Nephrology Madness: Meet the competitors for Proximal Tubule Region’s S-one Segment Group!

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(16) NCDS vs (1) HEMO

This is like father and son.  Both are seminal trials to the field.

NCDS

The National Cooperative Dialysis Study (NCDS) was the first randomized control trial in dialysis to test the importance of small and middle molecules as uremic toxins. Furthermore, this trial lead to the establishment of minimum standards for dialysis dose. The NCDS trial was published in the NEJM in 1981. Patients in the study were randomized to two different BUN concentrations averaged with respect to BUN: high or low, and to two dialysis treatment times: long or short, in a 2 x 2 factorial design. There was no difference in mortality between groups. However, more patients in the high BUN category were withdrawn from the study for medical reasons.

A subsequent paper by Gotch and Sargent introduced the measurement of Kt/V and also reanalyzed the primary data from the NCDS showing that Kt/V <0.8 was associated with a relatively high rate of patient morbidity, whereas Kt/V values between 1.0 and 1.2 were associated with a low rate of morbidity. Some feel that there has been an over interpretation of the NCDS results putting too much emphasis on achieving a target Kt/V and ignoring dialysis treatment time which missed significance with a P value of 0.06.

HEMO

After the NCDS trial, a large number of observational data suggested that a dose of dialysis substantially higher than the one provided in the NCDS trial was associated with a lower mortality rate. In response to this, national standards for dialysis dose were developed in the US advocating a minimum spKt/V of 1.2.

The Hemodialysis Study Group (HEMO) study was a large controlled trial designed to determine whether further increases in dialysis dose above current standards or the use of high-flux membranes would improve patient outcomes. The patients in the trial were randomized to a standard (Kt/V=1.25) or high dose (Kt/V=1.65) of dialysis, and a low- or high-flux dialyzer, in a 2 x 2 factorial design. The primary outcome was death from any cause. There was no difference in all-cause mortality between standard or high dose dialysis, and low or high-flux membranes.

The HEMO trial overturned 20 years of observational data and shocked the nephrology world.

(3) TREAT vs (14) EMERALD 1 and 2

TREAT

TREAT was a multicenter, randomized, double-blind controlled trial that compare darbopoetin alfa versus placebo in non-dialysis chronic kidney disease (CKD) patients with type 2 diabetes mellitus and moderate anemia targeting a hemoglobin of 13 g/dL in the intervention group. The primary endpoints were the composite outcomes of death or a cardiovascular event and of death or end-stage renal disease. The study showed that darbopoetin alfa not only did not reduce the risk of the primary outcome but was associated with an increased risk of stroke.

Although a negative study, darbopoetin is still in use and TREAT increased awareness that targeting Hb levels >13 g/dL in non-dialysis chronic kidney disease patients with type 2 diabetes is detrimental.

EMERALD 1 and 2

Peginesatide was a very promising drug. It is a synthetic peptide that activates the EPO receptor. Peginesatide is a PEGylated molecule and hence it has a long half-life allowing once a month administration. Because its amino acid sequence is unrelated to erythropoietin, it also does not cross react with erythropoietin antibodies or AMGEN patents.

The EMERALD 1 and 2 trials showed that peginesatide was safe and effective in maintaining the hemoglobin concentration among hemodialysis patients. However, the PEARL-1 and PEARL-2 trials in non-dialysis CKD patients showed that peginesatide (in comparison to darbopoetin) increased cardiovascular events, and was associated with a higher incidence of sudden death and AKI. To make matters worse, several cases of serious hypersensitivity reactions associated with peginesatide use have been recently reported to the FDA and the manufacturer has withdrawn the drug from the market.

(5) ALLHAT vs (12) ACCOMPLISH

ALLHAT

ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) is the biggest prospective blood pressure study ever performed and was sponsored by the NIH. Thus, freeing it from drug company bias that contaminate many other blood pressure trials. When the study was conceived it was designed to pit newer and more expensive anti-hypertensives:

• Doxazosin, an alpha blocker
• Amlodipine, a dihydropyridine calcium channel blocker
• Lisinopril, an ACE inhibitor
• against the old familiar chlorthalidone, a thiazide type diuretic.

Beta blockers were not a randomized arm of the trial but were kept in reserve as a second-line agent for all arms of the trial.

The Doxazosin arm was stopped early because of excess heart failure (RR, 2.04; 95% CI, 1.79-2.32) and stroke (RR, 1.19; 95% CI, 1.01-1.40).

After 4.9 years there was no difference in the primary outcome (combined fatal CHD or nonfatal myocardial infarction) among the three remaining arms (amlodipine v chlorthalidone P=0.65, lisinopril v chlorthalidone P=0.81) though the chlorthalidone group had slightly lower systolic but higher diastolic blood pressures compared to amlodipine and better better systolic and diastolic blood pressures than lisinopril. On secondary end-points, chlorthalidone was superior to:

• Amlodipine for
  • heart failure RR 1.38; 95% CI 1.25-1.52

• Lisinopril for
  • combined CVD RR 1.10; 95% CI 1.05-1.16
  • stroke RR 1.15; 95% CI 1.02-1.30
  • heart failure 1.19; 95% CI 1.07-1.31

Although it was a negative trial, ALLHAT was lauded as showing an older generic drug beating (on secondary end-points) newer branded competition and was the basis of much of JNC 7.

ACCOMPLISH

ACCOMPLISH (Avoiding Cardovascular events through COmbination therapy in Patient LIving with Systolic Hypertension) may have the most awkward, forced acronym for a title ever, but nonetheless is a critical study in the way we treat hypertension today. In the wake of the HOPE trial everyone with a whiff of cardiovascular risk was put on an ACEi. However that was rarely enough to get patients to their goal blood pressure. With JNC7 and ALLHAT in hand the logical next drug would be chlorthalidone. ACCOMPLISH put this under the blade of a RCT, benazepril plus hydrochlorothiazide versus benazepril plus amlodipine.

ACCOMPLISH used hydrochlorothiazide instead of chlorthalidone as the diuretic of choice. One of the missteps after ALLHAT may have been the general conflating of chlorthalidone and hydrochlorothiazide, though they are both thiazide type diuretics, they are different molecules and there is reason to believe that chlorthalidone may be superior to hydrochlorothiazide. Some may scream that ACCOMPLISH used a straw man diuretic, but I prefer to think of it as using the typically prescribed version (eighth most prescribed drug, wedged between Lipitor and Xanax), rather than the odd duck, chlorthalidone.

The ACEi-CCB group had a small blood pressure advantage, SBP was 0.9 mmHg lower and DBP was 1.1 mmHg lower, but that small advantage cannot explain a 20% relative risk reduction and a NNT of 45.

(10) MDRD Trial vs (7) IDEAL Trial

MDRD Trial

The MDRD trial (Modification of Diet in Renal Disease) was a seminal trial in the nephrology community.  This trial has given rise to 2 different teams in the NephMadness tournament.  The actual trial and the MDRD eGFR equation (not sure if this is fair). The results of the trial were published in the NEJM in 1994. This was a large [included 2 groups, 1- 1,585 patients with GFR 25-55 (mean creat 1.9) and 2- 255 patients with GFR 13-24 (mean creat 3.4)] multicentered clinical trial testing the hypothesis that restricting dietary protein and strict blood pressure control (MAP 107 vs 92 mm Hg) would delay the progression of kidney disease. The 2 groups were chosen (low and very low GFR) secondary to concerns that patients in the second low GFR group might not be able to consume the usual protein diet. The results of this study were not conclusive for the use of low protein diet to slow the progression of CKD. However, they did report

• slightly slower decline in GFR in the moderate GFR group using low-protein diet 4 months after the intervention (decline of 3.9 usual vs. 2.8mL/min/yr low protein diet).
• this benefit was not seen in the more severe CKD group.
• There was no delay in the time to the occurrence of end-stage renal disease or death.
• In both studies, patients in the low BP group who had more pronounced proteinuria at baseline had a significantly slower rate of decline of GFR.

IDEAL Trial

The decision to start a patient on dialysis is a frequent clinical issue faced by Nephrologists. The IDEAL (Initiating Dialysis Early and Late) trial published in the NEJM in 2010 shed some light onto this topic. Researchers from Australia and New Zealand randomized 828 patients to either starting dialysis early (eGFR of 10-14 regardless of uremic symptoms) or late (eGFR of 5-7 or uremic symptoms were present). No differences were seen in the primary or secondary outcomes after an average of 3.5 years of follow-up. Although, this trial doesn’t definitively answer this question, it does allow for more comfort when following a patient with with advanced CKD. The majority of patients in the late group were initiated on RRT secondary to symptoms of uremia. Waiting for symptoms to occur did not adversely affect the outcome in the late initiation group. Providing excellent pre-ESRD care to all patients with CKD is paramount. Getting timely access and providing medical therapy for complications of hypertension, fluid overload, electrolyte/acid-base derangements while listening closely to the patients symptoms of uremia, seems to trump the eGFR.

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