User blog: Meguid El Nahas
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.
I attended two plenary lectures:
The first by prof David Sacks on tolerance in renal transplantation. He highlighted the joruney related to research into induction of tolerance in recipients of allografts by T cell depletion followed by induction of chimerism through dual bone marrow an dkidney transplantationb. T cell depletion by using ATG seemed to deplete peripheral T cells but not those in lymph nodes or in the Thymus. So additional thymus irradiation may be needed. Also, T cell depletion alonbe may not be enough so additional B cell depletion with an anti-CD20 monoclonal antibody (Rituximab) may be necessary. Ultimately, such tolerance induction through chimerism has not been fully successful. He went on to discuss xenografting as an alternative to tolerance induction by chimerism. One of many problems with pig xenografting is that human develop anti-GAL antibodies that lead to hyperactute rejection. Advances have been made with transplantation of organs from pigs knock out to GAL making them more acceptable to humans. Also, chimerism with bone marrow + kidneys from pigs or kidneys + thymus (the thymus engrafted unde3r the renal capsule before transplantation) may improve outcomes. I personally don't see this research going anywhere; these researchers have been making these promising noises for the last 20 years to no avail...?! Better pharmacological induction of tolerance and better use of immunosuppressive agents is more likely to yield results in the short term. Early use of CNI but also early discontinuation of these agents and their replacement by less nephrotoxic agents may be a step in the right direction, providing alternate immunosuppression is effective with minimal side effects.
A truly spectacular lecture was given by Professor Douglas Wallace (Pennsylvania, USA) on mitochondrial disease and mtDNA mutations and their anthropological as well as medical implications. Professor Wallace explained hwo the mitochondria (an itracellular organelle/bacteria) invaded a eukariotic cells some 2 billion years ago during our evolution to produce this hybrid and symbiotic cell that we are made of. Consequently, we have the nuclear DNA but also the bacterial mitochondria DNA (mtDNA). He highlighted the key role in energy generation undertaken by the mitochondria; the main source of energy in power in our cells and in our body. He also showed how different capacity to generate or conserve energy in relation to intake (sugar/carbohydrates consumption) have evolved to adapt organisms and humans to live in different geographical parts of our planets. mtDNA can very accuraetly track human migration out of Africa and into the rest of the world with differing energy and mitochondrial phenotypes arising from the environment into which humans migrated. The mutation rate of mtDNA is 10 times higher than that of nuclear DNA because the mitochonderia lack protective histones and protective repair mechanisms. Kidney cells participate in many nergy-rich functions thus making the kidnye particularly suscpetible to mitochondrial damage and related disease. Professor Wallace pointed out to the huge nmber of diseases including common entities susch as hypertension and diabetes that may be influenced by mtDNA mutations; hypertension and its link to inflammtion and atherosclerosis; perhaps not consequential but linked to a mtDNA mutations, similarly diabetes mellitus and nephropathy; perhaps a mtDNA mutation predisposing to both. So increased awareness of this cellular/mitochondrial genome compared to the nuclear one may unravel the secret of many conditions not fully explained by nuclear genes mutations.
Jungraithmayr and colleagues in the March issue of JASN report the interesting observation that patients with FSGS and a SNP mutation in the NPHS2 gene coding for the podocyte protein (podocin) seem somewhat protected from NS and FSGS recurrence after renal transplantation compared to a recurrence rate of 48% in those without the mutations. This is of considerable interest as the recurrence rate and graft loss in FSGS recipients of renal allograft is high (around 30-40%) with a limited number of known predicotrs of recurrence. It is clear that those with a recurrence in a first graft are at higher risk of recurrence in the second. Other factors are more controversial; such as young age at transplantation, a rapid decline in CKD before transplantation etc... So this paper adds a useful predictor suggesting that the recipient should be screened for NPHS2 mutations (protective) but also that the donor to a mutation positive recipient should also be screened. Of note others (Bertelli et al. 2003) found an equal recurrence rate in geneitc versus non-genetic FSGS. Clearly, the debate and investigations continue.