User blog: Meguid El Nahas
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!
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.
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.
Another publication in a growing and confusing list of publications relating to the management of patients with IHD. The STICH trial investigator randomised 1212 patients with symptomatic CAD and EF <35% into medical therapy versus CABG. There was no signifcant difference in overrall survival (the primary endpoint). However, there was a lower rate of death from CV causes in those assigned to CABG (secondary end point). This paper is extremely well commented upon by James Fang (NEJM 2011;364:1671-2) who higlights the limitations of this trial including the doubtful significance of the difference in the secondary endpoints. The significance of differences in secondary endpoints is always questionable when the primary endpoint has not been met. Clearly, this study did not include patients with CKD (at least CKD3-5). Therefore, its relevance to the decision of the investigation and choice of treatment in asymptomatic patients for CAD remains uncertain in ESRD patients. Patients in the STICH trial had symptoms of angina. But, patients with ESRD who have significant LV systolic dysfunction should be investigated for CAD. Improved coronary circulation is one of the few interventions known to improve LV function. This is all the more relevant in those where renal transplantation is planned.
Conall O’Seaghdha and Caroline Fox update readers on data emerging from genomic wide associations studies (GWAS) linking a number of genes to the predisposition and progression of CKD. TCF7L2 gene polymorphism has been linked to increased type2DM in the general population. It is also associated with increased risk of CKD. Mutations of GREM1, coding for Gremlin, has been associated with a 70% increased risk of diabetic nephropathy. MYH9 (Non-muscle Myosin Heavy Chain) gene mutations have been associated with increased risk of FSGS, CKD and ESRD in African-Americans. The evidence for MYH9 as a nephropathy gene is compelling. The apolipropotein gene (APOL1), on chromosome 22, has also been associated with FSGS in African-Americans. In fact, a number of nephropathies in individuals of African descent are linked to MYH9 mutations including those affecting those who are infected by the HIV virus. Other genes have been identified to increase risk of CKD in the general populations. These include mutations of the gene coding for Uromodulin (UMOD) (Tamm-Horsfall protein) as such mutation has been associated with chronic interstitial disease. Uromodulin-associated kidney disease (UMAK) is also associated with an autosomal condition characterised by early onset, childhood, hyperuricemia and gout (in teenager) followed by progressive CKD reaching ESRD in adulthood. Clearly GWAS studeis are rapidly unravelling links between a growing number of genetic mutations/variations and CKD.
Interesting pilot study on the effect of the anti-inflammatory agent pirfenidone in patient with diabetic nephropathy. The study shows that over 12 months low dose pirfenidone (1200mg/d) improved GFR compared to placebo and high dose (2400mg/d). The drug had no effect on proteinuria. Whilst the number of patients in this study was very small and the drop out rate high due to side effects, the data are of interest as if confirmed they would add a therapeutic option in diabetic nephropathy. These data goes along those observed in experimental models and in a small study of patients with FSGS. Clearly, a phase 3 RCT is needed to confirm if this intervention has potential benefits in patients with diabetic nephropathy.
A paper by Rosolowsky et al from the Joslin Clinic in Boston reviews the incidence of ESRD in T1DM patients with macroalbuminuria over the last 15-20 years. Whilst ESRD risk increases with advancing stages of CKD, as expected.The incidence of ESRD seems to have changed little over the observation period from 1990 to 2006. A slight decrease in incident ESRD was noted in those between 20 and 29 years of age. But there was a steady increase in incident ESRD in older patients; 40-49 years. These observations are extremely interesting as they coincide with the age of RAAS (renin-angiotensin-aldosterone system) blockade era. It started with the paper by Lewis et al in 1993 and is ongoing to our days.
However, and in spite of the obsession with ACE inhibition and angiotensin-receptor blockade (ARBs) in patients with diabetes, proteinuria and nephropathy, there seems to be little noticeable impact of the progression of diabetic kidney disease as judged by the lack of impact on incident ESRD in a large cohort over 15 years of observation?! Could it be that these agents had little impact beyond the control of hypertension (as suggested a few years ago by Cassas et al.) and may have even been detrimental in older patients with diabetic nephropathy and macrovascular disease? Watch this space; the myth of the superiority of ACE inhibitors and ARBs may be unravelling...in the meanwhile more imaginative and novel interventions are urgently needed to stem the rising tide of ESRD due to diabetes.
Raggi and collaborators hav ereported the results of the ADVANCE study on the effect of the calcimimetic Cinacalcet of cardiac calcifications; CAC and Valvular calcifications. This was a RCT comparing the combination of Cinacalcet + low dose Vitamin D to Variable dose of Vitamin D. 360 patients on HD were randomised into th etwo experimental groups an dfollowed-up for 52 weeks. There was no significant difference in the primary end point; hanges in the rate of CAC. Howere, smaller changes in aortic valve calcifications were noted. Whilst the result can be considered negative and disappointing; there is a number of confounders/limitations:
1. There were differences in the weekly dose of paricalcitol given to the two groups with control group receiving a significantly higher dose. So, the marginal benefit on secondary endpoint ssuch as aortic calcifications mat be due to such difference in vitamin D sterols.
2. Of the 360 patients randomised only 280 completed the study (22% drop out!?); Efficay analysis was per protocol and did not include the whole randomised set of patients: only 235!?. I suspect a full analysis set would have made the results even more insignificant!
3. The duration of the study (1 year) is far too short to show significant changes in cardiac or aortic calcification. I would have expected a longer observation time such as 3 years.
4. This study does not address any hard clinical endpoint such as morbidity, MACEs or mortality?!
One could argue that it is a badly designed and overambitious study that led to insignificant results. It therefore doesn't answer the question of whether Cinacalcet offers a CVD therapeutic advantage.
The ongoing Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) study may provide clinicians with more useful information.