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.
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.
Renal Genetics: From Elitist Science to Clinically Practical and Relevant
A special issue has been Published by Nephron on Advances in Renal genetics in April 2011. Considerable advances have been made in recent years in identification of genes linked to the predisposition as well as progression of kidney diseases. This has translated to considerable clinical advances in understanding of CKD, prognosis and even management.
Genetics of CKD 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.
Albert Ong and Olivier Devuyst explore the integration of genetic knowledge into clinical practice in ADPKD. They use PKD as an example of translation of genetic knowledge to clinical practice and new treatments is most informative. Initially linkages were made between ADPKD and chromosomes 16 (PKD1) and 4 (PKD2). Soon it became apparent that these genes are linked to the coding of two key proteins; polycystins 1 and 2. Subsequently, the physiology and pathophysiology of these molecules became better understood.; polycystin1 being a large complex membrane receptor-like protein while polycystin2 resembling a non-selective calcium channel protein. Genetic abnormalities of these proteins predispose through a second-hit +/- modifiers to cysts formation in susceptible individuals through stimulation of intra-cellular transduction pathways involving a rise in cAMP as well as the activation of mTOR. This has led to a number of clinical trials aimed at reducing intracellular cAMP through a vasopressin type2 receptor antagonist (Tolvaptan: The TEMPO trial) or through mTOR inhibition by Sirolimus or Everolimus as well as a long acting Somatostatin analogue (octreotide). So far the latter studies have shown some effects on cysts size and kidney volume progression but little impact on the progression of renal insufficiency.
McCarthy and Saleem review advances in the genetics of nephrotic syndrome (NS). They provide a comprehensive list of genetic abnormalities linked to NS; these are invariably linked to podocytes associated proteins. These mutations impact on the integrity of the podocytes, slit diaphragm and filtration barrier causing NS and progressive FSGS. Mutations predisposing to childhood NS include that of NPHS1 associated with Nephrin abnormalities and Finnish type NS, NPHS2 associated with podocin abnormalities and familial FSGS and WT1 mutations associated with Wilm’s tumors. In adult NS, mutations of ACTN4 linked to actinin, CD2AP and TRPC6 cause autosomal dominant FSGS. A growing literature advocates the screening of children with SRNS for mutations in the genes encoding nephrin, podocin and WT1 in order to direct clinical management. Also screening for genetic polymorphism of, for instance, NPHS1 has been put forward to guide transplantation in FSGS and chances of recurrence.
Bleyer, Zivna and Kmoch comment on Uromodulin-associated kidney disease. Mutations of the gene encoding uromodulin [UMOD] (Tamm-Horsfall protein) are responsible for an autosomal dominant inheritance of hyperuricemia and chronic, progressive, tubulointerstitial disease leading to CKD from 3rd to7th decade of life. Those affected develop severe hyperuricemia in childhood and gout in their teens. UMAK (uromodulin-associate kidney disease) will undoubtedly become increasingly recognised.
Genetics of renal transplantation by Bernd Kruger and Bernd Schroppel. The authors review evidence derived from genomic wide associations studies (GWAS) on genetic variations/mutations and their impact on the different stages of renal transplantation. For Delayed Graft Function (DGF), they point to the key role of the Toll-Like Receptor network, in particular mutations of TLR4 and increased risk of DGF. Genes associated with acute rejection include those coding for TLR4, CCR5, THN-alpha and IL-6. VEGF mutations have been associated with improved long term graft survival whilst MDR1 polymorphism has been linked to chronic allograft injury. Pharmacogenetics and its understanding of the metabolism of CNIs and MMF are increasingly relevant to the management and dosing of these immunosuppressive agents.
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
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.