UoM administered thesis: Doctor of Medicine

  • Authors:
  • Ajay Dhaygude


ABSTRACTIntroduction: The two subtypes of Antineutrophil Cytoplasmic autoantibodyassociated systemic vasculitis (AASV) cANCA and pANCA associatedvasculitis are the commonest causes of rapidly progressive glomerulonephritis. Inspite of recent advances in the pathogenesis and development of new therapeuticagents, long term outcomes are still poor with five year mortality of 25%. Thereare epidemiological, histological, clinical and outcome related differencesbetween these two conditions. This strongly suggests that there must differencesbetween genetic factors and pathogenesis of these two conditions. There was alsoa perception amongst the clinicians that AASV is more common in GreaterManchester area. Hence in this study I calculated the incidence of pauciimmuneglomerulonephritis in Greater Manchester and analysed the genetic differencesbetween cANCA and pANCA associated vasculitis.Methods: Five year incidence of pauciimmune glomerulonephritis wascalculated in Greater Manchester between 1/1/1999 to 31/12/2003. I recruited147 patients with ANCA associated vasculitis. Clinical data was collected. Istudied single nucleotide polymorphisms (SNPs) of tumour necrosis factor alpha(TNFalpha), interleukin 8 (IL-8), transforming growth factor beta (TGFβ), plateletendothelial cell adhesion molecule 1 (PECAM-1), Chemokine (CC motif) ligand-5 C chemokine (CCL-5), interleukin 10 (IL-10) and interleukin 18 (IL-18) genesand compared the frequencies of genotypes and alleles in patients with cANCAand pANCA associated small vessel vasculitis and healthy volunteers. I alsostudied circulating cytokine profiles of IL-10 and IL-18. Results of IL-18 SNPswere validated in AASV cohort from South-East USA. Further I studied the geneexpression patterns of active and remission state of AASV and metabolomicsprofile of cANCA and pANCA positive patients during active and remissionstate of vasculitis. Clinical outcomes (relapses and renal survival) werecorrelated with the genotypes.Results: I found a significantly higher incidence (9.8/million population) ofpauciimmune glomerulonephritis in Greater Manchester compared to thepreviously published data from UK and USA (2.73 to 4.6/million). Renalfunction at the time of diagnosis predicted the long term renal survival.I also found a novel genetic association of increased frequency of high producerIL-18 SNPs 113T, 127C and 137G in pANCA positive patients compared tonormal volunteers (p=0.04) and cANCA positive patients (trend- p=0.08). Thiswas associated with increased levels of circulating IL-18 levels in these patients.This association was further confirmed in an independent cohort of AASV fromUSA. I also found a lower frequency of low producer GG genotype of IL-10 -1082 SNP (p=0.05) and this was associated with lower levels of circulating IL-10in these patients compared to pANCA positive patients.I found significant difference in the metabolomics profiles of cANCA andpANCA positive patients. In paired plasma samples, levels of some metaboliteswere high during remission state compared to active vasculitis.Conclusions: These findings strongly support the hypothesis that there is anincreased incidence of pauciimmune glomerulonephritis in Greater Manchester.There are genetic differences in cANCA and pANCA positive patients whichmay explain the different observed outcomes. Genomewide association studywould strengthen these findings and should guide the vasculitis community to -reclassify, assess and perhaps treat these two conditions separately.


Original languageEnglish
Awarding Institution
Award date1 Aug 2012