Dataset Information

Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy.

ABSTRACT:

Background and objectives

Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.

Design, setting, participants, & measurements

Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer.

Results

Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively.

Conclusion

Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.

SUBMITTER: van den Brand JA

PROVIDER: S-EPMC4046727 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Publications

Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy.

van den Brand Jan A J G JA van Dijk Peter R PR Hofstra Julia M JM Wetzels Jack F M JF

Clinical journal of the American Society of Nephrology : CJASN 20140522 6

<h4>Background and objectives</h4>Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.<h4>Design, setting, participants, & measurements</h4>Patients who attended the clinic were included prospectively from 1995 on. A crude ...[more]

PMID: 24855280

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Project description:BACKGROUND AND OBJECTIVES: Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ ?-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed. RESULTS: This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. CONCLUSION: This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.

Project description:Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups. RNA for 75 base-pair paired-end RNASeq was obtained by dissecting glomeruli via laser capture microdissection (LCM) from FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources. Results: Compared to normal glomeruli, glomeuli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of to the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MDC and were significantly less pronounced in MN. Conclusion: Our results demonstrate that archival FFPE-biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney-associated diseases. Here the latter provides a data-driven rationale to experimentally address these MCD-specific features as biomarkers and as novel drug targets. In this context inhibiting activation of the IL7 pathway may be particularly promising.

Dataset Information

Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy.

Background and objectives

Design, setting, participants, & measurements

Results

Conclusion

Publications

Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy.

Similar Datasets

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