User blog: Arif Khwaja
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 recent KDIGO guidelines on Hepatitis C have provided clinicians with useful guidance on how to work up Hepatitis C positive dialysis patients for renal transplantaion. A single centre observational study from David Roth's group in Miami, USA has been published in JASN this month which analysed long terms outcomes in 230 patients who were identified as having Hepatitis C during their transplant work up. 207 of the patients had a liver biopsy pre-transplantation and a total of 110 patients underwent a kidney tranplant. Key data from the study showed that:
i) 10% of all patients who underwent a liver biopsy had significant fibrosis supporting the KDIGO guideline that liver biopsies should be undertaken in all who are being evaluated for transplantation. Whether Fibroscan can replace liver biopsy remains to be seen. Interestingly in the 31 patients who underwent liver bioppsy post transplantation, only 23% had progression og liver fibrosis - in contrast to 625 of those patients who remained on the list - suggesting that for a significant cohort of people transplantation doesn not result in worse liver outcomes.
ii) whilst there was an increased relative risk of death (2.5) in the first 6 months post transplantation (predominantly from infection), the risk of death was significantly reduced after 6 months, with a significant reduction in risk of death between 6 and 84 months post transplantion in the transplanted hepatits C group. White race, age>55 and kidney-pancreas transplantation were more likely to be associated with adverse outcomes. The transplanted hepatitis C group had a lower risk of cardiovascular death though a higher risk of new onset diabetes after transplantation (NODAT).
In summary this study confirms previous registry analysis that kidney transplantation confers a survival benefit on Hepatitis C patients compared to haemodialysis. Whilst there is a higher early death rate post transplantion due to infection this is more than offset by the reduced death rate after 6 months.
The paper will be published shortly: Effect of Kidney Transplantation on Outcomes among patients with Hepatitis C. JASN May 5, 2011
Data from the DAC Graft Trial, in which 649 patients were assigned to either placebo or twice-daily extended-release dipyridamole (200 mg) and Aspirin (ASA) (25 mg; ERDP/ASA) after AV graft placement suggested that ERDP/ASA lead to a very modest, but significant reduction in graft thrombosis/need for graft angioplasty. Now a recent analyis of this study suggests compared outcomes associated with ASA use across and within randomized groups assigned to either ERDP/ASA or placebo. Thee key finding was that ERDP/ASA was no more effective than ASA onlone in preventing graft thrombosis/angioplasty. The message therefore is that Aspirin should be used in all patients with grafts but the benefits are modest. Vascular access remains a critical problem on dialysis units - share your thoughts. See accompanying editorial in JASN (http://www.ncbi.nlm.nih.gov/pubmed/21415154)
A very thoughtful piece by Professor Chapman from Sydney, Australia in this months AJT reviewing the literature around CNI nephrotoxicity ( see here ) Professor Chapman confirms the notion that whilst CNIs reduce the incidence of acute rejection the long term impact on graft function is significant especially in grafts older than 5 years. Furthermore nephrotoxoicity seems to be dose related. Attempts to manage immunsuppresion without CNIs have been variable. At present CNIs remain a 'cant live with you and cant live without you' medication in transplantation with CNI nephrotoxicity competing with other causes of longterm graft loss such as chronic transplant glomerulopathy.
There is an interesting article in this months cJASN analysing the effect of using the CKD-EPI formula (rather than the MDRD equation) on eGFR calculation and therefore CKD diagnosis. The CKD-EPI formula is believed to be more accurate than MDRD when the eGFR>60mls/min. Interestingly in an analysis of 53,759 patients with CKD 3-5 the authors compared the effect of CKD-EPI and MDRD equations on CKD diagnosis. Interestingly there was a 35% decrease in the diagnosis of CKD among patients 90 years. Women, non-African Americans, nondiabetics, and obese patients were less likely to be classified on the basis of CKD-EPI. in a way the research highlights the problem of 'disease-labelling' that has occured as a result of the CKD staging system and further highlights the paradox of differentiating CKD 1 and 2 on the basis of the MDRD equation when this equation is known to be inaccurate when the eGFR>60mls/min. See Implications of the CKD-EPI GFR Estimation Equation in Clinical Practice in this months cJASN. share your thoughts on the merits or otherwise of the CKD classification system and MDRD equation.
Patients with Chronic Kidney Disease (CKD) are at much higher risk of cardiovascular disease than the general population but the benefits of lipid reduction in this population have been far from clear. Recent data from the Study of Heart and Renal Protection (SHARP) study presented at the ASN 2010 may clarify the role of lipid-lowering therapy in this population. SHARP enrolled 9438 patients with chronic kidney disease either on dialysis or with a creatinine level of >1.7 mg/dL (150μmol/l) for men or >1.5 mg/dL (130μmol/l) for women, all with no history of MI or coronary revascularization. Patients were randomised to either ezetimibe/simvastatin (10 mg/20 mg) or placebo, with an additional 1000 patients randomised to simvastatin alone. After one year, patients in the simvastatin-alone arm were re-randomised.
After a median follow-up of nearly 5 years the simvastatin/ezetimibe group had 17% reduction in major atherosclerotic events compared with placebo (p=0.0022) and a 15.3% reduction (p=0.0012) in major vascular events. Approximately 1/3 of patients were on dialysis though the benefit in the dialysis population was not statistically significant. Further simvastatin/ezetimibe had no impact on the progression of CKD nor was there any difference in mortality between the two groups.
So where does this leave us in terms of daily clinical practice? It now seems sensible to use lipid-lowering therapy as a primary preventative measure in CKD patients at risk of vascular events but it is worth noting that even in this huge trial no effect on overall mortality was seen and the reduction in vascular events was quite modest. The simvastatin/ezetimibe combination is clearly safe (concerns about myositis and cancer were not borne out by the data) but it may be that alternative therapies such as atorvastatin could be a cheaper alternative. Whether prevalent dialysis patients should be treated in the same way isn’t so clear. Both the 4D and AURORA studies have failed to show any benefit of statins in the prevalent dialysis population. Clearly clinicians will be able to make more informed decisions once the data is finally published.
The SHARP study data can be seen at: http://www.ctsu.ox.ac.uk/~sharp/slides.htm
The ‘long and slow’ approach to haemodialysis as advocated by the group from Tassin, France has yielded impressive results in terms of blood pressure control and patient survival. This has lead to increasing interest in daily haemodialysis as more effective alternative to the standard thrice weekly prescription.
Chertow, Levin and other members of the Frequent Hemodialysis Network (FHN) report the early (12 months ) results of their study involving 245 patients comparing in center haemodialysis (HD) six times per week compared to three times per week. They conclude that frequent HD, as compared to conventional HD, was associated with a favourable outcome. Emphasis was on progression of left ventricular mass, death and quality of life based on a physical-health composite score. Whilst promising, this study is limited by the very short follow-up period that precludes any conclusion on long term outcomes in HD patients dialysed more frequently. Outcomes are also difficult to evaluate as left ventricular mass index may reflect a better fluid balance and reduced blood volume in those dialysed more frequently. Quality of life and evaluation of physical health through health surveys and questionnaires can be biased by the non-blinded nature of the study -patients dialysed six times weekly may be subject to the placebo effect of frequent medical attention.
Interestingly, the daily HD group were much more likely to experience vascular access problems. Furthermore the study was underpowered and the sample size too small to show differences in survival over such a short period of time in such patients population.
Reference: In-Center Hemodialysis Six Times per Week versus Three Times per Week. The FHN Trial Group. N Engl J Med 2010; 363:2287-2300