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Education, News in Research – CME

In a Canadian study of over 200,000 patients published in the American Journal of Transplantation, obese kidney transplant recipients with a BMI less than 40 kg/m² derived a similar survival advantage from transplantation as nonobese patients, amounting to a 66% lower risk of dying within 1 year. Obese patients with a BMI of 40 or higher derived a lower survival advantage from transplantation (48% reduced risk of dying within 1 year). Differences in obese and nonobese patients were not as profound with live donor transplantations.

Contrary to current recommendations, creating a fistula may not be superior to placing an arteriovenous graft (AVGs) in patients over 80 who will be needing hemodialysis, according to results from the US Renal Data System (USRDS). Using data from 115,425 hemodialysis patients aged 67 and older, the research team evaluated all-cause mortality based on the route of vascular access that was established predialysis. Most patients (78.4%) had a catheter as their first predialysis vascular access. Only 18.6% had an arteriovenous fistula (AVF) created in advance, and only 3.0% had an AVG. In the overall study population, having a catheter as the initial predialysis access was associated with 77% higher risk of mortality than having an AVF. Mortality rates were similar overall for patients having an AVG or an AVF as the initial predialysis access. For patients aged 67-79, however, the mortality risk was 10% higher when an AVG was placed first, predialysis, compared to when an AVF was created first. Among older patients, though, there was no significant mortality difference between receiving a graft predialysis, or having a fistula created predialysis.

The full paper is:

Desilva RN, Patibandla BK, Vin Y, Narra A, Chawla V, Brown RS, Goldfarb-Rumyantzev AS. Fistula First Is Not Always the Best Strategy for the Elderly. J Am Soc Nephrol. 2013 Jun 27. [Epub ahead of print] PubMed PMID: 23813216.

Adolescents and young adults with chronic kidney disease (CKD) have low quality of life (QOL) and are willing to trade life expectancy for perfect health, according to a cross-sectional study published online <> June 24 in the Journal of Pediatrics.
Utility-based QOL is used to examine the relative desirability of health states rated on a scale ranging from 0 (death) to 1 (full health). To assess utility-based QOL in adolescents and young adults with CKD, the investigators studied 27 patients aged 12 to 25 years with stage 3 to stage 5 and 5D CKD at 6 centers in Australia.
A visual analog scale allowed QOL measurement. For evaluation of utility-based QOL, the investigators used Health Utilities Index Mark 2 and 3 (HUI2/3), Kidney Disease QOL short form (SF)-12 transformed to SF-6D, and time trade-off (TTO). They identified predictors for TTO QOL weights, SF-6D, and visual analog scale scores using multiple linear regression.
On the utility scale of 0 (death) to 1 (full health), mean TTO QOL weight was 0.59 ± 0.40, HUI2 was 0.73 ± 0.28, HUI3 was 0.74 ± 0.26, and SF-6D was 0.70 ± 0.14. QOL weights had the lowest mean score and greatest variability in TTO responses but were consistently low using all 4 utility-based instruments.
Participants not yet receiving dialysis had higher mean QOL weights. The HUI2 showed variability in the emotion domain, which the study authors suggest may reflect the differences between a broad range of factors affecting emotion, such as individual personalities, support systems, adjustment to treatment, comorbidities, and other life circumstances.
All QOL domains were decreased on the Kidney Disease QOL measures. However, kidney disease accounted for a significantly higher burden among patients receiving dialysis compared with those not yet doing so dialysis.

In a recent paper in Nature Medicine investigators report the origins of cells that are responsible for kidney fibrosis. Four pathways appear to be involved. Half of all myofibroblasts are produced by the proliferation of pre-existing resting fibroblasts; 35% are produced by mesenchymal stem cells from the bone marrow; 10% are the products of endothelial to mesenchymal transition, in which blood vessel cells change into mesenchymal cells, then become myofibroblasts; and 5% come from epithelial to mesenchymal transition, in which functional cells of an organ behave like mesenchymal cells and myofibroblasts. (LeBleu et al, Nature Medicine 2013)

According to a recent paper in BMC Nephrology patients infected with H1N1 influenza have a very high rate of acute kidney injury. Of 562 individuals who suffered H1N1-related critical illness during Canada’s 2009-2010 pandemic,60.9% developed AKI, 24.9% received renal replacement therapy and 25.8% died. Obesity, mechanical ventilation, APACHE II score, and serum creatinine on the day of admission predicted the need for dialysis therapy.

Pulmonary Congestion Predicts Cardiac Events and Mortality in ESRD

Volume expansion is an independent risk factor for the high death risk occurring in patients with kidney failure on dialysis. Recently, lung ultrasound was validated for the measurement of extravascular lung water in patients with heart disease and in patients with acute respiratory failure (Frassi, F J Card Fail 13: 830-835, 2007). In end stage renal disease (ESRD) patients volume expansion is assessed usually by measuring weight change between dialyses in order to predict cardiovascular event and death among this population. Italian investigators on behalf of the Lung UltraSound in CKD Working Group now reported that a well validated ultrasound B-lines score (BL-US) can be an important predictor of death and cardiac event in ESRD patients (Zocalli et al J AM Soc Nephrol 24: 639-646, 2013). The authors published the validation of this method in 2010 (Mallamaci, F et al JACC Cardiac Imaging 3:586-594). Briefly, the assessment is based on the observation that in pulmonary congestion the ultrasound beam is reflected by thickened interlobar septa generating hyperechoic artifacts between the septa and the pleura. These so called “comets” are similar to Kerley’s b-lines (BL) observed on chest x-rays. The number of observed US bundles are directly associated with left ventricle filling pressure and allow quantification of lung water. There is also a short YouTube movie of the method (

The multicenter study involved 392 hemodialysis patients whom were grouped into three categories: mild or no congestion (41%), moderate-to-severe lung congestion (45%) and very severe congestion (14%). Ultrasound B-line detection was performed before dialysis and BL data were categorized into three groups: <15, 15-60, >60. Patients with very severe congestion had 4.2-fold higher risk of death and 3.2-fold higher risk of cardiac event then patients with mild congestion if the authors included the classic risk factors: age, smoking, cholesterol, pulse pressure and cardiovascular co-morbidities. Adding the degree of pulmonary congestion as independent risk factor, the authors were able to improve the prediction of cardiac events by 10%.

Sevelamer is indicated for the management of hyperphosphatemia in adult patients with stage 4 and 5 CKD on hemodialysis. Evidence from hemodialysis patients’ suggests that lowering serum phosphate may reduce left ventricular (LV) mass. Dr. Charles Ferro of Queen Elizabeth Hospital Birmingham and colleagues designed their study to test the hypothesis that reducing the phosphate absorbed from the diet would improve surrogate markers of cardiovascular health in patients with early stage 3 CKD. During a four-week open-label run-in period, 120 adults (mean age 55 years) with stage 3 nondiabetic CKD received sevelamer carbonate (1600 mg with each meal). Eleven patients withdrew during the run-in phase (five withdrew consent, two were intolerant to the medication, one had hypophosphatemia and three were non-compliant with the study). After the run-in period, 55 patients were randomly assigned to continue sevelamer and 54 to take placebo for an additional 36 weeks. An additional 12 patients withdrew from this phase of the study (five in the sevelamer group and seven in the placebo group) for similar reasons. Intention-to-treat analysis at 40 weeks showed “no statistically significant differences between sevelamer and placebo with regard to LV mass, systolic and diastolic function, or pulse wave velocity”. Only 56% of patients took 80% or more of their prescribed therapy, despite repeated reminders. In this compliant subgroup, treatment with sevelamer was associated with lower urinary phosphate excretion and serum fibroblast growth factor-23 (FGF-23) but not serum phosphate, klotho, vitamin D, or cardiovascular-related outcomes of interest.

An upcoming meta-analysis that included 14 trials found that fish oil supplements could reduce the risk for type 2 diabetes (Journal of Clinical Endocrinology & Metabolism). The putative mechanism of action for this effect is an increase in circulating adiponectin levels.

Exposure to stress at the workplace could contribute to type 2 diabetes (Diabetes Care). This effect was more pronounced in women, and especially in people who were under significant stress but had no decision-making power. The risk in men with stressful jobs and who had a high decision-making power was actually lower.

ESA in children

The authors assessed practices, effectors, and outcomes of anemia management in 1394 pediatric patients undergoing [PD] who were prospectively followed in 30 countries. In one quarter of patients, hemoglobin levels were below target levels (<10 g/dL in children older than 2 years or <9.5 g/dL in younger children). Levels were highest in North America and Europe and lowest in Asia and Turkey, with marked regional variation. Correlates of low hemoglobin levels were low urine output, low serum albumin, high parathyroid hormone levels, high ferritin, and use of bioincompatible PD fluid. Most (92%) of the children received ESAs. Neither the ESA type nor the dosing interval appeared to affect efficacy. Although weekly ESA dose was inversely related to age when normalized to weight, it was not related to age when normalized to body surface area. Positive correlates of ESA sensitivity were residual diuresis and serum albumin, and inverse correlates were serum parathyroid hormone and ferritin levels.

1: Borzych-Duzalka D, Bilginer Y, Ha IS, Bak M, Rees L, Cano F, Munarriz RL, Chua
A, Pesle S, Emre S, Urzykowska A, Quiroz L, Ruscasso JD, White C, Pape L, Ramela
V, Printza N, Vogel A, Kuzmanovska D, Simkova E, Müller-Wiefel DE, Sander A,
Warady BA, Schaefer F; International Pediatric Peritoneal Dialysis Network (IPPN)
Registry. Management of anemia in children receiving chronic peritoneal dialysis.
J Am Soc Nephrol. 2013 Mar;24(4):665-76. doi: 10.1681/ASN.2012050433. Epub 2013
Mar 7. PubMed PMID: 23471197.

Dr. Sener and colleagues compared “donation after cardiac death” (DCD) kidneys that were put on pulsatile perfusion with those placed in cold storage in terms of delayed graft failure and one-year graft survival, in a systematic review. Altogether they looked at nine studies: four randomized controlled trials, one prospective but nonrandomized trial, three retrospective studies, and one cohort study. The rate of delayed graft function was 36% lower in perfusion-pumped kidneys from DCD donors than in kidneys stored in static cold fluid (p=0.03). This finding held true in subgroup analyses of only randomized trials and only nonrandomized trials.As reported December 5th online in The Journal of Urology, graft survival at one year tended to favor perfusion pump kidneys, but the overall effect failed to achieve statistical significance, except in the subgroup analysis that included only nonrandomized studies.

1: Bathini V, McGregor T, McAlister VC, Luke PP, Sener A. Renal Perfusion Pump
Versus Cold Storage for Donation After Cardiac Death Kidneys: A Systematic
Review. J Urol. 2012 Dec 3. doi:pii: S0022-5347(12)05805-3.
10.1016/j.juro.2012.11.173. [Epub ahead of print] PubMed PMID: 23219548.

The risk of developing diabetes mellitus is increased in individuals with lower melatonin levels. In a nested case control study done within the Nurses’ Health Study cohort and published in JAMA, patients with the lowest levels of melatonin had a 2.17-fold higher risk of developing diabetes, compared to those with the highest melatonin levels. It remains to be seen if supplementation of melatonin could help prevent the development of diabetes mellitus.

In a study of almost 300,000 mostly male patients with non-dialysis dependent CKD published in the Journal of the American College of Cardiology, lower levels of urine microalbumin-creatinine ratio (a marker of proteinuria) showed a linear association with better clinical outcomes, down to levels as low as 5 mcg/mg. When these associations were examined in subgroups of patients categorized according to various key characteristics such as level of blood pressure and kidney function, and presence/absence of various comorbid conditions, the same linear associations were present in all except patients with advanced CKD (eGFR<45 ml/min/1.73m2), in whom there was a U-shaped association, and in whom a UACR of 10-20 mcg/mg was associated with the best outcomes.

Angiotensin receptor blockade fails to prevent chronic allograft nephropathy

It is known that immunosupressants help prolong the function of thransplanted organs. However, potential therapies targeting high blood pressure and the develpoing tissue fibrosis in kidney transplant patients have not been investigated. Hassan Ibrahim, MD, at the University of Minnesota, lead a randomized placebo-controlled trial to investigate whether angiotensin II blockers can slow down the fibrosis of the transplanted kidney. The trial included 153 kidney transplant recipients who were treated daily either with the angiotensin II receptor 1A (AT1A) blocker losartan (100 mg) or placebo. The treatment started within 3 months of transplantation and continued for 5 years. Angiotensin II blockade is known to slow progression of chronic kidney disease in non-transplant patients, therefore the investigators hypothesized that the drug will have beneficial effect in transplant recipients. Further, the investigators hypothesiezed that the beneficial effect of losartan is independent from its effect on blood pressure. Therefore, in the palcebo group calcium-channel blockers, followed by diuretics and β-blockers were used to maintain similar blood pressure levels as in the losartan group. The primary outcome of the trial was the development of end-stage renal disease from interstitial fibrosis and tubular atrophy. Interstitial fibrosis was estimated by doubling of the cortical interstitial compartment from baseline to 5 years.The investigator reported that losartan failed to slow down the developing fibrosis in the transplanted kidney. However, they found that the drug had good blood pressure control in the transplant patients, who tolerated well even the higher dose of losartan: there was only one subject who developed serious hyperkalemia during the study. The investigators therefore suggest that angiotensin receptor blockade should be re-evaluated as an important antihypertensive treatment in transplant patients.

The results were published in the 2013. February issus of the Journal of the American Society for Nephrology (JASN).

A functional analog of erythropoetin, peginesatide (Omontys, formerly hematide) was voluntarily recalled in the United States by its manufacturer, due to post-marketing reports of serious hypersensitivity reactions.

A recent large, randomized, placebo controlled clinical trial published in the Journal of the American Society of Nephrology found that the administration of losartan to kidney transplant recipients did not slow renal interstitial fibrosis and did not delay terminal kidney failure. This is contrary to what has been described in native kidney disease. Losartan was otherwise well tolerated and helped control blood pressure in study participants. Additional information may come in the future from a similar Canadian trial, which is in progress. Ibrahim et al., J Am Soc Nephrol 2013 24: 320-327

This multicenter, open-label, randomized controlled trial randomized chronic hemodialysis patients to conventional hemodialysis or high-efficiency postdilution online hemodiafiltration (OL-HDF).

Patients assigned to OL-HDF had a 30% lower risk of all-cause mortality compared to those on conventional hemodialysis (hazard ratio [HR], 0.70; 95% confidence interval [95% CI], 0.53–0.92; P=0.01). In addition, the OL-HDF group had a 33% lower risk of cardiovascular mortality (HR, 0.67; 95% CI, 0.44–1.02; P=0.06) and a 55% lower risk of infection-related mortality (HR, 0.45; 95% CI, 0.21–0.96; P=0.03).

Maduell F, Moreso F, Pons M, Ramos R, Mora-Macià J, Carreras J, Soler J,Torres F, Campistol JM, Martinez-Castelao A; for the ESHOL Study Group.: High-Efficiency Postdilution Online Hemodiafiltration Reduces All-Cause Mortality in Hemodialysis Patients. J Am Soc Nephrol. 2013 Feb 14. [Epub ahead of print] PubMed PMID: 23411788.

Previously reported benefits of hemodialysis performed 6 times per week compared with the conventional 3-day regimen include gains in physiology and health-related quality of life. However, a new study suggests these benefits come at a price. The researchers found that 48 of 125 patients receiving hemodialysis 6 days per week (the “daily” strategy) experienced a composite primary endpoint event of vascular repair, loss, or related hospitalization. In contrast, only 29 of 120 patients receiving conventional treatment experienced a similar event. These numbers translated to a rate of 40 vs 23 events per 100 patient-years. They found that daily hemodialysis significantly increased the risk of vascular access complications, as measured by time to first access repair, loss, or access-related hospitalization [(hazard ratio), 1.76; 95% (confidence interval), 1.11–2.79; P=0.017]. The investigators also compared these outcomes between nocturnal hemodialysis (6 nights per week) and conventional regimens. They found that 23 of 45 patients receiving nocturnal therapy experienced a vascular complication event compared with 15 of 42 patients receiving conventional therapy. The event per 100 patient-years rate was 58 in the nocturnal group vs 32 in the conventional cohort. A vascular access event was more likely with nocturnal hemodialysis (hazard ratio, 1.81; 95% confidence interval, 0. 94 – 3.48; P = .076).

Published online before print February 7, 2013, doi: 10.1681/ASN.2012060595
JASN February 7, 2013