In an editorial comment on the article appearing this month in NDT: Rajan T, Barbour SJ, White CT, Levin A. Low birth weight and nephron mass as a role in the progression of chronic kidney disease: a case report on identical twins with Alport disease.Nephrol Dial Transplant. 2011 May 12. [Epub ahead of print].
I highlighted that although identical twins sharing the same genotype share the same predisposition to nephropathies, that the course of a given nephropathy can vary due to the superimposed environmental factors including the severity of hypertension, its impact on proteinuria, smoking and compliance.
Genetic background impacts on susceptibility to diseases including CKD, but additional hits are needed to trigger and progress the disease. The article published this month in NDT describing the difference course of two identical twins affecetd by Alport's disease makes this point. The authors attributed the different CKD outcome in the two brothers to differences in birth weight with a disadvantage in the twin born with a low birth weight (LBW). I begged to differ...!!!!
In conclusion, as far as the progression of CKD in these two twins is concerned, the devil is in the details . . . or should I say the devil is in the confounders . . . LBW may have been one of the determinants, but others, possibly related or unrelated, such as hypertension, its control and treatment and albuminuria may have had the overwhelming impact on the observed differences in CKD progression. Nature provides good experiments, but life’s confounders make such experiments often less than perfect. Perhaps nature is not perfect or understandable after all!
Read full article in OLA's library
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.
Indexing of Renal Function Parameters by Body Surface Area: Intelligence or Folly? (Pierre Delanaye and Jean-Marie Krzesinski, Liege; Nephron Clin Pract 2011;119:c289-c292) The authors argue that indexing GFR for body surface area (BSA), as in the MDRD equation of estimated GFR (eGFR), could be misleading in certain individuals including obese subjects. This 'Opposite View' is consistent with the view that indexing eGFR to BSA does not necessarily account for changes in serum creatinine generation associated to muscle mass. Eriksen and colleagues recently suggested a modification of estimated GFR to account for total body water (TBW) thus allowing direct comparisons between individuals of different genders, weights, and heights. These authors propose that regression-based normalization of GFR to a standardized TBW of 40 L should replace the current practice of normalizing GFR to 1.73 m(2) of BSA (Eriksen, B.O. et al.: GFR normalized to total body water allows comparisons across genders and body sizes. J Am Soc Nephrol 2011;22:1517-1525).
Diabetic Nephropathy in the Arab Gulf Countries (Youssef Farag, Boston, Mass., and Jamal Al Wakeel, Riyadh; Nephron Clin Pract 2011;119:c317-c323) In this minireview, nephrologists are reminded of the major crisis facing some emerging countries including those of the Arab Gulf in relation to the global epidemic of type 2 diabetes mellitus. Data show that of the five countries with the highest diabetes prevalence in the adult population, four are within the Arab Gulf region - the United Arab Emirates (19.5%), Saudi Arabia (16.7%), Bahrain (15.2%) and Kuwait (14.4%). Such a crisis has to be put in the broader context of the global crisis related to the rise of non-communicable diseases (NCDs) and their impact on cardiovascular mortality in emerging economies. Two of three deaths every year are attributable to NCDs. Four fifths of these deaths are in low- and middle-income countries. Actions based upon changes in lifestyle, promotion of healthy eating and physical activity, salt reduction, accelerated tobacco control and reduction of harmful alcohol consumption are in urgent need of implementation in emerging countries including the Arab world. The Arab world has challenged political systems in 2011, it is high time it also challenges its healthcare systems if they do not address the growing crisis NCDs!
Control of Blood Pressure in Chronic Kidney Disease: How Low to Go? (Anadil Faqah and Tazeen Jafar, Karachi; Nephron Clin Pract 2011;119:c324-c332) The authors expose the issues related to BP target in CKD. Numerous statements suggested that the lower the BP, the slower the progression of CKD. A number of guidelines have stipulated target values around 130/80 mm Hg, and even lower ones in patients with diabetes and those with proteinuria. The evidence upon which these guidelines were based relied primarily on observational data as well as secondary or post hoc analyses of clinical trials and systematic and meta-analyses of heterogeneous data. They are weak at best. As so often in nephrology, evidence is gathered from observational studies that remain unsubstantiated by subsequent attempts at confirmation by RCTs. So often in nephrology, evidence is sought from secondary and post hoc analyses not intended or powered to answer the question raised...! Thus, dogma often prevails enforced by unsubstantiated guidelines...! The assumption that one size fits all with target systolic levels of less than 130 or 120 mm Hg is preposterous. Age, race and comorbidities may dictate different target levels. It is high time that BP-related guidelines in CKD are reviewed. It is also high time that nephrologists base their practice on substantiated guidelines.... And it is high time that nephrologists critically appraise the data submitted to them by 'experts' and refute assertions based on secondary and post hoc analyses as weak at best. We have a long way to go!
Management of Acute Coronary Syndrome in Patients with Chronic Kidney Disease: If We Don't Risk Anything, We Risk Even More (Muhammad Asim, Doha, and Robin Jeffrey, Bradford; Nephron Clin Pract 2011;119:c333-c337) Asim and Jeffrey encourage nephrologists to be more aggressive with investigations and management of CKD patients with symptomatic CAD, but nephrologists also need to be more aggressive in their approach to prevention, risk management and early treatment of CKD patients at risk of CAD. A number of studies have shown that CKD patients with CAD have suboptimal care and risk modification compared to others. In one large report from the United States, control of blood pressure and/or diabetes, management of dyslipidemia, and cessation of smoking were all suboptimally managed in CKD patients (McCullough, P.A. et al: Cardiovascular risk modification in participants with coronary disease screened by the Kidney Early Evaluation Program. Intern Med J 2010;40:833-841)
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.
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%.
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
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.
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
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.
Control of Blood Pressure in Chronic Kidney Disease: How Low to Go?
Anadil Faqah, Tazeen H. Jafar. Nephron Clin Pract 2011;119:c324-c332 (DOI: 10.1159/000331066)
The minireview by A. Faqah and T.H. Jafar exposes the issues related to BP target values in CKD. Numerous statements suggested that the lower the BP, the slower the progression of CKD. A number of guidelines have stipulated target values around 130/80 mm Hg and even lower in patients with diabetes and those with proteinuria. The evidence upon which these guidelines were based relied primarily on observational data as well as secondary or post hoc analyses of clinical trials and systematic and meta-analyses of heterogeneous data. This review exposes the weakness of such evidence. As so often in nephrology, evidence is gathered from observational studies that remain unsubstantiated by subsequent attempts at confirmation by RCTs. So often in nephrology, evidence is sought from secondary and post hoc analyses not intended or powered to answer the question raised...! So often in nephrology, dogma prevails enforced by unsubstantiated guidelines...!
Most RCTs mentioned in the review that attempted to answer whether intensive BP control is beneficial in slowing the progression of CKD failed to show a significant difference in renal functional outcomes. Furthermore, concern about harm has been raised in those submitted to intensive treatment with increased morbidity and mortality.
Finally, the assumption that one size fits all with target systolic levels of <130 or 120 mm Hg is preposterous. Age, race and comorbidities may dictate different target levels. This is becoming apparent in patients on hemodialysis where older and diabetic individuals had higher mortality rates at lower (<140/70 mm Hg) BP levels. More remarkable was the observation in this cohort analysis that survival did not seem to be harmed by higher systolic and diastolic values . In conclusion, it is high time that BP-related guidelines in CKD are reviewed; this is currently underway by KDIGO. It is also high time that nephrologists base their practice on substantiated guidelines.... It is also high time that nephrologists critically appraise the data submitted to them by ‘experts’ and refute assertions based on secondary and post hoc analyses as weak at best. We have a long way to go!
Myers OB, Adams C, Rohrscheib MR, Servilla KS, Miskulin D, Bedrick EJ, Zager PG: Age, race, diabetes, blood pressure, and mortality among hemodialysis patients. J Am Soc Nephrol 2010;21:1970–1978.