Final data from the Study of Heart and Renal Protection (SHARP) was presented at this weeks UK Renal Association and published in the Lancet online this week.The SHARP study was an RCT that involved 9270 patients with chronic kidney disease (of whom 3023 participants were dialysis-dependent), who were randomly assigned to receive simvastatin 20 mg daily plus ezetimibe 10 mg daily, or placebo, and followed up for a median of 4·9 years. There was a significant 17% proportional reduction (RR 0·83, 95% CI 0·74—0·94; log-rank p=0·0021) in major atherosclerotic events (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or arterial revascularisation) among those allocated to active treatment. There was also a significant one-fifth reduction in major vascular events (ie, major atherosclerotic events plus non-coronary cardiac deaths) amongst patients randomised to active lipid-lowering treatment. Whilst at first sight the effect appears more convincing in the non-dialysis population there is no statistical difference in outcomes between the dialysis and non-dialysis population. Reassuringly lipid lowering was safe and was not associated with cancer or rhabdomyolysis. As in previous trials there was a slight excess of haemorrhagic stroke in the lipid lowering group. there was no effect on CKD progression with lipid lowering.
The obvious question that arises is why do the results of SHARP appear to be positive when previous studies in the dialysis (4D and AURORA) population appear to be negative. However coronary revascularisation was not part of the primary endpoint in 4D and AURORA and the authors argue convincingly that the LDL-cholesterol-weighted proportional effects in AURORA, 4D and SHARP were statistically compatible for non-fatal myocardial infarction, non-fatal haemorrhagic stroke, non-fatal non-haemorrhagic stroke. Thus the results of SHARP are consistent with the effects of Cholesterol Treatment Trialists' (CTT) Collaboration metanalysis that shows statin therapy reduces the risk of myocardial infarction or coronary death, stroke, or coronary revascularisation by about a 20% per 1mmol/l reduction in LDL cholesterol. Furthermore the SHARP study included a large number of non-dialysis patients in whom the pathophysiology of cardiovascular disease maybe more similar to the general population.
So where does this leave the practicing clinician ? It seems that there is now good evidence to support lipid lowering in CKD patients as a primary prevention therapy to reduce cardiovascular events. This seems to be clear for the non-dialysis population ( even if they progress to renal replacement therapy) but the evidence is perhaps less clear in those on lifelong dialysis. For those who dont have access to ezetimibe the overall potency of the simvastatin+ezetimibe combination was broadly equivalent to atorvastatin 20 mg daily, rosuvastatin 10 mg daily, and fluvastatin 40—80 mg daily.
A number of articles including that by Cooper et al (IDEAL study) explored the notion that late initiation of RRT is not harmful and may be even beneficial (Rosansky et al, 2010). It strikes me that most of these papers advocating late onset RRT and the potential harm of early RRT initiation use the wrong parameter; namely MDRD derived eGFR, a test known to be unreliable at this late stage of CKD and GFR<15. Further, eGFR in these patients would be strongly influenced by changes in serum creatinine which in turn would be affected by changes in muscle mass. So a patient with eGFR of 15ml/min may have a lower serum creatinine than one with a eGFR of 5-10ml/min as a result of muscle wasting and malnutrition and would clearly fare worse on RRT! It is high time that nephrologists stop equating GFR derived from serum creatinine based equations in advanced stages of CKD.
It is also high time that more emphasis is put on early referral for RRT rather than the actual timing of initiation of RRT; considering that in the majority of emerging countries where mortality of RRT is very high, most patients are referred to Nephrologists within 60-90 days from theinitiation of RRT! Thus depriving them from adequate pre-dialysis care and monitoring!
Read: Early Start of Dialysis: A critical Review in CJASN May 2011.
Another paper, another antigen implicated in the pathogenesis of membranous nephropathy. The last few years saw a plethora of putative antigens from neutral endopeptidase (NEP), to PLA2R1 as well as superoxide dismutase and aldose reductase, all with auto-antibodies and immune deposits in the glomeruli of patients with idiopathic membranous nephropathy (IMN). Now a paper by Debiec and the Ronco team in Paris revisit the old hypothesis that cationic bovine serum albumin can be a causative factor in the pathogenesis of IMN in children. They demonstrate the presence of circulating cationic BSA in some children who have IMN along with anti-BSA antibodies and deposition of cationic BSA in the glomeruli. There evidence suggests that cationic BSA may be pathogenic through binding to anionic GBM and the formation of in situ immune complexes. Clearly, more antigens and antibodies are implicated in a disease that is likely to be initiated by damage to the GBM or podocytes with secondary formation of an array of auto-antibodies. BSA and milk proteeins is another story!
Interesting data is presented in this months JASN from Colin Hutchinson in Birmingham, UK presents data ( from Birmingham and Rochester) suggesting that early and aggressive reduction of serum free light chains (FLCs) associates with renal recovery in myeloma kidney. 39 patients with biopsy-proven myeloma kidney, the majority of whom had severe renal failure at presentation (median estimated GFR 9 ml/min per 1.73 m2) were analysed to see which variables associated with renal recovery. In a multivariable analysis FLC reduction significantly predicted renal recovery (P = 0.003). The relationship between renal recovery and FLC reduction was linear with a 60% reduction in FLCs by day 21 associated with recovery of renal function for 80% of the population. Unsurprsingly patient survival strongly associated with renal recovery: the median survival was 42.7 months (range 0 to 80) among those who recovered function compared with 7.8 months (range 0 to 54) among those who did not (P < 0.02). Patients had variable treatment but treatment broadly consisted of a combination direct removal of FLCs and aggressive chemotherapy often using bortezomib. In Birmingham FLC removal was achieved using extended hemodialysis using a protein permeable dialyser whilst plasma exchange was used in Rochester. This data suggests that early reduction of FLC aids renal recovery but also that the FLC immunoassay is an essential quantitative tool in monitoring response to therapy in multiple myeloma. For further details see http://jasn.asnjournals.org/content/22/6/1129.abstract
Trachtman and colleagues report in the June 2011 issue of KI the outcome of the phase 1 study of fresolimumab, a human monoclonal anti-TGF-beta antibody in 16 patients with FSGS. Patients were divided into 4 groups receiving fresolimumab doses ranging from 1mg/k to 4mg/kg given as a single intravenous dose. Patients had detectable levels of circulating fresolimumab at day 112. Fresolimumab was well tolerated. This publication is the first report of the use of an anti-TGF-beta antibody in patients with CKD. The safety profile confirms that reported in trials of patients with pulmonary fibrosis and cancer. There was no evidence that the administration of fresolimumab adversely affecetd teh course of the FSGS. Undoubtedly, larger proof of concept, phase 2, trials of efficacy of this form of therapy in nephropathies will soon be underway.
Molnar and colleagues in the May issue of JASN report a population based retrospective cohort study of 213,347 older patients who underwent elective surgery in Canada. They noted that statin use was associated with a 16% reduction in the risk of postoperative AKI. This adds support to previous experimental and smaller clinical observations suggestive of such protective effect as well as protection against preoperative cardiac events and even mortality. Statin are pleotropic agents that potentially exert a number of renoprotective actions including mitigating the renal ischema/reperfusion injury induced inflammatory response associated with AKI. One limitation of this study is the retrospective nature of the observation but the authors took great car to adjust for a large number of patients and healthcare confounders by multivariate analysis as well as propensity-based matching of patients on and off statin therapy. Until such observation is confirmed by a prospective RCT, it may be advisable to consider statin therapy to minimise AKI in elderly patients undergoing major surgical procedures.
Kohan et al in JASN April 2011 present data suggesting that endothelin A receptor blockade reduces albuminuria in diabetic nephropathy over and above RAAS Blockade. The study was conducted in diabetic patients with GFR>20 ml/min and albuminuria between 100 and 3000 mg/g. Patients were randonised into placebo, atrasentan 0.25, 0.75 and 1.75mg/day groups. Follow-up was 8 weeks. Analysis was on intention to treat (ITT). Atrasentan at 0.75 and 1.75 mg/day reduced albuminuria significantly. Atrasentan also reduced systolic and diastolic BP, thus making difficult any conclusion regarding a albuminuria lowering effect independently of BP reduction!
Of note, fluid retention and oedema was a significant side effecst affecting up to 46% of those on the highest dose of Atrasentan.
This observation is consistent with that made recently with another ETA Receptor antagonist, namely avosenta; in this study avosentan also erduced albuminuria in diabetic nephropathy but the trial had to be discontinued on safety ground due to increased death related to fluid retention and heart failure.
Endothelin A antagonists may prove useful adjuncts to the current management of Diabetic nephropathy. Whether, it adds much to tighter BP control remains to be elucidated.
An excellent randomised controlled trial is published in this weeks New England Journal of Medicine, from the INTAC study group, based at the University of Alabama, Birmingham, looking at the role of Alemtuzumab induction and steroid sparing immunosuppression. Alemtuzumab is a humanised anti-CD52 monoclonal antibody targeting both B and T lymphocytes. Increasingly a number of centres are using Alemtuzumab induction to enable steroid free immunosuppression. This RCT compared Alemtuzumab to Basiliximab for low risk recipients and Alemtuzumab to ATG for high risk recipients in patients on Tacrolimus and MMF with steroids being stopped after one week. High risk was defined as second allograft, black race or panel reactivity greater than 20%. Alemtuzumab was given as a single dose of 30mg. With respect to the 139 high risk patients there was no difference in biopsy proven acute rejection between the ATG group and Alemtuzumab with rejection rates of 18% vs 15%. in the low risk group the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab : 12 months (5% vs. 17%, P<0.001) and at 3 years(10% vs. 22%, P=0.003)There are some slightly concerning results however. Whilst the overall rejection rate was lower with Alemtuzumab the late rejection rate (between 12 and 36 months was higher). Further lymphopaemia persisted in Alemtuzumab group for well over 2 years. Overall the Alemtuzumab group had a slightly (and significantly) higher rate of cancer. Furthermore whilst the infection rate was lower than ATG it was higher when compared to Basiliximab.
The shortage of cadaveric and live donors has lead to increasing interest in ABOi transplantation. Much of this work has been pioneered in Japan where restrictions on cadaveric donation has necessitated the use of ABOi transplantation. Often aggressive immunosuppressant regimes were used including splenectomy coupled with use a rituximab. A report from Melbourne, Australia in this months AJT highlights how ABOi transplantation may now be moving to the mainstream. The Melbourne group report on 37 consecutive ABOi transplants who were followed up for more than 2 years. The immunosuppressive protocol was identical to the non ABOi transplants using Basiliximab, MMF, Prednisolone and Tacrolimus. ABOi transplants underwent plasma exchange pre-operatively and post-operatively to maintain low levels of ABO antibody. IVIG was given post-plasma exchange. There was no significant difference in any outcome between the ABOi and ABO compatible transplants. There was 100% graft survival in both groups and rejection rates were 14% & 17% respectively. Two patients in the ABOi group had antibody-mediated rejection which was treated by plasma exchange in one and required splenectomy in the second patients. The paper demonstrates that ABOi is deliverable and offers an exciting, practical approach to dealing with shortage of donors. As the authors point out an essential part of an ABOi program is to have excellent laboratory support to allow for frequent monitoring of ABO antibodies and quantification of antibody titre. Usually after the first month post-transplantation a rise in ABO antibody titres does not cause graft damage - a process known as accommodation - the underlying mechanism being unclear. The abstract can be found here http://www.ncbi.nlm.nih.gov/pubmed/21449947
The swedish SWEDEHEART study group reported data from their nationwide registry on 42,814 consecutive survivors of myocardial infarction (MI). They noted that the prescription of statins on discharge from hospital after an MI improved survival rate at 1 year mainly in patients with CKD2-4. The effect in those with CKD5 was less obvious. This observation is at variance with those made in recent clinical trials on the use of statins in CKD patients. Statins have failed to improve survival in patients with CKD5 on dialysis; 4D and AURORA trials. However, the SHARP study group presented (ASN 2010) the results of their trial on the use of simvastatin and ezetemibe in patients with CKD3-5 (including some on RRT) and showed a reduction in overall major cardiovascular events. This effect was more noticeable in those with CKD3-4 compared to those on dialysis where the impact was less significant. However, SHARP failed also to show improved overall survival. This is at variance with the SWEDEHEART data. This follows a common pattern of positive reports of interventions in CKD patients based on observational studies that are not fully substantiated when tested in an RCT setting.
So...to use or not to use Statins in CKD? that is the question!
I would personally say use it in CKD patients with a history of IHD. Wait for a more detailed anlysis and publication of the SHARP study before you prescribe them prophylactically to reduce CV risk in pre-dialysis patients. Do not prescribe them for primary prophylaxis in those on dialysis (in agreement with published guidelines). Of note, these drugs are not without side effects and have been associated with increased cerebrovascular accidents/hemorrhages in a number of clinical trials, including those in HD patients; 4D and AURORA.