Mediators of loin pain in IgA nephropathy

Supervisors

• Professor Jonathan Barratt (jb81@le.ac.uk)
• Dr Haresh Selvaskandan (hs328@le.ac.uk)
• Dr Róisín Thomas (rct21@le.ac.uk)

Project description

IgA nephropathy (IgAN) is the most common pattern of primary glomerular disease reported across the world following a renal biopsy. Significant and recurrent loin pain has long been recognised as a symptom of IgAN, but there is currently no understanding of what mechanisms drive this symptom or how it could be managed.

A study performed in Leicester, funded by Kidney Research UK, examined over 20,000 postings on social media and confirmed pain as a symptom widely experienced by those with IgAN (1). The incidence of IgAN peaks among young adults, and it is therefore likely this symptom confers significant psychosocial and socioeconomic impacts at both an individual and a societal level. A pilot survey we have since conducted found that over two thirds of patients with IgAN experience this pain, and available analgesics are of little benefit.

The mechanisms which drive loin pain in patients with IgAN is unclear. Inflammation is well established as a driver of pain (2). The cytokines, chemokines and metabolites released in states of inflammation stimulate nociceptors, also known as pain receptors (3). Markers of inflammation are known to be over expressed or up-regulated in IgAN, and it is therefore possible that the pain is being mediated by episodic states of inflammation, which likely involves lectin pathway activation (4). A further possible mechanism is kidney capsular stretch, but this is yet to be conclusively demonstrated in any setting (5).

This project aims to characterise the pathophysiological factors associated with loin pain in patients with IgAN, and will determine the pathological basis for episodes of loin pain in IgAN and the relationship with transient flares of IgAN and episodes of inflammation in the kidneys.

A separately funded project will investigate:

1. The proportion of IgAN patients who suffer with recurrent episodes of loin pain
2. The impact of loin pain on the lives of IgAN patients and their carers
3. The understanding of healthcare professionals on the significance of loin pain to the lives of patients with IgAN

These findings will complement the outcomes of the project proposed here.

Brief plan of research

Year 1

• Training and optimisation of proposed laboratory methods (Flow cytometry, luminex assays, ELISAs, rt-qPCR and western blots. 

Years 1 - 2

• Recruitment of IgAN patients with loin pain (n = 20). 
• A cohort of IgAN patients with loin has been established through a separate, funded, qualitative study, exploring the impact of loin pain on those with IgAN. This cohort will be approached for this PhD.
• Each patient will attend the John Walls Renal Unit within 24 hours of experiencing an exacerbation of loin pain. On attendance each patient will have a thorough physical examination, clinical observations recorded and blood, peripheral blood mononuclear cells (PBMC) and urine collected for future analysis (plasma, serum, PBMCs and urine all stored at -80oC) along with renal magnetic resonance imaging (MRI) to quantify kidney volume, shape and parenchymal changes consistent with inflammation. 
• Each patient will then be invited to return when they are pain free for at least 28 days and all assessments repeated
• Biomarker and imaging analysis.
• Levels of inflammatory chemokines, cytokines and metabolites in serum and urine that are associated with inflammation and pain will be measured using multiplex assays routinely employed in the laboratory. Those to be measured will be decided in conjunction with a team from the Liverpool Pain Institute. 
  Levels of complement components, complement activity and complement activation products of the lectin pathway will be measured in lithium heparin plasma and urine.
• Flow cytometric PBMC immunophenotyping will be performed.
• Kidney volumes, shape and parenchymal composition will be generated using software and expertise within the Academic MRI Imaging Department of the University of Leicester.
• Additional biomarker analysis on the remaining tissue samples will be directed by the results of the initial analyses.

Year 3

• Analysis of data, result validation and further investigation of notable result.

References

1. Vasilica et al. Indentiying information needs of patients with IgA nephropathy using an innovative social media stepped analytical approach. Kidney Int. Rep. 2021. 2;6(5): 1317
2. Ji R, Chamessian A, Zhang Y. Pain regulation by non-neuronal cells and inflammation. Science. 2016 -11-04;354(6312):572.
3. Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010 -11;120(11):3760-72.
4. Rauen T, Floege J. Inflammation in IgA nephropathy. Pediatr Nephrol. 2017 -12;32(12):2215-24.
5. Nishiura JL, Eloi SRM, Heilberg IP. Pain determinants of pain in autosomal dominant polycystic kidney disease. J Bras Nefrol. 2013 Jul-Sep;35(3):242-3.