I'm going to speak at ASN!

This came in the mail today:

Dear Dr. Topf:

On behalf of the American Society of Nephrology's (ASN) 2010 Program Committee and Postgraduate Education Committee, we are pleased to invite you to join the distinguished faculty for Renal Week 2010, November 16-21, 2010 at the Colorado Convention Center in Denver, CO.

Rocky Mountain High!

Nicest post about anything I've written on this blog

I got an e-mail from Lance Bukoff regarding the upcoming Boston Walk for PKD.

In my neighborhood the diseases that get the community involvement are breast cancer and special needs kids. Kidneys get almost no support though there is a great Zoo Kidney Walk by the NKF every Spring. Support the PKD walk.

Lance commented on my post about Sirolimus and ADPKD. I write this blog primarily for other medical professionals. I'm happy to have anyone read it, but the voice I use comes from my experience as a doctor and as a educator. Whenever a post gets picked up by patient groups I worry about how it will be perceived. I worry that I may have a glib when I mean to be funny or come across uncaring when I'm trying to be cooly scientific. I have had some close calls, but nothing has exploded, yet. This fear makes posts like Lance's extra special.

NephronPower's survey on Neph Ed

Kenar Jhaveri, MD, (Kidney 007), assistant professor of medicine at Hofstra Medical School and contributor to Nephron Power, is doing a survey on nephrology education. Go take the survey.

I don't want to spoil the survey but it mentions two resources I was not familiar with:

1. Detective nephron
2. Nephrology crossword puzzles

Check'em out so you can have an opinion.

Allopurinol a novel way to slow the progression of chronic kidney disease

In my grand rounds on uric acid's link to renal disease and hypertension I was not able to show any compelling data that allopurinol actually helped adults. There is convincing data on the use of allopurinol for the treatment of adolescent hypertension. The only adult data I could find was a VA study which used a retrospecitve electronic chart review to show that patients prescribed allopurinol had a lower risk of death. Pretty weak sauce.

Now we have more compelling data showing a reduction in the progression of CKD thanks to Goicoechea et al.

This is an interesting, single-center, randomized, controlled trial of allopurinol given to patients with chronic kidney disease. The patients had to have stage 3 CKD or worse (average eGFR was 39.5±12.4 for the control group and 40.6±11.3 for the allopurinol group) that was relatively stable. The patients had hyperuricemia at baseline but nothing too crazy (7.3±1.6 mg/dL for the controls and 7.9±2.1 mg/dL for allopurinol). The patients were not blinded and no placebo was used. Investigators either handled the patients or the laboratory results but no investigator dealt with both.

The primary end point was a little hazy by my read. The authors state:

The primary objective of this study was to analyze the effect of allopurinol in patients with moderate CKD in reduction of inflammatory markers and renal disease progression.

But I couldn't find a specific case definition of renal progression in Materials and Methods. In the results they showed significant reduction in renal disease progression by two means:

1. They showed less loss of eGFR over 24 months in patients treated with allopurinol. There was actually a modest increase in renal function in the allopurinol group. P=0.016 for eGFR between groups at 24 months.
   
   
   
   
2. They defined renal progression as a loss of more than 0.2 mL/min per month and after using a cox-regression model adjusted for age, gender, diabetes, uric acid, hs-CRP levels, renin-angiotensin system blockers, CKD etiology, and albuminuria they found a hazard ratio of 0.53 (0.28 to 0.99; P=0.048).

As part of the primary end point they also looked at inflammatory markers and those improved remarkably with allopurinol. The investigators saw significant reductions in CRP, C Cystatin. Albuminuria appeared to drop more in the allopurinol group but this was not significant.

One of the secondary end-points was looking at cardiovascular risk and hospitalization. The data looks really exciting. They had a 71% reduction in cardiovascular events and a 62% reduction in hospitalization.

This study is study suffers from the weaknesses often seen in the first studies of an exciting hypothesis. It is a single center study, it is too short and it is too small; that said, the investigators were able to show reductions in both patient oriented outcomes (cardiovascular events and hospitalizations) and important biochemical factors (CRP, loss of renal function). I'm also excited to see that this didn't come from Richard Johnson's lab. Too much of the data on fructose and uric acid comes from his group. Nice to see some fresh faces in this field. 

I am looking forward to a larger study with harder end-points than a change in the slope of eGFR. Show me a decrease in the doubling of serum creatinine and/or decrease in the initiation of dialysis.

I, personally, am already a believer in the fructose/uric acid model of hypertension and progression of chronic kidney disease. Goicoechea, et al. is an important brick in the wall but it is still not enough to warrant the blanket treatment of asymptomatic hyperuricemia.

First patient data on sirolimus for ADPKD

UPDATE: please see this post with newer, more definitive data.


Initial patient visits for autosomal dominant polycystic kidney disease are different from just about any other patient visits. It is the only disease in which I spend a significant amount of time discussing the areas of bleeding edge research that have promise but are not yet available. I tell my patients about three current research thrusts:

1. Combination ACEi-ARB
2. ADH-antagonists
3. mTOR inhibitors

I spend time doing this because the hardest thing for patients to accept with a new diagnosis of ADPKD is the twin truths of the disease: 1) the inevitability of the disease and 2) the lack of any effective intervention that can meaningfully make a difference. Most of the patients referred to me have a fair bit of knowledge about the disease. They have seen their siblings, a parent and a fair number of cousins, uncles and aunts go through dialysis, transplant and the other rigors of kidney failure. Everyone wants to know what they can do to reduce the progression, what can they do to avoid their genetic destiny. Tragically, I feel like a medical Cassandra because there is little I can do to intervene so I am left to weave tales of a happier tomorrow.

Well, tomorrow has gotten a little closer with the publishing of the first human study of mTOR inhibitors in ADPKD.

Polycystic kidney disease cells show abnormal activation of the Ser/Thr kinase target of of rapamycin. This enzyme coordinates cell growth and proliferation. In three animal models of PKD, there is evidence of inappropriate activation of mTOR in the renal cysts. Because of this, blocking mTOR with rapamycin (same thing as sirolimus) is one of the most promising research avenues in ADPKD. 

Up to now most of the data has depended on animal studies. Though there have been some retrospective analysis in humans with ADPKD who received a kidney transplant with sirolimus as part of their immunosupression. On average investigators found a 24% reduction in kidney volume with sirolimus compared to an 8% reduction with alternative agents (ref). Similar improvements in liver cysts were found, 12% reduction with sirolimus versus 14% increase without (ref).

In this latest study by Perica et al. they had 21 patients and they received either conventional therapy or sirolimus (initial dose: 3 mg daily) for six months and then each patient crossed over to the opposite arm, so every patient received both control and experimental therapy. Six patients dropped out for various reasons and the researchers ultimatly reduced their target sirolimus levels from 10-15 ng/ml to 5-10 ng/ml. The authors explained the adverse reactions in the discussion:

Three patients were prematurely withdrawn from the study because of the onset of an erythema nodosus in one case and thrombocytopenia in two cases after a few days of sirolimus therapy, when sirolimus dosage was titrated to target trough levels between 10 and 15 ng/ml (all events fully resolved with treatment withdrawal). The poor tolerability of this high-dosage regimen led us to reduce the target levels to 5 to 10 ng/ml. With this approach, no serious event requiring treatment interruption was observed.

The primary outcome was change in the kidney volume. The authors, additionally, looked at changes in cyst volume and renal parenchymal volume which was important as they found an increase in the renal parenchyma with stable cyst volume during sirolimus and a reduction in renal parenchyma and increase in cyst volume during usual care.

The primary outcome, a change in renal volume was not significant, P=0.45; however, cyst volume increased more on conventional therapy, P=0.013 and parenchymal volume increased more on sirolimus, P=0.005.

I know that the EBM snobs will turn their noses up at these secondary end-points but in a small pilot study I feel this shows real promise. It also indicates, to me, that total kidney volume might not be the best intermediate end point for ADPKD. It looks like sirolimus causes non-functioning cysts to be replaced with viable renal parenchyma, and it seems unfair to punished the drug for that but using total kidney volume as opposed to cyst volume does just that.

The authors then try to establish some dosing guidelines but this is probably a fool's errand to run with only 15 people completing the protocol. Regardless of its validity they come to 0.049 mg/kg as the optimal dose (3.5 mg per day for a 70 kg male).

The authors had an interesting angle on some of the more common side effects associated with sirolimus:

Hypercholesterolemia is another widely known adverse effect of mTOR inhibitors. Our data, however, show that in patients without concomitant medications that may also ad- versely affect the lipid profile, such as steroids or calcineurin inhibitors, hypercholesterolemia is mild and can be easily managed just with dietary counseling. Thus, this adverse effect does not seem to be a major drawback of sirolimus therapy, even in the case of prolonged exposure.

The frustration of ADPKD comes from the inevitability paired with our medical impotence. Every year at our conferences we are shown western blots and animal models that hint at a new day. I believe the first rays of that new day are poking over the horizon.

Rapamycin came from Easter Island

English: A plaque reminding of the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island), near Rano Kau. The plaque is written in Brazilian Portuguese, and reads: In this location were obtained, in January 1965, soil samples that allowed for the obtainment of rapamycin, a substance that inaugurated a new era for organ transplant patients. An homage from the Brazilian investigators, November 2000.

from Wikipedia

Boy, our fellows are smart!

The St. John Hospital and Medical Center has a nephrology fellowship where I am on the teaching staff. We currently have a particularly talented cohort of fellows but I had no idea how that talented compared on a national scale.

We just got the results of the Nephrology In-Service exam and our crew hit it out of the park. The average score was 69, only 4 programs (with five or more fellows) scored higher. Congratulations guys!

Volume, a new target for dialysis and acute renal failure?

One of the major advancements in nephrology in the first decade of the 21ast century was the rejection of Kt/V as a treatment target in dialysis. In a field that is lacking in randomized clinical trials we had three well done randomized clinical trials designed to verify the mounds of observational data. In all three Kt/V as an expression of dose failed.

Chronic hemodialysis: HEMO

• eKt/V of 1.05 vs 1.45 (or a spKt/V of 1.2 vs 1.6) 

Peritoneal dialysis: ADEMEX

• Increase in PD dose such that they move from less than 40% at Kt/V of 2.0 to 83% at Kt/V of 2.0

Dialytic support for acute renal failure: VA/NIH ATN trial

• 3 days a week dialysis versus 6 days a week all at a single-pool Kt/V of 1.2 to 1.4 per session
• Hemodynamicly unstable patients were randomized to one of two levels of CVVH 20 or 35 ml/kg/hour of total CRT effluent

All three looked at variations on Kt/V tuned to the individual clinical scenario. Varying Kt/V in each of these clinical scanrio made not a whif of difference to the patients.

In the aftermath of such intellectual carnage nephrology is desperately seeking a replacement. My experience with nocturnal dialysis and the amazing work coming out of Canada makes home hemo look like the most appealing option. Getting results comparable to transplant makes it look like an entirely new modality compared to traditional in-center hemo.

One of the aspects that made Kt/V so appealing was how it was a useful in any situation involving dialysis. (The lessons from NCDS study on chronic in-center hemodialysis guided the definition of adequate dialysis for ARF in the ATN trial)

What lessons does home hemo have to teach acute renal failure in the ICU? What lessons does it have for peritoneal dialysis. One could argue that one of the central problems in modern dialysis is fluid management. Too many of my patients are chronically fluid overloaded leading to hypertension and over worked hearts. Home hemo corrects hypertension. Is solving that cardiovascular problem accounting for much of the improved clinical outcomes?

If that is the case, then there is a clear lesson that we can take from home hemo and apply to the ICU. 

Don't let your patients get volume overloaded

We covered this in journal club last thursday: Fluid Overload and Mortality in Children Receiving Continuous Renal Replacement Therapy

The study is a retrospective interpretation of registry data on children with acute renal failure receiving continuous renal replacement therapy. Each patient was given a fluid overload score by calculating a percentage overload:

They divided patients into three strata:

1. <10% overload
2. 10-20% overload
3. ≥20% overload

They also used percentage overload as a continuous variable for the primary multivariate analysis.

The primary data is shown in table 2.

It should be immediatly obvious that the patients with more volume overload were sicker, they had signifigantly:

• longer ICU stay
• higher mortality
• more multi-organ dysfunction
• more likely to be intubated
• more inotropes
• more sepsis
• higher PRISM score

For that reason I am not going to spend time discussing the univariate analysis and go straight to the multivariate analysis:

Worse fluid overload severity remained independently associated with mortality (OR, 1.03; 95% CI, 1.01-1.05). The relationship was satisfactorily linear and the OR suggests a 3% increase in mortality for each 1% increase in degree of fluid overload at CRRT initiation.

That is impressive. If the results hold up and aplies to adults it should scare the crap out of anyone who regularly rounds in the ICU. Think of a typical 80 kg adult who has total input of 2,400 mL (100 mL/hr) and has 1,600 mL of urine output, 67 mL/hour. That is a positive balance of 800 mL or 1% of body weight. If that goes on for 3 days and then the patient becomes oliguric with only 400 mL of urine output for two days (2,000 mL positive per day) before initiating CRT. That patient would be up 6,400 mL or 8% of bodyweight: Those relatively innocuous seeming numbers would represent a 24% increase in mortality compared to someone with matched ins and outs. Yowsa!

This is an observational study and it is important not to accept he results as truth but it is certainly a suggestive lead.

Apple CEO Steve Jobs Live at D8

6:59 pm: Walt asks if Apple knew it would build a tablet before it built the iPhone.

Jobs: “I’ll tell you a secret. It began with the tablet. Jobs first charged his staff with developing a tablet, but after seeing their first efforts decided the way to go was a phone. “My God, I said, this would make a great phone … so we shelved the tablet and built the iPhone.”