UKidney Blog

In a stunning development, Novartis said Tuesday that it will terminate the late-stage ALTITUDE study investigating Rasilez (aliskiren) in patients with type 2 diabetes and renal impairment on the recommendation of an independent data monitoring committee. The company indicated that the committee concluded that "patients were unlikely to benefit" from the addition of Rasilez to standard anti-hypertensives and also identified higher adverse events in this group (source: FirstWord).

On a personal and professional note, these results come as a great disappointment to me. Not only does it suggest no further protection for our patients prescribed this strategy in an effort to reduce the burden of cardiorenal disease, but I was a great believer in the hypothesis and taught about it extensively throughout my career.

The long awaited ROADMAP trial was recently published in the New England Journal of Medicine. This randomized controlled trial enrolled 4,447 patients to determine whether treatment with the angiotensin receptor blocker olmesartan could delay or prevent microalbuminuria.

In the study, blood pressure was targeted at less than 130/80 mmHg, yet patients randomized to the ARB group had a lower clinic blood-pressure by 3.1/1.9 overall. The time to onset of microalbuminuria was increased by 23% in the olmesartan group [hazard ratio for the onset of microalbuminuria 0.77; 95% confidence interval, 0.632 0.94; P=0.01]. However surprisingly, there was fewer cardiovascular deaths in the placebo group [3 versus 15, P=0.01].

This fascinating video discusses the concept of organ generation as a method of bridging the enormous gap between supply and demand that exists among patients who experience organ failure.

This may well move from science fiction to the mainstream in the not-too-distant future.

Click 'Read more' below to see the video

This is a great post on chloroquine in lupus. It appears as below on Skin and Allergy News. A great and promising read:

SNOWMASS, Colo. – The past 12 months have brought a slew of studies making a persuasive case for hydroxychloroquine as a far more important drug in lupus than previously thought. Indeed, the drug could now even be considered essential.

"In 2011, all lupus patients should receive hydroxychloroquine," Dr. David Wofsy flatly declared at a symposium sponsored by the American College of Rheumatology.

"The indication for hydroxychloroquine in lupus is lupus," added Dr. Wofsy, professor of medicine and microbiology/immunology at the University of California, San Francisco.

There is now solid evidence that hydroxychloroquine (Plaquenil) prevents lupus flares, treats the skin manifestations of the disease, protects against thromboembolic events, prevents cardiac neonatal lupus, and prolongs life.

"It will be a very long time before we've proven that any biologic therapy can do all those things," Dr. Wofsy, who is also chief of rheumatology at the San Francisco Veterans Affairs Medical Center.

The Planet 1 and 2 studies are not widely publicized. However, they do provide some eye-opening information.

According to these studies, in patients with diabetes and intact renal function, there was a significant decline in renal function and failure to reduce urinary protein in patients randomized to rosuvastatin but not atorvastatin. Furthermore, there were more renal events in the rosuvastatin group (doubling of serum creatinine and episodes of acute renal failure).

These results are very surprising and difficult to rationalize at face value. Nevertheless, the design of the trials appears sound and the number of patients adequate.

Dr. Marecllo Tonelli from the University of Alberta walks us through this data in his outstanding presentation seen here on UKidney

The SHARP study was reported at the American Society of Nephrology Meeting in Denver on November 20th, 2010. The results are positive. This is excellent news indeed when previous lipid trials in patients with renal failure were a disappointment.

Here is a summary of the key findings:

• The patients allocated to take ezetimibe plus simvastatin had one-sixth fewer heart attacks, strokes or operations to unblock arteries ("major atherosclerotic events"), with similar reductions observed in all types of patient studied.
• During this long trial, the proportion of patients who stopped taking their allocated treatment was about one third, but this was not generally due to side-effects and was the same for both real and dummy treatments. If taken without interruption, however, ezetimibe plus simvastatin could have even larger effects than were seen in SHARP, potentially reducing risk by about one quarter.
• Adding 10mg daily of ezetimibe to 20mg daily of simvastatin produced a large reduction in LDL cholesterol safely. This combination treatment may be particularly good for kidney patients, as it avoids the possibility of side-effects with high statin doses.
• There was no support for previous concerns with ezetimibe about possible adverse effects on cancer, and no evidence of an increased risk of muscle or liver problems.

(Source: http://ukid.cc/atgiPN)

As with any study, a complete critical appraisal should be done on the published article once available. One key question is whether the observed benefit was the result of ezetimibe or simply the result of lower LDL in the treatment group, regardles how obtained (i.e. with higher statin dosing).

As nephrologists with a significant interest in mineral metabolism practicing in Ontario, we are writing to inform you about a class review of all phosphate binders in end-stage renal disease that has been initiated by the Ontario Public Drug Program to evaluate and review their funding, as well as associated reimbursement criteria.

Controlling serum phosphorus, serum calcium and secondary hyperparathyroidism is a day-to-day challenge in the management of patients with end-stage renal disease on dialysis. Strategies to limit dietary phosphate intake and/or increasing the frequency or duration of dialysis when possible do not succeed in maintaining serum phosphate levels below 1.8 mmol/L and the majority of our patients require the use of oral phosphate binders in addition.

Calcium salts are the mainstay of pharmacological treatment, but many of our patients develop hypercalcemia and vascular calcification. The limitations associated with calcium salts have led to the development of newer non-calcium based agents, such as sevelamer and lanthanum, which have been widely adopted and funded worldwide. Other major Canadian provinces, including Quebec and British Columbia, also reimburse them. In Ontario, we have limited or no access to these drugs and we are concerned that this class review could result in further restrictions.

The recently published comprehensive evidence-based clinical practice guidelines^1,2 stress the importance of maintaining serum phosphorus and calcium levels within an acceptable range. The Ontario Renal Network's (ORN) Clinical Advisory Committee has also established the percentage of dialysis patients who achieve a phosphate level of less than 1.8mmol/L as one of three patient outcome quality indicators for dialysis patients. http://www.renalnetwork.on.ca/quality/ Although the recent guidelines acknowledge the fact that there is limited evidence from randomized controlled clinical trials on the longer-term clinical outcomes, they support the need for a non-calcium based strategy in patients with high serum calcium levels.

While we acknowledge that the evidence from clinical trials to date does not entirely support the use of non-calcium based phosphate binders, we also believe that the federal and provincial committees responsible for recommending exclusion of these agents in the formularies have simultaneously ignored the evidence for harms arising from the use of calcium-based binders in the control subjects. Thus the need for access to non-calcium based phosphate binders should focus around issues of patient safety, and not simply those related to cost.

We would like to hear your opinions on this subject. We are also interested to learn whether terms of references have been established for this phosphate class review and whether the Ministry has involved the Ontario nephrology community, the Ontario Renal Network or the Ontario Association of Nephrologists

It is prevailing wisdom that patients with chronic kidney disease (CKD) progress more slowly if their blood pressure is well controlled. In fact, most modern guidelines suggest that for patients with CKD, a blood pressure of 130/80 should not be exceeded.

In the latest issue of the New England Journal of Medicine, investigators cast doubt on this widely-held belief. In this anticipated report, patients with CKD but without proteinuria (<300 mg per day) and blood pressure targets of 140/90 fared equally well to those with blood pressure targets of 130/80. However, in those with protein excretion above 300 mg per day, the lower blood pressure target was superior. The authors conclude that in non-proteinuric patients, we should be targeting a less stringent goal of <140/90.

While these data are very interesting, one should pay close attention to what was considered proteinuria. A cutoff of 300 mg per day is a very low threshold; meaning, that many patients with hypertension may still benefit from the lower target. This trial is a very welcome one but take care not to paint all hypertensive patients with the same brush.

Any news on promising treatments for Lupus is always welcome. Indeed, it has been years since any new therapies have provided much new hope for a disease which has very significant renal implications.

Benlysta is an investigational human monoclonal antibody drug and the first in a new class of drugs called BLyS-specific inhibitors. These drugs prevent b-cell proliferation and development in to mature plasma cells with a resuling drop in antibody production. This mechanism of action is very well-suited to Lupus whose pathophysiology is widely thought to involve autoantibody formation.

Results of phase-3 clinical trials have been previously reported showing positive results, a first in many years for the management of lupus. As a result,  the drug has been granted a priority review designation by the FDA (Food and Drug Administration, USA), an indication that this drug has an important role in managing lupus as other medications have left much to be desired.

What is not clear however, is the role that this medication will have in the management of lupus nephritis as it seems that these patients were excluded from the initial trials.

Genome-wide association studies have previously shown a strong signal between a region residing on chromosome 22 centered on MYH9 and African Americans with FSGS and hypertension attributed end-stage kidney disease (H-ESKD). On July 15, 2010, Science released online a publication revealing a strong association between the same but expanded interval containing a nearby gene encoding for apolipoprotein L-1 (APOL1) in a similar group of patients.

The investigators, led by Dr. Martin Pollak, the chief of the Division of Nephrology at Boston's Beth Israel Deaconess Medical Center, reasoned that because no causal mutations have been identified in MYH9, other alleles ought to be considered. Furthermore, recent selection pressures in Africans could lead to longer patterns of linkage disequilibrium (LD). More, but previously unavailable, data from African individuals whose DNA were sequenced in the 1000 Genomes Project (www.1000genomes.org) was used to identify polymorphisms that showed large frequency differences between Africans and Europeans.

This week in the New England Journal of Medicine, 2 studies reported on the use of mTor inhibitors in Autosomal Dominant Polycystic Kidney Disease (ADPKD). The results were mixed but overall, disappointing.

In the first study, investigators used open label sirolimus versus standard care in 100 patients with ADPKD and mean GFR of 70 ml / min, (stage 2 chronic kidney disease). After 18 months, there was no difference in kidney volume nor kidney function between the 2 groups while the sirolimus group had higher urinary albumin excretion.

In the second study, a 2-year, double-blind trial, 433 patients were randomly assigned to receive placebo versus everolimus. After 24 months there was less kidney volume but the mean decrement in the estimated glomerular filtration rate after 24 months was the same: 8.9 ml per minute per 1.73 m² of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). There were more side effects in the treatment group.

I had been awaiting these studies with great anticipation but the results over-all are disappointing, namely because renal function was no better in the treatment groups. It is not clear how to explain the disconnect between reduction in cyst growth in the everolimus group yet no change in kidney function. There is little doubt that cyst volume is a less important outcome than renal function, however, it is hoped that with longer term studies, possibly earlier in the course of the disease, that the sustained control of cyst growth by everolimus could lead to preservation of renal function. I hope to see such longer term studies done in this fashion.

In the June 2010 online version of the Lancet Oncology journal, a provocative report of a recently completed meta-analysis suggests that angiotensin receptor blockers might confer a modest but statistically significant increased risk for cancer.

These results were a mixture of both prespecified and non prespecified cancer outcomes in clinical trials where different ARBs were used though telmisartan was the study drug in approximately 86% of patients. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7·2% vs 6·0%, risk ratio RR 1·08, 95% CI 1·01—1·15; p=0·016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1·11 (95% CI 1·04—1·18, p=0·001).

This meta-analysis does suggest a modest but significant link between cancer use and ARBs. However, questions remain. Firstly, is this affect real? Secondly, can we generalize these results to other medications within the ARB class. An important limitation of this study is that much of the data were derived from the occurrence of cancer in patients from the ONTARGET Study in the treatment arm where both ramipril and telmisartan were used; there was no effect seen in the monotherapy arms.*

At this point, more study is required. It is tempting to draw conclusions from this meta-analysis, however, we must remember that research in this area is actually conflicting. For example, it has been suggested that ARBs can actually be protective against cancer, as seen here.

Therefore, further study is warranted before concluding that this very useful class of medications is harmful and whether this is a drug or class-specific effect.

*Below is a copy of the Forest plot for the meta-analysis. As you can see, the effect of telmisartan on cancer from ONTARGET (the largest study), was only present in the combination group, not when used alone:

Source: The Lancet Oncology, Early Online Publication, 14 June 2010 doi:10.1016/S1470-2045(10)70106-6

Have your say, have your vote:

I have never been a fan of vitamins. They fall in to a category of interventions with presumed safety and benefit. An important study in the Journal of the American Medical Association shows the opposite; that vitamins can cause harm in patients with chronic kidney disease.

The following appears on the BC Renal Agency Website:

In April, the Journal of the American Medical Association (JAMA) published a study that looked at whether high doses of B vitamins (folic acid, B12, B6) helped people with kidney disease due to diabetes. The study found that high doses of these vitamins were actually harmful. Study participants who took the vitamins had an increased risk of heart attack and stroke. They also had reduced kidney function.

Many studies have questioned the effectiveness of hydrochlorothiazide (HCTZ) versus chlorthalidone as a diuretic. In fact, most large scale trials that have used HCTZ have been disappointing (e.g. ACCOMPLISH) while those using chlorthalidone have been largely positive (e.g. ALLHAT). While this might seem like an over-simplification, many hypertension experts agree with it.

In the latest twist to this story, Takeda Pharmaceuticals have created a fixed dose combination with it's new ARB azilsartan with chlorthalidone - in stark contrast to all other ARB and ACE inhibitor counterparts. As it it turns out, they may be on to something ( continued ... )

ScienceDaily (May 6, 2010) — Two-year results from phase III clinical trials show the experimental immunosuppressive drug belatacept can better preserve kidney function in kidney transplant recipients while preventing graft rejection when compared with the standard immunosuppressive drug cyclosporine.

Much has been written over the years of a so-called J-point in blood pressure management; that point above which BP is too high and below which BP is too low (if one is arriving there by antihypertensive medications). The late breaking ACCORD BP Study, published online in the New England Journal of Medicine, casts doubt on the benefit of aggressively lowering systolic blood pressure towards 120 mmHg in patients with type 2 diabetes.

However, while much will be written on these very results, I want to issue a cautionary note that this trial not be interpreted as 'strict blood pressure management is unimportant'. Quite the contrary; tight blood pressure control is likely more important that tight glycemic control in patients with type 2 diabetes, but there is a limit to this effect. The ACCORD BP study should be interpreted as nothing more than the demonstration of a J-point in blood pressure management, a finding that actually support current published guidelines in patients with diabetes to target a BP below 130 rather than an even stricter threshold (NB: 130 as a target has not been firmly established by randomized trial data). We now understand however, that 'below' is not a bottomless term and that a range of 120 to 130 is likely appropriate.

Over the past 2 years, considerable excitement has been building over the results of the ACCOMPLISH study. This trial suggested that the combination of benazapril plus amlodipine is superior to benazapril plus hydrochlorothiazide for the prevention of a composite cardiovascular outcome. While there are methodological concerns regarding this trial that make me question its generalizability, it is thought-provoking to consider that one medication combination is superior to another even if blood-pressure between the 2 groups is negligible.

In the latest issue of Lancet, a follow-up paper suggests that benzapril-amlodipine prevented renal outcomes more-so than in the benazapril-hydrochlorothiazide arm. However, as the excellent accompanying editorial points out, all is not as it appears. (continued...)

Hyperphosphatemia has been been linked to poor patient outcomes, including a link to higher mortality. This relationship has been inferred by several retrospective and observational studies. In fact, the relationship between hyperphosphatemia and death is one of the most consistently espoused theories in all of nephrology. There is just problem however; there has never been a randomized trial to confirm this association.

In the latest issue of Nephrology Dialysis and Transplantation, Smith et al cast doubt on this long-held belief. In their retrospective CKD-inception cohort study, there was no association between hyperphosphatemia and death, though there was less risk of renal replacement therapy in patients with better phosphorus control.

This finding is by no means conclusive. I continue to aggressively treat hyperphosphatemia. However, it does lend further support for a large-scale randomized trial to study this seemingly unimpeachable belief.

In a fascinating article from November's Journal of the American Society of Nephrology, researchers present data suggesting that patients returning to dialysis after a transplant fails experience improved survival if the kidney is removed. In this study, despite correction for comorbidities and socioeconomic factors, graft nephrectomy prolonged survival. One explanation of the results might be that nephrectomy removes an inflammatory stimulant and would allow complete withdrawal of immunosuppression and its risks. This finding is somewhat contradictory to current dogma which suggests that immunosuppression should be continued once returning to dialysis in order to preserve residual renal function. This study's finding would need to be reproduced with a prospective randomized trial to reduce bias but in the meantime, is quite compelling.

The TREAT Trial was presented at the ASN in San Diego. This much publicized trial examined the role of Aranesp in the management of diabetic patients with CKD. One group was randomized to receive Aranesp with a hemoglobin target of 130 g/l while the control group was given placebo and treated with Aranesp only if their hemoglobin fell below 90 g/l.

There was no advantage to the group given Aranesp and a statistically significant increase in strokes observed in the the treatment group. Below is a link to the article from NEJM and the accompanying editorial written by renowned nephrologist, Dr. Phil Marsden of the University of Toronto.

It is worth noting, that the treatment group was targeted to a higher hemoglobin than we now conventionally use. Furthermore, the dose of Aranesp was more than double the typical dosages used by the majority of my predialysis patients. As has been observed in other studies where high hemoglobin seems harmful, the dose of Aranesp required might explain the observation of harm. Perhaps those patients who respond to lower dosages and those whose hemoglobins remain with target would be perfectly safe to continue.

More study is needed to clarify this and perhaps might be forthcoming from further analysis of the TREAT Study.

Click for:

A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease

Treatment of Anemia in Chronic Kidney Disease — Strategies Based on Evidence