Remission of steroid-resistant nephrotic syndrome due to focal and segmental glomerulosclerosis using rituximab

BACKGROUND: Therapeutic options are limited in cases of focal and segmental glomerulosclerosis (FSGS) that fail to respond to steroids and calcineurin inhibitors. We describe a case in which steroid-resistant nephrotic syndrome (SRNS) secondary to FSGS did not respond to conventional treatment, but was successfully treated with rituximab. Unlike previous reports in which rituximab was used in conjunction with a calcineurin inhibitor, we present the first case where rituximab was used as the sole therapeutic agent. CASE REPORT: An 11-month-old boy presented with severe manifestations of primary nephrotic syndrome with a subsequent non-responsive steroid course. A renal biopsy confirmed FSGS, with normal staining for podocin and nephrin. Genetic studies for podocin were normal. The child developed ciclosporin-induced hemolytic uremic syndrome (HUS), and the response to plasma exchange, following ciclosporin withdrawal, was only temporary. A trial of a combination of mycophenolate and dexamethasone did not have any effect on proteinuria or fluid status. Four weekly rituximab infusions at 375 mg/m(2)/dose induced a complete remission without any adverse effects. CONCLUSIONS: This case suggests that rituximab may be used as the sole therapeutic agent in the treatment of SRNS secondary to FSGS, especially in cases where calcineurin inhibitors are contraindicated.     

A prospective study evaluating the role of donor-specific anti-endothelial crossmatch (XM-ONE assay) in predicting living donor kidney transplant outcome

Anti-endothelial cell antibodies (AECAs) may play a role in allograft rejection. We prospectively tested 150 consecutive living donor kidney transplant recipients, with transplants performed at Northwestern Memorial Hospital between January and December 2010, using the donor-specific endothelial (XM-ONE) crossmatch. 88/150 Patients received standard of care (SOC) immunosuppression and analyzed separately, in addition to the complete study cohort. Patients were followed for one year and XM-ONE results were analyzed in relation to occurrence of acute rejection, proteinuria, serum creatinine levels, and biopsy proven fibrosis. No correlation was found between XM-ONE results and protocol or “for-cause” biopsy proven acute rejection or vasculopathy at 12 months. When IgG+ and IgM+ results of the XM-ONE assay were combined, a correlation with proteinuria at 12 months was observed (p = 0.047). Although IgG + XM-ONE results were associated with significantly higher creatinine at 6 months (p = 0.018), significance was lost at 12 months. Conversely, patients with an IgM + XM-ONE crossmatch had significantly lower creatinine at 1 month (p = 0.019), 3 months (p = 0.0045), and 6 months (p = 0.038) post-transplant, but lost statistical significance at 12 months (p = 0.67) post-transplant. In summary, the presence of AECAs as determined by a positive XM-ONE result was not predictive of overall poorer graft outcome after one year in our center.     

Low-dose of multi-glycoside of Tripterygium wilfordii Hook. f., a natural regulator of TGF-β1/Smad signaling activity improves adriamycin-induced glomerulosclerosis in vivo

Ethnopharmacological relevance

Transforming growth factor (TGF)-β1/Smad signaling pathway plays a critical role in the prolonged glomerulosclerosis (GS), which is an important determinant during the progression in chronic kidney disease (CKD). For recent 30 years, multi-glycoside of Tripterygium wilfordii Hook. f. (GTW), an extract from Chinese herbal medicine has been proved clinically effective in improving GS in CKD in China. However, therapeutic mechanisms involved in vivo are still unclear. In this study, we aimed to explain the dose-effects and molecular mechanisms of GTW on GS by regulating TGF-β1/Smad signaling activity in adriamycin (ADR)-induced nephropathy (ADRN).

Materials and methods

Rats with ADRN, created by unilateral nephrectomy and twice adriamycin injections (ADR, 4 mg/kg and 2 mg/kg) within 4 weeks, were divided into four groups, the Sham group, the Vehicle group, the low-dose GTW-treated group, and the high-dose GTW-treated group, and that, sacrificed at the end of the 6th week after administration. Proteinuria, blood biochemical parameters, glomerulosclerotic morphological makers, podocyte shape, and nephrin expression were examined, respectively. Protein expressions of key signaling molecules in TGF-β1/Smad pathway, such as TGF-β1, Smad3, phosphorylated-Smad2/3 (p-Smad2/3), and Smad7, were also evaluated individually.

Results

The results indicated that the characterizations of ADRN involved the typical prolonged GS, a small amount of abnormal proteinuria, and the failing renal function; TGF-β1/Smad signaling molecules, especially Smad3, p-Smad2/3, and Smad7 were activated in vivo, accompanied by the exasperation of glomerulosclerotic lesion; GTW at high-dose (100 mg/kg) and low-dose (50 mg/kg) could slightly ameliorate the prolonged GS and nephrin expression, furthermore, the anti-proliferative action of GTW at high-dose was superior to that at low-dose, but caused the significant liver injury; in ADRN model rats, protein expressions of TGF-β1, p-Smad2/3, and Smad7 in the kidneys could be regulated with the treatment of GTW at low-dose.

Conclusion

This study farther demonstrated that the low-dose of GTW, as a natural regulator in vivo, could effectively and safely ameliorate the prolonged GS in FSGS model, via the potential molecular mechanisms involving the reduction of ECM components and the suppression of TGF-β1 over-expression, as well as the bidirectional regulation of TGF-β1/Smad signaling activity.     

Lipo-PGE1对局灶节段性肾小球硬化患者血管内皮生长因子生成影响研究

目的 :观察前列腺素E1脂微球载体制剂 (Lipo PGE1)对原发性肾病综合征局灶节段性肾小球硬化 (FS GS)患者血管内皮生长因子 (VEGF)生成的影响。方法 :39例肾活检确诊为FSGS患者随机分为治疗组 2 0例 ,未治疗组 19例 ,另选性别、年龄相匹配的健康查体者 2 0例作为对照组。治疗组用Lipo PGE110 μg ,未治疗组用ATP 2 0mg ,两组药物均溶于 10 0ml生理盐水中静脉滴注 ,1次 /d ,2周为 1疗程。 1疗程完成后采用ELISA方法测定三组血、尿VEGF水平 ,同时测定三组内生肌酐清除率和 2 4h尿蛋白定量。结果 :FSGS组血、尿VEGF及 2 4h尿蛋白定量与对照组相比明显增高 ,内生肌酐清除率较低 ;治疗组血、尿VEGF浓度显著下降 ,2 4h尿蛋白定量明显降低 ,内生肌酐清除率上升。两两比较P <0 .0 5 ,差异有统计学意义。结论 :Lipo PGE1治疗FSGS可以有效减轻蛋白尿 ,改善肾功能 ,对早期防治慢性肾衰竭有重要意义 ,VEGF的表达生成与治疗作用有一定的关系。     

Renal transplant outcomes in primary FSGS compared with other recipients and risk factors for recurrence: A national review of the Irish Transplant Registry

Introduction

Primary focal segmental glomerular sclerosis (p‐FSGS) is commonly complicated by recurrence (r‐FSGS) post‐transplantation. Our objective was to describe Irish outcomes for transplantation after end‐stage renal disease (ESRD) due to p‐FSGS, specifically rates of, and treatments for, r‐FSGS.

Patients and Methods

Irish patients with biopsy‐proven FSGS were identified from the Irish National Kidney Transplant database (1982‐2015). Medical record review was performed to identify predictors of r‐FSGS and treatments for r‐FSGS. Transplant outcomes were compared to outcomes in all renal transplants performed during the same time period using registry data. Demographic and clinical predictors of r‐FSGS were identified. Statistical analysis was performed using Stata (version 13, College Station, TX, USA).

Results

Thirty‐eight transplant recipients had biopsy‐proven p‐FSGS, 16 received a second transplant. A total of 3846 transplants formed the comparator group. r‐FSGS complicated 60.5% (23/38) of first transplants. Eighty‐six percent (10/12) of patients with previous r‐FSGS developed recurrent disease after further transplantation. Patients with p‐FSGS receiving a first renal transplant had higher rate of graft failure than those with another cause of ESRD (HR 1.9, 95% CI 1.152‐3.139). Sixteen patients received immunotherapy for r‐FSGS; 12 (86%) had at least partial response, but two (14%) developed significant complications.

Discussion

We demonstrate high rates of r‐FSGS and describe modest success from with treatments for r‐FSGS.     

A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q₁₀ biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.