User blog: Arif Khwaja

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Bone disease post-transplantation remains a difficult clinical problem with an evidence base that can be difficult to interpret. In the landmark osteoporosis studies demonstrating benefit of bisphosphonates in the general population the sample size was huge (many RCTs with around 5000 subjects) in order to show a positive effect on patient fracture. Clearly such studies are not possible in the transplant population but several studies have shown significant loss of bone mineral density (BMD) particularly in the first 12-18 months after transplantation (1, 2). Furthermore bisphosphonates have been shown to significantly attenuate the decline in BMD in the early post-transplantation period (12). Whilst BMD is accepted as a reasonable surrogate marker in the general population it cannot capture the qualitative changes in bone histomorphometry that characterise CKD-MBD and so may not be a particularly useful surrogate post transplantation. Crucially the 'standard care' aspect of management post-transplantation may impact on BMD loss and a few recent studies have highlighted this.

In a study from Norway, Smerud and colleagues allocated 129 patients to receive either ibandronate or standard treatment (calcium and calcitriol supplementation) (3). Lumbar spine BMD was increased at 12 months in both groups and the change in BMD did not significantly differ between the patients who received ibandronate therapy and those who received placebo. Ibandronate did improve femoral BMD but interestingly there was no statistically significant loss in BMD at the femur in the placebo group. Coco and colleagues randomised 42 live related transplant recipients to either risedronate or placebo and found no significant impact on BMD (4) - nor did they find any evidence of adynamic bone disease, which remains an important theoretical concern when giving bisphosphonates to patients with CKD. Thus the more recent studies of bisphosphonates tend to show lesser loss in BMD in the control arm than the earlier studies. This probably relates to the fact the cumulative steroid exposure is less in the current era and that treatment with calcitriol and calcium in itself has a beneficial effect on BMD.
So where does this leave us in practical terms? Well it seems reasonable to ensure that all transplant patients should be kept vitamin D replete and levels should be monitored in the first year post-transplantation. Whether BMD should be measured in all patients is difficult to know but it would certainly be sensible to do in all those who are maintained on steroids. Given the fact that there will never be an adequately powered RCT looking at fracture rates in the post-transplant period I suspect the best that centres can do is develop local protocols based on risk factors such as vitamin D and steroid exposure with active audit to determine the utility of such protocols. A very practical approach was proposed by Mainra and Elder in Sydney, Australia who have developed an individualised approach to bone loss that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment (5). In the absence of definitive evidence this kind of approach seems very pragmatic.

References

1. Effect of ibandronate on bone loss and renal function after kidney transplantation. Grotz W et al. J Am Soc Nephrol. 2001 Jul;12(7):1530-7.

2.  Effect of pamidronate on bone loss after kidney transplantation: a randomized trial.Walsh SB et al. Am J Kidney Dis. 2009 May;53(5):856-65

3. A 1-Year Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Ibandronate on Bone Loss Following Renal Transplantation.Smerud KT et al. Am J Transplant. 2012 Dec;12(12):3316-3325.

4. Effect of risedronate on bone in renal transplant recipients.Coco M et al J Am Soc Nephrol. 2012 Aug;23(8):1426-37

5. Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation.Mainra R, Elder GJ. Clin J Am Soc Nephrol. 2010 Jan;5(1):117-24.

 

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by Arif Khwaja - Friday, 14 December 2012, 12:08 AM
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In the last week I have seen 2 patients who have had steroid resistant nephrotic syndrome due to minimal change disease. Both have had various immunosuppressives without success and have continued to have nephrotic range proteinura for 5 years. Despite this they both have normal kidney function!! Thus the obsession with microalbuminuria (MA) as a risk factor for progression in CKD is something I have always found puzzling. There has been a plethora of publications over the last 10 years focussing on the association between microalbuminuria (MA) and adverse renal and cardiovascular outcomes and its likely that MA identfcaton wll be central to the KDIGO approach to CKD.  In simple terms there are two schools of thought as regards proteinuria and CKD: 

1) proteinuria in itself is nephrotoxic (based predominantly on in vitro and in vivo studies showing evidence of inflammatory and fibrogenic effects on tubular epithelial cells) and cardiotoxic and so reducing proteinuria will positively impact on both cardiovascular and renal endpoints.

2)  Proteinuria and MA simply reflecting underlying glomerular and endothelial 'health' and improved levels of proteinuria simply reflect improvements in underlying glomerular or vascular disease.
 
The Altitude study which was published in NEJM recently seriously questions whether strategies designed to improve proteinuria  per se can in themselves have any impact on cardiovascular and renal outcomes. The Altitude study is a large RCT of 8561 patients studying the impact of combining aliskiren (direct renin inhibitor) with an ACEi\ARB on a range of cardiorenal endpoints. Despite a significant reduction in proteinuria and blood pressure, Aliskiren combined with ACE\ARB had no positive effect on any cardio-renal endpoint. This fits in with data from previous interventional (not observational) studies suggesting a disconnect between MA reduction and cardio-renal outcomes. For example in the ROADMAP study of olmesartan in type 2 diabetes showed that despite reducing MA, olmesartan had no effect on cardiovascular morbidity, kidney function and there were significantly more deaths in the treatment group. Similarly the huge ACCOMPLISH study demonstrated significantly superior cardiovascular outcomes with benazepril combined with amlodipine when compared with benazepril combined with a thiazide in hypertensive patients at risk of cardiovascular disease - DESPITE  improved MA in the thiazide group..
Taken together the interventional (as opposed to the observational) data clearly shows that proteinuria and MA are little more than biomarkers for renal and cardiovascular disease. Attempts to target MA per se are futile and as a wise colleague of mine once said MA is little more than a urinary ESR......
 
References
 
 
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by Arif Khwaja - Tuesday, 11 December 2012, 6:00 PM
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There is some interesting data published from Stevenage, England in this months cJASN describing differences in outcomes between patients on RRT and those opting Conservative Kidney Management (CKM). Observational data from the UK has already shown that in those elderly patients with significant co-morbidity RRT offers litlle survival advantage over CKM. Furthermore data from the Royal Free Hospital, London had suggested that much of the survival advantage that such comorbid patients get from RRT is at the price of days spent in hospital and the actual, 'hospital-free' days gained was marginal. Whats interesting about the current study is that it focuses on endpoints that matter to patients - namely objective quality of life measures using tools such as SF-36 and Hospital Anxiety and Depression Scale on a 3 monthly basis in a cochort of patients with CKD4/5. In their cohort of 170 patients 30 elected for CKM. Unsurprisingly these patients had more comorbidities and poorer functional status. Serial quality of life measures demonstrated no change from baseline EXCEPT a decline in life satisfaction associated with those starting dialysis. Median survival (after adjustment for comorbidity) was 13 months shorter in the CKM group.

Of course this data is observational and subject to signficant confounding bias but then there is never going to be an RCT comparing outcomes between RRT and CKM.

However it adds to what we already know - patients with poor functional status or comorbidity get little benefit from RRT either in terms of survival or quality of life. Making individual patient decisions about RRT is very difficult but in the UK, NHS kidney care have lauched an online decision aid to help patients make decisions about RRT ( see http://sdm.rightcare.nhs.uk/pda/established-kidney-failure/)... the decision aid incorporates the values and aspirations of individual patients to help them come to a decision and will hopefully help decision making in the UK.

Its important to bear in mind that this kind of data is almost certainly irrelevant for those practicing in emerging countries as the patient population and social care will be very different making it impossible to extrapolate such data to those countries. I am struck that in certain parts of the world there seem to be cultural barriers to CKM even though in selected cases it appears associated with a better quality of life and equivalent survival. The key here is to get *LOCAL* data starting probably with survival data for those starting RRT as accurate information is essential to help patients make decisions. Without that any discussions of the pros and cons of RRT are meaningless......

References

 1. Quality of Life and Survival in Patients with Advanced Kidney Failure Managed Conservatively or by Dialysis. http://www.ncbi.nlm.nih.gov/pubmed/22956262> *Da Silva-Gane M*, Wellsted D, Greenshields H, Norton S, Chandna SM, Farrington K. Clin J Am Soc Nephrol. 2012 Dec; 7 (12) 2002-2009.

2. Is there a rationale for rationing chronic dialysis? A hospital based cohort study of factors affecting survival and morbidity. Chandna SM, Schulz J, Lawrence C, *Greenwood* RN, *Farrington K*. BMJ. 1999 Jan 23;318(7178):217-23.

3. Is maximum *conservative* management an equivalent treatment option to dialysis for elderly patients with significant comorbid disease?Carson RC, Juszczak M, Davenport A, *Burns A*.Clin J Am Soc Nephrol. 2009 Oct;4(10):1611-9.

4. Dialysis or not? A comparative survival study of patients over 75 years with chronic kidney disease stage Murtagh FE, Marsh JE, Donohoe P, *Ekbal NJ*, Sheerin NS, Harris FE. Nephrol Dial Transplant. 2007 Jul;22(7):1955-62.

5. Conservatively managed patients with stage 5 chronic kidney disease--outcomes from a single center experience.Ellam T, *El-Kossi M*, Prasanth KC, El-Nahas M, Khwaja A. QJM. 2009 Aug;102(8):547-54

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by Arif Khwaja - Saturday, 20 October 2012, 11:27 AM
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Theres a very sensible article about how to use clinical practice guidelines (CPGs) in real world clinical settings in a recent KI. Radhakrishnan and Cattran argue very sensibly that CPGs are not diktats telling the clinician what to do in individual clinical situations but simply provide guidance to help the clinician make decisions.  They highlight how in a practical way one can use CPGs to inform decision making using real cases of patients with glomerular disease. Worth a read especially for those doctors who think guidelines should be /are prescriptive

Reference

The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines—application to the individual patient. Jai Radhakrishnan and Daniel C CattranKidney International (2012) 82, 840–856; doi:10.1038/ki.2012.280

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There are 2 great reads in a recent BMJ - charting the  journeys of 2 different patients through end stage kidney disease. Nicholas Evans author of The Horse Whisperer describes how both he and his wife developed AKI whilst on holiday secondary to mushroom poisoning with Cortinarius speciosissimus. Neither recovered and Evans gives an eloquent account of a gruelling life on dialysis - things such as the devastating impact of intradialytic hypotension and his naive belief that dialysis would give him more time to write - only to realise that he was simply too exhausted and disoriented to work either during dialysis or afterwards. Evans seemed to have had great care throughout and all ended happily as his daughter successfully donated a kidney to him. He movingly describes the transition from reluctance to accepting a kidney from his child to grateful acceptance.

Renata Carey is a diabetic lady in her 70s who describes a journey that all caregivers and patients will recognise. Much of the care she received at the Royal free Hospital, London was 'mostly excellent' but the sheer drudge and loneliness of dialysis takes its' toll.  She described how nobody warned her that she would become anuric and how upsetting this was. Furthermore she reminds us how our best intentions as caregivers can seem simply seem ghastly to patients. For example 'self care' for dialysis patients, which is very much in vogue in the UK, is described by Carey as something foistered upon her - when all she wants is for somebody else to do the caring for her - and quite frankly who can blame her?

Whats striking is that what matters most to her on the dialysis unit is for is for staff to show " kindness, thought and imagination."  Yet within the factory-like setting of the dialysis unit this is in short supply. Facing time-pressures, we get caught up in number watching - obsessing about about lab tests that mean little to patients and in many cases have only a marginal impact on  quality of life. Most of all these journeys remind us how that essential element of great healthcare - humanity - is fiendishly hard to deliver and frequently elusive....All staff involved in the care of dialysis patients will learn much from reading and reflecting on these journeys....

1. Kidney dialysis--the need for humanity. Carey R, Harber M. BMJ. 2012 Jul 19;345:e4492. 

2. Irreversible renal damage from accidental mushroom poisoning. Evans N, Hamilton A, Bello-Villalba MJ, Bingham C.BMJ. 2012 Aug 10;345:e5262.

 
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Anyone in the world

There is a great review of the Iranian model of living kidney transplantation by Mitra Mahdavi-Mazdeh in this months Kidney International. The process of unrelated transplantation is described in some detail but in essence involves a kind of regulated negotiation between donor and recipient at a patient 'kidney-foundation' clinic. Once a patient has been deemed suitable for a transplant the foundation provides a space for a negotiation between donor and recipient - this is a pure financial transaction and as in all such transactions there is hard negotiation over the price. Once the transplant goes ahead the government provides 1 years of medical insurance plus $900 USD to the donor. The recipient is covered for life for the cost of immunosuppressive drugs (a benefit not yet afforded to Medicare patients in the USA). There is no doubt that the donors were poorer and of lower socio-economic status than the recipients. Whilst many may feel uneasy about the ethics of the process its worth considering the following:

i) The program has delivered transplantation successfully to huge numbers of patients who previously would have been condemned to a life on dialysis. Without such a system patients would have quite simply died - there was no deceased donor program in Iran for many years. For those of us sitting in the luxury of our ivory towers its easy to get queasy about ethics.. for patients such transactions are quite literally a matter of life and death. The Iranian government is currently piloting a 'fixed-price' model which may perhaps remove some of the stress related to the transaction.

ii) the success of the live transplant program has been absolutely instrumental in developing a blossoming brain death donation (BDD) program - whilst change in legislation was the catalyst for the growth in the BDD program,  without the development of a successful live program with associated clinical expertise and infrastructure it is unlikely that the political establishment would have supported the initiation of BDD program.

iii) Disappointingly the live-related transplantation rate has remained relatively low and static over the last 10 years - perhaps confirming the impression that wealthier families would rather buy kidneys form poorer donors rather than 'gift' a kidney to a family member

iv) the Iranian experience is not only important to Iran but crucially provides a template to develop an active, high quality program in other emerging countries as well as in Islamic societies where kidney transplantation rates are often disappointingly low. What works in the USA and Europe often doesn't work in Africa, Asia or the Middle East. What Professor Mahdavi-Mazdeh has shown is that countries need to think outside the 'western paradigm' of transplantation and develop their own 'local' solutions to transplantation. 

v) Critical to the success of the Iranian program is the way clinical leaders engaged with politicians, religious organisations and wider society - irrespective of where we live this is something we can all learn from

vi) In an accompanying commentary, Francis Delmonico from Harvard University, Boston rightly points out that there is no long term outcome data on the donors from Iran.  Furthermore Delmonico states that donors tend to be 'poor, hapless, jobless and largely destitute' and argues that 'the exploitation of the poor that has enabled most Iranian kidney transplantations'. For Delmonico the fundamental unethical aspect of the process is the 'victimisation of the poor'. 

This may well be true and the concerns raised are valid but we need to remember that in many societies ESRD is an immediate death sentence. There is a more than a hint of 'academic imperialism' here - Delmonico does not have to look far to find evidence of 'victimisation of the poor' in healthcare - an astonishing 16% of Americans have no health insurance with catastrophic consequences - public health experts from Harvard estimating that this results in nearly 45,000 extra deaths per year. Now that really is 'fundamentally unethical'......

 

References

 

1. The Iranian model of living renal transplantation. Mahdavi-Mazdeh M. Kidney Int 82: 627-634; advance online publication, June 6, 2012; doi:10.1038/ki.2012.219

2. The Alternative Iranian model of living renal transplantation. Francis L Delmonico. Kidney Int 82: 625-626; doi:10.1038/ki.2012.247

3. Health Insurance and Mortality in US Adults. Wilper Ap et al. Am J Public Health. 2009 December; 99(12): 2289–2295.

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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 (http://bad4umedicine.blogspot.co.uk/) 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....

 

Reference

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 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.
 
References
 
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.
3. Spontaneous remission of nephrotic syndrome in membranous nephropathy with chronic renal impairment. Nephrol Dial Transplant 2012  Jan;27(1):231-4. Epub 2011 May 30. Polanco N, Gutiérrez E, Rivera F, Castellanos I, Baltar J, Lorenzo D, Praga M, Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN)

4. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Fervenza FC, Abraham RS, Erickson SB, Irazabal MV, Eirin A, Specks U, Nachman PH, Bergstralh EJ, Leung N, Cosio FG, Hogan MC, Dillon JJ, Hickson LJ, Li X, Cattran DC; Mayo Nephrology Collaborative Group. Clin J Am Soc Nephrol. 2010 Dec;5(12):2188-98. 

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by Arif Khwaja - Friday, 13 July 2012, 10:34 AM
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Both chronic kidney disease (CKD) and osteoporosis are emerging as major public health problems associated with an ageing population. Osteoporosis is characterised by reduced bone strength resulting in an increased predisposition to fragility fracture. Bone strength itself is a reflection of both bone mineral density (BMD) and bone quality. There is significant co-prevalence of osteoporotic fractures and CKD in the elderly population. The qualitative abnormalities in bone in CKD are reflected in the fact that fracture risk is much higher in both the dialysis and the non-dialysis CKD population and the outcomes of fractures are significantly worse with a 2 to 3 fold increase in mortality after hip fracture in the CKD population compared to the general population.

However the management of bone disease in CKD remains uncertain - the fundamental problem being that we simply do not know whether achieving biochemical 'targets'  (say PTH, calcium phosphorus) or whether the use of therapeutic agents (such as bisphosphonates, calcimimetics or vitamin D)  have any impact on outcomes that matter to patients - like death or fracture rates. Furthermore apart from bone biopsy (which is rarely performed) we don't have any tools to assess bone quality and predict fracture risk.

A recent paper from Yenchek and colleagues is published in this months cJASN and is the first prospective, longitudinal study to specifically test the hypothesis that bone mineral density (BMD) predicts fracture risk irrespective of CKD status. In a cohort of 2754 (of whom 587 had CKD stages 3-5) patients aged between 70-79 years old data was collected on incident fractures over a follow up of 11 years. There were 384 incident fractures and even after adjustment for factors such as age, sex, race, BMI, vitamin D and PTH, low femoral neck BMD as measured by DXA (Dual Energy X-Ray Absorptiometry)was associated with fracture risk irrespective of CKD status. The authors state "This argues against the current KDIGO guideline recommendations and suggests that there may be a role for DXA screening in CKD."

So should we start using DXA to identify fracture risk in CKD and prescribe anti-resorptive therapy to those with reduced BMD? Well I'm not sure I share their view and it is worth considering the following:

i) The study by Yenchek and colleagues is important but only 4% of patients had CKD4/5 so the jury remains out on whether DXA will be useful in CKD4/5

ii) We know from post-hoc analysis from the large registration studies that both Bisphosphonates and Denosumab can reduce fracture risk in osteoporotic patients with CKD3 and CKD4 (down to an eGFR of around 20mls/minute). However, it is worth noting the all patients with abnormal PTH or vitamin D levels were excluded from these studies. Therefore whilst these drugs probably reduce fracture risk in patients with CKD3/4 with 'pure' osteoporosis we simply do not know whether they have any impact in those with evidence of coexistent renal osteodystrophy.

iii) Whilst DXA may identify fracture risk in CKD3 a careful cost/benefit analysis study would need to be performed before such screening could be recommended as routine - indeed it may be cheaper just to focus on non-pharmacological strategies such as reducing risk of falls and improving neuromuscular strength.

iv) A key challenge is how to develop the evidence base for reducing fracture rates in CKD 4 and 5. In the general population huge studies with thousands of patients were required to show a beneficial effect of anti-resorptive therapy. The reality is that it will be almost impossible) to carry out such large studies in the CKD4/5 population - therefore perhaps a more realistic goal is to develop validated surrogate markers of fracture risk in this population (be they biochemical markers of bone turnover combine with bone biopsy data or imaging such as high resolution CT) and then evaluate whether modifying these factors can impact of fracture rates.

 

References

 

  1. Yenchek RH, Ix JH, Shlipack MG, Bauer DC, Rianon NJ, Kritchevsky SB, Harris TB, Newman AB, Cauley JA, Fried LF, for the Health, Aging, and Body Composition Study: Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol 7: 1130–1136, 2012
  2. Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE: Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res 20: 2105–2115, 2005
  3. Jamal SA, Bauer DC, Ensrud KE, Cauley JA, Hochberg M, Ishani A, Cummings SR: Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res 22: 503–508, 2007
  4. Jamal SA, Ljunggren O, Stehman-Breen C, Cummings SR, McClung MR, Goemaere S, Ebeling PR, Franek E, Yang YC, Egbuna OI, Boonen S, Miller PD. J Bone Miner Res. 2011 Aug;26 (8): 1829-35
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by Arif Khwaja - Friday, 29 June 2012, 7:24 AM
Anyone in the world

So when I was a medical student I was taught that colloids were the fluid of choice for the management of septic shock. We were not big on evidence in those days.... it was obvious, colloids expanded plasma volume much more effectively than crystalloid so why wouldn't you use colloid. Well now comes the evidence from the 6S study showing that starch is actually inferior to crystalloid. In this really well designed study  of fluid resuscitation  ICU with either 6% HES (hydroxyethyl starch)  or Ringer's acetate ( a crystalloid solution) at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization. The headline results are as follows:

At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.4 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.4 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09).

So clearly there is no benefit of expensive colloids over cheap crystalloids and in fact they are harmful. All very similar to the use of renal dose dopamine which made great sense on paper until people did the studies to show it was harmful....

 

See

http://www.nejm.org/doi/full/10.1056/NEJMoa1204242?query=featured_home

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