UKidney Nephrology News and Insights

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.

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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

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.