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A recent BMJ Minerva column alerted me to an interesting paper in the journal Transplantation. The authors used collaborative databases to compare overall and age-specific graft survival in first deceased donor transplants carried out in the US & Europe. They found that although there was broad similarity in 1-year graft survival, 5 and 10 year graft survival was considerably higher in Europe than in the US. The tendency towards worse graft survival in the US persisted across all ethnic groups and was largest for children and young adults. The gap between European and US survival was greater beyond 3 to 4 years post engraftment.

I am British and have only ever practiced in the UK NHS. I am therefore in no position to comment meaningfully on the following points made in the paper’s discussion section: "it is necessary to recall…the 3-year restriction in medication coverage for immunosuppression in the United States by Medicare…A policy change may contribute to improving graft survival and ultimately saving lives and also help to reduce health care spending." I imagine that other readers and contributors to this site may have informed and/or deeply held opinions.

Does nephrology need personalized medicine?

Systems biology is one of science’s growth areas. Sequencing technologies and software tools developed on the back of the human genome project have reduced the cost of, and therefore increased access to, large and complex datasets (ending in -ome) of genome sequences (genomics), gene expression (transcriptomics) and proteins and metabolites (proteomics and metabolomics). Systems biological techniques integrate these datasets and provide insights into how phenotypes may emerge from interacting biological processes rather than isolated genes or proteins.

A recent editorial in the journal Nephrology Dialysis Transplantation examined this field in general and its relevance to nephrology. The authors mention that –omic datasets have been useful in modeling “self-organized highly interconnected networks”, and that such networks have implicated unexpected candidates in disease pathogenesis (see for example, this paper on cardiac hypertrophy). 

The review goes on to suggest that using the tools of systems biology to finely phenotype individuals will usher in an era of truly personalized medicine. However, it is not clear to me that a definite sequel to this type of analysis will be the personalization of treatment or even that the concept of personalized medicine is particularly suited to our current view of what constitutes clinical evidence.

Diseases such as the ANCA-associated vasculitides (AAV) are now known to exhibit genomic variability. Randomised controlled trials (RCTs) in AAV (such as here and here) have been hampered by: 

1. Short follow-up times 
2. Inter-group heterogeneity which may have affected outcomes. These factors have contributed to ongoing debate about the applicability of the results of these trials (see correspondence here). 
3. Additionally a recent trial in membranous nephropathy, likely to represent another disease with distinct –omic subsets, was marked by slow recruitment. 

 

All these points together suggest that it may be difficult to conduct meaningful clinical studies of distinct –omic subtypes in nephrological diseases. Currently, primacy is given to RCTs when evaluating the efficacy of new treatments; and in nephrology the community is finally beginning to produce the RCTs which have been absent historically. 

If the focus is to switch away from RCTs with their large, well-matched study groups and towards splitting groups up by some -omic fingerprint I am able to envisage a time when one has to choose between giving more credence to the results of larger, “non-personalised” trials or smaller studies featuring –omic data but lacking the controlled element of RCTs.  Would this represent progress?

When IgA-ttacks!

To many of us IgA nephropathy (IgAN) is a disease to be watched and monitored.  Most cases of IgAN in which the clinical course is aggressive occur with one of two atypical presentations:

1. Acute kidney injury (AKI) and macroscopic haematuria or

2. Nephritic syndrome or RPGN with a crescentic nephritis on biopsy

The first thing to say is that both of these presentations are rare. Whilst visible haematuria coinciding with mucosal infections is a well-known feature of IgAN, development of coincident acute kidney injury is uncommon.  In fact, the largest published case series with this presentation I could find included only 38 patients.  With regards to crescentic nephritis, it is instructive that the recently produced Oxford classification of IgAN study found so few patients with a severe crescentic nephritis (median % gloms with crescents 9%) that the authors were unable to include crescents as having “independent value in predicting renal outcome.”

The AKI seen with visible haematuria is often due to tubular injury from intra-tubular erythrocyte casts and a possible direct nephrotoxic effect of haemoglobin.  The key issue in these patients is not so much treatment, which is through general supportive measures, but ensuring that protracted or repeated AKI is not due to a crescentic IgAN.  As a result, the recently published KDIGO glomerulonephritis guidelinesrecommend that any patients with known IgA exhibiting AKI and visible haematuria who fail to show improvement of kidney function after 5 days should undergo repeat renal biopsy.

Crescentic IgAN (defined as RPGN with crescents in >50% of glomeruli seen in the biopsy) although rare has a poor prognosis: end-stage renal disease in 75% of one cohort at 10-year follow-up.  The KDIGO guidelines suggest on the basis of low quality evidence initial treatment as for ANCA vasculitis with steroids and cyclophosphamide.  Interestingly, no suggestion is made for maintenance therapy in these cases.

I have only ever seen a single case of severe crescentic IgAN and no cases of AKI with visible haematuria.  However, I think it’s important to know some details about these presentations.  In the near future I’ll look at Henoch-Schonlein nephritis and that most thorny of issues in IgAN; who to treat with immunosuppression outside of an RPGN presentation.