User blog: Arif Khwaja

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by Arif Khwaja - Wednesday, 16 November 2011, 10:56 PM
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So the maintenance limb of the ALMS study is finally published in this weeks NEJM. Many will be aware that the induction phase of ALMS comparing Cyclophosphamide to MMF showed there was no difference between the two therapies in inducing remission in lupus nephritis (see http://jasn.asnjournals.org/content/20/5/1103.abstract). Patients who responded in the initial phase were then rerandomised to either MMF (2g/day) or Azathioprine (2mg/kg). The steroid dose could go no higher than 10mg and a total of 227 patients were randomised to Azathioprine or MMF in this double blind, RCT. Mycophenolate mofetil was superior to azathioprine with respect to the primary end point, time to treatment failure, time to renal flare and time to rescue therapy. Indeed on all measures MMF was significantly superior to Azathioprine including ESRD and doubling of creatinine. The study really establishes MMF as the treatment of choice for maintenance therapy in lupus nephritis. The findings of the ALMS study is different from the MAINTAIN study (Houssiau F et al Ann Rheum Dis 2010) which showed no difference between Azathioprine and MMF. However the study size was smaller than in ALMS and the study population were predominantly caucasian europeans who perhaps had milder disease than the ALMS cohort. Interestingly the rate of withdrawal due to adverse events was also commoner in the Azathioprine group.

Thus to summarise MMF can be used for both induction and maintenance in lupus nephritis. It is equally effective to cyclophosphamide for induction and superior to azathioprine for maintenance meaning many patients will just need to start and stay on MMF. Interestingly it is likely that KDIGO will reommend that cyclophosphamide be the treatment of choice for induction therapy in patients with severe lupus nephritis - on the grounds that the NIH studies included people with severe disease for whom there is longterm follow up. However the numbers in the original NIH studies were much smaller than ALMS and further analysis will take place of those patients with severe disease in the ALMS study. The ALMS study was a really well conducted and designed RCT  (rare in nephrology!) that has provided an evidence base for managing lupus nephritis.

See http://www.nejm.org/doi/full/10.1056/NEJMoa1014460

 

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by Arif Khwaja - Sunday, 13 November 2011, 11:02 AM
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Final post from Philadelphia! In 1993 the DCCT established the importance of tight glycaemic control in preventing diabetic complications. Now the 22 year follow up data has been presented. Reduction of GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. Thus early aggressive intervention in type 1 Diabetes has lsustained longterm benefits. The data has been simultaneously published in the New England Journal to coincide with the presentation. See NEJM Abstract.

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by Arif Khwaja - Sunday, 13 November 2011, 12:57 AM
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A few more updates from the clinical breaking trials session: Bragga and colleagues from AIMS, India presented a really well conducted RCT in children with steroid-resistant nephrotic syndrome (SRNS) comparing Tacrolimus to Cyclophosphamide. All patients were on the same reducing dose of prednisolone. 131 patients were in the study. the primary endpoint was complete or partial remission at 6 months. 83% of the tacrolimus group achieved the primary endpoint vs 46% of the cyclophosphamide group. This is the first RCT in children comparing these two therapies. Data from the RESCUE study was also presented. This Dutch study randomised transplant patients who had greater than 1 biopsy proven squamous cell carcinoma to either stay on their immunosuppression or switch to Sirolimus. The primary endpoint was recurrence of 1 SCC and the number of new SCCs per patient year. 155 patients were enrolled in the study though the dropout rate approached 50% in the sirolimus arm. In the intention to treat analysis Sirolimus significantly delayed the development and number of new SCCs with a relative risk reduction 48%.

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by Arif Khwaja - Saturday, 12 November 2011, 6:36 PM
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Breaking Clinical Trials Update:

Intriguing data from the FISH study ( FISH oils in haemodialysis patients with grafts). This study assessed the impact of fish oil therapy (deodorised, peppermint flavoured tablets to improve compliance!) in preventing graft thrombosis. It was an RCT with a primary endpoint looking at loss of graft patency at 12 months. patients were allocated therapy or placebo within 7 days of graft insertion. 48% of patients in the fish oil group lost graft patency whilst 62% in control group did BUT this was not statistically significant (p=0.06). However there was a significant reduction in time to graft loss and rate of graft loss in the fish oil group. Furthermore there was a significant reduction in prespecified  secondary endpoints of cardiovascular events (m.i, stroke, chf, cardiac death, PVD etc) and also a significant reduction in blood pressure in the fish oild group. Furthermore the fish oil group required less blood pressure medication at the end of the group.  It maybe that the study was underpowered with regard to graft patenct as certainly all the numbers favoured the effect on graft outcomes with Fish Oils. However the prespecified secondary endpoint results are very interesting... clearly need to await the results of the publication but it seems to me that the data at least justifies carrying out a larger RCT in the HD population

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by Arif Khwaja - Saturday, 12 November 2011, 1:16 PM
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A few highlights from the session on GN:

Hoxha and colleagues from Hamburg analysed a group of patients with membranous GN and found similiar rates of anti-phospholipase A2 receptor (anti-PLA2R) antibodies as other groups at around 69%. They then stained the biopsies for PLA2R and found that in primary memebranous virtually all biopsies were positive for PLA2R whilst in secondary membranous only half the biopsies were positive for PLA2R. If confirmed elsewhere this maybe of clinical utility as a biopsy which is negative for PLA2R may highlight the need to more carefully exclude secondary causes of membranous nephropathy such as malignancy.

Continuing with the membranous theme, Remuzzi's group presented data on 100 patients with membranous GN treated with Rituximab. Baseline creatinine was around 1.1-1.2mg/dl and on average pateints had around 9 grams of proteinuria. Patients had been nephrotic on average for 2 years before being given Rituximab (ie unlikely to go into spontaneous remission), and whilst some patients had had previous immunosuppression no detailed analysis of previous therapy or duration was given. There was good follow up of upto 5 years and virtually all patients achieved complete or partial remission. Clearly we need to await the publication to analyse in more detail but it would seem reasonable to try rituximab in patients with progressive disease who had previously failed treatment with cytotoxics and CNIs. Professor Ponticelli pointed out in the questions section that the prognosis of membranous is actually pretty good and that the old adage that 30% of people progress is probably incorrect ( see http://www.ncbi.nlm.nih.gov/pubmed/21685024)

There was an open label study from Gupta and colleagues AIMS, India looking at tacrolimus induction therapy in a small cohort of 20 patients with predominantly class3/4 Lupus Nephritis. Outcomes seemed to be similiar to historical controls treated with cyclophosphamide. A small series was presented from Lightstone and colleagues looking at using  Tacrolimus as a steroid sparing therapy in pregnant lupus patients. Clearly T-Cell help is a key part of auto-ab production in lupus and there is a need for larger RCTs to evaluate CNIs in lupus nephritis.

Finally long term data was presented from the MEPEX study (http://www.ncbi.nlm.nih.gov/pubmed/17582159) - this had previously shown that plasma exchange in patients with anca associated vasculitis and severe renal disease lead to reduced need for RRT at 3 months. The long term outcomes were disappointing in that although both death and RRT were numerically lower in the plasma exchange group this did not achieve statistical significance - perhaps due to underpowering. The PLEXIVAS study is a new larger study looking at plasma exchange in both severe and mild kidney disease which may help further clarify the role of plasma exchange.

 

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by Arif Khwaja - Friday, 11 November 2011, 11:46 AM
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Proponents of dual RAS blockade have pointed out that the ONTARGET study did not include many patients with heavy proteinuria. At this years ASN, there was a very well conducted RCT from Madrid (F.G. Maria and colleagues) randomising T2  diabetic patients who had significant proteinuria to Lisinopril, Irbesartan or a combination of the two. There was no difference at follow up in proteinuria, eGFR or blood pressure  between any of the groups irrespective of baseline proteinuria. This really adds to the body of data that suggests there is no role for dual blockade in diabetic nephropathy

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by Arif Khwaja - Friday, 11 November 2011, 4:29 AM
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Professor Mathieson presented results from the epic UK Renal Association study into membranous nephropathy. This study ( conducted over 10 years) compared supportive care to Cyclosporin therapy (12 months 5mg/kg/day) to clorambucil/prednisolone for 6 months. Over a 12 year period 108 patients were recruited to the study. Patients had to have declining kidney function to get into the study (>20% decline in GFR over 3 months) and therefore this study claims wih some justification to be the first clinical trial of membranous nephropathy specifically looking at this high risk cohort of patients. The primary endpoint was time to further decline in GFR by 20%. At 3 years follow up 40% of the chlorambucil/prednislolone group has not experienced this decline in kidney function whilst only  16-18% of the supportive and CyA groups had not experienced this decline in kidney function.  There was a greater reduction in proteinuria in the chlorambucil group. Serious adverse events were more common in the chlorambucil group but also common in the CyA group. In summary cytotoxic therpay is beneficial in slowing down kidney function decline in patients with declining idney function due to membranous GN but at a price of higher risk of infections.

 

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by Arif Khwaja - Friday, 4 November 2011, 11:57 AM
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A number of comments about the BEAM study ( Bardoxolone Methyl in Diabetic nephropathy) were posted on OLA a few months ago. Concerns raised by Professor El-Nahas amongst others was that the serum creatinine was used to estimate GFR and there was no formal measurement of GFR. these concerns have been echoed by a number of others in letters to the editor in this weeks New England Journal of Medicine. In particular Rogacev and colleagues point out that "Patients receiving bardoxolone had a significant weight loss of 7.7 to 10.1 kg, as compared with a weight loss of 2.4 kg in the placebo group" which in itself could account for the changes in eGFR. Others raised the possibility of whether Bardoxolone Methyl had an effect on tubular secretion of creatinine. Pergola and colleagues respond to these criticisms by saying that the reductions in urea, phosphate and uric acid cannot be explained by an effect on tubular secretion of creatinine. Furthermore they point out the potential difficulties of using Cystatin C as a measure of GFR but fail to answer the central question about the study... whether they have any evidence to show that Bardoxolone Methyl has any impact on measured GFR

See:
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by Arif Khwaja - Wednesday, 26 October 2011, 10:20 AM
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A number of trials have shown benefit of N-acetylycysteine (NAC) in preventing contrast nephropathy. One of the difficulties in interpreting the data with NAC is that it can promote the tubular secretion of creatinine - i.e. beneficial effect of NAC may simply reflect this rather than be truly nephroprotective. In our institution we use oral NAC and hydration to protect against contrast nephropathy - again Ive always found this confusing given the generally poor oral bioavailability of NAC.
A recent large RCT (published in Circulation) suggests that oral NAC has no beneficial effect beyond simple hydration in the prevention of contrast nephropathy. In this study 2308 patients undergoing an angiography with at least 1 risk factor for contrast-induced acute kidney injury (age >70 years, renal failure, diabetes mellitus, heart failure, or hypotension) were randomised to NAC 1200 mg or placebo. NAC 600mg twice daily orally was given for 2 doses before and 2 doses after the procedure. There was no difference in contrast nephropathy, dialysis or death in the two groups.
These results contrast with a few earlier studies suggesting that NAC was benefcial. Marenzi and colleagues in a previous smaller study of 354 patients had shown there to be a dose-dependent positive effect of NAC in patients undergoing angioplasty on a combined endpoint of death, RRT and need for mechanical ventilation. However in this study intravenous doses of NAC (600mg and 1200 mg ) were given prior to the procedure whilst oral doses were given post-procedure.
An earlier study from Kay and colleagues in Hong Kong in a smaller cohort did show a beneficial effect of oral NAC - but again the primary endpoint was a rise in creatinine and given the effects of NAC on creatinine secretion this data is hard to interpret.
In summary I think this large study shows that there is no beneficial effect of oral NAC on contrast nephropathy. There is data to support the use of IV NAC so for the time being clinicians should probably use either IV NAC with hydration or hydration alone to prevent contrast nephropathy.
 
 
References
 
1. ACT Investigators. Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography: Main Results From the Randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT). Circulation. 2011 Sep 13;124(11):1250-9.
 
2. Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli AL. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006 Jun 29;354(26):2773-82.

3.Kay J, Chow WH, Chan TM, Lo SK, Kwok OH, Yip A, Fan K, Lee CH, Lam WF. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA. 2003 Feb 5;289(5):553-8.

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by Arif Khwaja - Wednesday, 26 October 2011, 8:00 AM
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Last year there was much excitement when Kain and colleagues appeared to have made a significant breakthrough in the understanding of the pathogenesis of ANCA associated vasculitis. They reported that over 90% of patients with ANCA disease had lysosomal associated membrane 2 (LAMP2) antibodies and that these antibodies could trigger a crescentic glomerulonephritis when injected into rats. Furthermore LAMP2 antibodies appeared to be triggered by bacterial infections - infection with fimbriated gram negative bacteria such as E-Coli would result in the production of auto-antibodies against LAMP2 due to molecular similarity between the bacterial and LAMP2 epitopes.
In this months JASN, Falk and colleagues attempted to replicate these results in 329 patients with ANCA vasculitis from Chapel Hill and Massachusetts General Hospital. In this cohort anti-LAMP2 reactivity was only present in 21% of patients and administration of anti-LAMP2 antibody to rats did not produce a glomerulonephritis. There was no correlation between anti-LAMP2 titres and disease activity and sera from patients did not cross react with recombinant LAMP2.
Therefore in contrast to the studies from Kain this data suggests that the LAMP2/bacterial infection hypothesis is not relevant in ANCA-associated disease. Whether this is due to methodological differences between the two groups or differences in the population studied will only be clear when data from other groups are published.

References:

1. Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, Davidovits A, Raab I, Jahn R, Ashour O, Spitzauer S, Sunder-Plassmann G, Fukuda M, Klemm P, Rees AJ, Kerjaschki D. Nat Med. 2008 Oct;14(10):1088-96. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis.

2. Roth AJ, Brown MC, Smith RN, Badhwar AK, Parente O, Chung HC, Bunch DO, McGregor JG, Hogan SL, Hu Y, Yang JJ, Berg EA, Niles J, Jennette JC, Preston GA, Falk RJ. J Am Soc Nephrol. 2011 Oct 21. Anti-LAMP-2 Antibodies Are Not Prevalent in Patients With Antineutrophil Cytoplasmic Autoantibody Glomerulonephritis.

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