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by Meguid El Nahas - Sunday, 10 April 2011, 1:38 AM
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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. 

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Picture of Meguid El Nahas
by Meguid El Nahas - Saturday, 9 April 2011, 2:59 PM
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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.

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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.  

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by Arif Khwaja - Monday, 4 April 2011, 9:36 AM
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Data from the DAC Graft Trial, in which 649 patients were assigned to either placebo or twice-daily extended-release dipyridamole (200 mg) and Aspirin (ASA) (25 mg; ERDP/ASA) after AV graft placement suggested that ERDP/ASA lead to a very modest, but significant reduction in graft thrombosis/need for graft angioplasty. Now a recent analyis of this study suggests compared outcomes associated with ASA  use across and within randomized groups assigned to either ERDP/ASA or placebo. Thee key finding was that ERDP/ASA was no more effective than ASA onlone in preventing graft thrombosis/angioplasty. The message therefore is that Aspirin should be used in all patients with grafts but the benefits are modest. Vascular access remains a critical problem on dialysis units - share your thoughts. See accompanying editorial in JASN (http://www.ncbi.nlm.nih.gov/pubmed/21415154)

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by Arif Khwaja - Thursday, 31 March 2011, 9:57 AM
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A very thoughtful piece by Professor Chapman from Sydney, Australia in this months AJT reviewing the literature around CNI nephrotoxicity ( see here ) Professor Chapman confirms the notion that whilst CNIs reduce the incidence of acute rejection the long term impact on graft function is significant especially in grafts older than 5 years. Furthermore nephrotoxoicity seems to be dose related. Attempts to manage immunsuppresion without CNIs have been variable. At present CNIs remain a 'cant live with you and cant live without you' medication in transplantation with CNI nephrotoxicity competing with other causes of longterm graft loss such as chronic transplant glomerulopathy.

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by Arif Khwaja - Monday, 21 March 2011, 12:50 PM
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There is an interesting article in this months cJASN analysing the effect of using the CKD-EPI formula (rather than the MDRD equation) on eGFR calculation and therefore CKD diagnosis. The CKD-EPI formula is believed to be more accurate than MDRD when the eGFR>60mls/min. Interestingly in an analysis of 53,759 patients with CKD 3-5 the authors compared the effect of CKD-EPI and MDRD equations on CKD diagnosis. Interestingly there was a 35% decrease in the diagnosis of CKD among patients 90 years. Women, non-African Americans, nondiabetics, and obese patients were less likely to be classified on the basis of CKD-EPI. in a way the research highlights the problem of 'disease-labelling' that has occured as a result of the CKD staging system and further highlights the paradox of differentiating CKD 1 and 2 on the basis of the MDRD equation when this equation is known to be inaccurate when the eGFR>60mls/min. See Implications of the CKD-EPI GFR Estimation Equation in Clinical Practice in this months cJASN. share your thoughts on the merits or otherwise of the CKD classification system and MDRD equation.

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by Arif Khwaja - Thursday, 17 March 2011, 4:01 PM
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Much of the growth in the UK in transplantation has come from increased use of liver donors. Increasingly elderly donors are being used. A single centre retrospective cohort study from Ontario, Canada suggests that at 4 years of follow up there was no difference in graft survival between elderly donors and deceased donors. However baseline eGFR was a worrying 13mls/min lower in th older donor group. Clearly longer follow up is required before a proper risk assessment can be made of the risks of using elderly live donors - till then it would be sensible to use elderly donors for elderly recipients. See this months AJT - http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2011.03442.x/abstract
[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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The paper in the Lancet (2011;377, 721) by Navarra et al. reports the outcome of a large, phase 3, clinical trial on the use of Belimumab (a human monoclonal antibody that blocks BLyS (B-lymphocyte stimulator) activity. Increased activity of B lymphocytes and their products including BLyS are known to be increased in active SLE. This trial shows that blocking BLyS activity through infusion of Belimumab (1m/kg or 10 mg/kg) for up to 48 weeks, along with standard care,  leads to decreased SLE activity indices. Belimumab at 10mg/kg proved significantly more effective than standard care alone. Clearly Belimumab, which has recently been approved by the FDA for the treatment of SLE, will add a new therapeutic option to those currently available including Rituximab (anti-CD20) that also acts on B lymphocytes and their depletion (Rituximab treatment for vasculitis. Jayne D. Clin J Am Soc Nephrol. 2010 Aug;5(8):1359-62).

[ Modified: Thursday, 1 January 1970, 1:00 AM ]
 
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In this paper by Seliger and colleagues from Baltimore USA, the authors report an increased risk of stroke in CKD (mainly 3) who are using ESAs. This observational study of 12,426  patients individuals confirmed the previous observation made in diabetic CKD patients treated with Darbopoietin alpha (the TREAT study).  The current report highlights the fact that high dose of ESAs are associated with significantly increased risk of stroke in patients with a history of cancer (under active treatment) and those with a previous history of stroke. A posthoc analysis of the TREAT study showed increased risk in those who failed to respond to Darbopoietin raising the suspicion that it may be the high dose of ESA rather than the acheived Hb level that is associated with increased complications; strokes and cancer. The observation by Seliger and colleagues reinforces the FDA recommendations that Darbepoietin alpha and epoietin alpha should be prescribed at the lowest possible dose to achieve the lowest Hb level. Whether these agents should be used at all in patients with a history of cancer or stroke is very much questionable.  

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by Meguid El Nahas - Friday, 11 March 2011, 8:12 PM
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Albumin:Creatinine Ratio - A Flawed Measure. The Merits of Estimated Albuminuria Reporting (Tim Ellam, Sheffield; Nephron Clin Pract 2011;118:c324-c330) Ellam presents the Opposite View to the fact that urine Albumin:Creatinine Ratio (ACR) is a reliable indicator of urinary albumin excretion. He reminds the reader of the limitations of this calculation and the fact that confounders of urine creatinine excretion are seldom considered. For instance, a low urinary excretion of creatinine may reflect muscle wasting and ill health, thus raising ACR in the absence of changes in urine albumin excretion. Low urinary creatinine excretion, like that of albumin, is known to be associated with CVD and increased mortality, thus confoundingthe prognostic significance of a raised ACR. The author argues that urinary creatinine excretion needs to be adjusted for key confounders such as age, gender, race and muscle mass. This, in fact, has been recently suggested by Ix and colleagues (Clin J Am Soc Nephrol 2011;6:184-191) who have put forward urine creatinine excretion formulas that adjust for gender and age. So beware Nephrologists when you use ACR/PCR to bear in mind such important confounders; after all, they are the same that justified formulations that include age, gender and race for adjustments in serum creatinine measurements and eGFR calculations.

 

Proteinuria in Type 2 Diabetic Patients with Renal Impairment: The Changing Face of Diabetic Nephropathy (Packham and colleagues on behalf of the collaborative study group, Melbourne, Chicago, Ill., Nashville, Tenn., and Groningen; Nephron Clin Pract 2011;118:c331-c338) The authors note that over one fifth of patients with type 2 diabetic nephropathy and established renal impairment have proteinuria levels below those traditionally associated with overt nephropathy. They attribute this to the likelihood that these patients are receiving ACEis, ARBs, or a combination of both. Another important consideration is that the type of patients with so-called diabetic nephropathy has been changing since the early days of description of the natural history of diabetic nephropathy by Mogensen et al. (Scand J Clin Lab Invest 1976;36:383-388) in the seventies!? Those were predominantly younger patients with progressive nephropathy and heavy proteinuria, which was the rationale behind ACEis. Nowadays, the patients we see are older, with type2 diabetes mellitus and often suffer from longstanding hypertension preceding the diagnosis of diabetes mellitus by years. They often have diffuse and severe atherosclerosis with consequent renovascular disease and ischemic nephropathy. Proteinuria in these patients is mild to moderate and progression slow. ACEi, ARB or a combination of both is likely to be harmful (see results of the ONTARGET study, Lancet 2008;372:547-553). It is high time Nephrologists reconsider the use of ACEis/ARBs in such patients. Some have even stopped them in advanced nephropathy in patients with diabetes to good effects (Ahmed et al., Nephrol Dial Transplant 2010;25:3977-3982).

 

Treatment of HIV-Associated Nephropathies (Elewa and colleagues, Cairo, Porto Alegre and Rochester, Minn.; Nephron Clin Pract 2011;118:c346-c354) This review highlights a number of new and important issues including the perceived increased prevalence of CKD in HIV-infected individuals and the association with known predisposing factors such as the black race, low CD4 count, high HIV RNA copies level, but also new and interesting risk factors such as a family history of CKD and the presence of diabetes mellitus, hypertension or hepatitis C co-infection. In emerging countries/regions where HIV prevalence is high, CKD is likely to result from the triple hit of poverty, infections and westernization with increased incidence of hypertension and diabetes. Also, additional environmental or inherited factors may be necessary to initiate human HIVAN. Elewa and his colleagues remind us that the evidence upon which HAART treatment recommendations is based is weak. A recent search involving the Cochrane Central Register of Controlled Trials (CENTRAL) found no RCT-based evidence upon which to base guidelines for the treatment of HIVAN. Clearly, more research is needed to understand HIVAN, its epidemiology, classification and treatment.

 

Metformin: The Safest Hypoglycaemic Agent in Chronic Kidney Disease (Nye and  Herrington, Oxford; Nephron Clin Pract 2011;118:c380-c383). The authors remind the reader that lactic acidosis following treatment of patients with diabetic nephropathy with metformin is rare and unpredictable. It is usually precipitated by an additional acute condition predisposing to tissue hypoxia. Metformin is an effective oral agent in the treatment of type 2 diabetes and in the prevention of its complications, particularly in overweight patients. Although a number of reports have been published suggesting that metformin is a cause of lactic acidosis, a systematic review of all the available trials and cohort studies does not support this. In fact, the evidence suggests that type 2 diabetes mellitus itself may be associated with reduced lactate clearance and may be a more important risk factor for lactic acidosis than metformin.

We should be cautious not to deprive our diabetic patients from an excellent drug on the basis of a poor understanding of the published literature. This is one more proof that we seldom read the evidence upon which we base our practices; withdrawal of metformin in patients with a serum creatinine>150 micromol/l!? One would hope that those who draft guidelines do...?!

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