User blog: Arif Khwaja
The Raimipril Efficacy in Nephropathy (REIN) study has perhaps been one of the most influential studies in clinical nephrology over the last 20 years. It is cited as a seminal study in justifying the use of ACEi in proteinuric CKD though careful reading of the study shows that ACEi had little benefit on progression when the baseline proteinuria was less that 1.5 g/24hours and it's also with noting that the baseline GFR was better in the Ramipril group.
2 post-hoc analyses of the REIN study have been published this year - one implying that obese patients are more likely to benefit from ACEi and the second showing an association between the baseline serum phosphate and the response to ACEi.
I always find the value of post-hoc analysis difficult to interpret. I never quite know what the authors are trying to say. At best they can be hypothesis-generating but all too often they appear to be statistical quirks - Phosphate is a marker of kidney function and patients with worse kidney function are more likely to progress to ESRD .... Thus it's perhaps not surprising that those with worse serum phosphate are more likely to progress. i.e. The combination of serum phosphate and GFR may more accurately kidney function than GFR alone. Of course the other possibility as the authors suggest is that phosphate per se interferes with the response to ACEi and maybe a target for CKD progression. The only way this could be addressed is by a clinical trial assessing the impact of phosphate lowering on CKD progression.
1.Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect= of ACE Inhibition. Carmine Zoccali, Piero Ruggenenti, Annalisa Perna, Daniela Leonardis, Rocco Tripepi, Giovanni Tripepi, Francesca Mallamaci and Giuseppe Remuzzi for the REIN Study Group.J Am Soc Nephrol 2011, 1923-1930
2.ACE inhibition is renoprotective among obese patients with proteinuria. Mallamaci F, Ruggenenti P, Perna A, Leonardis D, Tripepi R, Tripepi G, Remuzzi G, Zoccali C; REIN Study Group. J Am Soc Nephrol. 2011 Jun;22(6):1122-8
As with many practices in nephrology, dialysis scheduling has evolved through historical accident rather than clinical design. Most patients around the world will dialyse 3 times a week for 3-4 hours either on a Monday, Wednesday and Friday or a Tuesday, Thursday, Saturday. This utilitarian approach has evolved through a combination of economic and capacity associated factors rather than any solid evidence base. Two randomised controlled trials ( the Frequent Hemodialysis Network study and the Canadian Frequent Nocturnal Hemodialysis Study) have shown improvements in surrogate markers such as left ventricular mass index and mineral metabolism in patients dialysed six times a week. Neither study was powered to evaluate the impact on mortality alone. Furthermore its long been recognised that sudden cardiac death is a common cause of cardiac death amongst dialysis patients. A study published by Rob Foley from the USRDS in this weeks NEJM highlights some interesting data. In an analysis of over 32000 haemodialysis patients the authors evaluated all-cause mortality and hospital admissions on the day after the long dialysis interval ( i.e. Monday or Tuesday) as compared to the rest of the week. All-cause mortality, mortality from cardiac causes, infection-related mortality, mortality from cardiac arrest, mortality from myocardial infarction and admissions for myocardial infarction, congestive heart failure, stroke, dysrhythmia and any cardiovascular event were all higher on the day after the long dialysis interval than on other days. While clearly one cant ascribe causality from observational data, it is interesting that mortality rises incrementally during the long interval and supports the observations of some that the long dialysis interval is a time of heightened cardiovascular risk due to metabolic disturbance. The data provides a compelling reason to do an adequately powered randomised controlled trial examing the impact of dialysis frequency and duration on clinical outcomes - though the logistical and funding issues around such a trial would be challenging to say the least.
Reference: Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis. Foley, Robert N. M.B.; Gilbertson, David T. Ph.D.; Murray, Thomas M.S.; Collins, Allan J. M.D. The New England Journal of MedicineIssue: Volume 365(12), 22 September 2011, p 1099–1107
There has been recent discussion of how to develop a vibrant transplant program in low income/developing economies. An inspiring article is published in this months AJT by Rizvi and colleagues in the Sindh Institute of Urology and Transplantation, Karachi, Pakistan charting the development of a renal replacement therapy program over the last 30 years.
Pakistan has a population of 184 million and 60% of the population live on less than $2USD a day. Yet the cost of dialysis in the private sector is upto $25USD per session whilst transplantation can cost upto $10000USD. Whilst treatment in the government sector is free the facilities are scarce with government dialysis centres only accounting for 38.5% of dialysis centres in the country. Only 1.3 % of GDP is spent on healthcare by the government. The result of this bleak economic backdrop is that the authors estimate that over 90% of the ESRD population being disenfranchised from RRT. Central to the success of this centre in developing a vibrant transplant and dialysis program has been it's ability to secure sustainable funding which has involved partnership with government, the community and business to sponsor individual patients, equipment and staffing resources. This unique partnership has enabled investment in human and physical infrastructure developing a sustainable RRT program.
Interestingly the institute has campaigned hard for the instigation of a transplant law that outlaws commercialism in transplantation - this actually resulted in an increase in transplant activity at the centre with a rising rate of live related donation amongst the relatives of wealthy patients who were no longer able to 'buy' kidneys. Despite the failure of a deceased donor program to take off, the centre transplanted 544 patients in 2009 and dialysed over 1300 patients. The success of the transplant program has enabled more people to be offered dialysis and the authors strongly argue that free transplantation has allowed the development of an altruistic donor program.
For those of us working in wealthy societies it is difficult for us to comprehend the decisions made by clinicians and patients in such countries. Rizvi and colleagues have achieved extraordinary things in an extraordinary environment - see here
A couple of interesting hypothesis-generating studies have been published recently suggesting that Allopurinol may have a beneficial effect on endothelial function in CKD. Elevated uric acid levels have been associated with endothelial dysfunction in humans and experimental animal data suggests that uric acid may elevate blood pressure via a number of mechanisms including oxidative stress, endothelial dysfunction and activation of the renin-angiotensin system. Rick Johnson and colleagues have postulated that dietary fructose leads to chronic state of ATP depletion that ultimately results in hyperuricaemia and have hypothesized that Allopurinol may have BP-lowering effects
In a recent study from Dundee, Kao and colleagues (see http://jasn.asnjournals.org/content/22/7/1382.long) performed a randomized, double-blind, placebo-controlled study in patients with stage 3 CKD and left ventricular hypertrophy (LVH). 67 subjects were randomized to allopurinol at 300 mg/dy or placebo for 9 months. In this study allopurinol resulted in a small but significant reduction in LV mass index (as assessed by cardiac MRI) even after correcting for age, blood pressure and baseline LV mass index. There were improvements in endothelial function as measured by flow mediated dilatation and arterial compliance and arterial wave reflection as measured by a reduced augmentation index. The authors conclude that the mechanism by which LVH was reduced was by the impact of allopurinol on arterial afterload – indeed this is the first study to show regression of LV mass index independently of blood pressure.
In the second study, Johnson and colleagues from Ankara (see http://cjasn.asnjournals.org/content/6/8/1887.long ) took 30 patients with normal kidney function and asymptomatic hypeuricaemia were randomized to 4 months treatment with allopurinol 300g/day. This group was compared to 30 hyperuricaemic controls and 37 normouricaemic controls. Interestingly in this study Allopurinol t resulted in a decrease in systolic BP (but not diastolic), an increase in flow mediated dilatation, and an increase in eGFR compared with baseline. Kidney function was effectively normal (eGFR assessed by cockroft-gault) but the blood pressure was rigorously evaluated using 24 hour blood pressure monitoring suggesting the effect was real. Why blood pressure fell in this study but not in the Kao study may be due to a number of reasons including small sample size and possibly differential effect of allopurinol depending on kidney function.
Either way both studies generate interesting data that suggest that allopurinol is a cheap therapeutic that warrants further investigation in CKD.
Results from the ORION study are published in this months AJT. This study involved 469 de-novo standard risk allografts who were randomised to either
1) Sirolimus and Tacrolimus aiming for Tacrolimus withdrawal at 3 months.
2) Sirolimus +MMF
3) Standard therapy with Tacrolimus and MMF.
All groups got Daclizumab induction and steroids. Due to higher rate of rejection the MMF+Sirolimus arm was terminated early in the study. The primary endpoint was Nankivell GFR at 12 months and there was no difference between standard therapy (group 3) and CNI withdrawal in group 1. The CNI-withdrawal group did not have any advantage over standard therapy with tacrolimus and MMF: patient (97.0% vs. 94.4%) and graft survival (95.4% vs. 88.5%), renal function (62.0% vs. 59.1 mL/min), rejection prophylaxis (12.3% vs. 17.4% biopsy-proven rejections), discontinuations (35.2% vs. 65.1%) representing overall tolerability and adverse events such as oedema (36.7% vs. 51.3%), anaemia (36.0% vs. 40.8%), hyperlipidaemia (20.1% vs. 36.8%), proteinuria (6.5% vs. 11.2%) and wound healing disorders including lymphoceles (14.4% vs.32.8%). Dyslipidaemia and thrombocytopenia and acne were significantly worse in the CNI withdrawal group whilst other secondary outcomes such as proteinuria whilst worse in the CNI withdrawal group did not reach significance.
Overall the study is consistent with the prevailing belief that Tacrolimus and MMF should be the standard therapy in renal transplantation at the moment both in terms of outcomes and tolerability. whether there is a role for switching from CNI to Sirolimus at a later date is not clear and is an issue that is being explored by the 3C Study in the UK which is evaluating the role of Alemtuzumab and steroid avoidance followed by switching from Tacrolimus to Sirolimus at 6 months. For the time being the role of Sirolimus in transplant immunosuppression remains unclear. (see Flechner SM et al. American Journal of Transplantation. Volume 11, Issue 8, pages 1633–1644, August 2011)
Progressive kidney disease remains a key clinical problem facing nephrologists all over the world. Despite the plethora of in vivo studies suggesting new therapies there has been an abject failure to translate these findings into meaningful clinical studies. This is partly because pharma have been reluctant to take on CKD as a therapeutic area given the inherent difficulties and expense of conducting a trial in this area. So Warnock and colleagues should be congratulated on completing a phase 2, randomized control trial assessing the effects of Bardoxolone Methyl (an oral anti-inflammatory and anti-oxidant) on progression of kidney disease in Type 2 Diabetes, which were presented this week at the EDTA and have now been published online in the New England Journal of Medicine (see here).
Bardoxolone methyl is an antioxidant inflammation modulator that activates the Keap-Nrf2 pathway, which is a key regulator of the body’s natural antioxidant, anti-inflammatory response to injury. Oxidative stress and inflammation are thought to be key drivers of the fibrotic process in CKD inducing structural changes within the glomerulus. In vivo data indicates that the Keap-Nrf2 pathway is suppressed in models of kidney fibrosis whilst there is a simultaneous increase in oxidative stress and inflammation. Thus the hypothesis underpinning the trial was that Bardoloxone Methyl could be protective in progressive kidney disease by inducing an antioxidant, anti-inflammatory response that would inhibit proinflammatory transcription factors such as nuclear factor κB
The BEAM study involved assigning 227 adults with type 2 diabetes and an eGFR of 20 to 45 mL/min per 1.73 m2 of body surface area to 1 of 4 groups: bardoxolone 25 mg, 75 mg, or 150 mg once daily, or placebo. Virtually all patients were on ACE-I or ARBs. At 24 weeks, there was significant improvement in eGFR in all bardoxolone methyl groups, as compared with the placebo group, with mean differences per minute per 1.73 m2 of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group (P<0.001 for all comparisons). The improvement in eGFR occurred within 4 weeks, peaked at 12 weeks and was maintained at 24 and 52 weeks. Bardoxolone Methyl therapy was associated with lower blood urea, uric acid, serum phosphorous and magnesium concentrations. It was generally well tolerated though muscle spasms and elevations in alanine aminotransferase were an issue. There was a slight, but significant increase in albuminuria with Bardoxolone Methyl.
Whilst the results of this trial are promising a number of issues arise from the study:
- The improvement in serum creatinine may simply reflect increased tubular excretion of creatinine rather than improvement in kidney function per se. The authors acknowledge that future trials need to formally measure GFR rather than just use the serum creatinine – though previous studies suggest that Bardoxolone Methyl does not impact on creatinine production or excretion. The changes in magnesium concentration suggest tubular toxicity may be an issue however the improvement in serum urea would suggest that the improvement in serum creatinine truly reflects improvements in glomerular filtration. This is a key issue for all trials in progressive kidney disease – how to measure kidney function and clearly the serum creatinine has significant limitations.
- The mechanism of action of improvement in eGFR is not clear – the fact that eGFR improved within 4 weeks suggest that the observed effects cannot have been due changes in glomerular structure but rather actions on glomerular inflammation and haemodynamics. No renal biopsies were performed to address this question however the data suggests eGFR is not determined solely by glomerular structure.
- There was no decline in kidney function in the placebo group (perhaps reflecting low levels of albuminuria) and its difficult to interpret the clinical significance of these results. A double-blind, placebo-controlled Phase 3 outcome study (BEACON) with cardiovascular disease and dialysis as key endpoints will help address this.
There is some nice data in this months cJASN from the Mayo clinic describing the results of extended follow up of screening for intracranial aneurysms (IAs) in patients with ADPKD. Four hundred and seven ADPKD patients were screened with MRA for asymptomatic IAs between 1989 and 2009. 38 patients were found to have IAs on screening equating to a prevalence of around 9%. The prevalence of unruptured IA (UIAs) amongst patients with a family history of IA and/or subarachnoid haemorrhage (SAH) was estimated at 21% whilst the prevalence of UIAs with no family history was much lower at 6.3%. During cumulative imaging follow-up of 243 years in only 3 patients did a de novo IA develop or increase in size.
Depending on case series the annual risk of rupture of IAs seems to be around 1.5 per year but the risk unsurprisingly is much less when Iess than 10mm. The authors conclude that screening MRA should be offered to those patients with a positive family history of aneurysmal rupture or to those with multiple family members with IAs. In such patients who are screened and found to have no IAs they recommend re-screening at 5 years. The risks of screening are made even more complex by the risks of intervention for IAs (either surgical or radiological). The data presented here justifies a selective approach to screening based primarily on family history. Click here for abstract.
Final data from the Study of Heart and Renal Protection (SHARP) was presented at this weeks UK Renal Association and published in the Lancet online this week.The SHARP study was an RCT that involved 9270 patients with chronic kidney disease (of whom 3023 participants were dialysis-dependent), who were randomly assigned to receive simvastatin 20 mg daily plus ezetimibe 10 mg daily, or placebo, and followed up for a median of 4·9 years. There was a significant 17% proportional reduction (RR 0·83, 95% CI 0·74—0·94; log-rank p=0·0021) in major atherosclerotic events (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or arterial revascularisation) among those allocated to active treatment. There was also a significant one-fifth reduction in major vascular events (ie, major atherosclerotic events plus non-coronary cardiac deaths) amongst patients randomised to active lipid-lowering treatment. Whilst at first sight the effect appears more convincing in the non-dialysis population there is no statistical difference in outcomes between the dialysis and non-dialysis population. Reassuringly lipid lowering was safe and was not associated with cancer or rhabdomyolysis. As in previous trials there was a slight excess of haemorrhagic stroke in the lipid lowering group. there was no effect on CKD progression with lipid lowering.
The obvious question that arises is why do the results of SHARP appear to be positive when previous studies in the dialysis (4D and AURORA) population appear to be negative. However coronary revascularisation was not part of the primary endpoint in 4D and AURORA and the authors argue convincingly that the LDL-cholesterol-weighted proportional effects in AURORA, 4D and SHARP were statistically compatible for non-fatal myocardial infarction, non-fatal haemorrhagic stroke, non-fatal non-haemorrhagic stroke. Thus the results of SHARP are consistent with the effects of Cholesterol Treatment Trialists' (CTT) Collaboration metanalysis that shows statin therapy reduces the risk of myocardial infarction or coronary death, stroke, or coronary revascularisation by about a 20% per 1mmol/l reduction in LDL cholesterol. Furthermore the SHARP study included a large number of non-dialysis patients in whom the pathophysiology of cardiovascular disease maybe more similar to the general population.
So where does this leave the practicing clinician ? It seems that there is now good evidence to support lipid lowering in CKD patients as a primary prevention therapy to reduce cardiovascular events. This seems to be clear for the non-dialysis population ( even if they progress to renal replacement therapy) but the evidence is perhaps less clear in those on lifelong dialysis. For those who dont have access to ezetimibe the overall potency of the simvastatin+ezetimibe combination was broadly equivalent to atorvastatin 20 mg daily, rosuvastatin 10 mg daily, and fluvastatin 40—80 mg daily.
Interesting data is presented in this months JASN from Colin Hutchinson in Birmingham, UK presents data ( from Birmingham and Rochester) suggesting that early and aggressive reduction of serum free light chains (FLCs) associates with renal recovery in myeloma kidney. 39 patients with biopsy-proven myeloma kidney, the majority of whom had severe renal failure at presentation (median estimated GFR 9 ml/min per 1.73 m2) were analysed to see which variables associated with renal recovery. In a multivariable analysis FLC reduction significantly predicted renal recovery (P = 0.003). The relationship between renal recovery and FLC reduction was linear with a 60% reduction in FLCs by day 21 associated with recovery of renal function for 80% of the population. Unsurprsingly patient survival strongly associated with renal recovery: the median survival was 42.7 months (range 0 to 80) among those who recovered function compared with 7.8 months (range 0 to 54) among those who did not (P < 0.02). Patients had variable treatment but treatment broadly consisted of a combination direct removal of FLCs and aggressive chemotherapy often using bortezomib. In Birmingham FLC removal was achieved using extended hemodialysis using a protein permeable dialyser whilst plasma exchange was used in Rochester. This data suggests that early reduction of FLC aids renal recovery but also that the FLC immunoassay is an essential quantitative tool in monitoring response to therapy in multiple myeloma. For further details see http://jasn.asnjournals.org/content/22/6/1129.abstract
An excellent randomised controlled trial is published in this weeks New England Journal of Medicine, from the INTAC study group, based at the University of Alabama, Birmingham, looking at the role of Alemtuzumab induction and steroid sparing immunosuppression. Alemtuzumab is a humanised anti-CD52 monoclonal antibody targeting both B and T lymphocytes. Increasingly a number of centres are using Alemtuzumab induction to enable steroid free immunosuppression. This RCT compared Alemtuzumab to Basiliximab for low risk recipients and Alemtuzumab to ATG for high risk recipients in patients on Tacrolimus and MMF with steroids being stopped after one week. High risk was defined as second allograft, black race or panel reactivity greater than 20%. Alemtuzumab was given as a single dose of 30mg. With respect to the 139 high risk patients there was no difference in biopsy proven acute rejection between the ATG group and Alemtuzumab with rejection rates of 18% vs 15%. in the low risk group the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab : 12 months (5% vs. 17%, P<0.001) and at 3 years(10% vs. 22%, P=0.003)There are some slightly concerning results however. Whilst the overall rejection rate was lower with Alemtuzumab the late rejection rate (between 12 and 36 months was higher). Further lymphopaemia persisted in Alemtuzumab group for well over 2 years. Overall the Alemtuzumab group had a slightly (and significantly) higher rate of cancer. Furthermore whilst the infection rate was lower than ATG it was higher when compared to Basiliximab.