MRSA in Dialysis patients

Risk for Invasive MRSA Multiplied 100-Fold in

Patients

Yael Waknine



Source : Medscape



March
9, 2007 — The incidence of invasive methicillin-resistant
Staphylococcus
aureus (MRSA) is 100
times greater among dialysis patients compared with the general population,
according to the results of a study published in the March 9 issue of
the
Morbidity and Mortality Weekly
Report.




Overall
results showed that 813 (15.4%) of 5287 reported invasive MRSA cases occurred in
dialysis patients; the overall incidence was 45.2 cases per 1000 dialysis
patients compared with 0.2 to 0.4 cases per 1000 general
population.



The
majority of infections (86%) were bloodstream infections, mainly occurring in
patients with catheters (85%) or other invasive devices in place at the time;
90% required hospitalization and 17% died as
inpatients.



The
authors note that infections account for nearly 14% of deaths and represent the
second most common cause of mortality in patients with end-stage renal disease,
about 70% of whom require long-term dialysis
treatment.



Although
patients receiving hemodialysis are particularly vulnerable to vascular-access
infections, catheters have the highest risk; intermediate risk for grafts; and
the lowest risk was seen for arteriovenous fistulas. Minimizing long-term
catheter use is therefore a basic strategy for preventing related bacteremias,
including invasive MRSA infections, according to the
authors.



According
to the authors, treatment of hemodialysis-associated infections is a key factor
in the increasing prevalence of antimicrobial resistance. MRSA strains of
healthcare origin (eg, USA100) are typically multidrug resistant; 5 of the first
6 cases of vancomycin-resistant
S
aureus occurred in
patients who had received dialysis and the first was reported in a hemodialysis
patient.

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Differential Diagnosis of Pulmonary-Renal Syndrome

Differential Diagnosis of Pulmonary-Renal Syndrome



Connective tissue disease



Polymyositis or dermatomyositis

Progressive systemic sclerosis

RA

SLE

Goodpasture's syndrome



Renal disease

Idiopathic immune complex glomerulonephritis

IgA nephropathy

Rapidly progressive glomerulonephritis with heart failure



Systemic vasculitis

Behçet's syndrome

Churg-Strauss syndrome

Cryoglobulinemia

Henoch-Schönlein purpura

Microscopic polyarteritis

Wegener's granulomatosis



Other



Drugs (penicillamine)

Heart failure

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Dialysis Recommended to Prevent NSF After Gadolinium-Based Imaging in Severe Renal Failure

Source - Medscape

Caroline Cassels

January 15, 2007 (updated March 6, 2007) — Following the recent US Food and Drug Administration (FDA) warning about an association between gadolinium-based contrast agents and nephrogenic systemic fibrosis (NSF) in patients with renal failure, a team from Yale University, which includes the world's foremost authority on the rare condition, says dialysis should be aggressively used as soon as possible after magnetic resonance (MR) investigations in such patients.

Yale maintains an international NSF registry, headed by world authority on the disease, Shawn E. Cowper, MD. The registry includes records on more than 215 NSF known cases worldwide. A survey now under way reveals that more than 95% of all NSF patients surveyed (approximately 100) were exposed to a gadolinium-based contrast agent 2 to 3 months before disease onset, said Dr. Kuo

First described in 1997 and named nephrogenic fibrosing dermopathy, the condition is characterized by increased deposits of collagen in tissue that results in thickening and hardening of the skin. In turn, this restricts movement of the joints and can result in patients being confined to a wheelchair within a matter of weeks.

The condition was renamed NSF after it was discovered that, in addition to the skin, the disease could also have systemic effects and an impact on internal organs, resulting in multiorgan failure and death.

"We estimate about 97% of the time when you give an MR contrast agent to a patient with severe renal failure, which is the susceptible population, they do not develop the disease. NSF develops in only a very small minority of cases, so there truly have to be other risk factors at play, and we're working to determine what those are," he said.

In addition to a first dialysis session within 3 hours of MR investigation with gadolinium contrast and a second session within 24 hours, the Yale team's recommendations, which they are publicizing for the purposes of information sharing and not as official practice guidelines, also include the following:

• Consider alternative imaging or nonimaging modalities that can provide the requested clinical diagnostic data at a lower potential risk.
• If administration of gadolinium-based MR contrast agent is deemed necessary, use the lowest possible dose to reliably provide the diagnostic information.
• Inform patients with stage 4 (eGFR 15–30 mL/min per 1.73 m²} or 5 (eGFR <15>2)CKD of the benefits, risks, and alternatives, based on current information.
• Perform any additional nonenhanced sequences that might be helpful and monitor the study to evaluate the continuing necessity of contrast agent.
• Consider hemodialysis in patients undergoing peritoneal dialysis and possible patients with CKD stage 4 deemed at higher risk.

The most recent FDA alert, issued on December 22, 2006, reports 90 cases of the condition in patients with moderate to end-stage renal failure who developed NSF, a debilitating and potentially fatal condition, within 2 days to 18 months of receiving gadodiamide , gadoversetamide , or gadopentetate dimeglumine for magnetic resonance imaging (MRI) or magnetic resonance angiography, where gadolinium doses are commonly 3 times higher to provide detailed imaging of the vasculature.

Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL)

(Circulation. 2007;115:1211-1217.)
© 2007 American Heart Association, Inc.

Coronary Heart Disease

Carlo Briguori, MD, PhD; Flavio Airoldi, MD; Davide D’Andrea, MD; Erminio Bonizzoni, PhD; Nuccia Morici, MD; Amelia Focaccio, MD; Iassen Michev, MD; Matteo Montorfano, MD; Mauro Carlino, MD; John Cosgrave, MD; Bruno Ricciardelli, MD; Antonio Colombo, MD

From the Laboratory of Interventional Cardiology and Department of Cardiology, Clinica Mediterranea, Naples (C.B., D.D., A.F., B.R.); Laboratory of Interventional Cardiology, "Vita e Salute" University School of Medicine, San Raffaele Hospital, Milan (C.B., F.A., N.M., I.M., M.M., M.C., J.C., A.C.); and Institute of Medical Statistics and Biometry, University of Milan, Milan (E.B.), Italy.

Correspondence to Carlo Briguori, MD, PhD, Interventional Cardiology, Clinica Mediterranea, Via Orazio, 2, I-80121, Naples, Italy. E-mail briguori.carlo@hsr.it

Received December 28, 2006; accepted January 5, 2007.

Background— Volume supplementation by saline infusion combined with N-acetylcysteine (NAC) represents an effective strategy to prevent contrast agent–induced nephrotoxicity (CIN). Preliminary data support the concept that sodium bicarbonate and ascorbic acid also may be effective in preventing CIN.

Methods and Results— Three hundred twenty-six consecutive patients with chronic kidney disease, referred to our institutions for coronary and/or peripheral procedures, were randomly assigned to prophylactic administration of 0.9% saline infusion plus NAC (n=111), sodium bicarbonate infusion plus NAC (n=108), and 0.9% saline plus ascorbic acid plus NAC (n=107). All enrolled patients had serum creatinine 2.0 mg/dL and/or estimated glomerular filtration rate <40>–1 · 1.73 m^–2. Contrast nephropathy risk score was calculated in each patient. In all cases, iodixanol (an iso-osmolar, nonionic contrast agent) was administered. The primary end point was an increase of 25% in the creatinine concentration 48 hours after the procedure (CIN). The amount of contrast media administered (179±102, 169±92, and 169±94 mL, respectively; P=0.69) and risk scores (9.1±3.4, 9.5±3.6, and 9.3±3.6; P=0.21) were similar in the 3 groups. CIN occurred in 11 of 111 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P=0.019 by Fisher exact test versus saline plus NAC group), and in 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P=1.00 versus saline plus NAC group).

Conclusions— The strategy of volume supplementation by sodium bicarbonate plus NAC seems to be superior to the combination of normal saline with NAC alone or with the addition of ascorbic acid in preventing CIN in patients at medium to high risk.

Diuretic Use, Residual Renal Function, and Mortality Among Hemodialysis Patients in the Dialysis Outcomes and Practice Pattern Study (DOPPS)

Jennifer L. Bragg-Gresham, MS1, Rachel B. Fissell, MD, MS2, Nancy A. Mason, PharmD23, George R. Bailie, PharmD, PhD345, Brenda W. Gillespie, PhD2, Volker Wizemann, MD6, Jose Miguel Cruz, MD7, Takashi Akiba, MD, PhD8, Kiyoshi Kurokawa, MD, PhD9, Sylvia Ramirez, MD1, Eric W. Young, MD, MS210

Received 7 July 2006; accepted 11 December 2006 published online 26 January 2007.

Background

Information about residual renal function (RRF) and outcomes associated with practices of diuretic use in patients with end-stage renal disease is not available worldwide.

Methods

Diuretic use was investigated in 16,420 hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study, a prospective observational study of hemodialysis patients selected from nationally representative facilities on 3 continents. Logistic regressions were used to investigate associations between diuretic use and patient characteristics. Outcomes of interdialytic weight gain, increased serum potassium and phosphorus levels, and odds of retaining RRF after 1 year were investigated. Cox regression was used to analyze the association between mortality and diuretic use.

Results

Facility diuretic use varied substantially from 0% to 83.9% of patients. Diuretic use decreased sharply after the start of dialysis therapy. Loop diuretic use ranged from 9.2% in the United States to 21.3% in Europe, whereas use within 90 days of starting dialysis therapy ranged from 25.0% in the United States to 47.6% in Japan. Diuretic use was associated with lower interdialytic weight gain and lower odds of hyperkalemia (potassium > 6.0 mmol/L). Patients with RRF on diuretic therapy had almost twice the odds of retaining RRF after 1 year in the study versus patients not on diuretic therapy. Patients administered diuretics had a 7% lower all-cause mortality risk (P = 0.12) and 14% lower cardiac-specific mortality risk (P = 0.03) versus patients not administered diuretics.

Conclusion

Variation exists in facility practices of diuretic use. In patients with RRF, there may be benefit associated with continuing diuretic use rather than automatically discontinuing diuretic therapy at dialysis initiation.

AJKD Volume 49, Issue 3, Pages 373-382 (March 07)

Simvastatin for Secondary Prevention of All-Cause Mortality and Major Coronary Events in Patients With Mild Chronic Renal Insufficiency

Michel Chonchol, MD1, Thomas Cook, MS2, John Kjekshus, MD3, Terje R. Pedersen, MD4, JoAnn Lindenfeld, MD5

Received 19 July 2006; accepted 27 November 2006 published online 20 January 2007.

Background

A potentially modifiable risk factor for cardiovascular disease in patients with mild chronic renal insufficiency is dyslipidemia. Few studies examined the effects of statins on all-cause mortality and major coronary events in patients with renal dysfunction.

Methods

We performed a post hoc analysis from the Randomized Trial of Cholesterol Lowering in 4,444 Patients with Coronary Heart Disease: The Scandinavian Simvastatin Survival Study. Of 4,444 participants, 2,314 (52.1%) had mild chronic renal insufficiency defined as an estimated glomerular filtration rate less than 75 mL/min/1.73 m2 (<1.25>

Results

During the follow-up period, simvastatin use was associated with decreased all-cause mortality (adjusted hazard ratio [HR], 0.69; confidence interval [CI], 0.54 to 0.89) in the 2,314 participants with mild chronic renal insufficiency. Rates of major coronary events (adjusted HR, 0.67; CI, 0.56 to 0.79) and coronary revascularization (adjusted HR, 0.62; CI, 0.49 to 0.77) also were significantly lower in the simvastatin group. No significant decreases in stroke incidence were observed in the simvastatin group (adjusted HR, 0.88; CI, 0.55 to 1.39). The side-effect profile was similar between the 2 treatment groups.

Conclusion

Simvastatin therapy appears to be effective and safe for the secondary prevention of all-cause mortality and major coronary events in patients with mild chronic renal dysfunction.

Clinical performance measures in CKD -MHD patients

In the Literature: On Clinical Performance Measures and Outcomes Among Hemodialysis Patients

Patrick S. Parfrey, MD, FRCP(C)

AJKD Volume 49, Issue 3, Pages 352-355 (March 2007)

Commentary on Rocco MV, Frankenfield DL, Hopson SD, McClellan WM: Relationship between clinical performance measures and outcomes among patients receiving long-term hemodialysis. Ann Intern Med 14:512-519, 2006.

The incidence and prevalence of patients treated by dialysis continues to increase.1 The mortality rate of dialysis patients is high, and worse than that of many cancers.1 Therefore it is important to identify modifiable mortality risk factors, to determine whether interventions to treat these risk factors are efficacious, to develop practice guidelines on the use of efficacious interventions in practice, and to define performance measures to monitor the outcomes of treatment.

In the October 2006 issue of Annals of Internal Medicine, Rocco et al reported that attainment of multiple performance measures in dialysis patients was associated with lower mortality and hospitalization rates.2

Rocco et al2 studied 15,287 prevalent patients

clinical performance measure targets were

1. hemoglobin value of 11 g/dL (110 g/L) or greater;
   
2. serum albumin value of 4 g/dL (40 g/L) or greater or 3.7 g/dL (37 g/L) or greater (bromcresol green and bromcresol purple laboratory methods, respectively);
   
3. use of a fistula for vascular access; and
   
4. measured single-pool Kt/V urea value of 1.2 or greater.
   

In multivariable analysis, they determined whether achieving these performance measures was associated with better mortality and hospitalization rates during the next 12 months.
During the initial period,

• 6% of patients did not meet any target,
  
• 24% met 1 target,
  
• 39% met 2 targets,
  
• 24% met 3 targets, and
  
• 7% met all 4 targets

During the 12-month follow-up,

• 55% of patients were hospitalized and
  
• 20% died.
  

Patients who met all targets were more likely to be

• male,
  
• younger,
  
• of white race,
  
• of Hispanic ethnicity,
  
• have hypertension or glomerulonephritis as the cause of ESRD,
  
• have a lower body mass index, and
  
• to have received dialysis for more years;
  
• they were less likely to have diabetes mellitus and comorbid conditions (both cardiovascular and noncardiovascular).

In other words they were healthier and they were survivors.

What Should Clinicians and Researchers Do?

Of the 4 quality indicators studied by Rocco et al,2 only a higher dialysis dose has RCT evidence to support the expectations that achievement of these targets would be associated with better hard clinical outcomes.13 Thus, a clinical performance measure to achieve Kt/V > 1.2 is justified. One cannot conclude from the Rocco et al analyses that achievement of other clinical performance targets will lead to reduction in mortality and hospitalization. However achievement of some targets should be associated with other clinical benefits. RCTs demonstrate that treatment of anemia to a target hemoglobin value of 11 g/dL (110 g/L) or greater will improve quality of life and limit blood transfusions.14 It is likely that preferential use of fistulas rather than grafts should lead to better vascular access outcomes.15 Consequently quality assurance initiatives to achieve these targets can be supported. However, a serum albumin target of 4 g/dL (40g/L) as a clinical performance measure is illusory at present, as it is not currently modifiable.

Identifying CKD in populations - SCORED

Nine-Question Survey Identifies Patients at Risk of Having Chronic Kidney Disease

Source - Medscape

The Screening for Occult Renal Disease (SCORED) questionnaire, which contains questions about demographic variables and health conditions, but does not require any laboratory test values, might be useful to identify individuals who are highly likely to have underlying chronic kidney disease (CKD).

Study Highlights

• This cross-sectional analysis included 8530 men and women 20 years or older in the NHANES, a nationally representative, US-population-based survey conducted from 1999-2000 and 2001-2002.
• Based on the literature, potential determinants of CKD evaluated for incorporation into SCORED were age, sex, race, marital status, anemia, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, hypertension, diabetes mellitus, peripheral vascular disease, history of cardiovascular disease, history of congestive heart failure, proteinuria, smoking status, physical activity, body mass index, educational and income levels, and health insurance status.
• The SCORED prediction model used univariate and multivariate associations between this comprehensive set of risk factors and CKD, defined as a glomerular filtration rate less than 60 mL/minute per 1.73 m². Optimal characteristics of the model were examined with internal measures, and a model-based numeric scoring system was developed. The Atherosclerosis Risk in Communities study was used for external validation.
• Combining NHANES 1999-2000 and 2001-2002 resulted in a data set of 10,291 individuals 20 years or older. Data from 8530 individuals were analyzed after exclusion of 1472 individuals with missing serum creatinine measurements and 289 with other missing covariates.
• 601 (5.4%) of 8530 participants had CKD. Their mean age was 46 years, and 52% were women; 72%, white; 10%, black; and 14%, Hispanic.
• Only 9 variables had statistically significant associations with CKD. These were age (P < .001), female sex (P = .02), hypertension (P = .03), diabetes (P = .03), peripheral vascular disease (P = .008), history of cardiovascular disease (P = .001), history of congestive heart failure (P = .04), proteinuria (P < .001), and anemia (P = .003). Age 50 to 59 years was assigned 2 points, 60 to 69 years was assigned 3 points, and 70 years and older was assigned 4 points. All other predictive features were assigned 1 point.
• The multivariate model was well validated in the internal and external data sets, with area under the receiver operating characteristic curve of 0.88 and 0.71, respectively.
• Based on both diagnostic and qualitative criteria and practical implementation considerations, a SCORED value of 4 or higher was chosen as a cutoff point for screening. This cutoff value yielded a sensitivity of 92%, specificity of 68%, positive predictive value of 18%, and negative predictive value of 99%.
• Study limitations include a model heavily weighted toward common risk factors for kidney disease, inability to determine family history of kidney disease, cross-sectional design, inability to rule out the possibility of developing CKD in the future, possible underestimation of CKD, and use of a statistical method unable to investigate complicated effect modifications among the risk and protective factors.

Diabetes Risk Score - German Study

German Diabetes Risk Score May Predict Development of Type 2 Diabetes

The German Diabetes Risk Score, which is based on anthropometric, dietary, and lifestyle factors, was an effective tool to identify patients at high risk or with undiagnosed diabetes, according to the results of a study reported in the March issue of Diabetes Care.

"The German Diabetes Risk Score (available at http://www.dife.de) is an accurate tool to identify individuals at high risk for or with undiagnosed type 2 diabetes," the authors write.

The European Union, the German Cancer Aid, the Federal Ministry of Science in Germany, the German Cancer Research Centre, the DFG, the German Ministry of Education and Science, and the Nationales Aktionsforum Diabetes Mellitus supported this study.

Diabetes Care. 2007;30:510-515.

Study Highlights

• The researchers applied their diabetes risk formula to several existing German study cohorts being followed up for incident diabetes. Study subjects were generally middle-aged adults, and diabetes was defined by a clinical diagnosis among most study subjects. A subset of participants underwent glucose tolerance testing.
• All subjects underwent an assessment of their health history and health habits, anthropometric data, diet, and exercise.
• The current diabetes risk scoring system was developed using one study cohort of 25,167 participants and was validated using another cohort of 23,398 subjects.
• The diabetes risk score was calculated using a formula involving waist circumference, height, age, the presence of hypertension, consumption of red meat, consumption of whole-grain bread, consumption of coffee, moderate alcohol use, physical activity, and a history of smoking.
• A score of 300 was associated with an incidence of diabetes of 0.3%, whereas a score of 750 portended a risk for diabetes of 23.2%.
• A score of 500 or more carried a sensitivity and specificity for predicting diabetes of 83.1% and 68.3%, respectively.
• Waist circumference was significantly and positively correlated with the risk for incident diabetes, even among younger participants.
• The German Diabetes Risk Score was also useful in diagnosing participants whose diabetes was diagnosed during glucose tolerance testing. A score of 500 or more carried a sensitivity between 82% and 93% and a specificity between 42% and 72% among this cohort.
• Overall, the German Diabetes Risk Score performed as well or better than previously used clinical risk assessments for type 2 diabetes.

Vit C Deficiency in MHD

NDT Advance Access originally published online on November 14, 2006
Nephrology Dialysis Transplantation 2007 22(2):328-331; doi:10.1093/ndt/gfl534

Vitamin C deficiency in dialysis patients—are we perceiving the tip of an iceberg?

Garry J. Handelman

University of Massachusetts, Lowell, MA 01854 and Renal Research Institute, New York, NY 10128, USA

Correspondence and offprint requests to: Garry J. Handelman, 3 Solomont Way, University of Massachusetts, Lowell, MA, 01854, USA. Email: garry_handelman@uml.edu

The occurrence of vitamin C deficiency has complicated the management of dialysis patients since the beginning of renal replacement therapy .
The major portion of dietary vitamin C is provided by potassium-rich foods such as orange juice, strawberries and broccoli, but these foods are restricted for haemodialysis (HD) patients .

Under these circumstances, low dietary vitamin C intake can readily occur.

Since vitamin C is partly metabolized to oxalate, which can accumulate in renal failure patients, many clinicians only recommend a dose of 60–100 mg/day, which may not be optimal.
The problem is made more severe by vitamin C losses during dialysis, which may remove several hundred mg of vitamin C in a single dialysis treatment .

Plasma vitamin C in dialysis patients is frequently <10> population. Normal plasma vitamin C levels in the non-dialysis population are 30–60 µM

Very high levels of vitamin C can also occur in dialysis patients, the effect of dialysis on vitamin C is highly variable. For patients who take large vitamin C supplements, the lack of the normal renal clearance mechanism can result in very high plasma levels (>200 µM)

Vitamin C deficiency can interfere with iron absorption and utilization, as well as leading to various abnormalities that are part of the syndrome of scurvy.

There is a situation where a large portion (10–25%) of dialysis patients have plasma vitamin C levels <10> plasma vitamin C <2> Epidemiological data suggest that these low plasma vitamin C levels are associated with increased mortality .

Although a 60–100 mg daily vitamin C supplement is generally recommended, prescriptions are provided only to 10–70% of patients, depending on nationality . Lack of compliance may lead to even lower levels of actual vitamin C usage.

The instability of vitamin C leads to problems in laboratory analysis , and vitamin C is not routinely measured in dialysis practice.

Concerns about oxalosis need to be vigorously addressed, but if vitamin C is demonstrated to be safe, its more active use could lead to reduction of iron burden, more efficient erythropoiesis and alleviation of some of the scorbutic symptoms seen in HD patients.

Mild renal failure as a marker for cardiovascular mortality

Eur Heart J. 2007 Feb;28(4):478-83. Epub 2007 Jan 12.

The glomerular filtration rate in an apparently healthy population and its relation with cardiovascular mortality during 10 years.

• Van Biesen W,
• De Bacquer D,
• Verbeke F,
• Delanghe J,
• Lameire N,
• Vanholder R.

Department of Internal Medicine, Renal Division, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.

AIMS: Moderate-to-severe chronic renal failure is an established risk factor for cardiovascular disease and mortality.

However, most studies have been performed in selected populations and the impact of very small decrements of renal function on long-term cardiac morbidity and mortality has not yet been established.

Also, the cut-off level of glomerular filtration rate (GFR) from which cardiovascular risk increases has not exactly been established. This study wants to address these questions.

METHODS AND RESULTS: Ten year follow-up of a representative population-based cohort comprised 8913 randomly selected, apparently healthy participants. Participants were randomly drawn from Belgian voting lists. Cardiovascular risk factors were noted.

Serum creatinine values were corrected to isotope dilution mass spectrometry standard, and GFR was calculated using the recently modified 'modification of diet in renal disease' equation.

Participants were followed for 10 years, and cause-specific death was registered by analysis of death certificates.

The probability to die from all causes or from cardiovascular causes during the 10 year follow-up period increased in each quartile of GFR, even after correction for different other comorbid conditions.

CONCLUSION: Even mild renal failure is an independent risk factor for cardiovascular mortality within 10 years in an apparently healthy unselected population.

This detrimental effect starts already at a relatively high GFR of 90 mL/min/1.73 m(2) and remains present after correction for other established cardiovascular risk factors.

----------------------------
A similar study published earlier
----------------------------

Kidney Int. 2002 Oct;62(4):1402-7.

Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study.

• Henry RM,
• Kostense PJ,
• Bos G,
• Dekker JM,
• Nijpels G,
• Heine RJ,
• Bouter LM,
• Stehouwer CD.

Institute for Research in Extramural Medicine, Department of Clinical Epidemiology and Biostatistics, VU University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

BACKGROUND: Cardiovascular mortality is extremely high in end-stage renal disease. Cardiovascular mortality risk also is increased in selected (high-risk) individuals with mild to moderate impairment of renal function.

It is not clear whether a similar association exists in the general population and, if so, through what mechanisms. We investigated the association of renal function with all-cause and cardiovascular mortality in a population-based cohort and explored potential mechanisms underlying any such relationship.

METHODS: An age-, sex-, and glucose-tolerance-stratified sample (N = 631) of a population-based cohort aged 50 to 75 years was followed prospectively. After up to 10.2 years of follow-up, 117 subjects had died (50 of cardiovascular causes).

At baseline, renal function was estimated by the serum creatinine level, the Cockcroft-Gault formula and Levey's equation.

RESULTS: At baseline, the mean age was 64 +/- 7 years, 48% were men, 55% had hypertension, and 27% (by design) had type 2 diabetes.

• Serum creatinine was 91.7 +/- 19.0 micromol/L;
  
• creatinine clearance as estimated by the Cockroft-Gault formula was 72.5 +/- 13.7 mL/min/1.73 m(2),
  
• glomerular filtration rate (GFR) estimated by Levey's equation was 67.8 +/- 12.1 mL/min/1.73 m(2).
  

Renal function was inversely associated with all-cause and with cardiovascular mortality.

Relative risks (95% confidence intervals) were

• 1.08 (1.04 to 1.13) and 1.11 (1.07 to 1.16) per 5 micromol/L increase of serum creatinine;
• 1.07 (0.98 to 1.17) and 1.15 (1.01 to 1.31) for each decrease of 5 mL/min/1.73 m(2) creatinine clearance;
  
• 1.15 (1.05 to 1.26) and 1.26 (1.12 to 1.42) for each decrease of 5 mL/min/1.73 m(2) of GFR.
  

These associations remained after adjusting for age, sex, glucose tolerance status, hypertension, prior cardiovascular disease, low-density lipoprotein cholesterol, homocysteine, (micro)albuminuria, von Willebrand factor, soluble vascular adhesion molecule-1 and C-reactive protein.
Analyses in diabetic and hypertensive subjects gave similar results.

CONCLUSION: Mild to moderate loss of renal function is strongly associated with an increased risk of cardiovascular mortality.
The mechanism behind this association is unclear but does not appear to involve common risk factors such as hypertension, diabetes or hyperhomocysteinemia.

Estimation of renal function by relatively simple methods therefore may be a valuable tool for cardiovascular risk assessment over and above that provided by conventional risk factors.

Our results were obtained in a general middle-aged to elderly population, and thus have broad applicability.

Hypertension biomarkers

Hypertension. 2007 Mar;49(3):432-8. Epub 2007 Jan 22.

Multiple biomarkers and the risk of incident hypertension.

• Wang TJ,
• Gona P,
• Larson MG,
• Levy D,
• Benjamin EJ,
• Tofler GH,
• Jacques PF,
• Meigs JB,
• Rifai N,
• Selhub J,
• Robins SJ,
• Newton-Cheh C,
• Vasan RS.

Framingham Heart Study, Framingham, Mass, USA. tjwang@partners.org

An understanding of mechanisms underlying the development of essential hypertension is critical for designing prevention and treatment strategies. Selected biomarkers may be elevated before the onset of hypertension, but previous studies are limited by cross-sectional designs or a focus on single biomarkers.

We prospectively studied 1456 nonhypertensive individuals who had baseline measurement of 9 biomarkers:

1. C-reactive protein (inflammation);
   
2. fibrinogen (inflammation and thrombosis);
   
3. plasminogen activator inhibitor-1 (fibrinolytic potential);
   
4. aldosterone, renin, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide (neurohormonal activity);
   
5. homocysteine (renal function and oxidant stress);
   
6. urinary albumin/creatinine ratio (glomerular endothelial function).
   

Incident hypertension, defined as blood pressure > or =140/90 mm Hg or antihypertensive therapy, developed in 232 participants over a mean follow-up of 3 years.

After adjustment for clinical risk factors, the biomarker panel was significantly associated with incident hypertension (P=0.002).

Three (of 9) biomarkers were significantly related to incident hypertension on backward elimination (multivariable-adjusted odds ratios, per SD increment in biomarker):

1. C-reactive protein (1.26; 95% CI: 1.05 to 1.51),
   
2. plasminogen activator inhibitor-1 (1.28; 95% CI: 1.05 to 1.57),
   
3. urinary albumin/creatinine ratio (1.21; 95% CI: 1.02 to 1.43).
   

The incidence of hypertension was 4.5, 6.4, and 9.9 per 100 person years for participants with 0, 1, and > or=2 elevated biomarkers, respectively (elevation defined as > or =1 SD above the mean).

The threshold of > or =2 elevated biomarkers for predicting hypertension was associated with high specificity (0.92) but low sensitivity (0.15).

Biomarkers of inflammation, reduced fibrinolytic potential, and low-grade albuminuria are jointly associated with the incidence of hypertension.
These data support the premise that abnormalities in multiple biological pathways antedate the onset of overt hypertension.

No more heplock??? its citlock now.

Nephrol Dial Transplant. 2007 Feb;22(2):477-83. Epub 2006 Oct 2.

Trisodium citrate 4%--an alternative to heparin capping of haemodialysis catheters.

* Lok CE,
* Appleton D,
* Bhola C,
* Khoo B,
* Richardson RM.

Department of Medicine, Division of Nephrology, The Toronto General Hospital, 11 EN-216, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. charmaine.lok@uhn.on.ca.

BACKGROUND: Central venous catheters (CVCs) continue to be used at a high rate for dialysis access and are frequently complicated by thrombus-related malfunction. Prophylactic locking with an anticoagulant, such as heparin, has become standard practice despite its associated risks. Trisodium citrate (citrate) 4% is an alternative catheter locking anticoagulant.

METHODS: The objective was to prospectively study the clinical effectiveness, safety and cost of citrate 4% vs heparin locking by comparing rates of CVC exchanges, thrombolytic use (TPA) and access-associated hospitalizations during two study periods: heparin period (HP) (1 June 2003-15 February 2004) and Citrate Period (CP) 15 March-15 November 2004. Incident catheters evaluated did not overlap the two periods.

RESULTS: There were 176 CVC in 121 patients (HP) and 177 CVC in 129 patients (CP).
The event rates in incident CVC were:

1. CVC exchange 2.98/1000 days (HP) vs 1.65/1000 days (CP) (P = 0.01);
   
2. TPA use 5.49/1000 (HP) vs 3.3/1000 days (CP) (P = 0.002);
   
3. hospitalizations 0.59/1000 days (HP) vs 0.28/1000 days (CP) (P = 0.49).
   
4. longer time from catheter insertion to requiring CVC exchange (P = 0.04) and TPA (P = 0.006) in the citrate compared with the heparin lock group.
   

Citrate locking costs less than heparin locking but a formal economic analysis including indirect costs was not done.

CONCLUSION:

• Citrate 4% has equivalent or better outcomes with regards to catheter exchange, TPA use and access-related hospitalizations compared with heparin locking.
  
• It is a safe and less expensive alternative.
  

Randomized trials comparing these anticoagulants with a control group would definitively determine the optimal haemodialysis catheter locking solution.

Vasopressin in ESRD - Maintainance HD patients.

Kidney Int. 2007 Feb;71(4):318-24. Epub 2006 Sep 27.

Vasopressin administration facilitates fluid removal during hemodialysis.

• van der Zee S,
• Thompson A,
• Zimmerman R,
• Lin J,
• Huan Y,
• Braskett M,
• Sciacca RR,
• Landry DW,
• Oliver JA.

1Department of Medicine, Columbia University, New York, New York, USA.

Inadequate secretion of vasopressin during fluid removal by hemodialysis may contribute to the cardiovascular instability that complicates this therapy and administration of exogenous hormone, by supporting arterial pressure, may facilitate volume removal.

To test this, we measured plasma vasopressin in patients with end-stage renal disease (ESRD) during hemodialysis and found that despite significant fluid removal, plasma vasopressin concentration did not increase.

We further found that ESRD did not alter the endogenous removal rate of plasma vasopressin and that plasma hormone is not dialyzed.

Finally, in a randomized, double-blinded, placebo-controlled trial in 22 hypertensive patients, we examined the effect of a constant infusion of a non-pressor dose of vasopressin on the arterial pressure response during a hemodialysis in which the target fluid loss was increased by 0.5 kg over the baseline prescription.

We found that arterial pressure was more stable in the patients receiving vasopressin and that while only one patient (9%) in the vasopressin group had a symptomatic hypotensive episode, 64% of the patients receiving placebo had such an episode (P=0.024).

Moreover, increased fluid removal was achieved only in the vasopressin group (520+/-90 ml vs 64+/-130 ml, P=0.01).

Thus, administration of non-pressor doses of vasopressin to hypertensive subjects improves cardiovascular stability during hemodialysis and allows increased removal of excess extracellular fluid.

Inadequate vasopressin secretion during hemodialysis-induced fluid removal is a likely contributor to the intradialytic hypotension that limits fluid removal.

MMF Rocks!!

Am J Transplant. 2007 Feb;7(2):366-76.

Mycophenolate mofetil is associated with altered expression of chronic renal transplant histology.

* Nankivell BJ,
* Wavamunno MD,
* Borrows RJ,
* Vitalone M,
* Fung CL,
* Allen RD,
* Chapman JR,
* O'Connell PJ.

Department of Renal Medicine, University of Sydney, Westmead Hospital, Westmead 2145, Sydney, NSW, Australia. Brian_Nankivell@wsahs.nsw.gov.au

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking.

We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry.

MMF reduced
acute rejection and OKT3 use (p < 0.05) compared with AZA.
MMF therapy was associated with
limited chronic interstitial fibrosis,
striped fibrosis and periglomerular fibrosis (p < 0.05-0.001),
mesangial matrix accumulation (p < 0.01),
chronic glomerulopathy scores (p < 0.05)
glomerulosclerosis (p < 0.05).
MMF was associated with
delayed expression of CSA nephrotoxicity,
reduced arteriolar hyalinosis,
striped fibrosis and
tubular microcalcification (p < 0.05-0.001).
The beneficial effects of MMF remained in recipients without acute rejection.

MMF therapy was associated with
substantially reduced fibrosis in the glomerular,
microvascular and interstitial compartments,
delayed expression of CSA nephrotoxicity.

These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.

Calciphylaxis

Dr Lobo asked this on the rounds to day so I read it up.
Source emedicine.com


Calciphylaxis is a poorly understood and highly morbid syndrome of vascular calcification and skin necrosis. Bryant and White first reported it in association with uremia.

Pathogenesis of calciphylaxis remains obscure and is likely the result of a multiplicity of comorbid factors or events. Disorders that are most often implicated in the pathogenesis of calciphylaxis include chronic renal failure, hypercalcemia,
hyperphosphatemia, an elevated calcium-phosphate product, and secondary hyperparathyroidism. Yet, although these abnormalities are extremely common in patients with end-stage renal disease (ESRD), calciphylaxis is relatively rare.

Selye defined calciphylaxis as a condition of hypersensitivity induced by a set of "sensitizing" agents, in which calcinosis occurred only in those subsequently subjected to a group of "challengers" and only after a critical lag time.

1-4% of the population with ESRD. A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran.

Mortality rate of calciphylaxis is reported to be as high as 60-80%. The leading cause of death is sepsis from infected, necrotic skin lesions. Mortality rate is higher in patients with proximal disease than in those with only distal or acral disease. A 2-fold increase in mortality is seen in those with ulcerative disease.

female-to-male ratio of approximately 3:1.

History :
long-standing history of chronic renal failure and renal replacement therapy.
renal allograft transplantation.
Lesions of calciphylaxis typically develop suddenly and progress rapidly. Lesions may be singular or numerous, and they generally occur on the lower extremities,however, lesions also may develop on the hands and torso.
Intense pain is a constant finding.

Triggers include the following:
o Long-term obesity
o Recent and sudden weight loss
o Infusion of medications such as iron dextran
o Remote and/or recent use of immunosuppressive agents, especially corticosteroids
o Concurrent use of warfarin anticoagulation: Current data suggest that warfarin therapy may lower protein C concentrations, leading to a procoagulant condition in the calcified vessel.

Clincial
* Early lesions of calciphylaxis manifest as nonspecific violaceous mottling; as livedo reticularis; or as erythematous papules, plaques, or nodules.
* More developed lesions have a stellate purpuric configuration with central cutaneous necrosis.
* Lesions are excruciatingly tender and extremely firm.
* The distribution of the lesions may be characterized as proximal or distal.
o Ninety percent of lesions of calciphylaxis occur on the lower extremities.
o Distal lesions are those that occur below the knee; proximal lesions occur on the thighs or the trunk.
* An intact peripheral pulse helps to distinguish acral calciphylaxis from atherosclerotic peripheral vascular disease.

Causes:
* The cause of calciphylaxis remains obscure. Most cases occur in the setting of chronic renal failure, abnormal calcium-phosphate homeostasis, and hyperparathyroidism.
o Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.
o Disorders associated with the development of calciphylaxis include the following:
+ Common – Chronic renal failure, hypercalcemia, hyperphosphatemia, elevated calcium-phosphate product, hyperparathyroidism, vascular calcification
+ Speculative – Aluminum toxicity, coagulation abnormalities, iron dextran infusion
+ Suggested from clinical observation – Renal transplantation, immunosuppressive agents, corticosteroid use, obesity

o Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, 2 pathologic roles may be attributed to this vascular calcification: (1) Calcification of the vascular endothelium may alter the local interaction of procoagulant and anticoagulant factors, predisposing to a microenvironment of hypercoagulability.
(2) Alternatively, extensive endothelial calcification and intimal hyperplasia, which are known to compromise the luminal size of vessels in calciphylaxis, may result in vascular occlusion. These mechanisms remain hypothetical and have not yet been proven in cases of calciphylaxis.

Imaging Studies:

* Plain films uniformly demonstrate an arborization of vascular calcification within the dermis and the subcutaneous tissue. However, this is common in ESRD and not specific for calciphylaxis.
* Bone scintigraphy may be used as a noninvasive diagnostic tool because the bone matrix protein osteopontin has recently been demonstrated in calciphylaxis lesions. Serial bone scans can also possibly be used to monitor progression or regression of disease.

Procedures:
* An incisional cutaneous biopsy is usually diagnostic.

Histologic Findings:
* Biopsy specimens typically demonstrate calcification within the media of small- and medium-sized arterioles with extensive intimal hyperplasia and fibrosis. A mixed inflammatory infiltrate frequently occurs. Subcutaneous calcium deposits with panniculitis and fat necrosis may sometimes be found. Vascular microthrombi are frequently evident.

Medical Care:
Medical care is mainly supportive. Aggravating conditions should be addressed, and trigger factors should be eliminated. This may mean the discontinuation of parenteral iron therapy, calcium, supplementation, and vitamin D supplementation. Although implicated as a trigger in the past, recent studies suggest that some patients may benefit early on from systemic glucocorticoids, unless ulcerated lesions are present.
* Serum calcium and phosphate concentrations must be brought to low-normal levels as quickly and safely as possible.
o Conservative therapy should be tried first, with dietary alteration; use of noncalcium, nonaluminum phosphate binders; and low-calcium bath dialysis. Some benefit may be achieved with increasing the frequency of dialysis sessions.
o If calcium and phosphate levels remain high, especially in the setting of hyperparathyroidism, intravenous use of a vitamin D analog may be beneficial.
o Although only speculative, calcimimetics such as cinacalcet hydrochloride may be beneficial in cases of hyperparathyroidism.
o Parathyroidectomy should be considered if conservative management fails and hyperparathyroidism is present.
* Marked improvement of calciphylaxis has now been reported with the use of intravenous sodium thiosulfate. Sodium thiosulfate increases the solubility of calcium deposits.
* Judicious use of antibiotics may be advantageous.
* In some cases, hyperbaric oxygen may be beneficial.
* Conditions of hypercoagulability should be sought and addressed.

Complications:
* Complications of calciphylaxis range from moderate interference with activity to death.
* Lesions of calciphylaxis frequently result in nonhealing ulcers and cutaneous gangrene. Acral lesions may fail to heal with conservative therapy and require amputation.
* Sepsis may result from the nonhealing wounds.
* Patients with internal involvement may develop gastrointestinal hemorrhage, infarction, or organ failure.
* Patients treated with calcimimetics, sodium thiosulfate, and parathyroidectomy must be monitored for hypocalcemia.

Prognosis:

* The prognosis is generally not good, with a mortality rate as high as 60-80% in patients with ulcerative disease. Patients who do not die of sepsis or organ failure frequently undergo amputation of an involved limb. Vascular calcification is theoretically reversible with aggressive management, but many patients have numerous comorbid diseases.

Currently, the 1- and 5-year survival rates are estimated to be 45% and 35%, respectively.

Lupus Nephritis - Classification update

Kidney International advance online publication 31 January 2007; doi: 10.1038/sj.ki.5002118

The ISN/RPS 2003 classification of lupus nephritis: An assessment at 3 years

G S Markowitz¹ and V D D'Agati¹

Abstract

The 2003 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Classification of lupus nephritis (LN) was designed to eliminate ambiguities and standardize definitions.

Major changes from the 1982 Modified WHO Classification include the elimination of the normal biopsy category and the subcategories of membranous Class V, the introduction of sharper distinctions between the classes, and the addition of subcategories within diffuse LN (class IV) for predominantly segmental (LN IV-S) and global (LN IV-G) lesions.It stipulates that sclerotic glomeruli owing to scarred LN should be taken into account when assessing the percentage of glomeruli affected by LN.

Since its publication, the ISN/RPS classification has been used successfully in a number of clinical-pathologic studies. Several studies addressing the relationship between LN IV-S and LN IV-G have failed to identify a significantly worse outcome in IV-S than IV-G, although there were some differences in presenting clinical and pathologic features.

Importantly, the ISN/RPS classification has achieved its goal of improved interobserver reproducibility. Its use has increased the percentage of LN biopsies meeting criteria for class IV. As it gains widespread acceptance, the ISN/RPS classification is already providing a standardized approach to renal biopsy interpretation needed to compare outcome data across centers.

Lanthanum does not make a terrific difference?

Kidney International (2007) 71, 252–259. doi:10.1038/sj.ki.5001932; published online 11 October 2006

Cognitive function in Stage 5 chronic kidney disease patients on hemodialysis: No adverse effects of lanthanum carbonate compared with standard phosphate-binder therapy

P Altmann¹, M E Barnett^2,3 and W F Finn⁴ on Behalf of the SPD405-307 Lanthanum Carbonate Study Group

Abstract

Patients with Stage 5 chronic kidney disease who have hyperphosphatemia require treatment with phosphate binders to lower serum phosphorus levels. Existing binders are effective but may be associated with important safety disadvantages. Lanthanum carbonate is a phosphate binder with demonstrated efficacy, safety, and tolerability in clinical trials.

Changes in cognitive function were evaluated over time using the Cognitive Drug Research computerized cognitive assessment system (Simple Reaction Time, Digit Vigilance Task, Choice Reaction Time, Numeric Working Memory, and Delayed Picture Recognition) in 360 hemodialysis patients who were enrolled in a 2-year, multicenter, comparative study of lanthanum carbonate versus standard therapy.

A decline in cognitive function from baseline was observed in both groups. The deterioration in cognitive function was similar in both the lanthanum carbonate and standard therapy groups. One parameter – Numeric Working Memory – showed a statistically significant between-group difference in favor of lanthanum carbonate (P=0.02).

Given the magnitude of the changes, however, and the differences that were observed at baseline between treatment groups, the clinical significance of this difference is doubtful.

This study demonstrates that cognitive function deteriorates in hemodialysis patients over a 2-year time period. Use of lanthanum carbonate as a phosphate binder does not adversely affect cognitive function compared with standard therapy.

Very low protein diet is anti hypertensive

Kidney International (2007) 71, 245–251. doi:10.1038/sj.ki.5001955; published online 11 October 2006

Very low protein diet supplemented with ketoanalogs improves blood pressure control in chronic kidney disease

V Bellizzi¹, B R Di Iorio¹, L De Nicola², R Minutolo², P Zamboli², P Trucillo², F Catapano², C Cristofano³, L Scalfi⁴ and G Conte² on behalf of the ERIKA Study-group

Abstract

Blood pressure (BP) is hardly controlled in chronic kidney disease (CKD).

We compared the effect of very low protein diet (VLPD) supplemented with ketoanalogs of essential amino acids (0.35 g/kg/day), low protein diet (LPD, 0.60 g/kg/day), and free diet (FD) on BP in patients with CKD stages 4 and 5.

Vegetable proteins were higher in VLPD (66%) than in LPD (48%). LPD was prescribed to 110 consecutive patients; after run-in, they were invited to start VLPD. Thirty subjects accepted; 57 decided to continue LPD; 23 refused either diet (FD group). At baseline, protein intake (g/kg/day) was 0.790.09 in VLPD, 0.780.11 in LPD, and 1.110.18 in FD (P<0.0001).>

After 6 months, protein intake was lower in VLPD than LPD and FD (0.540.11, 0.780.10, and 1.040.21 g/kg/day, respectively; P<0.0001). src="http://www.nature.com/__chars/plus/special/plusmn/black/med/base/glyph.gif" style="border: 0pt none ; vertical-align: baseline;" alt="plusminus">19/8410 to 12816/787 mm Hg (P<0.0001), src="http://www.nature.com/__chars/plus/special/plusmn/black/med/base/glyph.gif" style="border: 0pt none ; vertical-align: baseline;" alt="plusminus">1.1 to 1.81.2; P<0.001). src="http://www.nature.com/__chars/plus/special/plusmn/black/med/base/glyph.gif" style="border: 0pt none ; vertical-align: baseline;" alt="plusminus">32 to 13136 mEq/day; P<0.001).>

At multiple regression analysis (R²=0.270, P<0.0001),>P=0.023) and VLPD prescription (P=0.003), but not to the level of protein intake.

Thus, in moderate to advanced CKD, VLPD has an antihypertensive effect likely due to reduction of salt intake, type of proteins, and ketoanalogs supplementation, independent of actual protein intake.

Cystatic - C and relation to bio-inflammatory markers

Kidney International (2007) 71, 239–244. doi:10.1038/sj.ki.5002042; published online 20 December 2006

Kidney function and markers of inflammation in elderly persons without chronic kidney disease: The health, aging, and body composition study

C R Keller^1,2, M C Odden², L F Fried³, A B Newman⁴, S Angleman⁵, C A Green⁶, S R Cummings^1,7, T B Harris⁵ and M G Shlipak^1,2,8

Abstract

Inflammatory markers are elevated in persons with estimated glomerular filtration rates less than 60 ml/min/1.73 m². As cystatin C may detect small changes in kidney function not detected by estimated glomerular filtration rate, we evaluated the association between cystatin C and serum markers of inflammation in older adults with estimated glomerular filtration rate 60. This is an analysis using measures from the Health, Aging, and Body Composition Study, a cohort of well-functioning adults aged 70–79 years.

Cystatin C correlated with all five inflammatory biomarkers: C-reactive protein (r=0.08), interleukin-6 (r=0.19), tumor necrosis factor (TNF-) (r=0.41), soluble TNF receptor 1 (STNF-R1) (r=0.61), and soluble TNF receptor 2 (STNF-R2) (r=0.54); P<0.0005>

Participants with a cystatin C1.0 mg/l had significantly higher levels of all five biomarkers compared to those with a cystatin C<1.0>P<0.05).>

Cystatin C has a linear association with inflammatory biomarkers in an ambulatory elderly cohort with estimated glomerular filtration rates 60; associations are particularly strong with TNF- and the STNF-R.

Chronic acidosis and poor osteoblast function

Kidney International (2007) 71, 201–209. doi:10.1038/sj.ki.5002035; published online 20 December 2006

Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells

S Disthabanchong¹, P Radinahamed¹, W Stitchantrakul², S Hongeng³ and R Rajatanavin⁴

Abstract

Bone histology of distal renal tubular acidosis patients showed decreased bone formation with impaired bone matrix mineralization that is not entirely explained by an alteration in the mineral balance. Data from in vitro studies suggests a direct inhibitory effect of metabolic acidosis on osteoblast function. We investigated the effects of chronic metabolic acidosis on osteoblast differentiation from mesenchymal stem cells (MSCs). Human MSCs were allowed to differentiate into osteoblasts in culture. Concentrated hydrochloric acid was added to the medium to lower the bicarbonate concentration and pH. The expression of various osteoblastic genes and proteins and bone matrix mineralization were examined. Chronic metabolic acidosis enhanced the messenger RNA (mRNA) and protein expression of early osteoblast transcription factor, runx-2, whereas inhibiting osterix and having no effect on ATF-4. The expression of type I collagen, the most abundant bone matrix protein, was increased following the same pattern of runx-2. Likewise, metabolic acidosis slightly enhanced the expression of mature osteoblastic gene, osteocalcin. Study on mineralization revealed suppressed alkaline phosphatase mRNA and enzyme activity. Despite the augmented collagen deposit in acidic culture, bone matrix mineralization was impaired. In conclusion, chronic metabolic acidosis alters osteoblast differentiation from MSCs through its diverse effect on osteoblastic genes and proteins resulting in an impairment of bone formation.

Insula in cigarette smoking

Science 26 January 2007: Vol. 315. no. 5811, pp. 531 - 534 DOI: 10.1126/science.1135926

Reports

Damage to the Insula Disrupts Addiction to Cigarette Smoking

Nasir H. Naqvi,¹ David Rudrauf,^1,2 Hanna Damasio,^3,4 Antoine Bechara^1,3,4*

A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. We found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking.

¹ Division of Cognitive Neuroscience, Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
² Laboratory of Computational Neuroimaging, Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
³ Dornsife Cognitive Neuroscience Imaging Center, SGM 501, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Brain and Creativity Institute, HNB B26, University of Southern California, Los Angeles, CA 90089, USA.

Polypill - Mirage or Miracle

BMJ 2007;334:172 (27 January), doi:10.1136/bmj.39101.539352.DB

News

NEJM sees promise in polypill for low and middle income countries

Janice Hopkins Tanne

¹ New York

A "perspectives" commentary in the New England Journal of Medicine by a leading Indian cardiologist says that a "polypill" to combat heart disease "would be quite cost-effective in reducing the burden of cardiovascular disease even in low-income and middle-income countries" (New England Journal of Medicine 2007;356:3).

The polypill, a combination of a statin, aspirin, drugs to lower blood pressure, and folic acid, was first proposed by Nicholas Wald and M R Law of the Wolfson Institute of Preventive Medicine, Barts, and Queen Mary's School of Medicine and Dentistry at the University of London in the BMJ (2003;326:1419).

In the commentary, Srinath Reddy, president of the Public Health Foundation of India and professor of cardiology at the All India Institute of Medical Sciences in New Delhi, says that drugs for primary or secondary prevention of cardiovascular disease have not been widely used even in developed countries.

"Poor adherence to multidrug regimens is a common barrier to effective therapy. In low and middle-income countries, the unaffordable cost of such regimens represents another obstacle," he writes.

The polypill might prove useful, but Dr Reddy noted that other experts have proposed different combinations of four or five drugs.

"The availability of most of these drugs in a generic form may help to reduce the cost of a polypill, especially in countries such as India, with its active generic drug industry," Dr Reddy writes.

The World Heart Federation recently announced that it would support the development of a polypill containing aspirin, an angiotensin converting enzyme inhibitor, and a statin. Two Indian drug manufacturers have developed a combination pill that also includes a blocker and will soon begin clinical trials, he writes. However, trials are needed to show "whether the polypill is a miracle or a mirage."

Steroid free induction and maintainence protocols in kidney transplant

Excellent Kidney-Transplant Outcomes Seen After Early Steroid Withdrawal

Marlene Busko

January 18, 2007 — Primary kidney-transplant recipients maintained on sirolimus (Rapamune, Wyeth) and cyclosporine (Neoral, Novartis) immunosuppression after a 5-day induction with antithymocyte globulin (Thymoglobulin, Genzyme Transplant) and prednisone (Solu-Medrol, Pfizer) had excellent 1-year graft and patient survival, similar to that of a comparator group receiving steroids. In this single-center study, the steroid-free group also had a lower incidence of biopsy-proven acute rejection than the comparator group (4.9% vs 9.4%; P < .01).

"We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of Neoral and sirolimus," the group, led by Amer Rajab, MD, from Ohio State University in Columbus, write.

The article is published in the December 2006 issue of Clinical Transplantation.
The immunosuppressive regimens of the 2 groups were:

• Steroid-free-maintenance group (n=301) — Induction therapy with Thymoglobulin and prednisone over 5 and 4 days, respectively, followed by maintenance therapy with sirolimus and Neoral.
• Steroid-based-maintenance group (n = 502) — Induction therapy with basiliximab (Simulect, Novartis), followed by maintenance therapy with prednisone, mycophenolate mofetil (MMF, Cellcept, Roche), and Neoral.

The low rate of acute rejection is a "remarkable" contrast with studies from the early 1990s that suggested that early steroid withdrawal was associated with high rates of acute rejection, said Dr. Hricik. He added that the only logical explanation is that the combination of sirolimus and Neoral is more potent than earlier immunosuppressants, which is discussed in a recent review article about steroid sparing that he coauthored (Clin J Am Soc Nephrol. 2006;1:1080-1089). In the current study, therapy with sirolimus and Neoral produced no significant adverse effects.

He noted that 1 weakness of this study is that there were more cadaveric donors and fewer living donors in the comparator group than in the steroid-free group, possibly accounting for the different rejection rates. Also, it is also not clear whether the results can be extrapolated to high-risk patients such as non-primary-kidney-transplant recipients or African Americans.

Clin Transplant. 2006;20:537-546.