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. http://www.ncbi.nlm.nih.gov/pubmed/22894575
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: http://www.ncbi.nlm.nih.gov/pubmed/22450212. 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.
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. http://www.bbc.co.uk/iplayer/episode/b01lt2vn/Inside_Health_Overdiagnosis/
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. http://www.ncbi.nlm.nih.gov/pubmed/18388124) and that those with subclinical cerebrovascular disease also have accelerated CKD decline within the community. http://www.ncbi.nlm.nih.gov/pubmed/20537454
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...!!!!
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 m2 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. Spiegel, Matthew 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
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.
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.
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. . 2010 Dec;5(12):2188-98.