Dialysis Unplugged: “Peginesatide-Are Dialysis Patients Different from Patients with Advanced Kidney Disease?”

In a recent article in the New York Times, Andrew Pollack quoted from The Kidney Doctor post published here. One of the points that I made was that I am not sure that one can justify drawing a line between ESRD patients (ie patient’s on dialysis) and patients with CKD not on dialysis. Why?

First, let me concede that obviously dialysis patients are different than stage 4/5 CKD patients not on dialysis in at least two important respects. Dialysis patients usually have more severe impairment in native kidney function. By the time patients are on dialysis, and especially after patients have been on dialysis for a while, there is a decline in residual renal function. Besides, dialysis patients have more complications related to kidney disease: worse bone disease, greater deficiency in epo production, and underlying cardiovascular disease. Data also demonstrates more evidence of inflammation – higher baseline hsCRP, lower serum albumin, and higher baseline ferritin. These characteristics may modify the effect of ESAs on outcomes.

The other big difference is that patients with ESRD undergo dialysis, which has systemic effects. For example, patients undergo removal of fluid, fluxes in solute and electrolytes, and changes in hemodynamics. Dialysis patients also tend to become more hemoconcentrated as volume is removed.

But the question is not whether there are physiologic differences between ESRD and non-ESRD patients. The issue is whether one can comfortably assume that an ESA is safe in ESRD patients even though there is a safety signal in a non-ESRD setting. In essence, is it alright for the FDA to accept that approval is OK in dialysis patients “because these patients are different” from non-dialysis CKD patients?

The answer is that, like me, the FDA is hedging it’s bets. The FDA states the benefits of the drug narrowly: “This new drug offers patients and health care providers the convenience of receiving ESA therapy just once per month instead of more frequent injections.” And, “Omontys [peginesatide]  should not be used in patients with CKD who are not receiving dialysis or in patients with cancer–related anemia, according to the FDA-approved labeling. It also should not be used as a substitute for red blood cell transfusions in patients who require immediate correction of anemia. Omontys has not been shown to improve symptoms of anemia, physical functioning or health-related quality of life in patients with CKD on dialysis.”

The FDA is accepting the fact that the drug appears to be safe in dialysis patients, but, because of the PEARL data it is not sure. 

Recall that in the PEARL studies, the frequency of CSE events was higher in the peginesatide group (21.6 percent) versus the comparator (17.1 percent) (HR 1.34, 90 percent CI 1.03 - 1.73). Note: CSE is the adjudicated cardiovascular composite safety endpoint of death, stroke, myocardial infarction, congestive heart failure, unstable angina, and arrhythmia). 

Because of the safety signal in PEARL the FDA is requiring the drug manufacturer (Affymax) to perform additional studies in dialysis patients in the post-marketing phase.

Writes the Pharma Letter: In the approval action letter, the FDA outlined”post-marketing requirements: an observational study and a randomized controlled trial to be completed with final reports submitted in 2018 and 2019, respectively. The objectives of the studies are to evaluate cardiovascular safety and assess safety of long-term use in adult patients on dialysis, in particular in the incident patient population. In addition, the post-marketing commitment includes the initiation of pediatric studies with target dates for completion between 2016 and 2027.

The reason that the FDA is hedging is because there have been 4 randomized controlled trials reporting a safety signal. Of these 4 studies, 1 was in dialysis patients – the Normal Hematocrit trial, and 3 in non-dialysis patients – CHOIR, CREATE, and TREAT.

So I am hopeful that peginesatide will truly be safer in dialysis patients as compared to epoetin-alfa or epoetin-beta or CERA among dialysis patients, but I doubt that will be the case. More likely, the reason that peginesatide did not demonstrate a safety signal in EMERALD was because of either subtle differences in the enrolled study population, or because of differences in the studies of the ESA dose or treatment algorithm that was used, or because of differences in the Hb targets in PEARL compared to the earlier studies.

Therefore, my plan is to: 1. Not use peginesatide in non-dialysis CKD patients and, 2. use peginesatide in the dialysis population recognizing that it’s risk in dialysis patients is probably no different from the other ESAs tested in both CKD and non-CKD populations. Thus, I plan to individualize the use of the drug by identifying the Hb trigger for the patient that requires an ESA intervention, and generally using the lowest possible ESA dose.

iSEDIMENT

Source: Dr G.B Fogazzi 

What is the structure in this urine sediment?
(Hint - Portugal)

On Being A Doctor: “The Method Actor versus The Star”

Osler examining a patient

On the flight back from England to the US I watched the movie “My Week With Marilyn”. It’s a movie that’s based on the true story by Colin Clark of the time he spent working for Sir Laurence Olivier directing and acting in a movie featuring Marilyn Monroe. Ms. Monroe was at the height of her fame. One theme that emerges in the movie is the difference between "method acting" versus being a "star". Olivier’s career was founded on learning acting through school, the stage, and finally movies. Olivier was a star also but he started as a "method actor". Monroe had “star power” that captivated millions of movie-goers, but really would never be viewed as a method actor.

As I watched the movie my mind turned to the couple of weeks I attended on the general medicine service at the Brigham. As the attending physician I led a team of young doctors – interns and residents as they worked up and managed patients. The residents that I worked with were terrific. Smart, knowledgeable, and hungry to learn. I certainly couldn’t best them in knowledge.

One of the intern's asked me: “what do the years of practice bring?” Taken aback at first, I told him that experience brings intuition in diagnosis and perhaps more importantly in recognizing the sick patient. It comes from immersing oneself over many years in the practice of medicine. As I've thought more about it, similar to "method actors" using years of practice on stage in developing the ability to draw upon their own emotions and experiences, doctors use years of observation and trial and error in treating patients in developing this thing called "intuition".  Osler said: “He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all.” He goes on: “There is a tendency among young men about hospitals to study the cases, not the patients, and in the interest they take in the disease lose sight of the individual. Strive against this.”

But in addition to developing intuition, the experienced clinician brings to the table skills learnt by practice. Take the essence of Malcolm Gladwell‘s book “Outliers” or Atul Gawande’s “Better” - they both speak of the importance of practice; Gladwell of over 10,000 hours of practice and Gawande of practice in reducing error rates.

This brings me to an article that first appeared in in the Summer 2002 issue of the Harvard Medical Alumni Bulletin. It contains quotes from Harvard alumni the about the “art of doctoring”. The quote that caught my eye was as follows:

A River Runs Through It

The difficulties of training a man in the art of medicine remind us of Mark Twain’s description of how he became a Mississippi pilot. Successful piloting was not merely a matter of twirling the wheel, ringing bells, and looking important; one had to know the river, not only by day but also by night and in the fog, and since the river changed continuously one had to have foreknowledge of every change. Finally by some sort of growth of his intuition he became a first-class pilot —Medical School Notes [June 1941]

Even in 1941, “some sort of growth of [his] intuition” seemed important and it’s no less important today. With the constant hand-overs and shift changes the intuitive ability to figure out who is sick and who isn’t is even more important than it perhaps was. I have no doubt that knowledge is important and developing habits through practice are key, but I would suggest to you that it's the developing of intuition that seems the overarching benefit that comes from experience. Who would you rather have treat you? Dr. House “the star” or Dr. Marcus Welby the “method actor”? 

Dialysis Unplugged: Ferumoxytol – “Take A Chance on Me?”

Remember the ABBA song: "Take a Chance on Me"?

In 2008, Tejas Patel, a clinical research fellow that worked in my research group at the Brigham, and I published a paper in the American Journal of Kidney Disease on the safety of ferumoxytol in treating iron deficiency anemia in CKD patients.

The paper reported the phase 3 experience from a double-blind placebo-controlled, crossover, multicenter study of a single 510-mg dose of ferumoxytol versus saline as placebo. 750 patients with CKD stages 1 to 5 and 5D. The intervention comprised of an IV injection of either 17 mL of ferumoxytol or saline placebo over 17 seconds on day 0 and the alternate agent on day 7. Of 750 randomly assigned patients with CKD, 60% were not on dialysis therapy.

The main results of the study were the following:

• Of 420 adverse events reported; 242 in 152 patients (21.3%) with ferumoxytol and 178 in 119 patients (16.7%) with placebo.
• The incidence of related adverse events was 5.2% with ferumoxytol and 4.5% with placebo.
• The most common related adverse events after each treatment included symptoms related to the injection/infusion site, dizziness, pruritus, headache, fatigue, and nausea.



(Click to enlarge)

• Serious adverse events occurred in 21 patients (2.9%) after ferumoxytol and 13 patients (1.8%) after placebo.

We concluded: “Ferumoxytol is well tolerated and has a safety profile similar to placebo in anemic patients with CKD stages 1 to 5 and 5D.”

Since then several papers, review articles, and conference posters have reported that ferumoxytol is well tolerated in CKD patients, and following FDA approval for ferumoxytol, my only reason for not using ferumoxytol was price – it was priced well above the other approved intravenous iron medications on the market.

A few weeks back Tejas Patel, now a nephrology attending in Boston, sent me the abstract of a safety analysis on ferumoxytol; I tracked the paper down and am sharing some of these results, because you may not have seen it. I certainly sat up in my seat after reading the paper.

The paper published February 15, 2012 by George R. Bailie in American Journal of Health-System Pharmacy is unfortunately unavailable open access (the abstract is here). Ailie is a Professor of Nephrology Pharmacy at Albany College. I thought that it was a terrific paper.

Bailie used the Freedom of Information Act to collect all of the adverse effect (AE) reports to the US FDA that cited iron sucrose, ferric gluconate, high- and low-molecular-weight iron dextran products, or ferumoxytol from October 2009 through June 2010. He used two different ways to calculate AEs (by a per-unit-sold basis and in terms of 100-mg dose equivalents (DEq) of iron). Bailie also obtained commercial ales data from a market research vendor.

The key results were:

• A total of 197 reported AEs were identified (a cumulative rate of 14.1 AEs per million units sold).
• The rates of all AE classifications combined ranged from 5.25 to 746 per million units sold for iron sucrose and ferumoxytol, respectively; using the other method of calculation, the rates ranged from 5.24 per million DEq (iron sucrose) to 147 per million DEq (ferumoxytol).
• Relative to iron sucrose and sodium ferric gluconate, ferumoxytol was associated with significantly elevated risks of death (odds ratio [OR], 475 and 156, respectively; p < 0.0001), serious nonfatal AEs (OR, 263 and 121, respectively; p < 0.0001), and all evaluated AE classifications combined (OR, 142 and 109, respectively; p < 0.05).

Strengths and Weaknesses

Frankly, I liked the study for several reasons. 

• Bailie was upfront about who funded the study (American Regent). 
• He recognized that since ferumoxytol is newly introduced, the much higher reports of AE may reflect the weber effect. [“Weber Effect”: The peak reporting for events in a drug on market occurs within the first 2 years of approval during the initial 5 year marketing period. In 1984, Dr J. C. P. Weber plotted the mean number of ADR reports for seven non-steroidal anti-inflammatory drugs (NSAIDs) over the first 5 years of marketing and showed that they peaked at 2 years and then declined rapidly. Notably, Hartnell has replicated the Weber effect]. 
• Bailie also acknowledges that there may be imprecision in how AEs are reported and also in the classification of AEs.

The bottom-line is that the staggeringly high rates of AEs with ferumoxytol compared to the other iron preparations might be due to the Weber effect, so we need to be careful in not over-reacting. However, the magnitude of the difference is concerning. Since the main reason for using ferumoxytol is convenience-of-dosing and not cost in most dialysis patients and probably in the majority of non-dialysis CKD patients I don't see a rationale for using the drug. So, in the case of ferumoxytol the answer to “Take a Chance on Me?” is "No, Not Yet", because "First Do No Harm."

DIALYSIS QUIZ - answers

The correct answers to the Dialysis Quiz from March 26, 2012 are 1. C, 2. E, 3. D.

The Questions

1. When compared with single use disposable dialzyers, dialyzers reprocessed with bleach and formalin are associated with which of the following?

A. An increased risk of pyrogen reaction

B. Better membrane biocompatibility

C. More transmembrane albumin leaks

D. A higher incidence of viral hepatitis

E. Lower small molecule clearance

2. 43-year old white male with ESRD from IgA Nephropathy, on hemodialysis for 4 years. Dialysis going well without any hospitalizations or complications, but complaining of fatigue. Exam normal except for mild pallor. Hb has fallen from 12.2 g/dL to 9.8 over 3 months despite increased rhEPO dosing from 2000 units/treatment to 5000 units/treatment.

The most likely explanation for the worsening anemia is:

A. Inadequate rhEPO dose

B. Secondary hyperparathyroidism

C. Occult GI bleeding

D. Hemolysis from exposure to sterilants in dialyzer

E. Iron deficiency

3. A 58-year-old patient with ESRD from IgA nephropathy was initiated on hemodialysis using a tunneled cuffed internal jugular catheter. He has an immature left forearm fistula that was placed at the same time as his catheter approximately 6 weeks ago. Over the last week, he has developed fever to 100.8°F while on dialysis, but no fever between dialysis treatments. Blood cultures after the second episode of fever are positive for methicillinresistant S aureus. History and physical examination reveal no source of bacteremia other than possible infection of the indwelling catheter.

Which is the best therapy for this patient?

A. Intravenous nafcillin for at least 4 weeks

B. Intravenous vancomycin for at least 4 weeks

C. High dose nafcillin and gentamicin for synergy

D. Prompt removal of the dialysis catheter and treatment with intravenous vancomycin

E. Treatment of the catheter with urokinase to remove the biofilm and then treatment with vancomycin 

Explanation

For the reprocessing question (#1): more albumin leakage. There is no evidence of increased infectious risk with reuse. In the U.S., all dialysis centers that reuse dialyzers follow the guidelines developed by the Association for the Advancement of Medical Instrumentation (AAMI). There is conflicting data on hospitalization and mortality with reuse, but the consensus is that reuse is safe. Re-processing of dialyzers in the US has fallen dramatically from approximately 70% in the 1990’s to approximately 40% in 2005 and is probably even lower now. The reason for this is that Fresenius decided as company policy to switch to single use of a dialyzer. Bleach, however, removes protein deposits that confer the biocompatibility seen with reuse. Most centers use Renalin®(PAM; 28% hydrogen peroxide and 4.5% peroxyacetic acid). The NKF has published a comprehensive report on reuse, but it is a bit dated.

For the anemia queston (#2): virtually all hemodialysis patients develop iron deficiency from ongoing blood loss and synthetic demands of EPO use.  The average dialysis patient loses 1-3 g of iron/year from bleeding at sites, phlebotomy, and tubing.  Iron absolutely required for effective red blood cell production with EPO.  Anemia and EPO resistance can be seen with bone marrow fibrosis from hyperparathyroidism but there is no correlation with PTH levels. Hemolysis is more acute, and gastrointestinal bleeding should always be excluded.

For the line sepsis question (#3):with persistent fever, positive cultures with staph, and low rate of successful catheter salvage (16% in some studies), removal is safest option. This is particularly important with immature fistula at risk for getting infected. High risk of secondary complication. 

(Questions and Answers courtesy of Dr. Brad Denker, Beth Israel Medical Center/Harvard Medical School, Boston) 

DIALYSIS QUIZ

1. When compared with single use disposable dialzyers, dialyzers reprocessed with bleach and formalin are associated with which of the following?

A. An increased risk of pyrogen reaction

B. Better membrane biocompatibility

C. More transmembrane albumin leaks

D. A higher incidence of viral hepatitis

E. Lower small molecule clearance

2. 43-year old white male with ESRD from IgA Nephropathy, on hemodialysis for 4 years. Dialysis going well without any hospitalizations or complications, but complaining of fatigue. Exam normal except for mild pallor. Hb has fallen from 12.2 g/dL to 9.8 over 3 months despite increased rhEPO dosing from 2000 units/treatment to 5000 units/treatment.

The most likely explanation for the worsening anemia is:

A. Inadequate rhEPO dose

B. Secondary hyperparathyroidism

C. Occult GI bleeding

D. Hemolysis from exposure to sterilants in dialyzer

E. Iron deficiency

3. A 58-year-old patient with ESRD from IgA nephropathy was initiated on hemodialysis using a tunneled cuffed internal jugular catheter. He has an immature left forearm fistula that was placed at the same time as his catheter approximately 6 weeks ago. Over the last week, he has developed fever to 100.8°F while on dialysis, but no fever between dialysis treatments. Blood cultures after the second episode of fever are positive for methicillinresistant S aureus. History and physical examination reveal no source of bacteremia other than possible infection of the indwelling catheter.

Which is the best therapy for this patient?

A. Intravenous nafcillin for at least 4 weeks

B. Intravenous vancomycin for at least 4 weeks

C. High dose nafcillin and gentamicin for synergy

D. Prompt removal of the dialysis catheter and treatment with intravenous vancomycin

E. Treatment of the catheter with urokinase to remove the biofilm and then treatment with vancomycin 

Global Nephrology: Dialysis in the UK – "A Case of the Fox Guarding the Henhouse"?

I’ve been in London for the past week or so. I came across the following story on the BBC on March 22 about Fresenius laying off 29 health care assistants redundant across the West Midlands. In the report Dr Nick Richards, Fresenius' medical director, says that overall, patient-care is "exactly the same". The spokesperson for the University Hospitals Birmingham NHS Foundation Trust says: "We have been informed that Fresenius are implementing a staff reduction programme at Aston Cross, City, Hereford, Tipton and Kings Norton dialysis units….We will continue to closely monitor the service delivered to ensure that Fresenius uphold the standard of care required in accordance with the terms of the contract."

In January a similar story about a Fresenius clinic in Sheffield cutting evening shifts, also reported by the BBC.

Fresenius Medical Care is the largest independent provider of dialysis care in the UK with over 50 dialysis clinics. They are well aware that cutting health care assistants and access to evening dialysis services won’t improve dialysis quality, and if anything, will make things worse. After all, not being able to provide evening services is likely to affect younger patients’ who work and then have dialysis. Getting rid of staff in the name of efficiency is all very well when you're operating a factory but in my experience it doesn't translate well in health services.

While the UK does publish its unit specific dialysis outcome data, unlike the USRDS it doesn’t identify the dialysis provider. Still, I am sure that with some effort one could do an analysis to see if the units that have been affected by the cutbacks have had a reduction in one or more quality metrics. I hope the NHS scrutinizes whatever provider specific data it has very carefully.

In the US where across-the-board reduction in patient-nursing staff ratios have occurred over the past decade it’s still hard to figure out whether this has affected outcome because quality of life data by patients is not reported. The data we do have is that for mortality and dialysis treatment time; the "for-profits" lag behind "not-for-profits" and more generally, the US lags behind Europe and Japan.

My bottom line: When a dialysis provider cuts services by laying off staff I would ask is this another case of "the fox guarding the henhouse"?

Image Quiz

The answer to the image quiz from March 11, 2012 is ADPKD. The image shows enlarged kidneys with multiple cysts in an unenhanced axial computed tomography (CT) scan. The cysts are fairly well-defined, round or oval masses with low attenuation values similar to those of water.

The Question: What is the diagnosis on the CT image below?

10 Quick Facts on ADPKD

1. Autosomal dominant polycystic kidney disease (ADPKD) is the most common of all the hereditary cystic kidney diseases.

2. Incidence of 1 to 2:1,000 live births.

3. Accounts for 10% of ESRD patients in Europe and the U.S.

4. Characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts.

5. Three genetic mutations in the PKD-1, PKD-2, and PKD-3 gene with similar phenotypical presentations.

• Gene PKD-1 is located on chromosome 16 and codes for a protein involved in regulation of cell cycle and intracellular calcium transport in epithelial cells, and is responsible for 85% of the cases of ADPKD.
• A group of voltage-linked calcium channels are coded for by PKD-2 on chromosome 4.
• PKD3 recently appeared in research papers as a postulated 3rd gene. At this time, PKD3 has not been proven.

6. Fewer than 10% of cases of ADPKD appear in non-ADPKD families.

7. Patients present with hypertension and progressive renal failure after their third decade of life.

8. Between 29% and 73% of patients with the disorder have associated hepatic cysts, 9% have associated pancreatic cysts, and 5% have associated splenic cysts; pulmonary cysts occur but are uncommon.

9. Gardner and Evan showed that individuals older than age 40 years with a family history of ADPKD but without renal cysts are unlikely to develop the disease. Others have shown that when screening for evidence of ADPKD, if the kidney shows no signs of cysts or parenchymal abnormality in a patient by age 19 years, that individual is extremely unlikely to be affected.

10. Ultrasonography is the procedure of choice in the workup of patients with ADPKD, and it is an ideal modality for screening patients' families (see the images below). Plain radiographs offer limited information.

• Ravine criteria (Lancet 1994;343(8901):824-827): 
• diagnosis of ADPKD 
• if there is a positive family history
• two renal cysts either unilateral or bilateral in patients under the age of thirty. 
• In patients between the ages of 30 and 59, a minimum of two cysts must be present in each kidney. 
• In patients over the age of 60, four cysts in each kidney is necessary for diagnosis. 
• The use of these criteria reduces the false negative rate of diagnosis to less than 5%.

(Source: Wikipedia and emedicine)

ELECTROLYTE QUIZ

The answers to the Electrolyte Quiz from March 21, 2012 are: 1. A, 2. D, 3. C, 4. B.

The Questions

For each patient with hyperkalemia described below, select the best option (A.-E.) for treatment of their serum potassium.

A. Thiazide diuretic
B. Hydrocortisone
C. Insulin D. Hemodialysis
E. Sodium polystyrene sulfonate

1. 43-year-old man with Type II diabetes mellitus, hypertension, congestive cardiac failure, nephrotic-range proteinuria, and a serum creatinine of 1.6 mg/dL. His serum potassium has been in the range of 5.6-5.9 mEq/L since starting captopril, despite adhering to a potassiumrestricted diet.

2. 88-year-old woman who had partial colectomy for perforated diverticular abscess and septicemia two days previously, and has been anuric since the operation. Her serum potassium is 6 mg/dL.

3. 18-year-old man with no prior medical history who presents with one week of polyuria and polydipsia.=
Laboratory Studies Serum sodium 132 mEq/L Serum potassium 5.9 mEq/L Serum chloride 91 mEq/L Serum bicarbonate 16 mEq/L Blood urea nitrogen 56 mg/dL Serum creatinine 2.2 mg/dL Serum glucose 330 mg/dL

4. 26-year-old woman with acquired immune deficiency syndrome, fatigue, weight loss, lowgrade fever, and orthostatic hypotension. Serum cortisol level: Baseline at 8 AM7 mcg/dL  (nL 5-24 mcg/dL) 30 minutes after 250 10 mcg/dL mcg cosyntropin i.m. 60 minutes after 250.11 mcg/dL mcg cosyntropin i.m.

Explanation

The 43-year-old man likely has diabetic nephropathy and hyporeninemic hypoaldosteronism. He is volume-expanded and loop or thiazide diuretics are a useful way to correct his potassium and volume simultaneously. The 88-year-old with postoperative anuric acute renal failure requires dialysis. Enteral administration of a potassium-binding resin is contraindicated, and no other measure will remove potassium from her body. The 18-year-old man has newly-diagnosed diabetes and diabetic ketoacidosis. The hyperkalemia is due to shift of potassium from the intracellular to extracellular space, which can be readily reversed with insulin, and his renal failure is largely due to hypovolemia and may be reversible with fluid replacement. His whole body potassium content is actually reduced and any measures that remove potassium from the body would risk subsequent development of hypokalemia once insulin therapy is initiated. The 26-year-old woman has primary adrenal insufficiency, which can occur in patients with acquired immunodeficiency syndrome due to infectious agents such as cytomegalovirus or mycobacteria, and drugs such as ketoconazole and rifampin. Although her baseline serum cortisol level is normal, it fails to rise appropriately (increment from baseline > 7 mcg/dL, or 30 minute level > 15 mcg/dL) after administration of cosyntropin. Replacement with hydrocortisone is therefore indicated.

(Questions and answers provided courtesy of Dr. Alan Yu, University of Kansas Medical Center, USA). 

Journal Club: Is Longer Dialysis Treatment Time Associated with Better Outcomes?

Before we delve into the paper I plan to discuss lets get one key issue out of the way, namely, this is not a randomized controlled trial (RCT). Nevertheless, this is a terrific study addressing an important and timely issue.

In this paper in NDT, Tentori et al from DOPPS [based at Arbor Research, Michigan, USA] tested the hypothesis of whether longer treatment time (TT) is associated with improved outcomes – both intermediate outcomes, such as anemia parameters, hospitalization rates, phospohorus control, and more harder endpoints such as cardiovascular events and mortality. In addition, the authors also presented interesting data on regional differences in dialysis practice with respect to TT.

For me, the bottom-line is that this study provides further evidence to support using longer treatment times in managing dialysis patients. The short TTs in the US (only 12% had a TT >250 min in 2005–08) ought to be a wake-up call.

For some time, in my clinical practice, I have been pushing patients to accept longer treatment time. This analysis doesn't prove that longer TT's definitively make a difference - for that we need an RCT.

The sample comprised of

• N=37 414 patients on in-center HD three times per week with prescribed TT from 120 to 420 min in 930 facilities in 12 countries participating in the DOPPS (1996–2008)
• The cohort: The Dialysis Outcomes and Practice Patterns Study (DOPPS) prospective cohort study of in-center HD patients.

The key results

• Facility mean TT ranged from 214 min in the USA to 256 min in Australia–New Zealand.
• Among US DOPPS participants in 2005–08, only 12% had a TT >250 min, while 23% were dialyzed for <200 min.
• Mortality risk was lower for patients with longer TT {hazard ratio for every 30 min: all-cause mortality: 0.94 [95% CI: 0.92–0.97], cardiovascular mortality: 0.95 (95% CI: 0.91–0.98) and sudden death: 0.93 (95% CI: 0.88–0.98)}.
• The strong association between longer TT and lower risk of sudden death remained after adjusting for patient comorbidities (like diabetes and atrial fibrillation) that are risk factors for sudden death
• Patients with longer TT had lower pre- and post-dialysis systolic blood pressure, greater intradialytic weight loss, higher hemoglobin (for the same erythropoietin dose), serum albumin and potassium and lower serum phosphorus and white blood cell counts. 

Strengths of the study

• Large sample size and the established DOPPS infrastructure and representative sampling approach across 12 countries.
• The use of time varying models that adjusted for both patient characteristics and DOPPS country and study phase and accounted for facility clustering.
• Use of an instrumental variable approach - with the dialysis facility as the instrument - in order to address patient-level unmeasured confounders which might impact the relationship between TT and outcomes. 

Weaknesses of the study

• Observational design. The authors cannot completely attenuate the feffects of confounding, especially residual from unmeasured variables. An RCT would have been ideal.
• There was an increase in TT over time in both the study (from 208 ± 32 to 221 ± 31 min) and that publication (from 201 ± 61 to 213 ± 59 min) – the authors argue the change was relatively small  - but it may have had an impact on clinical outcomes. 

ELECTROLYTE QUIZ

The Questions

For each patient with hyperkalemia described below, select the best option (A.-E.) for treatment of their serum potassium.

A. Thiazide diuretic

B. Hydrocortisone

C. Insulin

D. Hemodialysis

E. Sodium polystyrene sulfonate

1. 43-year-old man with Type II diabetes mellitus, hypertension, congestive cardiac failure, nephrotic-range proteinuria, and a serum creatinine of 1.6 mg/dL. His serum potassium has been in the range of 5.6-5.9 mEq/L since starting captopril, despite adhering to a potassiumrestricted diet.

2. 88-year-old woman who had partial colectomy for perforated diverticular abscess and septicemia two days previously, and has been anuric since the operation. Her serum potassium is 6 mg/dL.

3. 18-year-old man with no prior medical history who presents with one week of polyuria and polydipsia.

Laboratory Studies

Serum sodium 132 mEq/L

Serum potassium 5.9 mEq/L

Serum chloride 91 mEq/L

Serum bicarbonate 16 mEq/L

Blood urea nitrogen 56 mg/dL

Serum creatinine 2.2 mg/dL

Serum glucose 330 mg/dL

4. 26-year-old woman with acquired immune deficiency syndrome, fatigue, weight loss, lowgrade fever, and orthostatic hypotension.

Serum cortisol level:

Baseline at 8 AM7 mcg/dL 

(nL 5-24 mcg/dL)

30 minutes after 250 10 mcg/dL mcg cosyntropin i.m.

60 minutes after 250.11 mcg/dL mcg cosyntropin i.m.

(Questions and answers provided courtesy of Dr. Alan Yu, University of Kansas Medical Center, USA). 

Dialysis Unplugged: Peginesatide for the Treatment of Anemia in Dialysis Patients

We are on the threshold of a new era in anemia treatment in dialysis patients, at least in the US, because it is likely that a new erythropoiesis stimulating agent (ESA) will get approved next week.

The prediction out there is that peginesatide is likely to be approved by the FDA at the scheduled PDUFA meeting on March 27, 2012.

Peginesatide would provide a potentially exciting alternative in the US to the conventional ESA, epoetin-alfa, in the treatment of anemia in dialysis patients. [More about the peginesatide clinical development program is available on Affymax’s web site].

Source: Affymax web site

Recall that December 8th, 2011, the FDA’s committee Oncologic Drugs Advisory Committee (ODAC) voted in favor of peginesatide for use in the treatment of dialysis patients with anemia due to chronic kidney disease (CKD) (15 to 1, with 1 abstention). Joyce Frieden has a nice summary of the ODAC deliberations here.

Why the decision by Affymax to seek approval for peginesatide in only dialysis patients? The company reported publically and to the FDA a safety signal in non-dialysis CKD patients. As the FDA noted in their report to ODAC in December 2011 “peginesatide appears to show similar safety results when compared to epoetin by both composite safety events (CSEs) and major adverse cardiac event outcomes.” However, among patients not on dialysis, “the hazard ratio for CSEs -- including the first occurrence of death, stroke, myocardial infarction, congestive heart failure, unstable angina, or arrhythmia -- was 1.32 (90% CI 1.02 to 1.72) for patients on peginesatide.” An article by Trevor Sherwood in the Biotech Investment Paradigm also provides further analysis.

While we await the formal publication of the paper reporting the data on which the FDA approval is based, it is likely that once FDA has approved peginesatide in the US, Affymax will start marketing it (European regulatory approval is still pending).

So what are peginesatide prospects? In my view: uncertain at this point.

This is because we don’t know the answer to two questions:

First, will Affymax price the drug competitively? Some in the media have speculated that Affymax will price peginesatide lower than Epogen. If they don’t then I doubt peginesatide will gain a significant market foothold. This is because Amgen has already signed long-term “sweet-heart” contracts with some of the large dialysis organizations (LDOs) for its already dominant product Epogen. This strategy worked for the iron companies in keeping ferumoxytol out of the dialysis market (see later) and it might work for Amgen if Affymax positions peginesatide’s once-monthly dosing schedule as its main competitive advantage rather than lower price. 

Take as an example the continuous erythropoietin receptor activator experience in Europe, (CERA is marketed by Roche as Micera). Like peginesatide, CERA is pegylated and has a prolonged half-life (t≈107 hours) and can be administered once monthly. However, CERA has only a relatively small market share in the European dialysis market because once-monthly dosing has not turned out to be important for dialysis patients who are at the dialysis center 3 times weekly and receiving drug intravenously. So in a price-conscious bundled dialysis environment in the US, the pricing strategy rather than dosing schedule for peginesatide will be key.

Besides the example of CERA, the effect of pricing one-self out of the market is exemplified by the ferumoxytol experience. Here, AMAG priced ferumoxytol as a treatment for iron deficiency in both dialysis and non-dialysis CKD patients believing that it’s superior dosing schedule would confer competitive advantage. AMAG priced ferumoxytol higher than other agents in the dialysis market. They mistakenly thought that many providers would opt to stay outside the bundle. Naturally, in a bundled cost-aware arena with aggressive contracting in place, ferumoxytol that was priced higher than it's competitors, failed to be a significant player.

Second, how will the safety concerns reported by Affymax in non-dialysis CKD patients’ impact on the use of peginesatide in dialysis patients? Since there have been no primary papers published as yet we have to hold final judgment. However, if the safety signal already reported publically holds true in the published papers, Affymax’s competitors may point to this as a reason to avoid use of the drug. Despite FDA approval, cautious nephrologists already smarting from the safety signals that have emerged with conventional ESAs, may take the “devil-you-know-is better-than-the-devil-you-don’t” approach. In fairness to peginesatide, no significant safety signals were reported in it’s EMERALD 1 and 2 trials that were conducted in dialysis patients, whereas there was clearly a safety signal from Epogen that emerged in Amgen's Normal Hematocrit study in dialysis patients. However, it's unclear if this division by the FDA of patient's into dialysis and non-dialysis - separated only by whether they undergo dialysis therapy - makes any sense from a safety perspective. It doesn't to me.

The bottom-line is that while all the indications are that the US FDA will approve peginesatide, its success as an alternative to either epoetin-alfa or darbepoetin remains uncertain and very much depends on it's price and how nephrologists view the safety signal that emerged from its non-dialysis CKD trials.