Hemodialysis.com Nephrology Research Interviews Sept 7 2013

Hemodialysis.com
Hemodialysis research, author interviews, dialysis updates and
information on chronic kidney disease and end stage renal failure.
Editor: Marie Benz, MD
info@hemodialysis.com
Sept 8 2013
For Informational Purposes Only: Not for Specific Medical Advice.

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CKD: Phosphate Binders and Wnt/β-catenin pathway
Hemodialysis.com Interview with:
Rosa M A Moysés, MD, PhD and Rodrigo B. de Oliveira
Nephrology Department – University of São Paulo School of Medicine
Av. Dr. Arnaldo, 455, São Paulo, SP, Brazil
• Hemodialysis.com: What are the main findings of the study?
• Answer: Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated serum sclerostin
and Dickkopf-1. The increase in the serum levels of these Wnt pathway inhibitors could help us to explain the physiopathology of
CKD-MBD. We also observed an elevation in of energy-regulating hormones such as leptin and serotonin.
• Hemodialysis.com: Were any of the findings unexpected?
• Answer: To the best of our knowledge, the modulation of serum leptin and sclerostin levels by sevelamer hydrochloride is
completely new. Another intriguing finding was the association between some mineral metabolism markers and energy
metabolism hormones.
• Hemodialysis.com: What should clinicians and patients take away from this study?
• Answer: Guidelines condense the most important available scientific evidence and are essential tools for the best practice.
However, even when the physician makes therapeutical efforts to keep several CKD-MBD parameters in the range, many non-
classical CKD-MBD markers could be disturbed, even at early CKD stages.
• Our results are preliminary, but they suggest that the connection between bone and energy metabolism hormones truly exists. In
addition, the Wnt pathway is an important anabolic pathway for the skeleton that has been studied by researchers that deal with
osteoporosis. Currently, we and other and researchers believe that this pathway could potentially be targeted for the therapy of
CKD-MBD. If this hypothesis is correct, we should manage not only the classical CKD-MBD parameters, but also other proteins
and hormones that were evaluated in our study. Therefore, probably in the near fut ure, patients and physicians will be able to
know better their diagnostic and therapeutic options, and have a more personalized care to prevent and treat CKD-MBD.
Read the rest of the interview on Hemodialysis.com

CKD: Phosphate Binders and Wnt/β-catenin pathway
Rosa M A Moysés, MD, PhD and Rodrigo B. de Oliveira
Nephrology Department – University of São Paulo School of Medicine
Av. Dr. Arnaldo, 455, São Paulo, SP, Brazil
• Hemodialysis.com: What recommendations do you have for future research as a result of your
study?
• Answer: Despite design limitations in the present work, many interesting aspects pointed out in our work
should be clarified by future research, at least, in three main issues: bone-kidney-energy axis regulation,
potential clinical usefulness of non-classical CKD-MBD molecules (either as potential markers or
therapeutic targets), and the impact of P binders on clinical outcomes.
• Regarding bone-kidney-energy axis regulation, experiments in knockout animal models and/or cell culture
experiments can shed light in our understanding about the connexions in this axis, to explore the hypothesis
of Wnt pathway inhibitors regulation by phosphate and/or FGF-23, as well as FGF-23 regulation by leptin.
Summarizing, we think that we should better understand the regulation of Wnt pathway and energy
metabolism in CKD. This information will provide us new therapeutic tools to manage the CKD-related bone
disease.
• Citation:
• Rodrigo B. de Oliveira, Fabiana G. Graciolli, Luciene M. dos Reis, Ana L.E. Cancela, Lilian Cuppari, Maria
E. Canziani, Aluizio B. Carvalho, Vanda Jorgetti, and Rosa M.A. Moysés
• Disturbances of Wnt/β-catenin pathway and energy metabolism in early CKD: effect of phosphate
binders
• Nephrol Dial Transplant. 2013 Aug 23. [Epub ahead of print]

Spontaneous Renal Artery Dissection: Characteristics, Course, Associations
Afshinnia, Farsad, M.D., M.S.
Research Fellow and Clinical Lecturer
Department of Nephrology
University of Michigan Health System
• MedicalResearch.com: What are the main findings of the study?
• Answer: Spontaneous Renal Artery Dissection (SRAD) is most commonly observed in middle aged
individuals. Although SRAD can have no association with other comorbidities at the time of presentation,
we have noticed association with a number of systemic disorders such as hypertension, cancer, congestive
heart failure, and rheumatologic diseases. In particular clustering of Fibromascular dysplasia (FMD), Ehlers-
Danlos syndrome, poly arteritis nodosa, Poland syndrome, and nail patella syndrome in our patients has
been striking. The most commonly observed presenting symptom is sudden onset severe flank pain which
may be spontaneous or following physical stress. Other presenting features may include uncontrolled
hypertension, groin and/or testicular pain, headache, nausea, vomiting, fever, dysuria, hematuria and blurry
vision.
• Read the rest of the interview on MedicalResearch.com

CKD: Vitamin D Anti-Proteinuria Effects
Dr. Pablo Molina
Servicio de Nefrología
Hospital Universitario Dr Peset
• Dr. Molina: The study showed the antiproteinuric effect of vitamin D repletion using cholecalciferol, with
potential effects on delaying the progression of CKD. The reduction in albuminuria was also consistent in
subgroup of patients with severely increased baseline albuminuria. In addition, we observed a modest but
significant decline in PTH levels after cholecalciferol administration.
• Dr. Molina: One of the most important findings of the study is the fact that the antiproteinuric effect was
observed in spite of the mean vitamin D concentration at the end of the study did not reach the optimal
recommended levels (> 30 ng/ml). This might be due to the moderate dose of vitamin D (666 IU per day)
administered in our study. Nevertheless, before recommending a higher vitamin D intake, the potential
benefits of increasing cholecalciferol dose should be balanced against the risk of calcium and phosphate
overload. In this regard, our study, with no confounding effects of the phosphate binders, showed a
significant rise in phosphate and CaxP levels in the cholecalciferol-treated patients.
• Other unexpected finding was the worsening in mineral-related endpoints observed in the control group,
with a significant decline in serum vitamin D and an increase in PTH levels. These data supports the
hypothesis that correcting vitamin D deficiency prior to elevations in serum PTH could delay the onset of
secondary hyperparathyroidism. It suggests that current guidelines could be limited because they
recommend treatment of secondary hyperparathyroidism as opposed to prevention.

CKD: Vitamin D Anti-Proteinuria Effects
Dr. Pablo Molina
Servicio de Nefrología
Hospital Universitario Dr Peset
• Dr. Molina: The study suggests that vitamin D repletion with daily mild doses of cholecalciferol may be effective to reduce
albuminuria in patients with CKD 3-4 stage, with potential long-term benefits for this population that should be tested in
future vitamin D supplementation trials. The reduction of proteinuria and PTH levels in proteinuric CKD patients with low
vitamin D status and secondary hyperparathyroidism suggests that vitamin D repletion should be considered the first
therapeutic approach in these patients, and this treatment should precede the use of active metabolites. All of these
benefits could be obtained without achieving suggested optimal vitamin D status, whereas higher doses of cholecalciferol
can lead to a calcium and phosphate overload, highlighting the need for a revision of the current guidelines. In the
absence of knowing the most favorable 25(OH)D level for CKD patients, we recommend caution when vitamin D is
supplemented.
• Hemodialysis.com: What recommendations do you have for future research as a result of your study?
• Dr. Molina: A long-term randomized trial is warranted to test whether the decrease in uACR after cholecalciferol
supplementation could be translated into a lower rate of progression of proteinuric CKD patients. It would be interesting to
study changes in additional bone related markers as FGF-23, calciuria or phosphaturia to help to balance the risk-benefit
of vitamin D supplementation, as well as to test other relevant clinical outcomes, as fracture risk, cardiovascular disease
and mortality.
• Citation:
• The effect of cholecalciferol for lowering albuminuria in chronic kidney disease: a prospective controlled study
• Molina P, Górriz JL, Molina MD, Peris A, Beltrán S, Kanter J, Escudero V, Romero R, Pallardó LM.
• Department of Nephrology, Hospital Universitario Dr Peset, Valencia, Spain.
Nephrol Dial Transplant. 2013 Aug 24.

Hemodialysis Patients: Effects of Magnesium Levels
Dr. Yusuke Sakaguchi & Dr. Yoshitaka Isaka
Osaka University Graduate School of Medicine Suita, Osaka, 565-0871, Japan
• Answer: Magnesium plays an important role in numerous biological processes and its deficiency leads to a
considerable variety of pathological conditions including atherosclerosis. Despite increasing evidence
showing an association of hypomagnesemia with worse cardiovascular outcomes in the general population,
few studies have examined their relationship in patients undergoing hemodialysis. In this nationwide
registry-based cohort study of 142,555 hemodialysis patients, we showed a J-shaped association between
serum magnesium level and 1-year all-cause, cardiovascular, and non-cardiovascular mortality. In a
multivariate logistic regession analysis, those with serum magnesium levels between 2.8 and 3.0 mg/dL had
the lowest risk of mortality.
•
• Answer: We unexpectedly found that the mortality risk increased not only in patients with hypomagnesemia
but also in those with high serum magnesium level (more than 3.0 mg/dL). Because there was a negative
association between serum magnesium level and intact parathyroid hormone (PTH) level, we assumed that
an oversuppression of PTH by high magnesium was a cause of the increased risk in patients with high
serum magnesium level. In fact, after excluding patients with intact PTH level less than 50 pg/mL, the
cardiovascular mortality risk in this patients group was attenuated.

Hemodialysis Patients: Effects of Magnesium Levels
Dr. Yusuke Sakaguchi & Dr. Yoshitaka Isaka
Osaka University Graduate School of Medicine Suita, Osaka, 565-0871, Japan
• Hemodialysis.com: What should clinicians and patients take away from this study? What
recommendations do you have for future research as a result of your study?
• Answer: Owing to the nature of the observational study design, our study cannot infer causality between
hypomagnesemia and the increased risk of mortality. Interventional studies are warranted to clarify whether
magnesium improves prognosis of hemodialysis patients. Because high serum magnesium level was also
associated with the increased risk of mortality which was attributed to some extent to the oversuppression
of PTH, serum magnesium as well as PTH level should be closely monitored when magnesium
supplementation is conducted.
•
• Citation:
• Hypomagnesemia is a significant predictor of cardiovascular and non-cardiovascular mortality in
patients undergoing hemodialysis
• Yusuke Sakaguchi, Naohiko Fujii, Tatsuya Shoji, Terumasa Hayashi, Hiromi Rakugi and Yoshitaka Isaka
• Kidney International , (28 August 2013) | doi:10.1038/ki.2013.327

Dialysis Patients: Mortality Association with High Resistin, Low Adiponectin
Hemodialysis.com Authors’ Interview:
Dr. Carmine Zoccali and Dr. Belinda Spoto
Nephrology, Dialysis and Transplantation Unit, and CNR-IBIM,
Clinical Epidemiology and Pathophysiology
of Renal Diseases and Hypertension Reggio Calabria, Italy
• Authors: In this study we found that in dialysis patients the link between resistin and mortality is modified
by adiponectin, the main molecule produced by adipose tissue. In particular, the risk of all-cause and CV
mortality associated with increasing levels of resistin is evident in dialysis patients with low levels of
adiponectin but absent in those with high levels of this adipokine. These data highlight the mutual
relationship between adipose tissue cytokines for amplifying cardiovascular risk in dialysis patients.
Hemodialysis.com: Were any of the findings unexpected?
• Authors: Previous studies reported that resistin was associated with mortality and incident heart failure in
patients with coronary heart disease or with acute myocardial infarction. Furthermore, a study by our
group showed that adiponectin and central obesity interact in determining death and cardiovascular
events in dialysis patients (Journal of Internal Medicine 2011;269:172-81 ). An interesting corollary of this
paper was that high levels of adiponectin attenuates the risk of adverse clinical outcomes in end stage
kidney failure patients. Thus, it is quite interesting that high circulating concentrations of adiponectin also
blunt the risk of mortality linked to high levels of resistin in this population.

Dialysis Patients: Mortality Association with High Resistin, Low Adiponectin
Hemodialysis.com Authors’ Interview:
Dr. Carmine Zoccali and Dr. Belinda Spoto
Nephrology, Dialysis and Transplantation Unit, and CNR-IBIM,
Clinical Epidemiology and Pathophysiology
of Renal Diseases and Hypertension Reggio Calabria, Italy
• Authors: The observational nature of our study does not allow to translate our findings into
recommendations for clinical practice. However, our data generate the hypothesis that interventions aimed
at reducing resistin in dialysis patients should be profiled according to levels of adiponectin.
study?
• Authors: Resistin antagonists are being developed. When these drugs will be available for testing them
in clinical research, their effect could studied in dialysis patients in a proper setting taking into
account adiponectin levels and visceral fat mass. Initial studies could look at surrogate end-points
like biomarkers of endothelial function including circulating biomarkers as well
as physiological studies looking at flow mediated vasodilatation.
• Citation:
• Resistin and all-cause and cardiovascular mortality: effect modification by adiponectin in end-stage
kidney disease patient
• Spoto Belinda, Mattace-Raso Francesco, Sijbrands Eric, Pizzini Patrizia, Cutrupi Sebastiano, D’Arrigo
Graziella, Tripepi Giovanni, Zoccali Carmine, and Mallamaci Francesca
• Nephrol. Dial. Transplant. first published online August 23, 2013 doi:10.1093/ndt/gft365

Cognitive Decline Associated with Albuminuria in Diabetes, even with Normal Kidney Function
Dr. Joshua Barzilay
Kaiser Permanente of Georgia 3650 Steve Reynolds Boulevard
Duluth, GA 30096.
Hemodialysis.com: Would you elaborate on the background and significance of your study?
• Dr. Joshua Barzilay: People with diabetes have an increased risk of cognitive impairment. Much of this impairment is due to
microvascular disease in the brain. The microcirculations of the kidney and brain share several common characteristics. It is
therefore likely that aberrations in the renal small blood vessels may have a parallel in the brain.
• Several studies have shown that albuminuria – the abnormal leaking of protein into the urine from the small vessels of the kidney
– is associated with brain disease, as measured by cognitive impairment. These studies have generally been done in older
people and in people with concomitant renal impairment, both of which can confound the relationship of albuminuria with cognitive
impairment.
• Our study has expanded on the association of albuminuria and cognitive impairment by showing that even at a relatively young
age (average age of the study cohort was 62 years) and with normal renal function (the estimated glomerular filtration rate was 90
ml/min/1.73 meter squared) the presence of albuminuria was associated with the development of subtle changes in cognitive
function.
• The subtle changes would not be recognized without detailed cognitive testing. Were the rate of decline in this cognitive function
to continue to decline at 5% over 3-4 years of follow up for another 15 years (when the person is over age 75 years) then
cognitive impairment would be clinically evident.
• Cognitive impairment is most common in adults over age 75 years. These findings should make the clinician aware that
microvascular cognitive impairment can begin at a very early stage of renal disease.
• Citation:
• Albuminuria and Cognitive Decline in People with Diabetes and Normal Renal Function
• Joshua I. Barzilay, James F. Lovato, Anne M. Murray, Jeff Williamson, Faramaz Ismail-Beigi, Diane Karl, Vasilios Papademetriou,
and Lenore J. Launer
• Albuminuria and Cognitive Decline in People with Diabetes and Normal Renal Function CJASN CJN.11321112; published ahead
of print August 29, 2013, doi:10.2215/CJN.11321112

Diabetes in Dialysis Patients: HbA1c levels Too High, Too Low Associated with Mortality
Hemodialysis.com Interview with
Christopher J. Hill, MB
Centre for Public Health, Queen’s University Belfast
Institute of Clinical Sciences Block B Royal Victoria Hospital, Grosvenor Road
Belfast, Northern Ireland United Kingdom BT12 6BA.
• Answer: Diabetes mellitus is the most common cause of end-stage renal disease in many countries. However, there has been
some debate in the medical community about the appropriate level of blood glucose control in diabetic patients treated with
hemodialysis. In this meta-analysis we pooled data from over 80,000 diabetic patients treated with maintenance hemodialysis
from North American, UK, European and Japanese studies.
• We demonstrated that HbA1c levels of 8.5% (69 mmol/mol) or higher are independently associated with up to a 29% increased
risk of death in diabetic patients on maintenance hemodialysis, when compared to patients who had HbA1c levels between 6.5%
(48 mmol/mol) and 7.4% (57 mmol/mol). In some sub-analyses of patients newly established on hemodialysis, very low HbA1c
levels (≤5.4%, 36 mmol/mol) were also associated with an increased risk of death.
• Hemodialysis.com: Were any of the study findings unexpected?
• Answer: The usefulness and accuracy of HbA1c as a marker of average blood glucose levels in diabetic patients treated with
maintenance hemodialysis is the subject of much debate. Due to the prolonged half-life of medications, nutritional deficiencies
and changes in haemoglobin metabolism which are common in advanced kidney disease some authors have suggested that
HbA1c levels are difficult to interpret on hemodialysis. The impact of blood glucose control in hemodialysis patients has also
been contentious with some authors arguing that other co-morbidities and dialysis-related factors may be of greater importance in
determining the increased risk of death.
• Therefore, prior to commencing the study, we were not certain whether any association between HbA1c and risk of death would
be evident. The pooled nature of the data and the large sample size were very important in demonstrating elevated mortality
risks at each end of the HbA1c spectrum.

Diabetes in Dialysis Patients: HbA1c levels Too High, Too Low Associated with Mortality
Christopher J. Hill, MB
Centre for Public Health, Queen’s University Belfast
Institute of Clinical Sciences Block B Royal Victoria Hospital, Grosvenor Road
Belfast, Northern Ireland United Kingdom BT12 6BA.
• Answer: Although this systematic review and meta-analysis was based on observational data it has potentially very important
implications for routine clinical practice. The results of our study suggest that, in diabetic patients treated with maintenance
hemodialysis, clinicians and patients should aim to achieve HbA1c levels less than 8.5% (69 mmol/mol) because of the increased
risk of death associated with higher HbA1c levels.
• The results also suggest that clinicians should avoid treating patients to achieve very tight blood glucose
• Answer: This meta-analysis was based only on observational data and is, therefore, open to potential confounding from other
factors which could not be adjusted for (such as dialysis adequacy or nutritional status). There is an urgent need to perform a
randomised controlled trial investigating the benefits of improved blood glucose control in diabetic patients treated with
maintenance hemodialysis. Further investigations should also be considered into the role of other markers of blood glucose
control in the hemodialysis population, such as glycated albumin.
• Citation:
• Glycated Hemoglobin and Risk of Death in Diabetic Patients Treated With Hemodialysis: A Meta-analysis
• Hill CJ, Maxwell AP, Cardwell CR, Freedman BI, Tonelli M, Emoto M, Inaba M, Hayashino Y, Fukuhara S, Okada T, Drechsler C,
Wanner C, Casula A, Adler AI, Lamina C, Kronenberg F, Streja E, Kalantar-Zadeh K, Fogarty DG.
• Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland; Regional Nephrology Unit, Belfast City Hospital,
Belfast, Northern Ireland
• Am J Kidney Dis. 2013 Aug 16. pii: S0272-6386(13)01013-5. doi: 10.1053/j.ajkd.2013.06.020. [Epub ahead of print]

Dialysis Patients: Carbamylation as Marker for EPO Resistance and Mortality
Dr. Sahir Kalim, MD
Research Fellow in Medicine (EXT)
Massachusetts General Hospital Boston MA 02114
•
Dr. Kalim: Carbamylation is a urea related, non-enzymatic, protein modification that is known to increase
with kidney failure. Carbamylation can occur on many different proteins in the body and can change the
function of various enzymes, hormones, and receptors.
• Our study of the effects of carbamylation had 2 main findings:
• 1) In incident dialysis patients, an individual’s carbamylation burden, measured by the carbamylated
albumin level, was positively associated with subsequent EPO resistance.
• 2) While EPO resistance was predictive of mortality in this cohort, carbamylation was a stronger mortality
predictor.
• Thus, it seems that protein carbamylation might play an important roll in both EPO resistance as well as
mortality in dialysis patients.
• Dr. Kalim: We looked at many different measures of EPO responsiveness—change in hemoglobin, EPO
dose, EPO resistance index—and in each instance, the association between higher carbamylation and
higher EPO resistance was robust. We were also surprised that carbamylation was a stronger predictor of
mortality than the well-established predictor EPO resistance.

Dialysis Patients: Carbamylation as Marker for EPO Resistance and Mortality
Dr. Sahir Kalim, MD
Research Fellow in Medicine (EXT)
Massachusetts General Hospital Boston MA 02114
• Dr. Kalim: Early mortality and EPO resistance are both problems we routinely face when caring for dialysis patients.
Understanding the underlying mechanisms for these problems may allow us to improve care. Carbamylation may be one
mechanism contributing to poor health outcomes in dialysis, and further studies are needed to better understand this process.
• Dr. Kalim: There are several interesting areas where this research could go. We could look at which specific proteins become
carbamylated, and how they might result in adverse effects. We could also study carbamylation burden and outcomes in other
populations (e.g. peritoneal dialysis patients and patients with CKD not yet on dialysis). Of course, we need to see if reducing
carbamylation can lead to meaningful clinical endpoints that will actually help our patients. We are conducting a pilot study looking
at this right now, so stay tuned!
• Citation:
Carbamylation of Serum Albumin and Erythropoietin Resistance in End Stage
• Kalim S, Tamez H, Wenger J, Ankers E, Trottier CA, Deferio JJ, Berg AH, Karumanchi SA, Thadhani RI.
• Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston,
Massachusetts;, †Department of Pathology, Division of Clinical Chemistry and, ‡Department of Medicine, Division of Nephrology
and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston,
Massachusetts.
• Clin J Am Soc Nephrol. 2013 Aug 22. [Epub ahead of print]

Predicting Renal Function: Using BMI and GGT
Prof. Dr. Gabriele Nagel, MPH
Firmensitz Bregenz, Firmengericht Feldkirch
FN164260i ATU 43679603, DVR-Nr. 0081485
• Hemodialysis.com: What are the main findings of the study? 
• Prof. Nagel: Our study confirms prior reports that BMI is a long-term predictor of eGFR and albuminuria.
This does not only apply to the association of BMI with CKD defined as eGFR < 60 ml/min and albuminuria
> 30 mg/g, but is already observed in the normal range of eGFR and albuminuria. In men each 1 kg/m² BMI
increase was associated with a decrease in eGFR of 0.99 ml/min and a 14% increase in albuminuria 25
years later. In addition, we found that gamma glutamyl transferase is another valuable long-term predictor
of albuminuria in men.
• Hemodialysis.com: Were any of the findings unexpected? 
• Prof. Nagel: The association of BMI with renal parameters was present in men but not in women. In
females waist-to-hip ratio seems to be a better marker of cardiovascular and renal risk than BMI.
Unfortunately WHR was not determined at previous health examinations in our study population.
• Prof. Nagel: What should clinicians and patients take away from this study? To measure BMI and GGT
may be valuable tools to identify individuals, especially men, who will develop renal disease in the future.

Predicting Renal Function: Using BMI and GGT
Prof. Dr. Gabriele Nagel, MPH
Firmensitz Bregenz, Firmengericht Feldkirch
FN164260i ATU 43679603, DVR-Nr. 0081485
study? 
• Prof. Nagel: Future research on anthropometric and metabolic factors as long-term predictors of renal
function should focus on gender differences. In addition, the connection of elevated GGT and renal disease
requires further investigation.
• Citation:
• Body mass index and metabolic factors predict glomerular filtration rate and albuminuria over 20
years in a high-risk population.
• Nagel G, Zitt E, Peter R, Pompella A, Concin H, Lhotta K.
• BMC Nephrol. 2013 Aug 20;14(1):177. [Epub ahead of print]

Lupus Nephritis Susceptibility Genes Identified
Hemodialysis.com Interview with: Dr. David W. Powell PhD
Associate Director of Clinical Proteomics
Assistant Professor of Medicine Assistant
Professor of Biochemistry and Molecular Biology
Department of Medicine/Nephrology Louisville, Kentucky
• Dr. Powell: We found a strong association for variants in the gene encoding ABIN1 (a physiologic inhibitor
of NF-B) and nephritis in systemic lupus erythematosus patients and that mice expressing a loss of function
mutation of ABIN1 develop pathophysiologic features of the most common and severe form of human lupus
nephritis.
• Hemodialysis.com: What should clinicians and patients take away from your report?
• Dr. Powell: Our work suggests that variations in the function of specific gene products is a major
determinant of susceptibility to Lupus nephritis. Our work identified one such gene as a regulator of the
inflammatory response. Our studies identify genes of the NF-B pathway as a focus for future work
understanding the pathogenesis and therapy of lupus nephritis. Understanding the role of genes in the NF-
B pathway in development and severity of lupus nephritis provides the hope that personalized therapy
may be possible.

Lupus Nephritis Susceptibility Genes Identified
Hemodialysis.com Interview with: Dr. David W. Powell PhD
Associate Director of Clinical Proteomics
Assistant Professor of Medicine Assistant
Professor of Biochemistry and Molecular Biology
Department of Medicine/Nephrology Louisville, Kentucky
• Hemodialysis.com: What recommendations do you have for future research as a result of this
study?
• Dr. Powell: Our findings suggest that the presented mouse model closely resembles human lupus nephritis
and therefore provides a useful tool for future drug screening studies.
• Citation:
• ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis
• Dawn J. Caster, Erik A. Korte, Sambit K. Nanda, Kenneth R. McLeish, Rebecca K. Oliver, Rachel T. G’Sell,
Ryan M. Sheehan, Darrell W. Freeman, Susan C. Coventry, Jennifer A. Kelly, Joel M. Guthridge, Judith A.
James, Kathy L. Sivils, Marta E. Alarcon-Riquelme, R. Hal Scofield, Indra Adrianto, Patrick M. Gaffney,
Anne M. Stevens, Barry I. Freedman, Carl D. Langefeld, Betty P. Tsao, Bernardo A. Pons-Estel, Chaim O.
Jacob, Diane L. Kamen, Gary S. Gilkeson, Elizabeth E. Brown, Graciela S. Alarcon, Jeffrey C. Edberg,
Robert P. Kimberly, Javier Martin, Joan T. Merrill, John B. Harley, Kenneth M. Kaufman, John D. Reveille,
Juan-Manuel Anaya, Lindsey A. Criswell, Luis M. Vila, Michelle Petri, Rosalind Ramsey-Goldman, Sang-
Cheol Bae, Susan A. Boackle, Timothy J. Vyse, Timothy B. Niewold, Philip Cohen, and David W. Powell
• JASN ASN.2013020148; published ahead of print August 22, 2013, doi:10.1681/ASN.2013020148

CKD: Exercise Program Improved Cardiovascular Fitness
Dr. Nicole Isbel, Renal Research, Department of Nephrology
Princess Alexandra Hospital
Ipswich Road Brisbane, Queensland, 4102, Australia.
Dr. Isbel:
• Our study had several novel findings.
• The study confirmed patients with chronic kidney disease (CKD) have poor baseline cardiorespiratory
fitness, with less than 50% able to achieve age predicted exercise capacity.
• It is possible for patients with CKD and other comorbidities such as ischemic heart disease, diabetes and
obesity to undertake a lifestyle program including aerobic and resistance training – safely. Previous studies
looking at exercise training in CKD have excluded patients with other health problems. Our findings are
consistent with studies in other populations with significant chronic disease such as heart failure.
• The program was successful in improving cardiorespiratory fitness. Patients in the intervention group
increased their fitness by a clinically significant amount, VO2 peak increased by 11% compared with a 1%
decrease in the control group. By 1 year more than 70% of intervention patients were able to meet their age
predicted exercise capacity.
• Increased cardiorespiratory fitness was associated with an improvement in diastolic heart function. This
was a secondary outcome of the study and needs to be interpreted cautiously, but does suggest that
improved fitness may provide cardiovascular benefits in a group of patients with a high burden of
cardiovascular morbidity and mortality and is well worthy of further study.

• Dr. Isbel: In spite of dietary intervention and psychological support and motivation, total energy intake and
macronutrient composition did not change at 12 months. There was a very modest degree of weight loss (-
1.8kg in the intervention group). This suggested to us that patients were more accepting of an exercise
program than of dietary change.
• Dr. Isbel: Lifestyle intervention including exercise training can be done safely and effectively in patients
with CKD and may have cardiovascular benefit. The inclusion criteria for this trial were deliberately made as
broad as possible so that the results could be generalized to the standard CKD clinic patient. Forty percent
of patients had diabetes and 12% a history of IHD. We did exclude patients with a recent cardiac event or
significant valvular heart disease and screened patients with a stress test prior to commencing the exercise
component of the study.

• Patients with a positive stress test were assessed by their cardiologist and the majority continued in the
study without event. The detailed clinical information provided by and clinical support of the multidisciplinary
team was essential to the exercise physiologist who tailored the programs to suit patients’ individual health
problems as well as patient interests and preferences. It was also important to be able to advise patients on
the adjustment of hypoglycemic medicines and diuretics as their fitness improves.
• There is much further to be learned about the benefits of improved cardiorespiratory fitness in this
population. Our study is ongoing and we hope to determine.
• The long-term adherence to lifestyle change and the impact on cardiovascular function overtime.
• The impact on patient quality of life.
• Additional studies on the benefits of different types and intensity of exercise prescription is required.
• Citation:
• Effects of Exercise and Lifestyle Intervention on Cardiovascular Function in CKD
• Erin J. Howden, Rodel Leano, William Petchey, Jeff S. Coombes, Nicole M. Isbel, and Thomas H. Marwick
CJASN CJN.10141012;
published ahead of print August 22, 2013, doi:10.2215/CJN.10141012

AKI: “Sunday Policy” did not affect dialysis patient outcomes
F. Perry Wilson, MD MSCE
Renal, Electrolyte and Hypertension Division
University of Pennsylvania Health System 3400 Spruce St. Philadelphia, PA 19104
• Dr. Wilson: We examined the risk of in-patient mortality among patients with Acute Kidney Injury at three
hospitals within our health system, and found no association between day of the week and mortality. This
was despite the fact that the rate of initiation of dialysis was markedly lower on Sundays.
Hemodialysis.com: Were any of the findings unexpected?
• Dr. Wilson: We performed the study because we were concerned that the differential treatment strategy
employed on Sundays might have an adverse effect on patient outcomes. Finding no such relationship was
reassuring, but raises the question of whether the ―Sunday policy‖ might be appropriate to extend to other
days of the week.

AKI: “Sunday Policy” did not affect dialysis patient outcomes
F. Perry Wilson, MD MSCE
Renal, Electrolyte and Hypertension Division
University of Pennsylvania Health System 3400 Spruce St. Philadelphia, PA 19104
• Dr. Wilson: The practice of triaging patients for initiation of dialysis on Sundays does not appear to have
adverse consequences, at least within our health system. Which patients benefit the most from initiation of
dialysis is an active area of research, and clinical judgment should be used.
study?
• Dr. Wilson: We need to examine factors at both the patient and system level that will help us determine
which patients would benefit from the initiation of dialysis for AKI and which would benefit from a watchful
waiting strategy. This question may be amenable to a randomized trial after observational studies
determine particular factors to target.
• Citation:
• Sundays and Mortality in Patients with AKI
F. Perry Wilson, Wei Yang, Sarah Schrauben, Carlos Machado, Jennie J. Lin, and Harold I. Feldman
CJASN CJN.03540413; published ahead of print August 22, 2013, doi:10.2215/CJN.03540413

Kidney Transplant Process: Risk Factors in Patient Communities
Dr. Jesse Schold, PHD
Quantitative Health Sciences, Assistant Staff
Cleveland Clinic Main Campus Cleveland, OH 44195
• Dr. Schold: The main findings of the study were that risk factors in patients communities were strongly
associated with processes of care and outcomes for patients placed on the waiting list for a kidney
transplant. These results were independent of demographic characteristics and traditional clinical risk
factors. In addition, the presence of risk factors in patients’ communities was highly variable between
centers and regions of the country.
• Dr. Schold: The strength and consistency of the findings were somewhat unexpected as the effect of
community risk was similar to many known clinical risk factors. In addition, the significance of the results
were dramatic despite the fact that community risk factors were only measured at the county level, which
was the manner in which the data were available. Given that counties can often be highly diverse with
respect to certain risk factors, it is likely that the effects of community risk factors is even stronger if they
were measured on a more granular level.

Kidney Transplant Process: Risk Factors in Patient Communities
Dr. Jesse Schold, PHD
Quantitative Health Sciences, Assistant Staff
Cleveland Clinic Main Campus Cleveland, OH 44195
• Dr. Schold: Beyond traditional clinical factors, the risk factors in patients communities are an important consideration for
characterizing potential risks of patients. Clinicians treating patients from higher risk communities may need to tailor protocols and
interventions to individual patient needs and conditions. Patients from higher risk communities should particularly be aware of all
available resources and seek assistance when resources are needed. The findings also should be considered in the context of
measuring the quality of transplant centers. Given that community risk factors vary substantially between centers and are not
considered (i.e. adjusted for) for center performance evaluations, centers that treat a high proportion of patients from higher risk
communities may receive ratings that are lower than their true quality of care.
• Dr. Schold: The findings suggest that tailored treatment protocols for patients from higher risk communities may be important to
develop to both improve outcomes and reduce disparities in this population. Further understanding of the mechanisms for the
observed differences in patient outcomes based on the presence of community risk factors may also prove highly important
towards developing future interventions.
• Citation:
• Prominent Impact of Community Risk Factors on Kidney Transplant Candidate Processes and Outcomes
• Schold JD, Heaphy ELG, Buccini LD, Poggio ED, Srinivas TR, Goldfarb DA, Flechner SM, Rodrigue JR, Thornton JD, Sehgal
AR. Prominent Impact of Community Risk Factors on Kidney Transplant Candidate Processes and Outcomes.
American Journal of Transplantation 2013

Dialysis Patients: ESA Prescribing After Safety Warnings
Hemodialysis.com: Interview with
Mae Thamer, PhD
Research Director, MTPPI
• Answer:
• * The FDA black box warning — issued in March, 2007 by the Food and Drug Administration to use the
lowest possible erythropoiesis-stimulating agents (ESA) doses for treatment of anemia associated with
renal disease – did not appear to influence ESA prescribing among the overall dialysis population.
• * However, significant declines in ESA therapy after the FDA warnings were observed for selected
populations:
• 1) Patients with a hematocrit >36% had a declining month-to-month trend before (-164 units/week) and
after the warnings (-80 units/week), and a large drop in ESA level immediately after the black box (-4,744
units/week);
• 2) Not-for-profit facilities had a declining month-to-month trend before the warnings (-90 units/week) and a
large drop in ESA dose immediately afterwards (-2,487 units/week); and 3) In contrast, for-profit facilities
did not have a significant change in ESA prescribing.
• * High hematocrit levels appear to be of more concern to nephrologists than high ESA doses following the
black box warnings. Implications of these findings require further investigation.

Mae Thamer, PhD
• Answer:
• Although there was a decline in ESA dose across the 60-month study period, the FDA black box warning
issued in March 2007 in itself did not appear to influence ESA prescribing for the overall dialysis population.
This was surprising given the FDA black box warning included the following important study results:
―Patients with chronic kidney failure had an increased number of deaths and of non-fatal heart attacks,
strokes, heart failure, and blood clots when ESAs were adjusted to maintain higher red blood cell levels
(hemoglobin more than 12 g/dL).‖
• In addition, a new patient medication guide accompanied the warnings and posed the following question
and answer, ‘What is the most important information I should know about Epogen? Using Epogen can
lead to death or other serious side effects’. Given these warnings, our findings raise questions as to
why providers did not lower ESA doses further than we observed when faced with mounting evidence of
risks based on randomized trials and FDA warnings. Moreover,the patient medication information was
neither read nor understood by this vulnerable group.
• In sharp contrast, a FDA black box warning on ESA use for oncology patients was also released on March
2007, and included a mandate that providers engage in a risk/benefit discussion with the patient and
document that this discussion occurred by completing and signing the Patient Acknowledgment Form; a
more stringent requirement that is absent from dialysis provider ESA prescribing. In contrast to the results
presented in this paper for dialysis patients, ESA use for oncology patients plummeted following the black
box warning.

Mae Thamer, PhD
• Answer:
• Evidence of adverse events commonly emerges after a drug has been on the market for several years
necessitating the issuance of a black box warning or other restrictive action. The type of facility in which a
patient recieves dialysis influences his or her quality of care, in this case, the adherence to the FDA black
box warning to avoid adverse events. Variations in treatment practice patterns across more than 4,000 US
dialysis facilities are well established and controversial.
• In our study, nonprofit facilities overall had a declining trend in ESA prescribing before the warnings and a
large drop in ESA dose immediately afterwards. In contrast, for-profit facilities overall that prescribed higher
ESA doses in both the period before and after the FDA warnings compared to nonprofit facilities, did not
change their ESA prescribing related to the FDA warnings, although chains are owned by different entities
that make individual corporate decisions regarding anemia protocols and anemia management goals
among their patients.

Mae Thamer, PhD
study?
• Answer:
• An enhanced ESRD Prospective Payment System (PPS) was initiated in January 2011 bundling separately
billable items (primarily ESA therapy) into the larger dialysis composite rate. Under PPS, facilities have no
financial incentive to use more drugs than are clinically necessary. Previously, during our study, ESA
therapy was an important source of profit and was reimbursed on a fee-for service basis, creating a
financial incentive for increased utilization of this therapy. A study should be conducted to compare the
influence of changes in reimbursement rates due to PPS compared to the FDA black box warning
regarding access and exposure to ESA therapy.
• Link to Abstract:
• Influence of safety warnings on ESA prescribing among dialysis patients using an interrupted time
series.
• Thamer M, Zhang Y, Lai D, Kshirsagar O, Cotter D.
• Medical Technology and Practice Patterns Institute, 5272 River Road, Suite 500, Bethesda, MD 20816,
USA.
• BMC Nephrol. 2013 Aug 9;14:172. doi: 10.1186/1471-2369-14-172.

Dialysis outcomes in those aged age 65 or Older – Study Protocol
Professor Robert Walker: Principal Investigator
Dialysis outcomes in those aged >65 years study.
University of Otago Dunedin NZ.
• Hemodialysis.com: What is the background for this study:
• Prof. Walker: Chronic kidney disease (CKD) is an increasingly common problem among older people in New
Zealand and all western countries: In New Zealand there has experienced a 400 per cent increase in those over the
age of 65 years commencing dialysis treatment.
• However, it is not always clear whether dialysis will have a net positive impact on the patient’s health-related quality
of life (HRQoL), particularly in the older age group who often have significant co-morbidities that also impact greatly
on their health. It is also important that offering a renal conservative care pathway, where appropriate, is informed by
good outcome data and is not seen a health care rationing process.
• The NZ dialysis in the elderly study is a study funded by the Health Research Council of New Zealand, to investigate
ways to improve how older patients (age >65 years) make informed decisions about their healthcare with respect to
the management of their CKD. The study protocol (Dialysis outcomes in those aged ≥ 65 years) has recently been
published in BMC Nephrology (ref). Currently, although the decision usually involves the patient, the family and the
medical team, there is little well-validated information about outcomes in this age group, in order to make an informed
decision.
• It is the first comprehensive longitudinal survey of health-related quality of life (HRQOL) and other patient centered
outcomes for individuals aged ≥65 years on, or eligible for, dialysis therapy and will link these data to survival
outcomes. Data collected by yearly structured interviews with participants, over 3 years, will be linked to co-morbidity
data, health service use, and laboratory information collected from health records, and analyzed with respect to
HRQOL and survival. In additional there is a qualitative arm that explores issues around the actual decision-making
process to consider dialysis or a conservative care pathway, as well as issues around the cessation of dialysis.

Dialysis outcomes in those aged age 65 or Older – Study Protocol
Professor Robert Walker: Principal Investigator
Dialysis outcomes in those aged >65 years study.
University of Otago Dunedin NZ.
• Hemodialysis.com: How will the information obtained from the study be utilized:
• Prof. Walker: The information obtained will inform the delivery of nephrology services in New Zealand and
facilitate improved decision-making by individuals in the older age groups, their family and clinicians, about
the appropriateness and impact of dialysis therapy on subsequent health and survival. Results from this
study will make possible more informed decision-making by future elderly patients and their families as they
contemplate renal replacement therapy including a renal conservative pathway. Results will also allow
health professionals to more accurately describe the impact of dialysis therapy on quality of life and
outcomes for patients.
• Citation:
• Dialysis outcomes in those aged >= = 65 years
• Walker R, Derrett S, Campbell J, Marshall MR, Henderson A, Schollum J, Williams S and McNoe B
BMC Nephrology 2013, 14:175 (14 August 2013)

Dialysis Patients: Sleep Complaints and Mortality
Fredrik B. Brekke
Medical student and researcher
Faculty of Medicine University of Oslo
• Answer: Sleep complaints are common in patients with chronic kidney disease and they often worsen after
initiation of dialysis, regardless of modality. Although reduced quality of sleep is associated with both
depression and quality of life, few studies have investigated the impact of sleep complaints on mortality in
dialysis patients. We used different questionnaires to investigate the quality of sleep and then followed the
patients for up to 4.5 years. Patients were among other asked to evaluate their sleep on a scale from 0
(very poor) to 10 (very good). We found that the patients who scored ≤ 5 had an almost twofold increase in
risk of all-cause mortality, but that daytime sleepiness was not related to mortality.
• Answer: Daytime sleepiness is in many cases conditioned by poor sleep quality. It was therefore
surprising that daytime sleepiness was not an independent predictor of mortality.
• We were also somewhat surprised to find that poor sleep quality had such drastic effects upon survival in
dialysis patients.

Fredrik B. Brekke
• Answer: This study provides important knowledge about quality of sleep as a risk factor for patients in
dialysis. Clinicians should be aware of the adverse consequences of having poor sleep quality and assess
these issues in all dialysis patients.
• Patients in dialysis experience a magnitude of symptoms and problems. Which symptoms that are the most
disturbing is an individual assessment, but this study might help patients to be more aware of sleep
problems and hopefully present them to their physician so they can be dealt with.

Fredrik B. Brekke
study?
• Answer: These results have shown an important implication of sleep problems in dialysis patients, but data
on how to relieve these symptoms lack. Both pharmacological and non-pharmacological treatment options
might be appropriate, but surprisingly little data on this problem exists. Future research should therefore, in
our opinion, focus on finding treatment strategies for sleep complaints in dialysis patients.
• Citation:
• Self-perceived quality of sleep and mortality in Norwegian dialysis patients.
• Brekke FB, Waldum B, Amro A, Osthus TB, Dammen T, Gudmundsdottir H, Os I.
• Faculty of Medicine, University of Oslo, Oslo, Norway.
• Hemodial Int. 2013 Jul 11. doi: 10.1111/hdi.12066. [Epub ahead of print]

Kidney Transplantation: Impact of Pre-Implantation Biopsy
Prof. Dr. Maarten Naesens, MD, PhD
Department of Nephrology, Dialysis and Renal Transplantation,
University Hospitals Leuven, Belgium Leuven, Belgium
• Answer: It was not well known whether assessing pre-implantation biopsies prior to transplantation for
allocation purposes is useful, and which histological cut-off values or score should be used for discarding or
allocating a kidney for transplantation. In our study, we evaluated the impact of the histological appearance
of pre-implantation biopsies on long-term renal allograft outcome, and assessed the histology of pre-
implantation biopsies as a prognostic clinical tool for kidney allocation.
• We found that the percentage of sclerosed glomeruli and the degree of chronic tubulo-interstitial were
significantly associated with graft survival. From this, we modeled and validated a new algorithm for
prediction of graft survival (the ―Leuven Donor Risk Score‖) that outperformed previously described
algorithms.
• Although our new algorithm for assessing donor kidney quality predicted graft outcome, we showed that the
predictive capacity is not sufficient to guide kidney discard. At most, our algorithm could guide kidney
allocation. A kidney with a high Leuven Donor Risk Score, and thus higher likelihood of early graft failure,
should probably not be allocated to a young recipient with many years ahead, but could be sufficient for an
elderly recipient. The Leuven Donor Risk Score could be included in kidney allocation protocols, although
we are well aware that the impact on accessibility and equity to transplantation need to be evaluated
carefully, as well as the logistical implications.

• Answer: We found it surprising that the previously described algorithms for evaluating pre-implantation
biopsies did not perform well, although these algorithms are used in many centers for deciding between
kidney discard and acceptance.
• In addition, it was unexpected that histological lesions like arteriolar hyalinosis and vascular intimal
thickening, which were closely related to donor history of hypertension, stroke, diabetes mellitus, and
smoking, did not associate with graft survival. In contrast, donor age-associated lesions, like global
glomerulosclerosis and tubular atrophy/interstitial fibrosis were highly significantly associated with graft
outcome. This unexpected discrepancy between age-associated histological lesions and age-independent
histological lesions warrants further study.

• Answer: Most importantly, we show that neither the previously described algorithms nor the Leuven Donor
Risk Score is able to guide kidney discard based on pre-implantation biopsy histology. The number of
discarded kidneys is relatively high in some countries, and kidney discard is often based on histological
examination. Our study suggests that we should probably not discard these kidneys, but use them in the
right patients.
• In addition, clinicians need to be aware that kidneys with a high Leuven Donor Risk Score are at higher risk
for failure, and could adapt the follow-up of the recipients of these kidneys. Whether dual transplantation is
the better solution, or whether the immunosuppressive regimen should be adapted in these cases, cannot
be answered from our data.

study?
• Answer: Because implementation of additional parameters in any allocation algorithm will have a certain
effect on the kidney transplant wait list and on the equity of access to transplantation, it was beyond the
scope of this study to calculate the potential effect of implementation of the Leuven Donor Risk Score in a
kidney allocation algorithm. Validation of our findings in an independent and larger cohort is necessary.
• In addition, proper computer simulations in very large data sets should calculate the effect on patient and
graft outcome of any change in the allocation system.
• Finally, the unexpected discrepancy between age-associated histological lesions and lesions that associate
with hypertension, stroke, diabetes mellitus, and smoking, is worth further study.
• Citation:
The Predictive Value of Kidney Allograft Baseline Biopsies for Long-Term Graft Survival
• De Vusser K, Lerut E, Kuypers D, Vanrenterghem Y, Jochmans I, Monbaliu D, Pirenne J, Naesens M.
• Departments of Nephrology and Renal Transplantation.
• J Am Soc Nephrol. 2013 Aug 15. [Epub ahead of print]

Dialysis Patients: Simple Exercise Program Improved Strength
Hemodialysis.com: Interview with:
Stig Molsted, Ph.d., fysioterapeut, post doc
Kardiologisk, Nefrologisk & Endokrinologisk Afdeling
Nordsjællands Hospital Dyrehavevej 29 3400 Hillerød
• Answer: In this study we analyzed the effects of high load resistance training on neuromuscular function
and rate of force development (also known as maximum speed of force production) in patients undergoing
dialysis. Recently we found an increase in muscle strength after resistance training in our patients. The
increased strength was not associated with muscle hypertrophy which was an unexpected result. Thus, we
hypothesized that the strength gain was associated primarily with neuromuscular changes.
• The main findings of the present study were, that not only neuromuscular function was improved. The
training was also associated with a greater rate of force development. An improved rate of force
development may be associated with the improved physical function, which we have reported recently.
Furthermore, the greater rate of force development may also be a relevant improvement in the prevention
of falling, a common problem in patients undergoing dialysis with an increased risk of complications.

• Answer: The only finding that may be unexpected was the low rate of drop-outs. Four of 33 patients
dropped out during the training program. We find the number of drop-outs relatively low taken the training
program into account. The program lasted 16 weeks and comprised of three exercise sessions per week.
• Furthermore, the compliance on 88% may also be more positive than expected, since patients undergoing
dialysis have a high rate of comorbidities and hospitalization. We think the high compliance was associated
with the training modality. Some patients may find resistance training easier to perform compared with
aerobic training due to anaemia, chronic heart disease and obstructive lung disease, which may limit the
endurance in aerobic exercises.

• Answer: Clinicians and patients should know that high load resistance training is associated with great
improvements in muscle strength and muscle power. These effects may occur even without muscle
hypertrophy. On the other hand, resistance training may prevent a loss of muscle mass.
• The results were achieved using a simple training program (five sets of three exercises), which could be
conducted within 30 min per exercise session. Furthermore, we did not see any serious adverse effects.
• Finally, it is important to note that the results were found in a sample of patients, who could perform the
high load exercises, without severe neuropathy.

study
• Answer: We think that the improved rate of force development may decrease the risk of falling. But studies
of long-term effects of training on falling are necessary to draw such conclusions.
• Future studies could have a focus on how we activate our patients not only for a limited period but also for
the long term. Longitudinal cohort studies are also relevant to investigate long term effects including
mortality risk reduction of physical training in patients undergoing dialysis.
• Finally, physical activity should be a part the self-management in patients undergoing dialysis, just like
managing fluid restriction, diet and the pharmacological treatment.
• Citation:
• The Effects of High-Load Strength Training With Protein- or Nonprotein-Containing Nutritional
Supplementation in Patients Undergoing Dialysis
• Stig Molsted, Adrian P. Harrison, Inge Eidemak, Jesper L. Andersen
• Journal of Renal Nutrition – March 2013 (Vol. 23, Issue 2, Pages 132-140, DOI: 10.1053/j.jrn.2012.06.007)

Kidney Stones: Febuxostat vs Allopurinol to Prevent Recurrence
David S. Goldfarb, MD
Clinical Chief, Nephrology, NYULMC
Professor of Medicine & Physiology, NYU School of Medicine
• Dr. Goldfarb: In patients with a history of recurrent kidney stones and higher urinary uric acid excretion (>
700 mg/day) febuxostat 80 mg per day lowered urinary uric acid excretion more than allopurinol 300 mg or
placebo. After 6 months there was no difference in the number of stones, or the size of a pre-existing radio-
opaque stone.
• Dr. Goldfarb: No. We did not anticipate that 6 months would be sufficient to affect stone size or number.
Most studies that have been successful in preventing stones or stone growth have lasted at least 3 years.
For instance, the study by Ettinger et al in the NEJM in 1988, showing that allopurinol 100 mg tid was
superior to placebo for calcium stone prevention, lasted 3 years.

Kidney Stones: Febuxostat vs Allopurinol to Prevent Recurrence
David S. Goldfarb, MD
Clinical Chief, Nephrology, NYULMC
Professor of Medicine & Physiology, NYU School of Medicine
• Dr. Goldfarb: We think that febuxostat may be an effective drug for lowering uric acid excretion in calcium stone
formers. However we have not yet shown that it is better than allopurinol. Note that the data regarding the risk of
calcium stones due to high uric acid excretion are unclear, since higher uric acid excretion was not associated with
greater risk of stones in observational studies in men and women.
• Dr. Goldfarb: We hope to repeat the study with a follow-up of at least 3 years to see if febuxostat is at least as
effective or superior to allopurinol in preventing recurrent calcium stones.
• Citation:
• Randomized Controlled Trial of Febuxostat Versus Allopurinol or Placebo in Individuals with Higher Urinary
Uric Acid Excretion and Calcium Stones.
• Goldfarb DS, Macdonald PA, Gunawardhana L, Chefo S, McLean L.
• Nephrology Section, New York Harbor VA Medical Center, and Division of Nephrology, New York University Langone
Medical Center, New York, New York;, †Global Medical Affairs, Takeda Pharmaceuticals International, Deerfield,
Illinois;, ‡Clinical Science, and §Statistics, Takeda Global Research & Development Center, Inc., Deerfield, Illinois,
‖Experimental Medicine, Takeda California, San Diego, California.
• Clin J Am Soc Nephrol. 2013 Aug 8.
[Epub ahead of print]

Hemodialysis Patient Survival Associated with Nephrologist’s Caseload
Dr. Kevin Harley, M.D.
Assistant Clinical Professor
and Dr. Connie M. Rhee MD
University of California Irvine, School of Medicine
• Answer: In this study, we examined data from a large dialysis organization limited to an urban area in
California. We observed that nephrologists with the lowest patient mortality rates had lower patient
caseloads than nephrologists with the highest mortality rates. Furthermore, we observed a 2% increase in
patient mortality risk for every 50 additional patients cared for by a nephrologist.
• Nephrologists with lower patient mortality rates also delivered cumulatively longer dialysis sessions and
had a greater number of patients transplanted.
• Answer: It might be expected that higher patient caseload confers greater experience in caring for patients,
resulting in improved patient survival, which has been shown in some studies examining non-hemodialysis
populations. Our study suggests this is not the case as pertains to hemodialysis patient care, and it is
possible that there is a limit to the number of hemodialysis patients one can care for before quality of care
is compromised. This plausible threshold remains to be defined, but this study suggests this threshold may
be lower than some providers may anticipate.

• Hemodialysis.com: What should clinicians and patients take away from this?
• Answer: First, we must acknowledge this study was limited to data from one dialysis provider database
restricted to a particular geographic locale, and may thus not be generalizable to other dialysis
organizations in other regions of the country. Although causality cannot be established by this
observational study, these findings may prompt nephrologists with higher caseloads to be particularly
attentive to the optimization of quality of care delivered with respect to metrics such as timely evaluation for
transplant candidacy and prescription of longer dialysis sessions.

• Hemodialysis.com: What recommendations for future research?
• Answer: This study is a first to examine the association between provider caseload and hemodialysis
patient adverse outcomes. Further study is needed to identify mechanistic factors and interventions. For
example, future studies could examine how outcomes may differ in:
• 1) In academic centers (where fellows are involved in patient care) versus non-academic environments;
• 2) If the involvement of nurse practitioners modifies these associations, and
• 3) If the number of patient encounters per month delivered by a provider (eg, two vs four) influences
outcomes.
• Citation:
• Nephrologist Caseload and Hemodialysis Patient Survival in an Urban Cohort
• Kevin T. Harley, Elani Streja, Connie M. Rhee, Miklos Z. Molnar, Csaba P. Kovesdy, Alpesh N. Amin, and
Kamyar Kalantar-Zadeh
• JASN ASN.2013020123; published ahead of print August 8, 2013, doi:10.1681/ASN.2013020123

CKD: Protein Wasting and Serum Resistin, Adiponectin Levels
Kubra Kaynar, M.D.
Department of Nephrology, School of Medicine
Karadeniz Technical University, Trabzon, Turkey
• Answer: Protein energy wasting of dialysis patients which is highly important for morbidity and mortality of
these patients were positively correlated with serum resistin and adiponectin levels.
• Answer: Yes, even though high serum resistin and adiponectin levels were found in chronic kidney disease
patients compared to patients with normal renal function, their relationship with protein energy wasting of
dialysis patients were not reported before.

CKD: Protein Wasting and Serum Resistin, Adiponectin Levels
Kubra Kaynar, M.D.
Department of Nephrology, School of Medicine
Karadeniz Technical University, Trabzon, Turkey
• Answer: For clinicians; adipocytokines especially resistin and adiponectin might have a positive
relationship with protein energy wasting of dialysis patients.
• For patients; protein energy wasting is a state of decreased body stores of protein and energy. It is
commonly seen (nearly 30%) among dialysis patients. Dietary approaches, infection
prophylaxis and dialysis prescriptions are very important to avoid protein energy wasting. Because
prevention is always better than treatment.
• Answer: I think it is important to know whether higher resistin and adiponectin levels are the result or the
etiology of protein energy wasting of dialysis patients.
• Citation:
• Is there any interaction of resistin and adiponectin levels with protein-energy wasting among
patients with chronic kidney disease?
• Kaynar, K., Kural, B. V., Ulusoy, S., Cansiz, M., Akcan, B., Misir, N., Yaman, S. and Kaya, N. (2013), Is
there any interaction of resistin and adiponectin levels with protein-energy wasting among patients with
chronic kidney disease. Hemodialysis International. doi: 10.1111/hdi.12072

Mortality in Hemodialysis Patients: Total Lymphocyte Count and Geriatric Nutritional Index
H. S. Shin, MD, Department of Internal Medicine
Kosin University College of Medicine
262 Gamcheon-ro, Seo-gu, Busan, 602-702, Korea.
• Answer: We examined the relationships between Geriatric Nutritional Risk Index (GNRI), total lymphocyte
count (TLC), and mortality in hemodialysis (HD) patients. Our findings suggest the TLC may be used as a
simple nutritional tool, but may not be a predictor of mortality in HD patients.
• Answer: Patients with a low GNRI had a lower survival rate than patients with a high GNRI in both low
and high TLC groups (P = 0.023). Life table analysis revealed that patients with a GNRI < 90 (n = 19) had
lower survival rates than did those with a GNRI ≥ 90 (n = 101) (Wilcox on test, P = 0.048), but subjects with
a TLC < 1500/mm3 (n = 76) had similar survival rates compared to subjects with a TLC ≥ 1500/mm3 (n=44)
(Wilcox on test, p=0.500).

Mortality in Hemodialysis Patients: Total Lymphocyte Count and Geriatric Nutritional Index
H. S. Shin, MD, Department of Internal Medicine
Kosin University College of Medicine
262 Gamcheon-ro, Seo-gu, Busan, 602-702, Korea.
• Answer: Malnutrition is highly prevalent in maintenance HD patients and is associated with an increased
risk of mortality. Regular nutritional assessment is recommended for all dialysis patients to reduce mortality
and morbidity. So, GNRI and TLC may be used as a simple nutritional tool in HD patients.
study?
• Answer: We will study the effect of the relationship between GNRI and subpopulation lymphocyte counts
on mortality in HD patients.
• Citation:
• Jung, Y. S., You, G., Shin, H. S. and Rim, H. (2013), Relationship between Geriatric Nutritional Risk Index
and total lymphocyte count and mortality of hemodialysis patients. Hemodialysis International.
doi: 10.1111/hdi.12077

Acute Kidney Injury: Timing of Initiation of Dialysis
Tukaram E. Jamale, MD, DM
Parel, Mumbai 400012.
• Dr. Jamale: Timing of initiation of dialysis in acute kidney injury is not clear. Data on Community acquired
AKI (CAKI) is scarce -which is the most common renal emergency in developing world and contribute to
one third of the global AKI burden. In the absence of sufficient data, practices regarding initiation of dialysis
therapy vary from Center to Center.
• We conducted a prospective, two arm randomized controlled trial to evaluate the impact of timing of
initiation of dialysis on outcome. We assigned patients with severe CAKI to earlier initiation (blood urea
nitrogen 70 and/serum creatinine 7mg/dl) or usual initiation (dialysis only when clinically indicated as
decided by treating nephrologist). Earlier start of dialysis therapy didn’t improve the patient or renal survival
and led to delayed recovery of kidney function.
• Dr. Jamale: We hypothesized an improvement in the survival with earlier start of dialysis therapy; however
earlier start did worse than the usual start-higher (statistically insignificant ) mortality and delayed recovery.

Acute Kidney Injury: Timing of Initiation of Dialysis
Tukaram E. Jamale, MD, DM
Parel, Mumbai 400012.
• Dr. Jamale: In patients with CAKI, optimum conservative management can postpone ( or in some cases avoid) the
need of dialysis. Earlier start of dialysis therapy doesn’t offer any survival benefit and can potentially be harmful. Our
finding doesn’t mean than one should wait for life-threatening uremic complications to develop before dialysis
start. Close clinical monitoring by team of nurses, physicians and dieticians can identify patient who need dialysis
early as highlighted by the fact that some of the usual start subjects needed dialysis below BUN 70 and creatinine
7mg/dl.
• Dr. Jamale: CAKI is substantially different from the AKI encountered in intensive care units-often associated with
sepsis. Although our findings can’t be generalised to this population; they provide rationale for design of large,
multicenter trial to identify the correct timing of dialysis initiation in this patient population.
• Citation:
• Earlier-Start Versus Usual-Start Dialysis in Patients With Community-Acquired Acute Kidney Injury: A
Randomized Controlled Trial
• Tukaram E. Jamale, Niwrutti K. Hase, Manjunath Kulkarni, K.J. Pradeep, Vaibhav Keskar, Sunil Jawale, Dinesh
Mahajan
• American Journal of Kidney Diseases – 12 August 2013 (10.1053/j.ajkd.2013.06.012)

Hemodialysis: Protocol Approach to Anemia Management
Martin Gallagher | MBBS, FRACP, MPH (Hons), PhD
Director, Renal & Metabolic Division
The George Institute for Global Health | Camperdown NSW 2050 Australia
• Answer: Implementation of an agreed treatment protocol for anaemia management in haemodialysis
patients is associated with greater consistency with clinical guidelines and significantly lower use of
recombinant erythropoietin without evidence of increased iron overload.
• Answer: There have been many clinical guidelines for the use of erythropoietin agents but limited data
exploring methods that support translation of these guidelines into practice. The most surprising finding was
the deterioration in guideline consistency when two important elements of the program were absent for 12
months, with the Anaemia Coordinator going on leave and the clinical database undergoing a prolonged
upgrade. The other finding worth noting, which has been seen by other investigators, is that only around
50% of patients met the haemoglobin target range at any one time.

Hemodialysis: Protocol Approach to Anemia Management
Martin Gallagher | MBBS, FRACP, MPH (Hons), PhD
Director, Renal & Metabolic Division
The George Institute for Global Health | Camperdown NSW 2050 Australia
• Answer: The implementation of well-supported treatment protocols in haemodialysis units can increase
consistency with clinical practice guidelines and be associated with reductions in the use of erythropoietin.
The distribution of serum ferritin values across a unit are probably a better guide to guideline consistency
than haemoglobin levels.
study?
• Answer: There is a need for more data from real world applications of treatment protocols to direct
guideline implementation. We still don’t know whether this real-world application of guideline evidence is
associated with better patient outcomes.
• Citation:
• Comparative efficacy of a team-led treatment protocol for the management of renal anaemia
• Sradha S Kotwal MBChB, Patrick Lan MBBS, Avril MacLeod RN, Meg Jardine PhD, Paul Snelling MD,
Jonathon Craig PhD,Alan Cass PhD, Martin Gallagher PhD
• DOI: 10.1111/nep.12144
• Nephrology June 2013

Kidney Transplantation: FGF23 and CV Risk, All-Cause Mortality
Dr. Martin de Borst, MD, PhD
University Medical Center Groningen
The Netherlands
• Answer: We found that higher levels of the hormone fibroblast growth factor 23 (FGF23) are linked with an
increased risk of cardiovascular and all-cause mortality after kidney transplantation. FGF23 is a
phosphaturic hormone, which means that it stimulates the kidneys to excrete phosphate. When renal
function is impaired, renal phosphate excretion is impaired and FGF23 levels increase in an attempt to
increase phosphate excretion. Our findings suggest that deregulated phosphate metabolism, as a result of
an imbalance between phosphate intake and renal phosphate excretion, is unfavorable in patients who
have received a kidney transplant.
• Answer: The most surprising finding was that none of the currently known risk factors for cardiovascular
disease could explain the association between FGF23 and cardiovascular mortality. This suggests that
higher FGF23 levels, representing deregulated phosphate homeostasis, is a novel independent risk factor
for mortality after kidney transplantation.

The Netherlands
• Answer: For clinicians, it is important to realize that FGF23 significantly improved the risk prediction of
cardiovascular or all-cause mortality compared to a model with only traditional (Framingham) risk factors.
This suggests that FGF23 levels could be used for risk stratification in this population. For patients, it is
important to realize that many dietary products contain phosphate. Especially junk food and preproduced
food contains high amounts of inorganic phosphate, which is almost entirely absorbed by the intestine, and
could form a potential burden for transplant patients or any patient with impaired renal function, given the
effect of dietary phosphate on circulating FGF23 levels.

The Netherlands
• Answer: What is needed are clinically feasible strategies to lower FGF23 in CKD patients and renal transplant
recipients. We believe that dietary interventions aiming at lowering phosphate intake are most likely to be successful.
However, also pharmacological interventions such as phosphate binders may play an important role. The effects of
such interventions should be assessed in prospective randomized trials on hard end points (mortality, renal function
loss, graft failure). A study aiming at FGF23 lowering by dietary phosphorus restriction and phosphate binders in
renal transplant recipients is needed to prove that FGF23 is really a target for intervention and lowering FGF23 can
put and end to the increased cardiovascular risk in these patients.
• Citation:
• Fibroblast Growth Factor 23 and Cardiovascular Mortality after Kidney Transplantation
• Baia LC, Humalda JK, Vervloet MG, Navis G, Bakker SJ, de Borst MH; on behalf of the NIGRAM Consortium.
• Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center
Groningen, The Netherlands;, †Department of Nephrology, UNIFESP, Sao Paolo, Brazil, ‡Department of
Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
• Clin J Am Soc Nephrol. 2013 Aug 8.
[Epub ahead of print]

Chronic Dialysis Patients: What Factors into Clinical Decision to Transfuse?
Cynthia Biddle Whitman, MPH
Principal Research Coordinator
UCLA/VA Center for Outcomes Research and Education (CORE)
Los Angeles, CA 90073
• Answer: Our research team found that absolute hemoglobin (Hb) level was the most influential clinical
factor associated with a provider’s decision to recommend a blood transfusion, all other patient
characteristics being equal, accounting for 29% of all decision making. Functional status and cardiovascular
comorbidities also influenced decision-making. The clinical context for red blood cell (RBC) transfusion
decisions does not stop at Hb level alone, but rather, is a complex consideration of patient medical
diagnosis and anemia symptoms.
• In our subgroup analysis, we found that compared to all other providers, those at the Veterans
Administration were 83% less likely than others to wait to transfuse patients until Hb fell to 7.5 g/dL, and
instead transfused when Hb was 8.0 g/dL. Additionally, we found that nephrologists value a patients’
transplant eligibility more than non-nephrologists, suggesting that non-nephrologists may lack awareness
about the impact that transfusion-induced allosensitization may have on transplantation success (or lack
thereof). Provider years of experience also played a role in their decisions to recommend transfusions for
certain patient profiles, with those with more experience (>20 years) were more selective about whom they
recommended receive transfusions.

• Answer: Most providers were averse to transfusion when Hb was greater than 8.5 g/dL. Our research team
did not expect the aversion to transfusion threshold to be so low.
• Hemodialysis.com: What should patients and providers take away from your study:
• Answer: Clinicians and patients should take away that the decision-making process regarding
recommendation of transfusions should involve a profile of clinical factors, and that no one factor should be
taken out of context of another.

study?
• Answer: We would recommend that future researchers continue to look at clinical profiles of patients, and
not just hemoglobin level, in order to make a correct determination of the recommendation of a transfusion.
We also recommend that the use of conjoint analysis be employed as an alternative method to presenting
patient vignettes. The conjoint analysis process not only involves the presentation of a clinical vignette, but
also has the ability to pull out and decipher preferences relating to each component of the vignette in a
systematic process.
• Citation:
• Clinical Factors and the Decision to Transfuse Chronic Dialysis Patients
• Cynthia B. Whitman, Sanatan Shreay, Matthew Gitlin, Martijn G. H. van Oijen, and Brennan M. R. Spiegel
CJASN CJN.00160113; published ahead of print August 8, 2013, doi:10.2215/CJN.00160113

Hemodialysis.com Nephrology Research Interviews Sept 7 2013

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Hemodialysis.com Nephrology Research Interviews Sept 7 2013