Complement is a fluid phase amplification system which is a key element of the innate immune system. For a long time understanding complement did not  seem a high priority in clinical research. Most  diseases associated with complement dysfunction were rare, and dissecting that dysfunction has seemed an esoteric pursuit for much of the last sixty years.

Nevertheless several complement-mediated disorders affect the kidney, and UK nephrologists and immunologists have been at the forefront of work to unravel these abnormalities.

A justification for pursuing such work is that detailed (and now molecular) analysis of rare abnormalities can provide insight into disease processes which eventually lead to the formulation of agents with specific actions suitable for clinical application. And that furthermore these agents would prove relevant not only to treatment of the rarities but also more widely as the impact of complement abnormalities was better understood.

This has always been a ‘long game’ but over a period of more than fifty years much of this has now come to pass. Agents which interfere with the complement cascade are now available and are proving safe and highly effective in several clinical settings within and beyond nephrology.

This work is fully summarised in a 2022 review article by Keith Peters , which demonstrates well the important and sustained   achievements of the UK contributors to this field.

The focus of much this work was the patterns of glomerulonephritis associated with hypocomplementaemia, particularly those apparently with an inherited basis.  In early years these were usually designated membranoproliferative GN or mesangiocapillary GN based on the pattern of light microscopic injury seen on renal biopsy. In some cases there was a  curious association with partial lipodystrophy, which  turned out to also to be a consequence of   complement dysfunction.

The work started with Peter Lachman (immunologist) and Keith Peters (nephrologist) who had  a long and productive collaboration on complement at RPMS (Royal Postgraduate Medical School, Hammersmith Hospital) from the beginning of the 1970s. This work drew in a  number of young academic nephrologists who cut their first research teeth under Keith Peters’ direction in the field of complement – including Patrick Sissons (later Regius Professor of Physic, Cambridge), Gwyn Williams (later at Guy’s), Andy Rees (later Regius Professor of Medicine, Aberdeen), Patrick Naish (later at Stoke), Bruce Pussell (who returned to Australia)  and Peter Mathieson (later Professor of Nephrology, Bristol).

Important contributions were not confined to RPMS. Early valuable clinical observations were made by Stewart Cameron and colleagues at Guy’s, and Colin Short and colleagues in Manchester. Given that a number of the complement dysfunctions being identified  were inherited it is not surprising that paediatricians made important observations – for example John Soothill at Great Ormond Street, as well as Mike Winterborn and Richard White, both  in Birmingham.

More recently the field has been reshaped and reclassified, and C3 glomerulopathy is a clinical category subject to intense scrutiny. At RPMS Terry Cook (renal pathologist) and Matthew Pickering joined by Nick Medjeral-Thomas are at the forefront of this field. And are now exploring the importance of complement in  IgA nephropathy, in which complement deposition has been  well documented, but poorly understood.

RCTs of these new complement-modifying agents are now underway in a number of glomerular diseases.

—

This page focuses on complement in the  context of glomerulonephritis. The role of complement in atypical haemolytic-uraemic syndrome has been  analysed in detail over the last two decades, and work in Newcastle led by Tim Goodship and now David Kavanagh has been world leading. It is bearing therapeutic fruit now that the complement inhibitor, eculizumab, is widely available. This is  discussed elsewhere within  Great British Contributions

Last Updated on May 24, 2023 by John Feehally