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.

An initial association analysis was done comparing 205 African-American sporadic cases with biopsy proven FSGS to 180 African-American controls. The strongest signals were found in the last exon of APOL1. More specifically, two closely spaced alleles that are in perfect LD (i.e. no recombination events) showed the strongest association. This two-allele haplotype termed “G1” consisted of the non-synonymous coding variants rs73885319 (S342G) and rs60910145 (I384M). Logistic regression analysis to control for G1 led to the identification of a second strong association with a 6 base pair deletion in APOL1 termed G2.

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.

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.*

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 cardiovacular outcome. While there are methodological concerns regarding this trial that make me question its generlizability, 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.