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.
Professor Neil Powe (USA) discussed the issue of healthcare disparities and inequalities in the USA where ethnic minorities have worse outcomes than Caucasians. he noted that by 2050, whites would be in a minority (<50%) in the USA; this already the case in certain cities such as San Francisco where Hispanics, Asians and African-Americans (AA) constitute the majority of the population. He reviewed the poorer outcomes of AA in CKD and higher prevalence in ESRD where they usually start RRT at a younger age than Whites. But he explained that such difference depends on modifiable factors and some such as genetic predisposition (MYH9 and APOL1 genetic polymorphism) which are not modifiable. The modifiable include low socio-economic status, lifestyle, access to care and care quality.
For instance most Black patients with CKD are seen clinics and emergency rooms where they have no follow-ups as most don't have healthcare insurance. Whites on the other hand tend to be referred early to private healthcare facilities where they are treated and followed up. It is hoped that the new Healthcare system in the US may address some of these inequalities. If changes are allowed to go through and be implemented. Of note, the latest US government guidelines on CKD referral stress that patients should be referred "early" at CKD stages 4 and 5.....If that is early referral, I don't know what is late; probably the current situtation of more than 80% referred with GFR<20 within 3 months from starting RRT...?! Some talk about early detection and prevention of CKD in the US. Perhaps a place to start is to make sure that all those with CKD3 and proteinuria are detected and properly referred and treated...!!!
Plenary lecture by Professor David Salant (USA) highlighting his discovery of the relevance of autoantibodies against the podocyte antigen M-type phospholipase A2 R, present on podocytes, to the pathogenesis of idiopathic membranous nephropathy (iMN) (Beck et al. 2009). These autoantiboides are specific to iMN and are not detectable in secondary forms of MN. They appear in high titres during the active phase of iMN with nephrotic syndrome and decrease considerably during treatment and remission; they reappear when the NS relapses. Up to 82% of patients with iMN have anti-PLA2R antibodies. Autoantibodies titre correlate with the severity of proteinuria in these patients. More recent data also showed a SNP mutation in the gene coding for PLA2R on chromosome 2 in patients with iMN, this along with another mutation on HLA DQ1A (Stanescu et al. 2011).
Of interest, another antibody directed against neutral endopeptidase (NEP) has been described in iMN (Professor P Ronco, Paris, France). This was observed in a woman deficient in this enzyme who was sensitised during a first pregancy and transmitted the antibody to her second born leading to a neonatal membranous nephropathy and nephrotic syndrome. Professor salant claimed that this antibody is seldom found in adults with iMN; I wonder whether Professor Ronco would have a different take on the whole story???!!! More research is also needed to determine what triggers the autoimmunity directed against podocytes PLA2R.
Professor Ricardo Correa-Rotter from Mexico reviwed the issue of very high CKD and ESRD in central America. MesoAmerican Endemic Nephropathy. This has been attributed to a number of factors but more recently to involvements of those working in mining as well as farmers and agricultural workers dealing with sugar cane. The evidence for incriminating sugar cane is very limited (Torres et al, AJKD 2010). But a high incidence of CKD/ESRD in countries like El Salvador and Nicaragua is clearly observed with clinical features of chronic tubulointerstitial disease; small kidneys, low GFR and minimal proteinuria. Enviromental factors including soil pollution as well as exposure to minerals and heavy metals could be implicated. Clearly, this is an issue that warrants regional attention and research. It is reminiscent of the Balkan Endemic Nephropathy that was eventually attributed to contamination of soil and wheat by aristolochic acid. Aristolochic Associate Nephropathy (AAN) is not confined to the Balkans herbal remedies and intake contaminated with aristolochic acid can be seen all over the world and has been implicated in the very high incidence of CKD in Taiwan where herbal Mu Tong consumption contains AA. The latter does not seem to be involved in Central America.
Second plenary lecture by Prof Wendy Hoy (Australia) on the nephrological plight of Australian aborigines.
Native australians are amongst the most deprived populations in the world. They suffer high morbidity and mortality rates. The incidence of ESRD in some of these populations exceeds 1000pmp/year!
Prof Hoy argues that the high ioncidence and prevalence of CKD and ESRD in these populations is due to a number of factors: Multi-hits:
Low birth weight and reduced nephrons number, later life hypertension, obesity and diabetes as well as repeated bouts of post-infectious glomerulonephritis. They express a strong association between albuminuria and all cause as well as CVD mortality. This fits with observations made in other populations stressing the links between poverty, inflammtion/infections, CVD and albuminuria. The latter is most likely to be a manifestations of the formers. She also reminded the audience of the association between chronic H. Pylori infections and the risk of microalbuminuria. Once more, albuminuria seems to be a marker of a number of underlying infectious, inflammatory as well as CV diseases.