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.
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.
A group of researchers from the Royal Free, London, headed by Prof Paul Griffiths have published the result of a phase 2, proof of concept, study on the efficacy of a cytomegalovirus glycoprotein-B protein vaccine in recipients of transplanted kidneys and livers. they noted an increased antibody titre in both previously seronegative and seropositive patients. In those who developed viremia after transplantation, the severity of the viremia correlated inversely with the antibody titre. Also, in those who were seronegative and received a seropositive transplanted organ, the number of days of ganciclovir was significantly reduced. This observation highlight teh role of humoral immunity in resistance to CMV infection; it goes some way to explain the beneficial effect observed in some patients with severe CMV infections who respond to high dose intravenous immunoglubulin (IVIG). Confirmation of the efficacy of such an antibody would be a significant advance in the management of seronegative patients on the transplant waiting list.
This genetic study relying of Genome wide association study (GWAS) showed an association between a missense variant in the CUBN gene, which encodes cubulin, and both albuminuria. This association was noted in the general population independently of diabetes. Cubulin, or vitamin B12 intrinsic factor, is also expressed on the brush border of the proximal tubules. Along with megalin (LRP2) and amnionless (AMN), cubulin is a key factor in receptor-mediated endocytosis of albumin and low molecular weight proteins. The association of cubulin and megalin to for a receptor complex is key to teh proximal tubules reabsorption of albumin. Experimental and human mutations of the cubulin gene (CUBN) is associated with albuminuria. Of interest, in diabetic nephropathy, shedding of cubulin an dmegalin in the urine is associated with microalbuminuria. These studies emphasise two important points:
1. The important contribution of tubular reabsorption of albumin to the extent of albuminuria.
2. The role of cubulin and megalin in albuminuria control.
3. The association of albuminuria with cubulin/megalin abnormalities.
A very interesting lecture by Professor Caroline Fox (USA) on the genetics of hypertension and CKD. Data derived from a number of genetic stduies consortia, including the CKD Gen, CHARGE and Global BP Gen, has explored gentic associations with hypertension. A number of single nucleotide polymorphism (SNP) have been identified linked to systolic as well as diastolic hypertension. In fact, 16 SNPs have been linked to raised BP. Of those, one of the most exciting is SNPs in the UROMOD (Uromodulin/Tamm Horsfall protein) gene. Such association was noted with hypertension independently from eGFR. Clearly, more investigations are underway to determine the nature of changes in urinary Uromodulin in relation to the pathogenesis of hypertension and possibly CKD.
Another lecture by Prof Rashad Barsoum detailed how bacterial toxins affect the kidneys. He described how bacterial endotoxins and exotoxins affect the kidneys. Endotoxins appear to have glomerular as well as tubular recpetors called Toll-Like receptors (TLR). A number of TLRs, 1, 2 4 etc...are present on the surface of kidney cells, bind endotoxins and lead to activation of intracellular inflammtory mediators. Exotoxins on the other hand seem to bind specific receptors present on the surface of renal vascular endothelium as it is the case with those linked to HUS. He stressed that direct bacterial toxin injury plays a major role in thepathogenesis o fAKI during systemic bacterial infections.
Other causes of AKI include changes in renal hemodynamics, volume depletion, hemolysis, rhabdomyolysis, immunological responses to bacterial antigens, bacterial antigens such as Ding and LAMP-2 causing antigen mimicry, superantigen and finally the toxicity of the antibiotics used to treat bacterial infections.