User blog: Meguid El Nahas

Picture of Meguid El Nahas
by Meguid El Nahas - Wednesday, 22 August 2012, 9:26 AM
Anyone in the world


Professor Rashad Barsoum wrote:
The question of renal transplantation in patients with a history of schistosomiasis infections raises a number of issues:

a) Surgical risk; b) pharmacokinetics and potential toxicity of immunosuppressive agents; c) short- and long-term outcomes; d) recurrence of the original disease; e) Reinfection.
In urinary schistosomiasis, the surgical risk is related to the presence of infection, motor abnormalities of the bladder, outflow or upstream obstruction. All these issues are amenable to adequate management, which may be simple or highly complicated. Pre-transplant urological procedures may be necessary for ensuring adequate bladder capacity and function. In some cases, persistent infection may require bilateral nephrectomy.
In hepatosplenic schistosomiasis the surgical risk is assessed by the usual CHILD criteria, which are quite valid in schistosomiasis. Please mind the frequent association with HCV infection, which has its own constraints with regards to transplantation. The presence of portal hypertension with ascites and porto-systemic shunts should be seen as a contraindication to transplantation.
A thesis presented to Alexandria University has evaluated the metabolism of immunosuppressive agents in patients with hepato-intestinal transplantation. It concludes that if the patient is fit for surgery, the liver function should be good enough not to impose a significant perturbation to the pharmacokinetics of commonly used immunosuppressive agents. We have not been able to show that the toxicity of antiproliferative agents, PSI’s or CNI’s is increased in patients with hepatosplenic schistosomiasis with fair liver functions that permit surgery.
The short-term outcomes of transplantation in patients with schistosomiasis are generally non-inferior to those without schistosomiasis, so long as the pre-operative criteria are favorable as described above. In one study, the incidence of ureteric leaks was relatively higher in patients with urinary schistosomiasis. Some surgeons prefer uretero-ureteric to uretero-vesical anastomosis to avoid cutting through the fibrotic bladder wall. I am unaware of any studies that compare this approach to standard uretero-vesical anastomosis.
In the few reports that addressed long-term outcomes, there have not been any significant alterations in patient or graft survival at 5 years. But all patients included were well selected according to the above criteria.
Recurrence of schistosomal nephropathy has been reported in Brazil, not in Egypt. I presume that adequate pre-transplant exclusion of active infection should obviate this remote possibility.
Re-infection has been addressed in a nice paper from Mansoura. Since many recipients eventually resume their social habits of contact with contaminated water, their chances of getting re-infected are obviously high, particularly with their immunosuppression. In the mentioned study, re-infection occurred in a higher proportion of patients receiving kidney transplants compared the norms in the same community.
So, the key for a good transplant outcome is good selection, which brings us back to the second and third paragraphs of this comment.
Rashad Barsoum


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


    Anyone in the world

    In this wek's NEJM, an article by Olesen and colleagues from Denmark shows that CKD is associated with increased risk of stroke and thromboembolism in patients withatrial fibrillation (AF); hazard ration in CKD ~2, and HR in ESRD ~3 (compared to general, non CKD, population).The data was derived from Danish National Registries and from an observational cohort of around 4,000 patients with CKD (3587 non-ESRD CKD) and 901 with ESRD.

    They also show that warfarin therapy is associated with significantly decreased risk. But there was a 33% increased risk of bleeding with warfarin therapy in CKD patients compared to those without CKD. Aspirin was not associated with decreased risk.

    This analysis supports a recently published meta-analysis showing the beneficial effect of warfarin anticoagulation in incident AF patients: In this anlysis, there was a significant increase in the annual incidence of stroke with progressively increasing CHADS(2) (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores.

    The implications of the Olesen et al study would be to recommend warfarin therapy in patients with AF with CKD/ESRD. This would be all the more justified in view of the fact that most of the ESRD patients would have a CHADS score>2; old, hypertensive, diabetic with underlying CVD!

    What the authors dont mention is the risks associated with warfarin therapy in ESRD.

    There is growing evidence and concern that warfarin therapy is potentially harmful in this population due to the impact of warfarin on vascular calcifications as well as calciphylaxis. There is also evidence to link warfarin use and increased mortality in this population. The impact of warfarin on vascular calcifications has been l;inked to its inhibitory effect on vitamin K synthesis as well as that of other proteins. Apart from clotting factors, vitamin K-dependent proteins include regulatory proteins like protein C, protein S, protein Z, osteocalcin, growth arrest-specific gene 6 protein, and matrix Gla protein (MGP). MGP is a known natural inhibitor of vascular calcifications present in vascular walls and strongly inhibited by treatment with warfarin.

    In addition to bleeding and vascular calcifications, other risks have been associated with the use of warfarin, including an increased susceptibility to fractures caused by a reduction in the levels of vitamin K dependent carboxylated enzymes, matrix Gla-protein (MGP) and bone Gla-protein or osteocalcin (BGP).

    Consequently, anticoagulant therapy in patients with with CKD/ESRD and AF requires careful evaluation because its benefits i.e. prevention of thromboembolism, must be greater than the risk of bleeding. Patients at higher risk of thrombosis are evaluated through specific scores, such as the CHADS(2), coupled with scoring systems for assessing bleeding risks, such as the HAS-BLED score.

    Caution should therefore be exerted in using Warfarin in patients with AF and advanced CKD.

    Alternate therapies may have to be considered with a more favourable RISK:BENEFIT profile. Newer anticoagulants such as dabigatran and rivaroxaban offer promise as future therapeutic options in such cases.

    Drugs including statins and vitamin K are currently under study as therapies to prevent or treat warfarin-associated calcification. A large EU study of the effect of vitamin K1 (precursor of K2) in HD patients is underway.

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


      Picture of Meguid El Nahas
      by Meguid El Nahas - Friday, 17 August 2012, 11:31 AM
      Anyone in the world


      This is the real problem of CKD....Ageing and the associated Co-Morbidities!
      Age-associated increased Co-Morbidities impacts on kidney function from the age of 45 onward!
      Consequently, CKD increases with age and represents the majority of those detected within communities with impaired kidney function. 
      In order to reduce the incidence of CKD, attention (Prevention & Detection) should focus on predisposing NCDs:
      Data from the National Health Interview Survey, 1999–2000 and 2009–2010
      • Between 1999–2000 and 2009–2010, the percentage of adults aged 45–64 and 65 and over with two or more of nine selected chronic conditions 
      increased for both men and women, all racial and ethnic groups examined, and most income groups.
      • During the 10-year period, 
      the percentage of adults aged 65 and over with both hypertension and diabetes increased from 9% to 15%; 
      prevalence of hypertension and heart disease increased from 18% to 21%;
      and prevalence of hypertension and cancer increased from 8% to 11%. 
      • The percentage of adults aged 45–64 with two or more of nine selected chronic conditions who did not receive or delayed needed medical care due to cost increased from 17% to 23%, and the percentage who did not receive needed prescription drugs due to cost increased from 14% to 22%.
      [ Modified: Thursday, 1 January 1970, 1:00 AM ]


        Picture of Meguid El Nahas
        by Meguid El Nahas - Wednesday, 15 August 2012, 5:31 PM
        Anyone in the world

        I listened with considerable interest to a BBC radio debate today relating to a published report claiming that 1.8million UK residents are "diagnosed" as suffering from CKD.

        On the program, Dr Donal O'Donaghue (Salford, UK) was defending such a growing vue calling for more detection and prevention as well as resources to manage this growing healthcare challenge. In effect, he was championing the prevaling, fashionable, view of rising CKD prevalence, the value of early detection and prevention and so many more often repeated but unsubstantiated and unproven assertions.

        Dr Chritopher Winearls (Oxford, UK) was challenging this dogmatic vue, pointing out the inaccuracies of such prevalence statements, issues with detection and prevention programs as well as the grave concern over medicalisation of age-related decline in kidney function.

        As often is the case, when the advocate of rising CKD are in trouble with their argument, they fall back on the "But CKD is a major CVD risk factor, so we need to detect it and prevent it...." argumement. One by the way totally refuted by most cardiologists and many nephrologists such as myself for the following reasons:

        1. CKD is a MANIFESTATION of underlying CVD not its primary CAUSE, as I stated on many occassions on OLA; I even called the condition Cardio-Kidney-damage (C-K-D) in a 2010 Publication in KI.

        2. In support of such argument is that subclinical CVD often precedes incident CKD in older individuals and accelerates its decline.

        Here I refer to a number of publications showing that baseline atherosclerosis deteceted by raised carotid intima-media thickness predicts incident CKD (Choncol et al. and that those with subclinical cerebrovascular disease also have accelerated CKD decline within the community.

        This month in cJASN an article by Park et al. report on an observation from the Multi-Ethnic Study of Atherosclerosis (MESA) were they followed up 3,866 individuals (mean age 60) in the USA for approximately 5 years. They reported that those who go on to develop CKD have underlying CVD defined as subclinical cardiac hypertrophy detected by MRI. The presence of ventricular concentricity/hypertrophy increased risk of CKD develkopment (eGFR<60) but also that of increased risk of faster eGFR decline. This was independent of confounders such as hypertension and diabetes. 

        This supports once more the notion that older individuals with CKD have underlying CVD rather than the other way round. Consequently, it is not surprising that patients with CKD, a marker of underlying diffuse vascular pathology, have a worse CV outcome.

        3. And perhaps more importantly, it is most likely that the underlying subclinical CVD that precede CKD may be the reflection of subclinical or underdiagnosed hypertension. In this week's Lancet a series of article stress the fact that systemic hypertension is both underdiagnosed and undertreated in developed as well as developing countries. The fact that casual/office blood pressure measurement is most unreliable and does not reflect 24h ambulatory blood pressure measurements or nocturnal hypertension known to be more closely associated with CVD.

        It is likely that it is hypertension and the associated CVD that lead to CKD not the other way round.

        30-40% of the population sufferes from hypertension.

        Prevention and early Detection of Hypertension: YES, this should be the nephrologists' message!

        Ultimately, CKD would, undoubtedly through hypertension and other uremia related factors, accelerate the progression of CVD; a vicious cycle described by Sir Richard Bright almost two centuries ago...!!!!


















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


          Picture of Meguid El Nahas
          by Meguid El Nahas - Tuesday, 14 August 2012, 8:36 AM
          Anyone in the world


          I have argued for years that the so called CKD epidemic is no more or less the result of a number of factors:
          1. Increased awareness of reduced GFR through automatic eGFR reporting in many countries since the mid-2000.
          2. Flawed screening and analysis methodologies; including the use of microalbuminuria to define CKD and eGFR formulas that underestimated true GFR in the general population.Most often tested once and define as chronic....
          3. The fact that it is mostly the aged who seem to have CKD in the communities.
          I used the label Cardio-Kidney-Damage (C-K-D) to explain this so-called epidemic and based it on the rise of Non-Communicable Disease (NCD); mainly hypertension and Diabetes and their impact on endorgans over a lifetime explaining reduced kidney function along with CVD in the elderly..
          I argued that NCD are the main problem that needs to be tackled; namely HYPERTENSION & DIABETES to prevent CKD, CVD, CAD, Strokes, etc....
          I argued that DETECTION & PREVENTION Programs should focus on detection of HYPERTENSION & DIABETES rather than CKD. 
          I argued that BP measurement should be generalised in the communities before sCr or urinalysis.
          I argued that such an approach would be much more effective and cost-effective worldwide including in developing countries.
          This week in the Lancet, Ibrahim and Damasceno highlight the plight of hypertension in developing countries. They state that by 2025 3/4 of those suffering from hypertension will live in developing countries. They highlight the very high prevalence of hypertension in developing countries varying from 15 to 40%. They also draw attention to the differential prevalence of hypertension with higher rate in rural regions compared to urban conglomerations.  
          Alarmingly, Ibrahim and Damasceno draw attention to the very low awareness rates of hypertension in developing countries and the fact that control of BP is achieved in an appalling low (<10%) of those treated.
          They stress in their excellent articles the importance of salt restrictions and its impact on BP control in some countries drawing attention to national government initiatives to reduce salt consumption and its impact.
          Ernesto Schiffrin in an accompanying editorial reiterate these facts and call for global action.
 is HYPERTENSION....HYPERTENSION....and  HYPERTENSION that we need to focus on in our communities if we want to reduce the burden of CVD including CKD. 
          It is high time the Nephrology community puts aside its professional egocentric approach to CKD and acknowledge that the main problem with CKD in communities is primarily one of NCDs: HYPERTENSION, HYPERTENSION, HYPERTENSION, OBESITY-DIABETES. 


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


            Picture of Meguid El Nahas
            by Meguid El Nahas - Saturday, 4 August 2012, 5:43 PM
            Anyone in the world


            Lancet. 2012 Jun 20. [Epub ahead of print]

            Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial.


            Department of Infectious Diseases, Sahlgrenska University Hospital, Göteborg, Sweden.



            Acute pyelonephritis is a common infection in adult women, but there is a paucity of controlled trials of its treatment and the optimum duration of antibiotic treatment has not been properly defined. We compared the efficacy of ciprofloxacin for 7 days and 14 days in women with community-acquired acute pyelonephritis.


            In a prospective, non-inferiority trial undertaken at 21 centres of infectious diseases in Sweden, women (aged ≥18 years) who were not pregnant and had a presumptive diagnosis of acute pyelonephritis were randomly assigned to oral treatment with ciprofloxacin 500 mg twice daily for 7 days or 14 days. The first week was open label. A computer-generated randomisation list in block sizes of two was used for treatment allocation in a 1:1 ratio. The study was double-blind and placebo-controlled during the second week of treatment, which was either continuation of ciprofloxacin 500 mg or placebo tablets twice daily according to the randomisation code. Patients, carers, site investigators, and trial coordinating centre staff were masked to group assignment. The primary endpoint was the clinical and bacteriological outcome 10-14 days after completion of treatment with active drug. Analysis was by per protocol. This trial is registered with EudraCT, number 2005-004992-39, and, number ISRCTN73338924.


            126 of 248 patients were randomly assigned to 7 days and 122 to 14 days of ciprofloxacin. 73 and 83 patients, respectively, were analysed. Short-term clinical cure occurred in 71 (97%) patients treated with ciprofloxacin for 7 days and 80 (96%) treated for 14 days (difference -0·9%; 90% CI -6·5 to 4·8; p=0·004; non-inferiority test). Cumulative efficacy at long-term follow-up was 93% in each group (68 of 73 vs 78 of 84; -0·3%; -7·4 to 7·2; p=0·015). Both regimens were well tolerated. Two patients discontinued ciprofloxacin because of myalgia with 7 days of treatment and itching exanthema with 14 days. Four (5%) of 86 patients assigned to 7 days of treatment who complied with study criteria and six (6%) of 93 assigned to 14 days reported an adverse event after the first week of treatment that was possibly or probably related to the study drug. In those assigned to 7 days, no patient had mucosal candida infection after the first week versus five treated for 14 days (p=0·036).


            Our results show that acute pyelonephritis in women, including older women and those with a more severe infection, can be treated successfully and safely with oral ciprofloxacin for 7 days. Short courses of antibiotics should be favoured in an era of increasing resistance.


            Swedish Strategic Programme against Antibiotic Resistance (Strama).


            OLA BLOG COMMENT:


            Excellent study showing the non inferiority of 7 days cirofloxacin tratement compared to 14 in women with acute pyelonephritis.


            This is good news in view of the fact that most uropathogens, including E.Coli, are susceptible to fluoroquinolones such as ciprofloxacin that effectively eradicate enterobacteria from rectal and vaginal flora.


            Also good news as far as prolonged antibiotic therapy can be avoided in this era of concern over growing antibiotic resistance.


            However, my reservation regarding the validity of this non-inferiority RCT is the high drop out rate (almost 40% were not included in the final analysis), and consequent per protocol analysis rather than an all inclusive intention to treat analysis.


            Per protocol analysis or underpowered studies may lead to false negative results (typeII statistical error).


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


              Picture of Meguid El Nahas
              by Meguid El Nahas - Tuesday, 31 July 2012, 8:58 PM
              Anyone in the world

              Dr Bassam Saeed submitted this blog to OLA:


              High-quality health care for children with certain inherited nephrotic syndrome

              Nephrotic syndrome (NS) is a disorder of the glomerular filtration barrier, a highly specialized tri-layer structure with unique functional properties. Recent advances emanating from the field of molecular genetics have revealed the podocyte as probably the central player in the control of glomerular filtration, more specifically, the cell-cell junction between adjacent podocyte foot processes, namely, the slit diaphragm, has been revealed to be made up of a sophisticated multi-protein complex which dynamically `controls foot process architecture via signaling to the acting cystoskeleton. Key genes that have been identified from the study of inherited nephrotic syndrome include those encoding nephrin, podocin, TRPC6, and α-actinine-4.
              NS may be classified by response to steroids, i.e. steroid responsive and steroid resistant, with the possibility that there is a different pathophysiology which confers response to steroid. Most genetic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) represent structural changes in the glomerulus or, more specifically, the podocyte, which are unlikely to respond to current therapy. In total, this only explains a small percentage of total cases.
              The nature of the condition and the proportion of familial forms have led to much work on the genetics of NS, with a resultant expansion in the knowledge of genes involved
              In a large European cohort of 89 children from 80 families, 66.3% of patients presenting within the first year of life were found to carry a mutation in one of four genes: NPHS1, NPHS2, WT1 and LAMB2
              Mutations have been described in phospholipase C epsilon 1 (PLCe1; genetic nomenclature is NPHS3), which belongs to the phospholipase C family and is involved in cleavage resulting in the formation of the second messengers DAG and IP3, thereby activating certain cell signaling cascades. Hinkes et al. described truncating mutations in PLCe1 (NPHS3) leading to isolated (non-syndromic) diffuse mesangial sclerosis (DMS) and missense non-truncating mutations leading to FSGS (1). These mutations are increasingly being recognized as resulting in isolated DMS with rapid progression to ESRD and a poor outcome generally; however there are features which differ from the other hereditary forms of NS (2). The initial study described two of the 14 children reported who responded to immunosuppression (one on steroid, one on cyclosporine). Both of these children presented within the first year of life, and both had siblings similarly affected who had progressed to end stage rapidly
              Mitochondrial (mt) cytopathies as a cause of NS are rare, but are very important to recognize as interventional treatment to modify the disease may be possible. Modification of disease progression is potentially possible because the mutations affect the co-enzyme Q10 biosynthesis pathway, and this enzyme can be orally supplemented.
              Mutations that cause MELAS (mt myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and coenzyme Q10 (CoQ10) deficiency can also cause FSGS in isolation. In the later case, 3 genes are recognized: COQ2, PDSS2, and recently a third gene COQ6, has been reported in 13 individuals from seven families, causing early onset SRNS and sensorineural deafness. Two of these individuals were treated with COQ10 supplementation orally and appeared to respond with a lowering proteinuria; in one patient, the deafness also improved (3)
              Nephrologists still have something to learn about whether patients with certain genetic mutations, such as PLCe1, can respond to immunosuppression. For the rare patient for whom a COQ10 biosynthesis pathway defect is discovered, supplemental enzyme therapy to delay or avoid renal failure could be instituted.
              1) Hinkes BG et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, LAMB2). Pediatrics 119:e907-e919
              2) Gbadegesin R. et al. (2008) mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant 23:1291-1297
              3) Heeringa SF, et al. (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013-2024
              [ Modified: Thursday, 1 January 1970, 1:00 AM ]


                Anyone in the world


                In a mini review soon to be published in Nephron,  Professor Neveen Soliman highlights the issues related to Orphan and Rare Kidney Diseases (ORKD). This is a timely reminder of the challenges facing patients who suffer from orphan diseases as well as their healthcarers.  Orphan drug development has been at the forefront of renal and nephrology research in the last decade, the cost of such treatment is increasingly prohibitive. Western governments have supported orphan drug development, granting incentives of up to 10 years of exclusivity for manufacturers of such drugs receiving regulatory approval. In recent years, up to 1500 drug applications have been filed in the EU alone with more than 70 drugs have been approved in Europe.  Also regulatory bodies have facilitated rapid marketing by granting conditional approvals based on limited data and conditional to ongoing monitoring and risk of withdrawal of approval if treatment impact was negative.  However, work on orphan drugs could be under threat due to the economic downturn and the exhorbitant cost; a single patient with an orphan disease can cost between £100,00 to £400,000 a year!  Consequently, the foreseen EU expenditure on orphan drugs will reach 4.6% of total EU pharmaceutical expenditure by 2016. It is therefore not surprising that due to the economic downturn, Western economies are finding such cost increasingly unaffordable. On the other hand,  emerging economies, such as Egypt, have never been able to afford the price of orphan therapies. 
                Access to Orphan therapies has encouraged a new brand of activism bringing patients groups, researchers and specialists together to facilitate access to healthcare for orphan disease. Professor Soliman herself has set up EGORD (Egyptian Group for Orphan Renal Disease) with for a mission raising significant funds and increasing awareness for research and treatment of Orphan disease such as cystinosis. This group, along with other organisations and networks highlighted in this mini review by Professor Soliman, may be shifting the pharmaceutical industry’s attitude to developing and marketing Orphan drugs. Whilst some industrialists continue to justify the cost based on years of research and the small market, others such as Moncef Slaoui, head of research at GSK, recently stated that the industry need to take a more responsible approach to pricing. It is imperative that pressure is put on the industry to provide affordable care for Orphan and Rare Disease. It is unacceptable that economic downturns impact on the healthcare of those who are sick and most vulnerable in our societies. It is one of the responsibilities of our nephrological community to engage manufacturers of orphan drugs in partnerships to deliver affordable healthcare to those with orphan disease.  Nowhere are such initiatives more urgent than in developing countries. 
                The ORKD Campaign on OLA hopes to position itself as a key player in the fight for access for Affordable Therapies for Orphan and Rare Kidney Disease.

                Abbott A. Rare-disease project has global ambitions. Nature. 2011 Apr 7;472(7341):17.

                 Simoens S, Cassiman D, Dooms M, Picavet E. Orphan Drugs for Rare Diseases: Is it Time to Revisit Their Special Market Access Status?

                Drugs. 2012 Jul 30;72(11):1437-43. 



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


                  Picture of Meguid El Nahas
                  by Meguid El Nahas - Friday, 20 July 2012, 9:08 AM
                  Anyone in the world


                  This study by Giovanni Stallone1,etal published early online -NDT Advance Access published July 10, 2012 added to the 3 previously published studies about the role of Rapamycin for the treatment of ADPKD.

                  Rapamycin for treatment of type I autosomal dominant polycystic kidney disease (RAPYD-study): a randomized, controlled study

                  In this prospective, open-label randomized clinical trial, 55 ADPKD patients followed in the outpatient clinic of the two participating centres (University of Foggia and Bari, Italy) were enrolled between November 2007 and November 2008. The duration of the planned follow-up was
                  24 months.
                  The inclusion criteria were clinical, genetic and ultrasonographic diagnosis of type I ADPKD, age between 18 and 65 years and an estimated glomerular filtration rate (eGFR) between 40 and 80 mL/min/1.73 m2, evaluated by the abbreviated Modification of Diet in Renal Disease (MDRD) formula

                  The primary objectives were to assess whether rapamycin may reduce the progressive increase in single cyst and total kidney volume in type I ADPKD and the decline in renal function and to identify the optimal rapamycin dose to achieve the beneficial results without incurring inmajor side effects.
                  After a screening assessment, all patients entered a run-in phase of 2 months in which eGFR and 24 h proteinuria were evaluated every 2 weeks. At the beginning of this period, in patients already treated with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs), these drugs were withdrawn for at least 4 weeks before performing the laboratory tests.

                  At the end of the run-in phase, all eligible patients were randomly assigned to ramipril alone (Group A) or ramipril plus high-dose rapamycin (Group B) or ramipril plus low-dose rapamycin (Group C). In Group B, rapamycin administration was given with a loading dose of 3 mg. The maintenance dose was 1 mg/day aiming at a blood trough level between 6 and 8 ng/mL. In Group C, the patients did not receive a
                  loading dose and the maintenance dose of rapamycin was 1 mg/day to reach a blood trough level between 2 and 4 ng/mL.
                  Magnetic resonance imaging technique .All patients recruited for our study underwent a standardized magnetic resonance imaging (MRI) examination at the baseline (T = 0) and after 24 months of initiation of drug therapy (T = 24) with the same MRI scanner.
                  Genetic analysis
                  DNA isolation and linkage analysis. Genomic DNA was derived from whole blood using Purelink Genomic DNA Mini kit (Invitrogen), according to the manufacturer’s protocol.
                  Epidermal growth factor urinary concentration:
                  was evaluated by ELISA and the results were normalized to urine creatinine excretion.
                  The mean rapamycin trough levels were 6.4 ± 0.3 ng/mL for Group B and 3.2 ± 0.4 ng/mL for Group C. The differences between the two groups were statistically significant at each time point for Group C.
                  Primary outcomes:
                  In all three groups of patients, They observed an increased total kidney volume. Specifically,
                  in Groups A and B, there was a statistically significant increase in kidney volume after 24 months of treatment (P = 0.003 and 0.02, respectively), while in Group C, the increase failed to reach the statistical significance However, they did not observe any significant difference in change of kidney volume among the three study groups at the end of the observational period.
                  On the contrary, the cyst volume was increased in Group A patients after 24 months of treatment (P < 0.0001 versus basal), whereas it was significantly reduced in Group B (P < 0.0001 versus basal) and Group C (P <0.0001 versus basal) Also, in the case of single cyst volume, they did not observe any
                  significant difference among the three study groups at the end of the observational period.
                  Renal function analysis. They observed a decline in estimated creatinine clearance in Group A patients (P = 0.01, T24 versus T0),whereas in Groups B and C after 24 months, they observed
                  a slight increase in GFR, although the differences did not reach statistical significance .
                  The changes in the estimated creatinine clearance in the three groups at
                  the end were not significantly different.
                  EGF urine excretion. an increased EGF urinary excretion in Group A patients (P =0.001 versus T0) was observed, whereas the treatment groups were characterized by a significant reduction after 24 months
                  (Group B: P = 0.0001 versus T0; Group C: P = 0.0001 versus T0)
                  In conclusion:
                  The results of this pilot study suggest that rapamycin treatment at a dose effectively inhibiting p70S6 kinase in circulating PBMCs does not significantly slow down cyst growth and renal function decline featuring the natural history of ADPKD

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


                    Picture of Meguid El Nahas
                    by Meguid El Nahas - Monday, 9 July 2012, 1:23 PM
                    Anyone in the world

                    In the June issue of cJASN Rahman and colleagues from the ALLHAT Collaborative Group report the long-term (9 year) renal and cardiovascular outcomes of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

                    This is a randomised, double blind, multicentre clinical trial that compares the impact of 5 year treatment with an ACE inhibitor (lisinopril), a calcium antagonist (Amlodipine), an alpha blocker (Doxazosin) and a thiazide diuretic (Chlorthalidone) on the incidence of major coronary heart disease (CHD) in high risk hypertensive patients. The initial analysis over a 5 years observation and follow-up period showed that neither lisinopril not amlodipine were superior to the diuretic chlorthalidone. The Doxazosin arm had to be discontinued earlier due to side effects and increased mortality (ALLHAT Collaborative Research Group: JAMA 283:1967-1975, 2000).

                    The current posthoc analysis reports on 31,350 participants followed up for up to 9years, based on hospitalisation records, in term of cardiovascular outcomes; total mortality, CHD, CVD, Stroke, Heart Failure and ESRD.

                    In the whole study group, there was no difference between lisinopril, amlodipine and chlorthalidone isn relation to CVD or renal outcomes/ESRD. Subgroup analysis of pateints with CKD and an eGFR<60 (with minimal proteinuria), also showed no difference in renal or cardiovascular outcomes between the groups. Of interest, the morbidity and mortality from CVD causes was similar to those observed in the RENAAL and AASK trials.

                    The authors conclude that independently of BP lowering effect, no antihypertensive drug class has significant advantage over others in preventing CVD; morbidity and mortality. Of note amlodipine was less effective than chlorthalidone in preventing heart failure; although this may simply reflect that the former favours fluid retention whilst the latter minimises it...!!!

                    This observation agrees with a review of controlled trials by Segall et al (J Nephrol 2008;21:374-383) that showed no specific benefit of anti-hypertensive drug class beyond BP control. Other studies suggested a therapeutic advantage of RAAS inhibition  on CVD but it was unclear whether this was independent from improved BP control. Of note the much quoted HOPE study, also failed to dissociate the CVD protective effect of Ramipril from its antihypertensive impact. More recently, HOPE study posthoc analysis based on 24h ambulatory BP Monitoring failed to convincingly dissociate cardioprotection from improved BP control (Svensson et al. Hypertension. 2001;38:e28-e32).

                    From the above one is entitled to ask whether the much publicised cardioprotective effect of RAAS inhibitors is real or a bais generated by:

                    1. Poorly designed clinical trials (RCT); with unequal BP control between groups

                    2. Inadequate BP measurements in RCT; with occasional office BP measurements now known to be poorly reflective of 24h BP recordings measuring nocturnal BP and nocturnal dip in BP, both known to be closely associated with CV events.

                    3. An industry led brainwashing of ill informed Nephrologists; who follow the trend without asking questions....?!

                    I suspect the answer lies in all three...!!!







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