Chou et al (Critical Care 2011, 15:R134; doi:10.1186/cc10252) revisited an important and controversial subject: the timing for renal replacement therapy (RRT) in acute kidney injury in septic patients. The objective of their study was to determine the impact of early or late initiation of RRT, as defined using the simplified RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal failure) classification on hospital mortality among septic AKI patients. For this, patient with sepsis and AKI requiring RRT in surgical intensive care units were enrolled from 01/2002 to 10/October 2009. They found that among the 370 patients, 192 (51.9%) underwent early RRT and 259 (70.0%) died during hospitalization. The mortality rate in early and late RRT groups were 70.8% and 69.7% respectively (P > 0.05). Early dialysis did not relate to hospital mortality by Cox proportional hazard model (P > 0.05). They concluded that the RIFLE classification is not good enough to find patients that could benefit from early or late RRT in the context of septic AKI.
Some authors have advocate the institution of early RRT as a measure to improve prognosis in AKI patients. While this is clear in some presentations, as AKI associated white leptospirosis or AKI after major abdominal surgery, this is not clear in others. In the septic patient, in special with severe sepsis or shock, RRT can harm the patient if the haemodinamic stability is not previously achieved. In particular for the development countries, the timing to start RRT depends on the skills of the local service, the availability of equipment and trained personnel. Before thinking in RRT, be sure that the initial targets for the critical patient were achieved, as hemodynamic stability and adequate oxygen delivery. After that, many patients will improve the renal function without RRT. Some trials in AKI found that early RRT had better prognosis, but without a intention-to-treat design, meaning that they could have included patients that would not need RRT.
The paper is available at: http://ccforum.com/content/pdf/cc10252.pdf.
There is some nice data in this months cJASN from the Mayo clinic describing the results of extended follow up of screening for intracranial aneurysms (IAs) in patients with ADPKD. Four hundred and seven ADPKD patients were screened with MRA for asymptomatic IAs between 1989 and 2009. 38 patients were found to have IAs on screening equating to a prevalence of around 9%. The prevalence of unruptured IA (UIAs) amongst patients with a family history of IA and/or subarachnoid haemorrhage (SAH) was estimated at 21% whilst the prevalence of UIAs with no family history was much lower at 6.3%. During cumulative imaging follow-up of 243 years in only 3 patients did a de novo IA develop or increase in size.
Depending on case series the annual risk of rupture of IAs seems to be around 1.5 per year but the risk unsurprisingly is much less when Iess than 10mm. The authors conclude that screening MRA should be offered to those patients with a positive family history of aneurysmal rupture or to those with multiple family members with IAs. In such patients who are screened and found to have no IAs they recommend re-screening at 5 years. The risks of screening are made even more complex by the risks of intervention for IAs (either surgical or radiological). The data presented here justifies a selective approach to screening based primarily on family history. Click here for abstract.
An analysis by Clase and colleagues (Ann Intern Med. 2011;154:310-318) based on the ONTARGET cohort shows that adding albuminuria or eGFR to traditional CVD risk factors adds little to the CVD predictive value of the latter. This analysis is in agreement with that made by Chang and Kramer in Nephron that reviewed studies a number of studeis showing that traditional predictive scors for CVD improve little by adding parameters of renal function. Whilst there is little doubt that Albuminuria and eGFR predict CVD outcomes as well as CVD mortality and all cause mortality, doubt is emerging whether they have added predictive value when combined to traditional risk scores such as the Framingham Risk Score. Further analysis is needed to clarify this issue. After all, the majority of CKD in communities are older individuals over the age of 65. In those traditional CVD risk scores may suffice. On the other hand, albuminuria and/or eGFR may have a useful additional predictive value in lower risk and young individuals with little underlying CVD. Further analysis is needed to clarify that important issue.
Increasingly, I come to realise that the two and three days intensive CME meetings packed with endless lectures by an endless list of eminent senior nephrologists that is favoured by so many nephrology CME orgainsers and societies is a waste of time. I wonder how many of those young nephrologists sitting in the back of some of these CME meetings digest the heavy content of lectures???? I wonder is that old fashioned didactic style of teaching with often recirculated and regurgitated lectures help anybody other than the travelling party of lecturers visiting yet another nice country...
It is high time that we, as educators, pay more attention to the educational needs of our younger colleagues.
It is high time we design CME programs that involves them in the planning; how often do we ask an audience to choose from a list of topics "Menu". I did that recently and there was panic in the audience...surprise, even dismay, that they can choose themselves the teaching topic that I was about to give them. They are so used to be told what to learn...what to do... and has lost the courage to take initiatives and the responsibility of their own learning!?
The Global Kidney Academy (GKA) has been set up to address some of these needs in emerging countries and also teach young emerging nephrologists to become educators themselves and take the lead in organising their own teaching requirements. Leadership in Education has to come from them and we should support their initiatives. For that I have also founded the international Nephrology Education Foundation (iNEF) to support their initiatives through grants and other means of support.
Teaching should consist more of Workshops aimed at young emerging nephrologists based on their choice of topics and relying on case-based small group discussions and breakout sessions facilitated by a regional as well as international faculty.
Gone the endless 45minutes rehashed lectures!
It is time to move on with Nephrology education Worldwide into a more user friendly format owned by the user and facilitated by those who support their training!
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.