User blog: Meguid El Nahas
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...!!!!
Ciprofloxacin for 7 days versus 14 days in women with acute: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial.
Dr Bassam Saeed submitted this blog to OLA:
BLOG POSTED BY PROF ALAA SABRY:
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.
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
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 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.
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.
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)
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
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...!!!