130 research outputs found
Endothelin system & its antagonism in chronic kidney disease
Since its discovery in 1988 the powerful vasoconstrictor endothelin-1 (ET-1) has been
widely implicated in the pathophysiology of chronic kidney disease (CKD) as well as
the cardiovascular disease with which it is associated. ET receptor antagonists have
favourable effects in experimental models of these conditions and orally acting
antagonists are now licensed for the treatment of pulmonary arterial hypertension.
However, there is a paucity of human data regarding the role of ET-1 in CKD. In this
thesis, I have therefore explored the utility of ET-1 as a biomarker in CKD, and, using
selective ET receptor antagonists, the beneficial renal and cardiovascular effects of ET
receptor antagonism in CKD.
I have shown that as glomerular filtration rate (GFR) declines plasma ET-1 increases
linearly whereas urinary ET-1 shows an exponential increase. Furthermore, urinary ET-1
may be a useful marker of disease activity in patients with lupus nephritis. Its levels are
high in those with biopsy-proven active renal inflammation and these fall with treatment.
I have shown that in subjects with stable non-diabetic proteinuric CKD, acute selective
ETA receptor antagonism reduces blood pressure and arterial stiffness and that these
systemic benefits are associated with an increase in renal blood flow and reduction in
proteinuria. Importantly, these effects are seen on top of those achieved with maximal
therapy with angiotensin converting enzyme inhibitors and/or angiotensin receptor
blockers.
Following a study confirming unchanged pharmacokinetics in CKD, I have used an oral
selective ETA receptor antagonist to show that the reductions in BP, arterial stiffness and
proteinuria seen in my acute studies are maintained longer term. This results of this
study also suggest that the mechanism for the reduction in proteinuria is haemodynamic
and relates to a reduction in GFR and filtration fraction. In summary, these studies suggest that ET-1 may act as a potential biomarker of renal
inflammation, and confirm its role in the pathophysiology of the systemic and renal
vasoconstriction seen in CKD. They also suggest that selective ETA receptor antagonism
may provide a novel therapeutic approach in proteinuric CKD on top of standard
therapies. Larger and longer term studies are now warranted to confirm this potential
TWEAK: a novel biomarker for lupus nephritis?
Renal involvement is common in systemic lupus erythematosus. Early diagnosis of lupus nephritis (LN), allowing the instigation of appropriate therapy, remains an important clinical challenge. Current biomarkers in clinical practice are less than ideal, lacking both sensitivity and specificity. In the previous issue of Arthritis Research & Therapy, Schwartz and colleagues demonstrated the potential value of urinary TNF-like weak inducer of apoptosis (uTWEAK) as a biomarker for LN. They showed that uTWEAK is elevated in subjects with LN at diagnosis compared with those with systemic lupus erythematosus but no renal disease, and correlates with the degree of clinical disease activity. These data are thought-provoking and provide the platform for future longer-term studies
Haemolytic anaemia complicating the concurrent use of allopurinol & azathioprine after kidney transplantation
Gout is a common problem in renal transplant recipients but often difficult to treat. Allopurinol can be combined with azathioprine but clinicians should be aware of the need for dose reduction, the potential to measure azathioprine breakdown products and the possible side effects of this combination. Leucopenia is a known side effect but this case report shows that haemolytic anaemia can also occur
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