Jha's Notes

The very high levels of vitamin D that are often recommended by doctors and testing laboratories — and can be achieved only by taking supplements — are unnecessary and could be harmful, an expert committee says. It also concludes that calcium supplements are not needed.

The group said most people have adequate amounts of vitamin D in their blood supplied by their diets and natural sources like sunshine, the committee says in a report that is to be released on Tuesday.

“For most people, taking extra calcium and vitamin D supplements is not indicated,” said Dr. Clifford J. Rosen, a member of the panel and an osteoporosis expert at the Maine Medical Center Research Institute.

Dr. J. Christopher Gallagher, director of the bone metabolism unit at the Creighton University School of Medicine in Omaha, Neb., agreed, adding, “The onus is on the people who propose extra calcium and vitamin D to show it is safe before they push it on people.”

Over the past few years, the idea that nearly everyone needs extra calcium and vitamin D — especially vitamin D — has swept the nation.

With calcium, adolescent girls may be the only group that is getting too little, the panel found. Older women, on the other hand, may take too much, putting themselves at risk for kidney stones. And there is evidence that excess calcium can increase the risk of heart disease, the group wrote.

As for vitamin D, some prominent doctors have said that most people need supplements or they will be at increased risk for a wide variety of illnesses, including heart disease, cancer and autoimmune diseases.

And these days more and more people know their vitamin D levels because they are being tested for it as part of routine physical exams.

“The number of vitamin D tests has exploded,” said Dennis Black, a reviewer of the report who is a professor of epidemiology and biostatistics at the University of California, San Francisco.

At the same time, vitamin D sales have soared, growing faster than those of any supplement, according to The Nutrition Business Journal. Sales rose 82 percent from 2008 to 2009, reaching $430 million. “Everyone was hoping vitamin D would be kind of a panacea,” Dr. Black said. The report, he added, might quell the craze.

“I think this will have an impact on a lot of primary care providers,” he said.

The 14-member expert committee was convened by the Institute of Medicine, an independent nonprofit scientific body, at the request of the United States and Canadian governments. It was asked to examine the available data — nearly 1,000 publications — to determine how much vitamin D and calcium people were getting, how much was needed for optimal health and how much was too much.

The two nutrients work together for bone health.

Bone health, though, is only one of the benefits that have been attributed to vitamin D, and there is not enough good evidence to support most other claims, the committee said.

Some labs have started reporting levels of less than 30 nanograms of vitamin D per milliliter of blood as a deficiency. With that as a standard, 80 percent of the population would be deemed deficient of vitamin D, Dr. Rosen said. Most people need to take supplements to reach levels above 30 nanograms per milliliter, he added.

But, the committee concluded, a level of 20 to 30 nanograms is all that is needed for bone health, and nearly everyone is in that range.

Vitamin D is being added to more and more foods, said Paul R. Thomas of the Office of Dietary Supplements at the National Institutes of Health. Not only is it in orange juice and milk, but more is being added to breakfast cereals, and it now can be found in very high doses in supplement pills. Most vitamin D pills, he said, used to contain no more than 1,000 international units of it. Now it is easy to find pills, even in places like Wal-Mart, with 5,000 international units. The committee, though, said people need only 600 international units a day.

To assess the amounts of vitamin D and calcium people are getting, the panel looked at national data on diets. Most people, they concluded, get enough calcium from the foods they eat, about 1,000 milligrams a day for most adults (1,200 for women ages 51 to 70).

Vitamin D is more complicated, the group said. In general, most people are not getting enough vitamin D from their diets, but they have enough of the vitamin in their blood, probably because they are also making it naturally after being out in the sun and storing it in their bodies.

The American Society for Bone and Mineral Research and other groups applauded the report. It is “a very balanced set of recommendations,” said Dr. Sundeep Khosla, a Mayo Clinic endocrinologist and the society’s president.

But Andrew Shao, an executive vice president at the Council for Responsible Nutrition, a trade group, said the panel was being overly cautious, especially in its recommendations about vitamin D. He said there was no convincing evidence that people were being harmed by taking supplements, and he said higher levels of vitamin D, in particular, could be beneficial.

Such claims “are not supported by the available evidence,” the committee wrote. They were based on studies that observed populations and concluded that people with lower levels of the vitamin had more of various diseases. Such studies have been misleading and most scientists agree that they cannot determine cause and effect.

It is not clear how or why the claims for high vitamin D levels started, medical experts say. First there were two studies, which turned out to be incorrect, that said people needed 30 nanograms of vitamin D per milliliter of blood, the upper end of what the committee says is a normal range. They were followed by articles and claims and books saying much higher levels — 40 to 50 nanograms or even higher — were needed. Read the rest of this entry »

*High dose epoetin beta in the first weeks following renal transplantation and delayed graft function: Results of the Neo-PDGF Study. *

Martinez F, Kamar N, Pallet N, Lang P, Durrbach A, Lebranchu Y, Adem A, Barbier S, Cassuto-Viguier E, Glowaki F, Le Meur Y, Rostaing L, Legendre C, Hermine O, Choukroun G; NeoPDGF Study Investigators. Am J Transplant. 2010 Jul;10(7):1695-700.

Erythropoietin promotes nephroprotection in animal models of ischemia-reperfusion injury. Neorecormon and Prevention of Delayed Graft Function (Neo-PDGF) is a French open-label multicenter randomized study to evaluate the effect of high doses of epoetin beta (EPO-beta) during the first 2 weeks of renal transplantation on renal function in patients at risk for delayed graft function (DGF). One hundred and four patients were included in the study. Patients randomized in treatment group (A) received four injections of EPO-beta (30.000 UI each), given before surgery and at 12 h, 7 days and 14 days posttransplantation. Patients randomized in control group (B) did not receive EPO-beta. Immunosuppression included induction with basiliximab and maintenance therapy with steroids, mycophenolate mofetil and tacrolimus. At 1 month posttransplant, the estimated glomerular filtration rate (MDRD formula) was 42.5 +/- 19.0 mL/min in the EPO-beta group and 44.0 +/- 16.3 mL/min in the control group (p = ns). The frequency of DGF was similar in both groups (32% vs. 38.8%; p = ns). No difference in the incidence of serious adverse events was observed. (ClinicalTrials.gov number, NCT00815867.).

*The CLEAR study: a 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.*

Gourishankar S, Houde I, Keown PA, Landsberg D, Cardella CJ, Barama AA, Dandavino R, Shoker A, Pirc L, Wrobel MM, Kiberd BA. Clin J Am Soc Nephrol. 2010 Jul;5(7):1282-9. Epub 2010 May 24.

BACKGROUND AND OBJECTIVES: Adequate early mycophenolic acid (MPA) exposure is associated with lower rates of acute rejection in renal transplantation. The aim of this randomized controlled trial was to determine if higher initial mycophenolate mofetil (MMF) doses increased the proportion of patients reaching therapeutic MPA levels (30 to 60 mg.h/L) by day 5. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: De novo renal transplant patients were randomized to receive intensified dosing of MMF (1.5 g twice daily on days 1 to 5, then 1.0 g twice daily) or standard dosing (1.0 g twice daily). All recipients received tacrolimus and prednisone. Full MPA areas under the curve (AUCs) were completed on days 3 and 5, whereas a limited sampling strategy was utilized at four subsequent time points. RESULTS: At day 5, 47.5% of the MMF 3-g arm achieved the MPA therapeutic window versus 54.4% of the MMF 2-g arm. However, MPA AUC levels were significantly higher in the 3-g arm at day 3 and 5. This resulted in a trend for fewer treated acute rejections at 6 months. Significantly more acute rejections (treated, biopsy-proven including and excluding borderline) occurred in patients with MPA AUC levels<30 mg.h/L compared with those >or=30 mg.h/L at day 5. No significant differences were seen in common adverse events. CONCLUSIONS: A limited intensified dose of MMF increased early MPA exposure and was well tolerated. Further studies are required to determine whether limited intensified MMF dosing can reduce acute rejection.

*Mycophenolic acid exposure in high- and low-weight renal transplant patients after dosing with mycophenolate mofetil in the Opticept trial.*

Kaplan B, Gaston RS, Meier-Kriesche HU, Bloom RD, Shaw LM. Ther Drug Monit. 2010 Apr;32(2):224-7.

The Opticept trial was an open-label, randomized, multicenter trial involving 720 kidney recipients. Three immunosuppressant dosing regimens were evaluated, including both fixed and concentration-controlled dosing of mycophenolate mofetil in combination with standard and reduced calcineurin inhibitor levels. Mycophenolic acid (MPA) levels were measured, yielding one of the largest databases to assess the impact of variables on MPA exposure. The present subset analysis evaluated the effect of baseline body weight in three noncontiguous weight categories on MPA exposure at steady state (Day 90) in patients receiving tacrolimus. Multivariate linear regression models assessed the relationship between area under the concentration-time curve (AUC) and several variables. In all, 219 patients had baseline weights in the three categories and an MPA AUC at Day 90: 50 kg or less (n = 12, all female); 60 to 80 kg (n = 136); or 100 kg or greater (n = 71). In overall comparisons by weight class, clearance increased with increased weight, resulting in an inverse relationship between dose-corrected MPA AUCs and weight at Day 90 (P < 0.0001). In patients of extreme weight, wide disparities of MPA exposure were measured despite the mean mycophenolate mofetil dose, notably in those 50 kg or less who had comparatively high dose-corrected MPA AUCs. Patients at the extremes of weight might be at risk of over- or underimmunosuppression unless doses are adjusted.

*Bicarbonate versus lactate solutions for acute peritoneal dialysis. *Bai ZG, Yang K, Tian J, Ma B, Liu Y, Jiang L, Tan J, Liu TX, Chi I. Cochrane Database Syst Rev. 2010 Sep 8;(9):CD007034.

BACKGROUND: The high mortality rate among critically ill patients with acute kidney injury (AKI) remains an unsolved problem in intensive care medicine, despite the use of renal replacement therapy (RRT). Increasing evidence from clinical studies in adults and children suggests that the new peritoneal dialysis (PD) fluids may allow for better long-term preservation of peritoneal morphology and function. Formation of glucose degradation products (GDPs) can be reduced and even avoided with the use of newer “biocompatible” solutions. However, it is still unclear if there are any differences in using conventional (lactate) solutions compared with low GDP (bicarbonate) solutions for acute PD. OBJECTIVES: To look at the benefits and harms of bicarbonate versus lactate solutions in acute PD. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1966), EMBASE (from 1980), Latin American and Caribbean Health Sciences Literature Database LILACS (from 1982), and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing bicarbonate to lactate solution for acute PD. DATA COLLECTION AND ANALYSIS: Two authors independently assess the methodological quality of studies. One author abstracted data onto a standard form, and a second author checked data extraction. We used the random-effects model and expressed the results as relative risk (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included one study (20 patients) in this review. In shock patients, bicarbonate did not differ from lactate with respect to mortality (RR 0.50, 95% CI 0.06 to 3.91); however there were significant differences in blood lactate (MD -1.60 mmol/L, 95% CI -2.04 to -1.16), serum bicarbonate (MD 5.00 mmol/L, 95% CI 3.26 to 6.74) and blood pH (MD 0.12, 95% CI 0.06 to 0.18). In non-shock patients there was a significance difference in blood lactate (MD -0.60 mmol/L, 95% CI -0.85 to -0.35) but not in serum bicarbonate (MD 1.10 mmol/L, 95% CI -0.27 to 2.47) or blood pH (MD -0.02, 95% CI -0.02 to -0.06). Other outcomes could not be analysed because of the limited data available. AUTHORS’ CONCLUSIONS: There is no strong evidence that any clinical advantage for patients requiring acute PD for AKI when comparing conventional (lactate) with low GDP dialysis solutions (bicarbonate).

*Defining acute kidney injury in database studies: the effects of varying the baseline kidney function assessment period and considering CKD status.*

Lafrance JP, Miller DR. Am J Kidney Dis. 2010 Oct;56(4):651-60. Epub 2010 Jul 29.

BACKGROUND: Existing acute kidney injury (AKI) definitions are not well adapted for database studies, leading to a great variety of methods used in research. Variations in time before hospitalization used to assess baseline kidney function when identifying episodes of AKI may lead to different case samples and mortality risks in database studies, but the magnitude of these effects is not known. STUDY DESIGN: A retrospective cohort study. SETTINGS & PARTICIPANTS: 1,126,636 veterans hospitalized at least once within the US Department of Veterans Affairs health care system between 2000 and 2005. PREDICTOR: AKI was defined by comparing (using ratio [?1.5] or difference [increase of 0.3-0.5 mg/dL]) the highest serum creatinine level during hospitalization with the lowest level during 4 different baseline assessment periods (in-hospital only and 3, 6, or 12 months preadmission). OUTCOMES & MEASUREMENTS: In-hospital mortality risk was estimated using multivariable logistic regression models. RESULTS: Using the ratio definition, the cumulative incidence of AKI ranged from 12.5% (in-hospital only) to 18.3% (12 months preadmission). Newly added cases had milder AKI and lower mortality risk. The discriminative power increased slightly (C statistic increased from 0.846 to 0.855; P = 0.001) by extending the baseline period to at least 3 months. Both the ratio and difference definitions did not perform well in patients with chronic kidney disease stages 4 and 5. LIMITATIONS: Possibility of residual confounding and under-representation of women (4.5%). CONCLUSIONS: Many additional AKI cases may be identified by extending the baseline assessment period; however, added cases may be less severe with lower mortality risk. The relative strengths of these biases and combined effects of reducing misclassification (identification of more AKI cases) and increasing risk dilution (identifying milder cases) may vary across populations. Consensus regarding how baseline kidney function should be determined in database studies should be reached.

*Impact of RIFLE classification in liver transplantation.*

Ferreira AC, Nolasco F, Carvalho D, Sampaio S, Baptista A, Pessegueiro P, Monteiro E, Mourão L, Barroso E. Clin Transplant. 2010 May;24(3):394-400. Epub 2009 Sep 11.

Acute renal failure (ARF) is common after orthotopic liver transplantation (OLT). The aim of this study was to evaluate the prognostic value of RIFLE classification in the development of CKD, hemodialysis requirement, and mortality. Patients were categorized as risk (R), injury (I) or failure (F) according to renal function at day 1, 7 and 21. Final renal function was classified according to K/DIGO guidelines. We studied 708 OLT recipients, transplanted between September 1992 and March 2007; mean age 44 +/- 12.6 yr, mean follow-up 3.6 yr (28.8% > or = 5 yr). Renal dysfunction before OLT was known in 21.6%. According to the RIFLE classification, ARF occurred in 33.2%: 16.8% were R class, 8.5% I class and 7.9% F class. CKD developed in 45.6%, with stages 4 or 5d in 11.3%. Mortality for R, I and F classes were, respectively, 10.9%, 13.3% and 39.3%. Severity of ARF correlated with development of CKD: stage 3 was associated with all classes of ARF, stages 4 and 5d only with severe ARF. Hemodialysis requirement (23%) and mortality were only correlated with the most severe form of ARF (F class). In conclusion, RIFLE classification is a useful tool to stratify the severity of early ARF providing a prognostic indicator for the risk of CKD occurrence and death.

*Urinary L-type fatty acid-binding protein as a new biomarker of sepsis complicated with acute kidney injury. *Doi K, Noiri E, Maeda-Mamiya R, Ishii T, Negishi K, Hamasaki Y, Fujita T, Yahagi N, Koide H, Sugaya T, Nakamura T. Crit Care Med. 2010 Oct;38(10):2037-42.

OBJECTIVE: This study is aimed to examine whether urinary L-type fatty acid-binding protein can detect the severity of sepsis with animal sepsis models and septic shock patients complicated with established acute kidney injury. DESIGN: Experimental animal models and a clinical, prospective observational study. SETTING: University laboratory and tertiary hospital. SUBJECTS AND PATIENTS: One hundred fourteen human L-type fatty acid-binding protein transgenic mice and 145 septic shock patients with established acute kidney injury. INTERVENTIONS: Animals were challenged by abdominal (cecal ligation and puncture) and pulmonary (intratracheal lipopolysaccharide injection) sepsis models with different severities that were confirmed by survival analysis (n = 24) and bronchoalveolar lavage fluid analysis (n = 38). MEASUREMENTS AND MAIN RESULTS: In animal experiments, significant increases of urinary L-type fatty acid-binding protein levels were induced by sepsis (severe cecal ligation and puncture 399.0 ± 226.8 ?g/g creatinine [n = 12], less-severe cecal ligation and puncture 89.1 ± 25.3 [n = 11], sham 13.4 ± 3.4 [n = 10] at 6 hrs, p < .05 vs. sham; 200 ?g of lipopolysaccharide 190.6 ± 77.4 ?g/g creatinine [n = 6], 50 ?g of lipopolysaccharide 145.4 ± 32.6 [n = 8], and saline 29.9 ± 14.9 [n = 5] at 6 hrs, p < .05 vs. saline). Urinary L-type fatty acid-binding protein predicted severity more accurately than blood urea nitrogen, serum creatinine, and urinary N-acetyl-d-glucosaminidase levels. In clinical evaluation, urinary L-type fatty acid-binding protein measured at admission was significantly higher in the nonsurvivors of septic shock with established acute kidney injury than in the survivors (4366 ± 192 ?g/g creatinine [n = 68] vs. 483 ± 71 [n = 77], p < .05). Urinary L-type fatty acid-binding protein showed the higher value of area under the receiver operating characteristic curve for mortality compared with Acute Physiology and Chronic Health Evaluation (APACHE) II and Sepsis-related Organ Failure Assessment (SOFA) scores (L-type fatty acid-binding protein 0.994 [0.956-0.999], APACHE II 0.927 [0.873-0.959], and SOFA 0.813 [0.733-0.873], p < .05). CONCLUSIONS: Our results suggest that urinary L-type fatty acid-binding protein can be a useful biomarker for sepsis complicated with acute kidney injury for detecting its severity.

The number of people dying from malaria in India has been hugely underestimated, according to new research. The data, published in the Lancet, suggests there are 13 times more malaria deaths in India than the World Health Organization (WHO) estimates. The authors conclude that more than 200,000 deaths per year are caused by malaria. The WHO said the estimate produced by this study appears too high. The research was funded by the US National Institutes of Health, the Canadian Institute of Health Research and the Li Ka Shing Knowledge Institute. The new figures raise doubts over the total number of malaria deaths worldwide. Read the rest of this entry »

From The New York Times

By TINA ROSENBERG AND DAVID BORNSTEIN

Most of us tend to be better informed about problems than solutions. This presents two challenges: if we rarely hear about success when it occurs, it’s hard to believe that problems can, in fact, be solved. Also, knowledge about how to solve problems ends up being concentrated in too few hands. It needs to circulate more broadly so that it can be applied where needed.

Today, we will examine one solution to a vexing problem: many diseases that we know how to prevent and cure remain widespread. For nearly all of human history, lives were short and miserable because there was little anyone could do about disease. Now we know what to do. The science is there. The technology is there. But we have a different problem ? a happier one, but no less challenging: how do we get these interventions to people everywhere? And this problem doesn’t just apply to health care, it applies to almost every modern good or service, whether it’s education, energy, clean water or job opportunities. As the science fiction writer William Gibson has said, “The future is here ? it’s just not evenly distributed.” Read the rest of this entry »

After 50 years of loyal service, traditional CPR is being replaced by a new, bare-bones version of the life-saving emergency procedure.

The American Heart Association has created a short web tutorial that shows how to do effective CPR. It’s available at handsonlycpr.org/.  Forget about yucky mouth-to-mouth contact — the P in cardiopulmonary resuscitation (CPR) — and get right down to pumping hard and fast on the chest, the American Heart Association said on Monday, that will keep oxygen-rich blood flowing to the brain until trained rescuers can take over.

“Chest compressions are the most important part of CPR,” said Dr. Michael Sayre, a spokesman for the American Heart Association. “The major change is switching to starting CPR with chest compressions rather than opening an airway and doing rescue breathing.” Read the rest of this entry »

How many of the medical studies are flawed?

IN 2001, RUMORS were circulating in Greek hospitals that surgery residents, eager to rack up scalpel time, were falsely diagnosing hapless Albanian immigrants with appendicitis. At the University of Ioannina medical school’s teaching hospital, a newly minted doctor named Athina Tatsioni was discussing the rumors with colleagues when a professor who had overheard asked her if she’d like to try to prove whether they were true—he seemed to be almost daring her. She accepted the challenge and, with the professor’s and other colleagues’ help, eventually produced a formal study showing that, for whatever reason, the appendices removed from patients with Albanian names in six Greek hospitals were more than three times as likely to be perfectly healthy as those removed from patients with Greek names. “It was hard to find a journal willing to publish it, but we did,” recalls Tatsioni. Read the rest of this entry »

Comparison of Active Vitamin D Compounds and a Calcimimetic in Mineral Homeostasis * Loan Nguyen-Yamamoto*, Isabel Bolivar*, Stephen A. Strugnell[image: {dagger}] and David Goltzman* *

* * Department of Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and [image: {dagger}] Genzyme Corporation, Middleton, Wisconsin * The differential effects between cinacalcet and active vitamin D compounds on parathyroid function, mineral metabolism, and skeletal function are incompletely understood. Here, we studied cinacalcet and active vitamin D compounds in mice expressing the null mutation for *Cyp27b1*, which encodes 25-hydroxyvitamin D-1[image: {alpha}]-hydroxylase, thereby lacking endogenous 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Vehicle-treated mice given high dietary calcium had hypocalcemia, hypophosphatemia, and marked secondary hyperparathyroidism. Doxercalciferol and 1,25(OH)2D3 each normalized these parameters and corrected both the abnormal growth plate architecture and the diminished longitudinal bone growth observed in these mice. In contrast, cinacalcet suppressed serum parathyroid hormone (PTH) cyclically and did not correct the skeletal abnormalities and hypocalcemia persisted. Vehicle-treated mice given a “rescue diet” (high calcium and phosphorus, 20% lactose) had normal serum calcium and PTH levels; cinacalcet induced transient hypocalcemia and mild hypercalciuria. The active vitamin D compounds and cinacalcet normalized the increased osteoblast activity observed in mice with secondary hyperparathyroidism; cinacalcet, however, increased the number and activity of osteoclasts. In conclusion, cinacalcet reduces PTH in a cyclical manner, does not eliminate hypocalcemia, and does not correct abnormalities of the growth plate. Doxercalciferol and 1,25(OH)2D3reduce PTH in a sustained manner, normalize serum calcium, and improve skeletal abnormalities.

Published ahead of print on July 22, 2010 J Am Soc Nephrol 21: 1713-1723, 2010

Free full text: http://jasn.asnjournals.org/cgi/content/full/21/10/1713

By DANIEL GILBERT

RECENTLY the doctor gave me a prescription for a week’s worth of antibiotics, along with the usual stern warning about the importance of completing the full course.

I understood why I needed to complete the full course, of course. What I didn’t understand was why a full course took precisely seven days. Why not six, eight or nine and a half? Did the number seven correspond to some biological fact about the human digestive tract or the life cycle of bacteria? As I walked out of the emergency room that night with my prescription in hand, I couldn’t help but suspect that I’d just been treated with magic. Read the rest of this entry »

By By Jessica Wapner

The war against industry-sponsored medical education is in full tilt. In recent anti-pharma news, industry employees have been barred from giving talks during at least two important upcoming medical meetings, and oncologists from Vermont, Minnesota, and Massachusetts were forbidden from partaking in the snacks provided at corporate exhibit booths during a recent annual cancer society meeting. These developments come on the heels of a movement already well under way at medical centers around the country: ending the free lunch. Read the rest of this entry »