completely disappeared after 20.8+/-8.4 (range 12-40) days. The treatment was ineffective in the remaining three patients with persistent proteinuria at the end of the second month posttransplantation. Plasma exchanges were performed in four patients during the first 2 months, and proteinuria regressed in three cases and persisted in one. Persistent remission was observed in 11 patients with a follow-up of 3.7+/-3 (range 0.3-9) years. Actuarial graft survival was 92% and 70% at 1 and 5 years. CONCLUSION: IV CsA is a safe and effective treatment in children with recurrent nephrotic syndrome after renal transplantation.     

Surgical Therapy for Gastrointestinal Stromal Tumours of the Upper Gastrointestinal Tract

Aim  This study aimed to examine clinicopathological features and outcomes after primary resection of gastrointestinal stromal tumours (GIST) of the upper gastrointestinal tract Method  Fifty consecutive patients were identified as having a mesenchymal tumour of the upper gastrointestinal tract resected at our institution, of which 47 were GISTs. The influence of clinicopathological variables on disease-free survival was evaluated using Kaplan–Meier estimates and Cox hazard model. Results  The median age was 62.8 (21.3–94.7). The commonest presenting symptoms were anaemia (43%) and pain (34%). Tumours were located in the stomach (64%), small bowel (34%) and oesophagus (2%). Median follow-up was 20.4 (2–106) months. Fletcher low/intermediate-risk tumours had a significantly better (p = 0.0008) 2- and 5-year actuarial survival of 100% compared with 88% and 58% for high-risk group. Recurrence-free survival at 2 and 5 years was 100% for low/intermediate-risk group compared with 68% and 45% for the high-risk group (p = 0.0008). Univariate analysis of predictors of recurrence identified male sex, high mitotic rate and tumour size as significant. Multivariate analysis showed high mitotic rate as the only poor prognosticator (Hazard ratio = 16.7, p = 0.02). Conclusion  Surgical excision of low- and intermediate-grade GIST has an excellent prognosis. Surgery remains the mainstay of treatments, and high-grade tumours carry a significantly worse prognosis. High mitotic rates are an independent poor prognosticator. Presentation: This work has not been presentedDisclaimers: The authors indicated no potential conflicts of interest Grant Support: None Note all graphs produced using StatView statistical software and further edited with Adobe Photoshop.     

Partial remission with cyclosporine A in a patient with nephrotic syndrome due to NPHS2 mutation

Autosomal recessive steroid-resistant nephrotic syndrome (NS) is a rare, genetically determined nephropathy caused mainly by a mutation in the NPHS2 gene. This type of NS is usually resistant to other immunosuppressive therapy as well, but a few cases of cyclosporine A-induced partial remission of inherited NS have been reported. We present a boy that developed NS at the age of 18 months. There was no decrease of proteinuria on standard prednisolone therapy, and a diagnosis of steroid-resistant NS was established. However, the proteinuria decreased significantly following the initiation of cyclosporine A therapy (from 1280 to 380 mg/m² per day) without any negative effects on renal function (stable glomerular filtration rate 130–150 ml/min per 1.73 m²). The molecular genetic test revealed a homozygous R138Q mutation in the NPHS2 gene. Our case demonstrates that cyclosporine A can induce partial remission in patients with genetic forms of NS without influencing the glomerular filtration rate. However, its long-term effect and safety in children with hereditary forms of nephrotic syndrome have yet to be investigated.     

Familial steroid-sensitive nephrotic syndrome in Southern Israel: clinical and genetic observations

Reports on genetically informative steroid-responsive (sensitive) idiopathic nephrotic syndrome (SSNS) families are lacking. We studied an extended SSNS Bedouin (B) family with a high rate of consanguinity. The clinical presentation and steroid response of its 11 affected individuals were similar to those of sporadic SSNS (spontaneous remission towards puberty and minimal change disease by kidney biopsy). Genome-wide linkage analysis, using a 382 microsatellite-markers mapping set and additional markers adjacent to 80 candidate genes of the index family, did not support linkage to any chromosomal locus. Retrospective analysis of all additional children with SSNS treated by our institution in the past 20 years (n = 96, 50% of them of Jewish origin) revealed another five non-related B families with 2–3 first-degree cousins affected with SSNS in each. The overall familial SSNS rate among the B population (excluding the index family) was 28%, compared with 4% among Jews (Js) (OR 1.8–64, P < 0.005). There were more Bs with simple SSNS than there were Js (71% and 40%, respectively; OR 3.58, 95% CI 1.41–9.23, P < 0.01). In summary, SSNS in this index family was not linked to any of the presently known chromosomal loci nor predicted to be caused by mutation in any one of a list of genes associated with nephrotic syndrome (NS). The presence of other B families affected by SSNS supports the role for susceptibility genes enrichment, exposing highly consanguineous populations to an increased incidence of SSNS. An erratum to this article can be found at     

Rituximab for refractory cases of childhood nephrotic syndrome

Rituximab has been used over the last decade as a rescue therapy for refractory cases of nephrotic syndrome (NS). Here we report the use of rituximab in four children with idiopathic steroid-resistant nephrotic syndrome (SRNS) with various histological backgrounds (two cases with focal segmental glomerulosclerosis, one case with IgM nephropathy, and one case with minimal change disease), who failed to respond to other immunsuppressions. Their median age (range) was 10 (8–11) years. NPHS2 genetic mutation was negative in all of them. All patients received a single dose of rituximab (375 mg/m²) and achieved complete B cell depletion as CD19 was <1% for 3 months following rituximab infusion. Only one patient achieved non-sustained remission as he relapsed after 4 months despite zero CD19 level. Patients received no further doses of rituximab as B cell was depleted in the peripheral circulation. We conclude that a single dose of rituximab was not effective in inducing sustained remission in children with idiopathic SRNS, despite complete B cell depletion in the peripheral circulation. Further doses might be indicated to deplete non-circulating B cells.     

Quality of Life and Symptomatic Response to Gastric Neurostimulation for Gastroparesis

Background  Gastroparesis can be a difficult problem with patients suffering from nausea, vomiting, bloating, and pain intractable to medical management. Gastric neurostimulation has been developed as an adjunctive treatment for patients with diabetic and idiopathic gastroparesis unresponsive to pharmacologic and dietary treatment. The purpose of this study is to report symptomatic and quality-of-life response to gastric neurostimulation. Methods  This study was approved by the institutional review board, and patients had informed consent. The gastric neurostimulation device (Enterra therapy, Medtronic, Inc., Minneapolis, MN, USA) is approved by the Food and Drug Administration under the Humanitarian Device Exemption. Candidates for placement were patients with either idiopathic or diabetic gastroparesis who had symptomatic failure to dietary changes and to prokinetic and antiemetic drugs. Before placement, the patients’ symptoms were recorded, and patients completed the Gastrointestinal Symptom Rating Scale (GSRS, three domains: dyspeptic syndrome, indigestion syndrome, and bowel dysfunction syndrome) and the Short Form-36 (SF-36, eight domains: physical functioning, role-physical, role-emotional, bodily pain, vitality, mental health, social functioning, general health, plus a health transition item). The device was surgically placed using a hybrid laparoscopic/open technique. Patients were followed and adjustments made on the device until satisfactory symptom control was achieved. At that time, patients completed both the GSRS and SF-36, and comparisons were made to preoperative values. Results  Forty-two patients had the device placed, 29 women, aged 41 (SD +14) years, 24 diabetic patients, 17 idiopathic patients, one postgastrectomy patient. Median follow-up was 12 months (range 1–42 months). There was a 2% immediate postoperative morbidity rate and 7% long-term morbidity rate (device extrusion). Thirty-one patients (74%) responded to gastric neurostimulation of variable degrees. Eleven patients had no response or had worsening symptoms. Of the patients who responded, there were statistically significant improvements in all three domains of the GSRS. Median scores (with interquartile ranges): dyspeptic syndrome, 9 (7–11.5) to 4 (2.5–6), p = 0.02; indigestion syndrome, 5 (2–7) to 4 (0–5), p = 0.05; bowel dysfunction syndrome, 3 (2–3) to 1 (0–1), p = 0.01. In the SF-36, there were statistically significant improvement in the health transition item, 4 (4–5) to 1.5 (1–3), p = 0.01; and social functioning domain, 25 (12.5–62.5) to 75 (50–87.5), p = 0.03. Conclusions  Three quarters of gastroparesis patients responded to gastric neurostimulation to variable degrees. Gastrointestinal-specific symptoms are improved in responders. Patients felt that there health and social functioning (SF) improved, although there was no significant difference in the other domains. These results are encouraging considering that these patients had intractable symptoms with no other effective treatments available. Presented in part at the Annual Meeting of the Society for Surgery of the Alimentary Tract, San Diego, CA, May 18–21, 2008 [oral presentation].     

Do glutathione-S-transferase polymorphisms influence response to intravenous cyclophosphamide therapy in idiopathic nephrotic syndrome?

The response to cyclophosphamide (CP) is variable and difficult to predict in children with idiopathic nephrotic syndrome (INS). The polymorphic expression of glutathione-S-transferase (GST) may affect the remission rate after CP therapy. In this study, we evaluated the correlation of GST polymorphism and response to CP in INS. We studied GST polymorphism in 74 children with steroid-sensitive (44) and steroid-resistant (30) INS receiving intravenous cyclophosphamide (IVCP) therapy. We correlated GSTM1, GSTT1, and GSTP1 genotypes with response to IVCP. Thirty-seven (50%) out of 74 children responded to CP therapy. A synergistic effect of three genotypic combinations showed significant correlation with remission in the steroid-sensitive group. These combinations were GSTP1 and GSTM1 null genotype (p = 0.013) and GSTP1 together with GSTM1 and GSTT1 null genotypes (p = 0.026). Further, a significant difference was observed with a combination of GSTM1 and GSTT1 null genotypes and Val105 polymorphism. No association was observed among steroid-resistant patients. Our results indicate that among children with steroid-sensitive NS, there is an association with response to IVCP therapy and combination of GSTP1 Val105 polymorphism and the null genotypes of GSTT1 and GSTM1. GST polymorphism may be of significance in the management of children with INS receiving CP therapy.     

Long-term follow-up after cyclophosphamide therapy in steroid-dependent nephrotic syndrome

Cyclophosphamide (CP) has been used for over 40 years in patients with steroid-sensitive nephrotic syndrome (SSNS) presenting frequent relapses or steroid dependence (SD). We evaluated retrospectively and tried to identify parameters possibly associated with a prolonged and sustained remission (PSR+) ≥5 years in 108 children with steroid-dependent nephrotic syndrome (SDNS) treated with oral CP. Patients had a follow-up time ≥5 years and were divided into two groups according to achievement of PSR (+ and –). Gender, histological injury, cumulative doses of CP, age of onset of illness, and start of treatment and prednisone dose on the occasion of relapse were analyzed. The overall cumulative sustained remission for 5 and 10 years was 25 and 21.6%, respectively. The only factor that influenced a PSR was the degree of SD: the group PSR+ relapsed at prednisone dose of 0.96 ± 0.51 mg/kg vs. 1.29 ± 0.59 mg/kg in group PSR– (p = 0.01). Also, patients who relapsed in the presence of prednisone doses ≤1.4 mg/kg showed a cumulative sustained remission of 43, 35, and 32.7% at 2, 5, and 10 years, respectively, versus 22.5, 12.5, and 5% in those with prednisone >1.4 mg/kg (p = 0.001). Our findings suggest that patients with SDNS who relapse on prednisone dose >1.4 mg/kg are especially prone to an unfavorable response to CP use.     

Endovascular versus open revascularization for chronic mesenteric ischemia: a comparative study

Background  The aim of our study was to evaluate and compare short- and long-term outcomes of percutaneous angioplasty and open revascularization for chronic intestinal ischemia. Materials and methods  Twenty-nine consecutive patients undergoing percutaneous angioplasty (n = 14) or open revascularization (n = 15) for chronic intestinal ischemia were prospectively studied from 2000 to 2006. All patients were symptomatic with at least thrombosis or 80% stenosis of superior mesenteric artery. Results  No patient was lost to follow-up. Patients were older in percutaneous angioplasty than in the open revascularization group (p = 0.0009). Open revascularization allowed to revascularize more vessels (1.4 versus 1, p = 0.01). There was no difference between groups regarding major complications, mortality, hospital length of stay, and symptomatic recurrence. Primary re-stenosis was only observed in three patients (21.4%) in the percutaneous angioplasty group. Survival at 2 years estimated by the Kaplan–Meier method was 58% in the percutaneous angioplasty group and 70% in the open revascularization group (p = NS). Conclusion  Percutaneous angioplasty should be preferentially offered to older patients and those unable to undergo open revascularization.     

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.     

Association of the macrophage migration inhibitory factor −173*C allele with childhood nephrotic syndrome

Macrophage migration inflammatory factor (MIF) is a proinflammatory cytokine with a unique role as the physiologic counterregulator of the immunosuppressive effects of glucocorticoids. MIF has been implicated in the pathogenesis of glomerular inflammation. The MIF promoter contains a G/C polymorphism that is functionally relevant, with the C allele being associated with higher MIF production and linked to susceptibility to inflammatory diseases. We genotyped the MIF −173 polymorphism in 257 children with idiopathic nephrotic syndrome (INS) and 355 controls. Frequency of carriers of the high-producer MIF −173*C allele was higher in patients with INS (31.7%) than in controls (22.0%) [odds ratio (OR) 1.67, p = 0.006] The MIF −173 C allele was more frequent in steroid-resistant patients (43.5%) compared with steroid responders (22.8%) (OR 2.61, p = 0.0005). This difference was particularly evident in focal segmental glomerulosclerosis patients (OR 14.0, p = 0.002). No association with response to cyclosporin A was found. Carriers of the MIF −173*C allele had a significantly higher probability of end-stage renal disease (ESRD) compared with G/G homozygous patients within 5 years from onset (log rank 5.11 p = 0.024). These results underscore the role of MIF in INS disease progression and in the response to glucocorticoid treatment and suggest that screening of MIF genotype at disease onset may identify patients requiring a more aggressive therapeutic approach. Marina Vivarelli and Leila Emma D’Urbano contributed equally to the work.     

Short- and long-term efficacy of levamisole as adjunctive therapy in childhood nephrotic syndrome

Many children with steroid-dependent nephrotic syndrome (NS) have significant sequelae despite steroid-sparing therapies. Levamisole may reduce short-term relapse frequency (RF) with minimal side effects. Little data exist, however, as to its long-term effect. To assess both short- and long-term efficacy in NS, RF and cumulative annual steroid burden were quantified in ten consecutive children with steroid-dependent NS treated with levamisole. Data were analyzed for three time periods: 1 year prior to levamisole therapy (Pre-Lev), during 1 year of levamisole therapy (During-Lev), and the year after cessation of all levamisole therapy (Off-Lev). Median RF fell from 6.0 (4.0–9.0) relapses/patient per year Pre-Lev to 0.0 (0.0–4.0) During-Lev (p = 0.002) with 6/10 patients having no relapse and 0.5 (0.0–8.0) Off-Lev (p = 0.01) with 5/10 patients without relapse. Concurrently, cumulative annual steroid burden fell from 6,067 (1,660–8,691) mg/m² per year Pre-Lev to 2,920 (782–5,271) During-Lev (p = 0.002) and 716 (0–3,637) Off-Lev (p = 0.002). In 4/5 hypertensive children, blood pressure normalized During-Lev. Somatic indices also improved: height Z scores, which fell from 0.8 (−2.4 to 3.6) at diagnosis to −0.6 (−2.7 to 0.4) Pre-Lev (p = 0.004), remained stable at −0.6 (−3.0 to 0.6) after 1 year of therapy and –0.5 (−2.6 to 0.2) Off-Lev. Height velocity improved from 3.0 (0.3–6.0) cm/year Pre-Lev to 3.7 (0.0–8.0) cm/year During-Lev and 5.4 (0.0–9.1) Off-Lev. We conclude that levamisole is an effective short- and long-term steroid-sparing agent in pediatric NS.