Site blog

Picture of Arif Khwaja
by Arif Khwaja - Monday, 15 August 2011, 8:53 PM
Anyone in the world

A couple of interesting hypothesis-generating studies have been published recently suggesting that Allopurinol may have a beneficial effect on endothelial function in CKD.  Elevated uric acid levels have been associated with endothelial dysfunction in humans and experimental animal data suggests that uric acid may elevate blood pressure via a number of mechanisms including oxidative stress, endothelial dysfunction and activation of the renin-angiotensin system. Rick Johnson and colleagues have postulated that dietary fructose leads to chronic state of ATP depletion that ultimately results in hyperuricaemia and have hypothesized that Allopurinol may have BP-lowering effects

In a recent study from Dundee, Kao and colleagues (see http://jasn.asnjournals.org/content/22/7/1382.long) performed a randomized, double-blind, placebo-controlled study in patients with stage 3 CKD and left ventricular hypertrophy (LVH). 67 subjects were randomized to allopurinol at 300 mg/dy or placebo for 9 months. In this study allopurinol resulted in a small but significant reduction in LV mass index (as assessed by cardiac MRI) even after correcting for age, blood pressure and baseline LV mass index. There were improvements in endothelial function as measured by flow mediated dilatation and arterial compliance and arterial wave reflection as measured by a reduced augmentation index. The authors conclude that the mechanism by which LVH was reduced was by the impact of allopurinol on arterial afterload – indeed this is the first study to show regression of LV mass index independently of blood pressure.

In the second study, Johnson and colleagues from Ankara (see http://cjasn.asnjournals.org/content/6/8/1887.long ) took 30 patients with normal kidney function and asymptomatic hypeuricaemia were randomized to 4 months treatment with allopurinol 300g/day. This group was compared to 30 hyperuricaemic controls and 37 normouricaemic controls. Interestingly in this study Allopurinol t resulted in a decrease in systolic BP (but not diastolic), an increase in flow mediated dilatation, and an increase in eGFR compared with baseline. Kidney function was effectively normal (eGFR assessed by cockroft-gault) but the blood pressure was rigorously evaluated using 24 hour blood pressure monitoring suggesting the effect was real. Why blood pressure fell in this study but not in the Kao study may be due to a number of reasons including small sample size and possibly differential effect of allopurinol depending on kidney function.

Either way both studies generate interesting data that suggest that allopurinol is a cheap therapeutic that warrants further investigation in CKD.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]

Comments

     
    Picture of Meguid El Nahas
    by Meguid El Nahas - Monday, 15 August 2011, 2:56 PM
    Anyone in the world

    An interesting controversy and debate is taking place in the Lancet relating to the impact of dietary salt diction on cardiovascular disease (CVD) outcomes. A recent Cochrane review by Taylor and colleagues based on a meta-analysis of 7 trials with 6250 individual implied that dietary salt reduction did not reduce CVD or impact on mortality. This publication led to headlines implying that salt reduction is unnecessary and unjustified. A rebuttal of this publication appears this month in the Lancet by He and MacGregor who criticize the first analysis and reanalyses the data by including all the patients and combining normotensive as well as hypertensive individuals in the new analysis. This draw different conclusions; they show that a dietary salt reduction leads to a significant reduction in CVD events by 20% but no significant reduction in all causes mortality. I would side on He and McGregor side and remind readers that there a large body of evidence in favour of salt reduction for the prevention and treatment of hypertension; hypertension is one of the major causes of CVD morbidity and mortality. The WHO recommends salt reduction as one of the top priorities along with smoking cessation and fighting obesity to reduce the rising tide of non-communicable disease. This debate in the Lancet highlights once more that different results and conclusions can be obtained from the analysis of a single dataset; it all depends on the investigators bias as well as the statistical methods applied. Beware, of the manipulation of statistics to prove a point. Investigators arvall too often i cloned to call statistics as an ally to prove their Pints. Truth is often hostage to statistical analyses...!?

    References:

    Taylor et al. Reduced dietary salt for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;7:CD 009217 
    He and MacGregor. Salt reduction lowers cardiovascular risk: meta-analysis of outcome trials. Lancet 2011:378:380-82.

    [ Modified: Thursday, 1 January 1970, 1:00 AM ]

    Comments

       
      Picture of Meguid El Nahas
      by Meguid El Nahas - Wednesday, 10 August 2011, 8:50 AM
      Anyone in the world

      Circulating urokinase receptor as a cause of focal segmental

       

       

      (
      Nature Medicine
      17,
      952–960, 2
      011)
       

      For Review read: McCarthy ET, Sharma M, Savin VJ.Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010 Nov;5(11):2115-21.

      [ Modified: Thursday, 1 January 1970, 1:00 AM ]

      Comments

         
        Picture of Denise Smith
        by Denise Smith - Monday, 8 August 2011, 11:39 AM
        Anyone in the world

        Drug-Induced Nephrotoxicity in Inflammatory Bowel Disease(A.K. Oikonomou and colleagues, Larissa; Nephron Clin Pract 2011;119:c89-c96) The authors review the renal complications of treatment of inflammatory bowel disease (IBD). Whilst most nephrologists would be familiar with the risks associated with short- and long-term use of 5-aminosalycylates (5-ASAs) containing compounds such as sulphasalazine and mesalazine, they need to become aware of the potential nephrotoxicity of newer therapies. Patients not receiving treatment should be monitored annually. It would be advisable to monitor renal function at regular intervals (every 3 months) after initiation of 5-ASAs. Monitoring should include urine albumin as well as serum creatinine measurement and eGFR. Caution should be exerted in interpreting these results. Microalbuminuria has been associated with disease flare-ups and is often transient. eGFR levels may be confounded in patients with IBD and wasting by sarcopenia and associated decreased serum creatinine levels/falsely raised eGFR. Most eGFR formulations correct poorly for changes in body muscle mass. Overall, close monitoring of renal function in patients with IBD is warranted probably through closer coordination between gastroenterologists and nephrologists. Also, improved education of general physicians caring for these patients relating to monitoring of renal function is warranted.

         

        Post-Parathyroidectomy (PTx) Parathyroid Hormone Levels: The Impact on Patient Survival - A Single-Centre Study in a Stage 5 Chronic Kidney Disease Population(J. Fotheringham and colleagues, Sheffield; Nephron Clin Pract 2011;c119:113-c120) This paper reviews a single-centre experience with the impact of PTx on survival. 235 stage 5 CKD patients who underwent PTx between 1990 and 2007 were identified, and iPTH levels following surgery were used to divide patients according to the quartile of maximum iPTH recovery during the 5 years following PTx. Adjusting for age, time on renal replacement therapy and the presence of diabetes identified an increased hazard for mortality of 2.459 in the quartile of lowest iPTH levels after PTx. Thus, an association between the lowest quartile of iPTH recovery in the 5 years following PTx and poorer patient survival was found. This raises concern over post-PTx low PTH levels as this is increasingly recognised as a risk factor for vascular calcifications in the face of adynamic bones unable to incorporate calcium supplements. Careful subtotal PTx or total PTx with re-implantation of a small amount of parathyroid tissue are recommended to avoid excessive PTH depletion. Undoubtedly, the risk of excessive calcium and vitamin D supplementation in terms of vascular calcifications and mortality is higher in patients with low PTH levels.

         

        Treatment of Hepatitis C-Mediated Glomerular Disease(A.M. Sandri and colleagues, Ponto Alegre, Cairo and Rochester, Minn.; Nephron Clin Pract 2011;119:c121-c130) The authors describe the broad spectrum of HCV-associated renal disease, which is traditionally attributed to the immune response to the virus. While immune complexes and cryoglobulins are the principal causes of renal disease as well as many associated extrarenal manifestations of HCV infection, several observations suggest that other mechanisms may be involved. A direct cytopathic effect has been blamed for the pathogenesis of HCV-associated interstitial nephritis as viral replication was documented in tubule cells. Also, a possible cytopathic effect of the virus on podocytes has been postulated to explain the occurrence of FSGS in some patients with HCV disease. Further research in this area may lead to considerable strategic changes in our understanding of the disease and its treatment targets. In the meanwhile, underlying HCV should be considered as a possible underlying aetiology to a range of glomerulonephritis in emerging countries.

         

        Acute Kidney Injury Caused by Bothrops Snake Venom(L. Rodrigues Sgrignolli and colleagues, Sao Jose do Rio Preto; Nephron Clin Pract 2011;119:c131-c137) The authors highlight the issue of Bothrops snakebite nephrotoxicity with emphasis on Brazil. Envenoming by snakebites is an important public health concern in tropical and subtropical regions. According to the WHO, in excess of 20,000 occur annually due to snakebites. Consequently, snakebites were added by the WHO in 2009 to the list of neglected tropical diseases. Whilst Brazil and Latin America are commonly affected, the highest numbers of envenoming are estimated to be in South Asia (121,000), followed by South-East Asia (111,000) and East Sub-Saharan Africa (43,000). Of interest, Papua New Guinea has one of the world's highest incidence rates of snakebites. The range of systemic and renal manifestations is well described in the minireview by Rodrigues Sgrignolli et al. Clearly, snakebite is an underestimated and ignored public health problem that causes considerable illness, death, and socioeconomic hardship to poor populations living in rural tropical regions of the globe. It is likely to be an additional cause of AKI and possibly CKD in the tropics along with poverty, infections and the growing impact of globalisation.

        [ Modified: Thursday, 1 January 1970, 1:00 AM ]

        Comments

           
          Picture of Meguid El Nahas
          by Meguid El Nahas - Tuesday, 2 August 2011, 10:54 AM
          Anyone in the world

          Dr Arif Khwaja wrote:

          Results from the ORION study are published in this months AJT. This study involved 469 de-novo standard risk allografts who were randomised to either

          1) Sirolimus and Tacrolimus aiming for Tacrolimus withdrawal at 3 months.

          2) Sirolimus +MMF

          3) Standard therapy with Tacrolimus and MMF.


          All groups got Daclizumab induction and steroids. Due to higher rate of rejection the MMF+Sirolimus arm was terminated early in the study. The primary endpoint was Nankivell GFR at 12 months and there was no difference between standard therapy (group 3) and CNI withdrawal in group 1. The CNI-withdrawal group did not have any advantage over standard therapy with tacrolimus and MMF: patient (97.0% vs. 94.4%) and graft survival (95.4% vs. 88.5%), renal function (62.0% vs. 59.1 mL/min), rejection prophylaxis (12.3% vs. 17.4% biopsy-proven rejections), discontinuations (35.2% vs. 65.1%) representing overall tolerability and adverse events such as oedema (36.7% vs. 51.3%), anaemia (36.0% vs. 40.8%), hyperlipidaemia (20.1% vs. 36.8%), proteinuria (6.5% vs. 11.2%) and wound healing disorders including lymphoceles (14.4% vs.32.8%). Dyslipidaemia and thrombocytopenia and acne were significantly worse in the CNI withdrawal group whilst other secondary outcomes such as proteinuria whilst worse in the CNI withdrawal group did not reach significance.

          Overall the study is consistent with the prevailing belief that Tacrolimus and MMF should be the standard therapy in renal transplantation at the moment both in terms of outcomes and tolerability. whether there is a role for switching from CNI to Sirolimus at a later date is not clear and is an issue that is being explored by the 3C Study in the UK which is evaluating the role of Alemtuzumab and steroid avoidance followed by switching from Tacrolimus to Sirolimus at 6 months. For the time being the role of Sirolimus in transplant immunosuppression remains unclear. (see Flechner SM et al. American Journal of Transplantation. Volume 11, Issue 8, pages 1633–1644, August 2011)

           
          [ Modified: Thursday, 1 January 1970, 1:00 AM ]

          Comments

             
            Picture of Meguid El Nahas
            by Meguid El Nahas - Sunday, 31 July 2011, 4:15 PM
            Anyone in the world

             

            Posted by Dr Mostapha HabibAllah
            CDC recommendations for prevention and screening of HIV infection in prospective living organ donors:
            • All prospective living organ donors should have their initial serologic tests for HIV supplemented with repeat testing with a combination
            of an HIV serologic test and HIV NAT as close to the time of organ donation as feasible logistically, but no longer than 7 days preceding
            organ donation.
            • All living donors should be advised of their obligation to avoid behaviors that would place them at risk for acquiring HIV infection before
            transplant surgery.
            • For living donors with a history of high-risk behaviors (e.g., high-risk sexual activity or injection drug use) identifi ed during evaluation, individualized
            counseling and a detailed discussion of specifi c strategies to avoid high-risk behaviors should be provided.
            • Consistent with current policy, documents and counseling information used in the recipient consent process should explain that organ
            transplantation carries a risk for transmission of HIV and other pathogens because no available testing can completely eliminate the risk
            for transmission of all pathogens.
            [ Modified: Thursday, 1 January 1970, 1:00 AM ]

            Comments

               
              Picture of Meguid El Nahas
              by Meguid El Nahas - Sunday, 31 July 2011, 1:15 PM
              Anyone in the world

               

              [ Modified: Thursday, 1 January 1970, 1:00 AM ]

              Comments

                 
                Anyone in the world

                Results from the ORION study are published in this months AJT. This study involved 469 de-novo standard risk allografts who were randomised to either

                1) Sirolimus and Tacrolimus aiming for Tacrolimus withdrawal at 3 months.

                2) Sirolimus +MMF

                3) Standard therapy with Tacrolimus and MMF.

                All groups got Daclizumab induction and steroids. Due to higher rate of rejection the MMF+Sirolimus arm was terminated early in the study. The primary endpoint was Nankivell GFR at 12 months and there was no difference between standard therapy (group 3) and CNI withdrawal in group 1. The CNI-withdrawal group did not have any advantage over standard therapy with tacrolimus and MMF: patient (97.0% vs. 94.4%) and graft survival (95.4% vs. 88.5%), renal function (62.0% vs. 59.1 mL/min), rejection prophylaxis (12.3% vs. 17.4% biopsy-proven rejections), discontinuations (35.2% vs. 65.1%) representing overall tolerability and adverse events such as oedema (36.7% vs. 51.3%), anaemia (36.0% vs. 40.8%), hyperlipidaemia (20.1% vs. 36.8%), proteinuria (6.5% vs. 11.2%) and wound healing disorders including lymphoceles (14.4% vs.32.8%). Dyslipidaemia and thrombocytopenia and acne were significantly worse in the CNI withdrawal group whilst other secondary outcomes such as proteinuria whilst worse in the CNI withdrawal group did not reach significance.

                Overall the study is consistent with the prevailing belief that Tacrolimus and MMF should be the standard therapy in renal transplantation at the moment both in terms of outcomes and tolerability. whether there is a role for switching from CNI to Sirolimus at a later date is not clear and is an issue that is being explored by the 3C Study in the UK which is evaluating the role of Alemtuzumab and steroid avoidance followed by switching from Tacrolimus to Sirolimus at 6 months. For the time being the role of Sirolimus in transplant immunosuppression remains unclear. (see Flechner SM et al. American Journal of Transplantation. Volume 11, Issue 8, pages 1633–1644, August 2011)

                 

                [ Modified: Thursday, 1 January 1970, 1:00 AM ]

                Comments

                   
                  Picture of Meguid El Nahas
                  by Meguid El Nahas - Tuesday, 26 July 2011, 2:19 PM
                  Anyone in the world
                  A recently published article on IgG4-TIN was published (Raissian Y, Nasr SH, et al. Diagnosis of IgG4-Related Tubulointerstitial Nephritis. J Am Soc Nephrol 2011 Jul 22(7):1343 -52. The authors proposed diagnostic criteria that are divided into 4, namely: histological features (plasma cell rich-TIN with > 10 IgG4 + plasma cells/ hpf, TBM immune complex deposits on IF, Immunohistochemistry, and/or EM), radiological features (small peripheral low-arttenuation cortical nodules, round or wedge-shaped lesions, or diffuse patchy involvement), serological findings (elevated serum IgG4 or total IgG level or hypergammaglobulinemia), and other organ involvement (autoimmune pancreatitis, sclerosing cholangitis, inflammatory masses in any organ, sialadenitis, inflammatory aortic aneurysm, lung involvement, retroperitoneal fibrosis). Several important differential diagnoses included: "idiopathic hypocomplementemic TIN with extensive tubulointerstitial deposits," Sjogren's syndrome, and lupus nephritis. Similar to the previously recommended article (Saeki T, Nishi S, Imai N, Ito T, et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int.2010 Nov; 78:1016-23), the authors of this one also observed a decrease in serum creatinine in most patients treated with corticosteroids at one month follow up. Interestingly, some patients responded favorably (decreasing serum creatinine) to a treatment regimen combining prednisone anmd mycophenolate. Such steroid-responsiveness was observed even in those with fibrotic lesions, probably because of the 'patchy' distribution. It is important to be aware that such a disease entity exists, especially since it is quite responsive to corticosteroids. Dr Edgar Lerma
                  [ Modified: Thursday, 1 January 1970, 1:00 AM ]

                  Comments

                     
                    Anyone in the world

                    Another piece of the puzzle!

                    The rapidly increasing knowledge of the molecular basis of nephrotic syndrome (NS) continues to advance.

                    An interesting work by Heeringa et al, J Clin Invest. 2011;121(5):2013–2024, reporting a novel cause of SRNS that appears to respond to oral Coenzyme Q10 (CoQ10) supplementation.

                    CoQ10 is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ10 is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ10 supplementation. CoQ10 deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome.

                    Since the molecular cause of more than 80% of all cases of SRNS is unknown and treatment options have yet to be discovered, the authors performed total genome search for linkage to identify further causative recessive genes. They identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Patients manifested with proteinuria at a median age of 1.2 years (range, 0.2–6.4 years) and progressed to ESRF by a median age of 1.7 years (range, 0.4–9.3 years). Renal biopsy revealed FSGS in all cases except for one patient with diffuse mesangial sclerosis (DMS).

                    Whereas most other forms of monogenic childhood NS are characterized by a lack of response to therapy, the identification by mutation analysis of individuals with NS caused by CoQ10 biosynthesis defects is important because those individuals may respond to treatment with CoQ10 (potentially treatable).

                    Nevertheless, this adds greater complexity to clinical nephrologists’ decisions as to when to suspect and in which NS patients should we look for CoQ6 mutations?

                    [ Modified: Thursday, 1 January 1970, 1:00 AM ]

                    Comments