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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.

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by Meguid El Nahas - Friday, 17 August 2012, 11:31 AM
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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%.
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by Meguid El Nahas - Wednesday, 15 August 2012, 5:31 PM
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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...!!!!


















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by Meguid El Nahas - Tuesday, 14 August 2012, 8:36 AM
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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.
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by Meguid El Nahas - Saturday, 4 August 2012, 5:43 PM
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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).




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).


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by Meguid El Nahas - Tuesday, 31 July 2012, 8:58 PM
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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
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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. 



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by Arif Khwaja - Wednesday, 25 July 2012, 6:46 PM
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One of my favourite non-nephrology medical writers has to be Des Spence whose blog ( is rapidly becoming a must read. After previously dismissing chronic kidney disease as ' a failed experiment, a mockery of evidence-based medicine', Spence turns his attention to the $3 billion fine imposed Glaxo Smith Kline over amongst other things suppression of data concerning the cardiovascular risks of rosiglitazone. Spence points out that despite its' faults, pharma is essentially an industry ' doing untold good' and that its far too easy to blame pharma -  he argues the real problem is a 'global medical culture' that encourages naivety and deference rather than respect and scepticism. In particular he is scathing about expert panels who he describes as 'educational mercenaries'. 

Now whilst I don't agree all of his arguments reading his article reminded me of the time I visited a pharma-sponsored symposium at the WCN/ISN in Milan a few years ago. At that symposium Dr Geoffrey Block from Denver gave an impassioned talk on the evils of phosphorus in CKD. Phosphorus increased vascular calcification in CKD and the only way to reduce phosphorus was to use more dialysis and/or more phosphate binders (presumably the rather expensive non-calcium binders). What i remember more than anything was the call for phosphorus to be recognised as a cardiac toxin in CKD patients with a plea for food labelling - so that high phosphorus foods would receive some kind 'health warning' analogus to say high salt warnings that appear on much food packaging now. There was not much discussion of the negative DCOR study (a huge study showing sevelamer had no impact on mortality in dialysis patients) but instead a focus on how we probably needed to reduce phosphorus in the predialysis population. 

So hows that all going?  Well a recent publication in JASN online by Block suggests that the ' calcium bad, sevelamer/lanthanum good' narrative that has been pushed very hard by pharma (with I am afraid the collusion of some 'experts' in the CKD-MBD field), does not as yet stand up to any critical scrutiny...In this study 148 patients with estimated GFR=20–45 ml/min per 1.73 m were assigned to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline whilst secondary endpoints looked at effects on FGF23, vascular calcification and bone mineral density. No surprise that the study met its primary endpoint - yes phosphate binders reduce serum phosphorus more effectively than placebo! As expected iPTH levels were significantly higher in the placebo group compared to the binder group at 9 months though interestingly FGF-23 levels were unchanged. In a subset of 90 patients (60 with binders and 26 placebo) imaging was performed which revealed some interesting results. Patients on phosphate binders had a small but significant increase in bone mineral density but a also a significant increase in progression of coronary artery calcification! The authors rather optimistically state that 'The apparent adverse effects on vascular calcification and salutary effects on BMD were most pronounced among patients randomized to calcium acetate' yet no statistics are provided - probably because only 20 patients on binders had an increase in calcification over 9 months and so any meaningful analysis of these 20 patients on three different binders was not possible!!

So what do I make of it all?

i) There is absolutely no RCT evidence to show that non-calcium binders are superior to calcium-based binders in the dialysis population on key patient centred outcomes such as death

ii) Whilst many have argued that the thresholds for serum phosphorus in the pre-dialysis population should be lowered, there is as yet no evidence to support this. In fact what this study shows is that further lowering of serum phosphorus with binders in predialysis patients with CKD may actually not be safe. Until an RCT comes out the honest answer is that we just dont know what to do..

iii) As nephrologists we can spend money in all sorts of ways... prescribing expensive drugs, employing more nursing staff, more dieticians, more counsellors, more dialysis... For those of us who work in an environment where money is an issue, if we are going to prescribe expensive drugs (in the UK the non-calcium binders are around ten times as expensive as calcium binders) we need to have solid data to show that these drugs have a significant impact on outcomes that matter to patients such as death, fractures, hospitalisations, quality of life.. I am afraid I see no robust data for the non-calcium binders

iv) It is entirely appropriate for pharmaceutical companies to push agendas that are going to maximise sales of their products. As Des Spence says we need experts who have a sense of scepticism and are not simply 'educational mercenaries'. But more than that as individual nephrologists we have a duty not to blindly accept expert opinion in the absence of data....



1. Effects of Phosphate Binders in Moderate CKD. Geoffrey A. Block, David C. Wheeler, Martha S. Persky, Bryan Kestenbaum, Markus Ketteler, David M. SpiegelMatthew A. Allison, John Asplin, Gerard Smits, Andrew N. Hoofnagle, Laura Kooienga, Ravi Thadhani, Michael Mannstadt, Myles Wolf and Glenn M. Chertow. JASN online July 2012


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Anyone in the world

Using measured GFR (by iohexol plasma clearance) the GFR study investigators released new results on progression of type 2 diabetes associated nephropathy, showing that blood pressure and metabolic control are the most important factors associated with slow long-term GFR decline. They based the analyses in data from 2 previously published trials using ACE inhibitors and calcium channel blockers (BENEDICT-B and DEMAND). The most important finding was that controlling hyperfiltration in the first 6 months of treatment was associated with slower progression. That control was most impressive in patients with improved blood pressure and metabolic control, despite of using or not ACE inhibitors. That information is important once, so far, ACEi are ascribed as the first line drugs for the treatment of hypertension in those patients. In fact, manidipine and delapril association showed beneficial effects on cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity, but had no effect on GFR decline (DEMAND trial). Despite of efforts to find particular drug interventions on complex diseases, as type 2 DM, we should rely on the old and solid concept that blood pressure and glycemic control are the most important, no matter how it is achieved.


Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, Cella C, Ferrari S, Stucchi N, Parvanova A, Iliev I, Dodesini AR, Trevisan R, Bossi A, Zaletel J, Remuzzi G; for the GFR Study Investigators (see Study Organization). Glomerular Hyperfiltration and Renal Disease Progression in Type 2 Diabetes. Diabetes Care. 2012 Jul 6. [Epub ahead of print]

Ruggenenti P, Fassi A, Ilieva AP, Iliev IP, Chiurchiu C, Rubis N, Gherardi G, Ene-Iordache B, Gaspari F, Perna A, Cravedi P, Bossi A, Trevisan R, Motterlini N, Remuzzi G; BENEDICT-B Study Investigators. Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. J Hypertens. 2011 Feb;29(2):207-16.

Ruggenenti P, Lauria G, Iliev IP, Fassi A, Ilieva AP, Rota S, Chiurchiu C, Barlovic DP, Sghirlanzoni A, Lombardi R, Penza P, Cavaletti G, Piatti ML, Frigeni B, Filipponi M, Rubis N, Noris G, Motterlini N, Ene-Iordache B, Gaspari F, Perna A, Zaletel J, Bossi A, Dodesini AR, Trevisan R, Remuzzi G; DEMAND Study Investigators. Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial. Hypertension. 2011 Nov;58(5):776-83. Epub 2011 Sep 19.

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Anyone who read my ASN blog will know that Remuzzi's group from Bergamo presented what appeared to be very positive data on the role of Rituximab in idiopathic membranous glomerulonephritis (IMN) at the ASN in 2011.  Well the data has finally been published and serves as a salutory reminder to me that one always needs to see the final paper before being able to assess the impact on ones' practice. Remuzzi presents data on a 100 consecutive patient with IMN treated with Rituximab. The median duration of persistent proteinuria prior to rituximab therapy was over 2 years and follow up data was available for a median of 29 months. 27% achieved complete remission whilst 38% achieved partial remission (defined as less than 3g/24 hours and a 50% reduction in proteinuria from baseline). The authors suggest that 'Rituximab might be considered as first line therapy' for IMN. Does the data justify such a statement? Almost certainly not and its worth considering the following:
i) Given the very variable remission and progression rate with IMN, any therapeutic data without a control group is of limited value (some would say meaningless...). IMN runs a highly variable course with a high rate of spontaneous remission that occur can occur even quite late after presentation. This was observed not only by the GLOSEN group in Spain but by Remuzzi himself who when publishing in the NEJM on presumably another cohort of of 100 IMN patients found that 65% of patients went into complete or partial remission after 5 years of observation prompting him to note that 'Most untreated patients with idiopathic membranous nephropathy maintain renal function for prolonged periods and are likely to have spontaneous remission'......
ii) Following on from the above its worth noting that the serum creatinine and 24 hour urinary protein excretion was lower and the serum albumin was higher at baseline in the complete remission group versus the no remission group.. so the question arises did the complete remission group have milder disease that would just get better anyway. Of course unless you have a control you just dont know!
ii) Only 32 patients had recieved prior immunosuppression and of these only 24 had prior steroids in combination with an alkylating agent - this is currently the KDIGO recommended first line therapy as as Gerald Appel points out in an accompanying editorial, given the fact that we have placebo controlled RCTs with both CNIs and alkylating agents, but not with Rituximab, why should we use Rituximab as first line therapy?
iii) the authors cite safety concerns of cyclophosphamide although the cumulative dose of cyclophosphamide used in IMN is relatively low and the safety of Rituximab in auto-immune disease (in terms of side effects such as progressive multifocal leucoencepholopathy) maybe different than in those with lymphoma.
iv) Rituximab is expensive. The authors state that as they only use one dose (375mg/m2) costs are reduced though its worth noting that 18 patients with rituximab relapsed and required a second dose. The use of phospholipase A2 receptor antibodies as a guide to dosing schedule may make more sense.

Taking this work together with Fernando Fervenza's data from the Mayo  Rituximab is probably better than placebo in IMN. Its expensive and until there is an RCT comparuing it with an alkylating agent or a CNI I would only use in those patients with progressive IMN who are refractory to  (or have contraindications to) alkylating agents therapy and/or calcinuerin inhibitors.
1.Rituximab in Idiopathic Membranous Nephropathy. Piero Ruggenenti, Paolo Cravedi, Antonietta Chianca, Annalisa Perna, Barbara Ruggiero, Flavio Gaspari, Alessandro Rambaldi, Maddalena Marasà, and Giuseppe Remuzzi. J Am Soc Nephrol published 19 July 2012, 10.1681/ASN.2012020181 
2. Prognosis of untreated patients with idiopathic membranous nephropathy. Schieppati A, Mosconi L, Perna A, Mecca G, Bertani T, Garattini S, Remuzzi G, N Engl J Med. 1993 Jul 8;329(2):85-9.
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