Dialysis & transplantation

In this issue of D&T, it is our privilege to introduce a new regular department that will feature content written by and specifically for nephrology fellows. “From the Fellows” (p. 172) has been specifically designed to give fellows the opportunity to achieve scholarly research activity.1 The primary goal of this department is to continue to advance education regarding clinical concepts relating to the diagnosis, complications, and treatment of interesting and unique cases involving renal-replacement therapy or renal transplantation. We also aim to achieve scholarly activity, stimulate fellows to develop careers in academic medicine, and enhance the awareness of new clinical discovery and its application. This venue for fellows in training to publish is unique. It offers an opportunity to facilitate collaboration between trainees, experienced clinicians, and physician scientists. D&T's wide circulation of 25,000 nephrologists, nephrology nurses, dialysis technicians, and allied health professionals will allow our fellows in training to showcase their work and contribute to the overall fund of medical knowledge and patient care. By publishing their interesting or problematic case reports, brief reviews, and editorials and commentaries, we aim to provide a structured platform from which nephrology fellows can articulate and integrate the knowledge acquired from their day-to-day clinical encounters. We welcomeBrahmVasudev,MDas section editor for this exciting new department. Dr.Vasudev is currently Assistant Professor of Medicine in the Division of Nephrology at the Medical College ofWisconsin in Milwaukee. He is also director of the institution's Nephrology Fellowship Program. We encourage you to work with your fellows to contribute to this new section, and look forward to their submissions. Andrew Fenves, MD Larry Melton, MD

Citation: Tan JC, Ho B, Busque S, et al. Imprecision of creatinine-based GFR estimates in uninephric kidney donors. Clin J Am Soc Nephrol 2010; 5: 497–502. Analysis: In 2009, there were 6,388 living kidney donations in the U.S.1 Data compiled over the past several decades support the view that the overall survival and risk of end stage renal disease is no different in screened donors after donation than that observed in the general population.2 While many centers use standardized criteria for donor evaluation, the basic measure of kidney function, glomerular filtration rate (GFR), and its subsequent evaluation in the patient after single kidney donation, remain areas of con-troversy.3 Although most will agree that creatinine-based estimates of GFR are potentially inaccurate, they remain the most commonly employed method for determining GFR. In this study, Tan and colleagues compare measurements of GFR in 64 patients after kidney donation to evalu-ate the estimation of GFR (eGFR) by measurement of a creatinine clearance, by the Modification of Diet in Renal Disease (MDRD) equation, and the CKD-EPI equation compared to the “Gold-standard” of a GFR measured by iothalamate clearance. Poor correla-tion to the iothalamate value was found with all methods to estimate GFR, par-ticularly amongst older kidney donors, resulting in substantial misclassifi cation of individuals as having chronic kidney disease when in truth they did not have substantial CKD. Validity and threats to validi-ty: The study population consisted of donors representing a wide variety of ages (21–70 yrs), with a good inclu-sion of women (47%) and differing ethnicities. Time from donation to the measurement of GFR for this study also varied broadly from 5 to 86 months. All of these characteristics are important to help identify genetic, normal aging, and time-dependent factors that may have affected the results. This sample represents well the population of living donors and as such has broad clinical applicability. The measurements and calculations were described in detail, with standardized protocols and strin-gent statistical analyses that would allow for replication. Although the study may be some-what limited by the small number of patients (n = 64) resulting in some imprecision and variation in the GFR measurements, the rigorous statistical analysis still demonstrated a lack of accuracy for all of the estimation meth-ods. The creatinine clearance overesti-mated the GFR with an accuracy rate (defined as a value within 10% of the measured value by iothalamate clear-ance) of only 11%. The MDRD and CKD-EPI estimations underestimated the GFR and were only accurate 25% of the time. Increasing sample size may improve the apparent accuracy rates for each of these measures, but likely not to a level that would be clinically accept-able. The data from this study are also consistent with the data from numerous other studies showing a lack of correla-tion of true GFR with creatinine based estimations.4 Clinical bottom line: So then, what degree of accuracy do we need to achieve in measuring the GFR in fol-low-up among living kidney donors? Does it make a difference? In patients with measurements on both ends of the spectrum, either completely normal or with advanced disease, achieving precision in GFR estimations to within less than 10% may not have clinical importance, that is, glomerular fi ltration rates of 110 vs. 95 ml/min/1.73 m2 and rates of 15 vs. 12 ml/ min/1.73 m2 while differing by more than 10% probably do not change clinical management or prognosis. The population likely to be affected most are those in the mid-dle, where determining the pres-ence or absence of chronic kidney disease is likely to have fundamen-tal importance in terms of monitoring function and reducing CKD specifi c comorbidities. Small inaccuracies in measurements could signifi cantly impact who is classified as having chronic kidney disease, as well as therapeutic targets, drug dosing, and availability of imaging studies. Inaccurate estimations of GFR may also lead to incorrect con-clusions with respect to the safety and suitability of living kidney donation. Clinicians must be cautious about making assumptions based on these measures. Future research is needed to identify other non-invasive practi-cal ways of accurately measuring renal function longitudinally in this patient population. Citation: Franz S, Regeniter A, Hopfer H, Mihatsch M, Dickenmann M. Tubular toxicity in sirolimus- and cyclosporine-based transplant immunosuppression strategies: an ancillary study from a ran-domized controlled trial. Am J Kidney Dis. 2010;55:335–343. Analysis: Sirolimus, an mTOR inhibitor, has been favored as a less nephrotoxic immunosuppression agent for organ transplantation when compared with the calcineurin inhibitors (CNI). However, sirolimus is increasingly recognized for its proteinuric side-effect in renal allografts, ranging from low grade proteinuria to nephrotic range proteinuria. Franz and colleagues compared biomark-ers of tubular and glomerular damage comparing sirolimus and cyclosporine to determine whether the proteinuria and other evidence of renal injury were due principally to glomerular, tubular, or interstitial lesions. In the current study, all cadav-eric and living donor kidney transplant patients at the University Hospital in Basel, Switzerland, between January 2001 and July 2004 who were screened for an ancillary study of a prospec-tive single-center, randomized, open-label trial comparing sirolimmus (SRL) and cyclosporine (CsA) were included. 172 patients (Cadaveric; n = 58) were randomly assigned before transplants to immunosuppression ther-apy with either SRL (n = 64) or CsA (n = 63), plus myconphenolate mofetil (MMF) and steroids. Transplants from HLA-identical donors or recipients with PRA > 25% or graft loss due to rejec-tion within the prior 3 years, or with ABO-incompatibility, or with kidneys from donor >68 years, or with cold ischemia time >36 hours were excluded from the study. The primary outcome was the eval-uation of kidney function by eGFR. Secondary outcomes included patient and graft survival, number of rejec-tions, and evidence of site specifi c kid-ney damage as assessed by glomerular and tubular urine biomarker. Urine and serum were collected at 0, 7, 30, and 90 days after transplants. Kidney function was estimated using serum creatinine, and urinary biomarkers including α 1-microglobulin and retinol-binding protein (proximal tubular damage), transferrin and albumin (glomerular damage) and a semi-quantitative assessment of glucosuria at various time points. Protocol kidney biopsies were performed at 90 and 180 days post-transplant. Kidney function by eGFR was sim-ilar in both groups, whereas levels of biomarkers associated with glomerular damage and of tubular damage were higher beginning at day 7 in the SRL group, and through 90 days post-trans-plant. The incidence of glucoseuria, associated with tubular dysfunction, was also higher in SRL group beginning by 30 days post-transplant. By histologi-cal examination, the overall severity of tubular lesions was signifi cantly higher in the SRL group. The prevalence of Banff IA/B histology and peritubular capillary C4d staining was signifi cantly higher in SRL group. The authors concluded that their SRL-based regimen was associated with de novo low-grade glomerular protein-uria, increased excretion of biomark-ers associated with proximal tubular and glomerular damage, and evidence of tubular damage on kidney biopsy, when compared with their CsA-based regimen in kidney transplant patients. Subclinical rejection was also higher in the SRL group. Validity and threats to validity: This is a robust prospective randomized clinical study in which bias and threats to validity were minimized by the study design. The risks of an ascertainment bias or a measurement bias were mini-mized since serum creatinine, urinary biomarkers, and protocol biopsies that were prospectively collected in all study patients. The limitations of the study include the small sample size and the relatively short duration of follow-up. The follow-up may not have been long enough to see beneficial or unwanted effects of either SRL or CsA, espe-cially related to eGFR. Additionally, the paper by Tan et al. reviewed above would suggest that eGFR determined from a creatinine clearance might not have accurately identified patients with depressed renal function.5 In addition, the baseline data of urinary biomark-ers were not available in all patients. Furthermore, the pathologist reviewing the transplant kidney biopsies were not masked to group allocation allowing for some potential bias in the interpretation of the biopsies. Application of results and clinical bottom line: This study demonstrated that the proteinuric effect of SRL may be due to proximal tubular damage ini-tially and reversible in the early stage. In addition, others have shown that SRL can cause podocyte dysfunction pos-sibly either via a decrease in vascular endothelial growth factor (VEGF) or through the dysregulation of mTOR signaling importance for the normal maintenance of human podocyte differ-entiation. These effects are thought to lead to a de novo form of focal segmen-tal glomerulosclerosis, most typically recognized in patients with high SRL levels whether they received SRL at the time of transplant or are later switched to SRL.6 Clinical predictors of protein-uria after conversion to SRL have also been reported.7 Proteinuria after kidney transplantation has been associated with poor graft survival.8 Therefore, “CNI sparing” regimen with SRL to avoid nephrotoxicity may not be truly benign due to SRL's nephrotoxicity that is by a different mechanism from the nephro-toxicity seen with the CNIs. This study supports the view that the use of SRL in kidney transplants should be re-evaluated carefully and that the patients already on SRL-based regimens should be monitored for the development of proteinuria and proxi-mal tubular damage. One approach sup-ported by the results of this study would reserve SRL for use with those kidney transplant patients who do not tolerate other immunosuppressive regimens. On the other hand, one might consider halt-ing the use of SRL more judiciously in those patients successfully maintained on SRL since in this study patients on SRL with proteinuria did not show more rapid progression in their renal dysfunc-tion when measured by creatinine clear-ance compared to patients on CNIs. Finally when considering applica-bility, the demographic characteristic in the study such as ethnicity and causes of CKD may be different from the transplant population in U.S. and this might affect the impact of SRL on U.S. transplant patients. Citation: Fishbane S, Delmez J, Suki WN, et al. A randomized, parallel, open-label study to compare once-daily sevelamer carbonate powder dosing with thrice-daily sevelamer hydro-chloride tablet dosing in CKD patients on hemodialysis. Am J Kidney Dis. 2010;55:307–315. Analysis: The holy grail of phos-phate binder therapy for ESRD patients would be an agent that is entirely non-absorbed, can be taken once daily with a persistent PO4 binding effectiveness, and is well tolerated without signifi cant side-effects. In an earlier crossover study trial by Fisher and co-workers, sevelam-er carbonate (Renvela) in a once-daily dose appeared well tolerated and as effective for some patients (but maybe not all) as thrice-daily sevelamer hydro-chloride (Renagel).9 This study was not sufficiently powered nor designed to determine if, in general, the two dosing regimens were equivalent. The current study by Fishbane and colleagues was designed to determine if once-daily sevelamer carbonate was as effective or more precisely, not infe-rior to thrice-daily dosing in control-ling serum PO4 for dialysis patients in general. The study was a randomized controlled non-inferiority trial where patients were assigned in a ratio of 2:1 to sevelamer carbonate once-daily versus thrice-daily sevelamer hydro-chloride and followed for 24 weeks (6 months). In such a study, investiga-tors predefine a threshold for the dif-ference in effectiveness beyond which one would no longer claim that the new therapy was not inferior to the compara-tor (standard therapy). Frequently, this threshold is defined statistically in terms of the standard deviation (SD) or sometimes twice the SD. If either the standard deviation or confi dence interval around the estimate of standard treatment effect is large, relying strictly on the SD can result in the demonstra-tion of non-inferiority when in practical clinical terms this may not be the case. In the current study, the authors chose to define the threshold conserva-tively as a difference of greater than 1 mg/dL change in PO4 beyond the upper bounds of the confidence interval. By this criteria, for the dialysis population repre-sented by the participants in this study, once-daily sevelamer given with the larg-est meal of the day did not perform as well as thrice-daily sevelamer given with meals in lowering serum PO4. While once-daily dosing of sevelam-er carbonate powder was not quite as good in lowering serum PO4 to target as thrice-daily dosing of Renagel; neverthe-less, a significant improvement in PO4 was demonstrated even in those patients assigned to the once-daily PO4 binder regimen. Serum PO4 levels declined by 1.9 + 1.7 mg/dL from a pretreatment PO4 level of 7.3 + 1.4 mg/dL to 5.4 +1.4 mg/dL in the intention to treat analysis. 54% of those on the once-daily dosing achieved the KDIQI recommended PO4 target of 3.5 to 5.5 mg/dL (versus 64% on customary care). Furthermore, adverse gastrointestinal side-effects, the most commonly reported side-effect in clinical trials with any PO4 binder, occurred in only 22.7% of patients on once-daily dosing at a level commensu-rate with other phosphate binders evalu-ated in clinical trials.10 Validity and threats to validity: The study by Fishbane and colleagues is a well designed study that was designed, conducted, and reported as a non-inferiority trial. This latter characteristic is important to consider. In a non-inferiority trial, the null hypothesis is that a difference exists when in truth one does not. This is opposite to the statistical assumption governing the tra-ditional RCT study that is designed to demonstrate that one therapy is superior to another, where the null hypothesis is that, in truth, the two therapies are iden-tical. These differing assumptions about the underlying hypothesis lead to dif-ferences in the statistical tests for error. Additionally, a non-inferiority trial of long duration ideally will evaluate whether the pre-determined threshold is achieved as various points during the trial, thus, requiring a statistical “cost” for each predetermined statistical evalu-ation. Traditional RCT's are sometimes reported as non-inferiority trials even though they were not designed as such. When this occurs the conclusions about non-inferiority are suspect. The CONSORT criteria on non-inferiority trials emphasize the impor-tance of complete follow-up.11 In the current study, follow-up in the per-pro-tocol analysis was less than optimal. Fortunately, the intention-to-treat analy-sis which included a much higher per-centage of the originally allocated par-ticipants demonstrated similar results to the per-protocol analysis. Additionally, when evaluating for harm (e.g. side effects and tolerability) the per-protocol analysis is generally thought to be supe-rior, as harm is generally more likely to occur with exposure. Clinical bottom line: The study by Fishbane and colleagues demonstrates that once-daily Renvela does not con-trol PO4 as well as thrice-daily Renagel in some patients. However, for a large fraction of patients once-daily dosing is effective in achieving the KDOQI serum PO4 target. This study is too short in duration to address the issue of the impact of these alternative treatment strategies on patient-centered outcomes such as cardiovascular progression, major GI events, or mortality. Nor does this study address whether an interme-diate dosing schedule of twice daily powder versus thrice-daily sevelamer might be equally effective. Each of these questions will require additional clinical trials. Ad Index Fresenius Medical Care…………………............….C4 Fresenius Renal Pharmaceuticals………........251-253 Genzyme Corp.……..………………….....……C2-221 Rockwell Medical Technologies, Inc.......….........223,230-231,257 Shire/Fosrenol………….....………………….237,238266 Dialysis & Transplantation June 2010

Dialysis is a fast-moving field and new, important studies come out each month. When you understand some of these common research terms, you'll be better equipped to know what the results may mean for your patients.

Dialysis & TransplantationVolume 39, Issue 7 p. L143-L150 Home Dialysis CentralFree Access A how-to manual: The art of teaching buttonhole self-cannulation Stuart Mott, Stuart Mott Vascular Access Nurse Columbia, MOSearch for more papers by this author Stuart Mott, Stuart Mott Vascular Access Nurse Columbia, MOSearch for more papers by this author First published: 21 July 2010 https://doi.org/10.1002/dat.20458AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Hakim R, Himmelfarb J. Hemodialysis access failure: A call to action. Kidney Int. 54(4), 1029–1040, 1998. 2 Huber T. S., Carter J. W., Carter R. L., & Seeger J. M.. Patency of autogenous and polytetrafluoroethylene upper extremity arte riovenous hemodialysis accesses: A systematic review. J Vasc Surg. 38(5): 1005–1011, 2003. 3 Mehta S. Statistical summary of clinical results of vascular access procedures for hemodialysis. In Vascular Access for Hemodialysis, ed B Sommers and M. Henry, pp. 145–157, Precept Press Chicago, IL, 1991. 4 Perera G. B., Mueller M. P., Kubaska S. M., Wilson S. E., Lawrence P. F., & Fujitani R. M. Superiority of autogenous arterio venous hemodialysis access: Maintenance of function with fewer Secondary interventions. Ann Vasc Surg. 18, 66–73, 2004. 5 Poisoni R. L., Young E. W., Dykstra D. M., Greenwood R. N., Hecking, E., Gillespie, B., et al. Vascular access use in Europe and the United States: Results from DOPPS. Kidney Int. 61(1): 305316, 2002. 6 National Kidney Foundation (NKF). KDOQI clinical practice recommendations for 2006 Updates: Hemodialysis adequacy, peritoneal dialysis adequacy and vascular access. Am J Kidney Dis. 48(suppl 1), S1–S322, 2006. 7 Verhallen AM, Kooistra MP, van Jaarsveld BC. Cannulating in hemodialysis: rope-ladder or buttonhole technique? Nephrol Dial Transplant 22(9): 2601–2604, 2007. 8 Ball LK. The buttonhole technique for arteriovenous fistula can nulation. Nephrol Nurs J. 33(3): 299–304, 2006. 9 DaVita Rope ladder and constant site or buttonhole technique -Cannulation methods for hemodialysis patients with a fistula, 2007. Retrieved May 9, 2009, from www.davita.com/dialysis/treatment/a/1332. 10 Figuerido AE, Viegas A, Monteiro M, Poli-de-Figueiredo CE. Research into pain perception with arteriovenous fistula (avf) cannulation. J Ren Care. 34(4): 169–72, 2008. 11 Van Loon MM, Goovaerts T, Kessels AG, van der Sande FM, Tordoir JH. Buttonhole needling of hemodialysis arteriovenous fistulae results in less complications and interventions compared to the rope ladder technique. Nephrol Dial Transplant. 2009 Sep 4 [Epub ahead of print]. 12 National Kidney Foundation: KDOQI Clinical Practice Guidelines for Hemodialysis Adequacy, 2000. Am J Kidney Dis 37: S7–S64, 2001 (suppl 1) 13 Core Curriculum for the Dialysis Technician: A Comprehensive Review of Hemodialysis. Fourth Edition. Module 5, Vascular Access. Editors: Ball Lynda, Dillon Tim, Dinwiddie Lesley, Holland Janet E. 2008 Amgen Inc. Developed by the Medical Education Institute. Available for free in PDF form from http://www.meiresearch.org. 14 Mott S, Moore H. Using ‘Tandem hand’ technique to facilitate self-cannulation in hemodialysis. Nephrol Nurs J. 36(3): 313–3166, 2009. 15 Mott S, Prowant BF. The “touch cannulation” technique for hemodialysis. Nephrol Nurs J. 35(1): 65–66, 2008. 16 Twardowski Z, Kubara H. Different sites versus constant sites of needle insertion into arteriovenous fistula for treatment by repeated dialysis. Dial Transplant 8: 978–80, 1979. 17 Toma S, Shinzato T, Fukui H, Nakai S, Miwa M, Takai I, Maeda K. A timesaving method to create a fixed puncture route for the buttonhole technique. Nephrol Dial Transplant. 18(10): 2118–2121, 2003. 18 Marticorena RM, Hunter J, Cook R, Kashani M, Delacruz J, Petershofer E, Macleod S, Dacouris N, McFarlane PA, Don nelly SM, Goldstein MB. A simple method to create buttonhole cannulation tracks in a busy hemodialysis unit. Hemodial Int. Jul; 13(3): 316–321, 2009. Volume39, Issue7July 2010Pages L143-L150 ReferencesRelatedInformation

As our awareness of chronic kidney disease (CKD) rolls over into a new era of bundling, improved treatment options, and medicinal choices, so our knowledge of nutrition and its impact on disease management also evolves. For decades, vegetarianism and kidney disease has been seen as an oil-and-water amalgamation. Dietitians have been challenged to align diet recommendations with vegetarian-type diets. Dietitians may struggle with concerns that more plant-based diets would be lacking in protein or would be high potassium and phosphorus. However, just as we have advanced in our understanding of so many aspects of kidney disease, we can now appreciate that a plant-based diet can work to our patient's advantage and, by learning these advantages, feel more comfortable with working these foods into patient meal planning. Although studies are small, several support the idea that plant-based diets can delay the progression of CKD, provide endothelial protection, control high blood pressure, and decrease proteinuria.1-10 These days, our dialysis patients seldom die secondary to high potassium or uremia. Many of our patients now face the same diseases as the general population: heart disease, cancer, and strokes.11 A plant-based diet provides nutrients that not only assist in kidney disease management but also can provide an edge of protection against costly, debilitating complications.8 It is now well documented that a plant-based diet can provide as high a quality protein diet as one that is animal based. In 1989 the International Food and Agriculture Organization (FAO), the World Health Organization (WHO), and the United Sates Department of Agriculture (USDA) adopted the Protein Digestibility-Corrected Amino Acid Score (PDCAAS) as the official assay for evaluation of protein quality.12 The PDCAAS takes into account a protein's essential amino acid composition corrected for digestibility and referenced to a 2- to 5-year old human requirement. This new method of evaluating protein quality found that many plant proteins provide high-quality protein suitable to meet adult requirements. Although animal proteins are lower in phosphorus when compared with plant-based proteins, the phosphate in plant proteins is only 50% bioavailable, compared with animal protein, including milk and cheese, which is estimated to be 70% bioavailable. This occurs because many plant-based proteins are high in phytates, which bind phosphorus and prevent its absorption.13 In general, the potassium-to-protein ratio (mEq to mg) in legumes is higher (∼7:7) than equal amounts of protein from animal meats (∼4:7). Legumes have the advantage that they contain other nutrients that can be of benefit to patients. Through planning and education, legumes can be safely included in the renal diet. For those patients with potassium concerns, higher potassium plant proteins such as seitan or tofu can be replaced with nuts or soy beans. Specific dried cooked beans higher in potassium content can be replaced with lower potassium choices. Examples include navy or soybeans being replaced with lower potassium beans such as lima or black-eyed peas. If the patient is on hemodialysis, lower dialysate potassium concentrations may also be an option. Plant proteins offer meals with whole grains, dried cooked beans, soy, nuts and seeds, and wheat gluten—all of which can add variety and taste to a patient's diet. Often, patients complain about diminished taste for meats. Plant proteins offer options that may be more tolerable for taste preferences. Tofu can adopt the flavor of other foods and seasonings as well. Patients with CKD are prone to an increase in advanced glycation end products (AGEs) .14, 15 An increase in proinflammatory cytokines occurs.16 Renal patients are at increased risk for inflammatory diseases such as cardiovascular disease, atherosclerosis, and stroke. Plant-based diets are a source of anti-inflammatory components, and can play a role in combating this inflammation.16 The oxygen radical absorbance capacity (ORAC) measure was developed by the National Institutes of Health in the early 1990 s. The ORAC score is a measurement of the antioxidant capacity of food. The higher the ORAC, the more a food has the capacity to neutralize free radicals.17 Many fruits and vegetables have high ORAC scores, but may be limited in a CKD diet due to potassium content. However, the diet can be designed to include high ORAC foods while remaining within potassium guidelines. Items with a high ORAC include such foods as blueberries, blackberries, broccoli and cabbage, and several herbs and spices like cinnamon, rosemary, tumeric, and pepper. Animal proteins are sources of saturated fat and have been associated with vascular diseases. Plant proteins are low in total fat and offer monounsaturated and polyunsaturated fats, which have been associated with cardioprotection. In addition, all animal products are devoid of fiber and the phytochemicals known to be protective to the vascular system.18 One cup of whole grain rice adds 3.5 g of fiber and 5 g protein and no fat.; ½ cup of dried cooked kidney beans adds 11 g of fiber and 7.5 g of protein, and no fat. An average ounce of meat contains 7 g of protein, no fiber, and up to 9 g of saturated fat. Medications, stress, and disease affect the gut flora. Since an estimated 70% of immunity occurs in the digestive tract, gut flora are important.19 A plant-based diet promotes digestive tract health by promoting butyrate-producing bacteria, which are important in maintaining epithelial cell health.20 Plant-based diets are naturally high in the pre-biotics that are required for pro-biotic formation. Research has also found that vegetarians tend to have higher production of the metabolite equol, which increases absorption of the isoflavone daidzein found in soy.21 It is speculated that increasing plant-based foods improves equol production through the benefits of the isoflavone content of soy. Soy has been associated with many benefits in kidney disease, including cardiovascular protection, decreased proteinuria, and cancer prevention.9 In a poll conducted by the Vegetarian Resource Group in 2009, it was found that 3% of American adults did not eat red meat, fish, or poultry, and a third of those did not eat dairy, eggs, or honey. The same survey found that 8% of American adults did not eat red meat. As a result, the chances of having a patient who chooses to eat vegetarian based on preference may be low, and a dietician may choose to encourage plant-based options for beneficial health reasons. This includes preventing the co-morbid conditions associated with kidney disease, kidney disease progression, or possibly kidney disease itself. Add ½ cup dried cooked beans to a meal per day. This can be added to a salad or soup or mixed into a pasta. Sprinkle ¼ cup nuts on salad or in cereal. Try high-protein grains such as quinoa, amaranth, or barley (see below). Use tofu in place of cream cheese or ricotta cheese in recipes, such as a lasagna. Replace regular milk with an organic soymilk. Make a smoothie (see recipe below). Try seitan, a high-protein alternative with a meaty taste. It can be replaced in any meat dish or sliced in sandwiches. See recipe below. Add one low-potassium, high-ORAC value food per day such as blueberries, cranberries, raspberries, or strawberries. If potassium restriction is not needed, encourage up to nine servings of fruits and vegetables per day. Add two or more healthier herbs to food every day, such as rosemary, garlic, oregano, turmeric, or sage. Encourage color. Many low-potassium fruits and vegetables are high in antioxidants (i.e., cabbage, beets, carrots, broccoli, peppers, yellow and green zucchini, green peas, broccoli, and cauliflower).

Hemodialysis today has evolved into a highly technical treatment in which knowledge of the physics and chemistry of the dialysis treatment system as well as knowledge of individual patient's pathology allows for a better understanding of how the treatment is best performed and individually modified. The “treatment prescription” is a set of specific treatment parameters that includes the treatment duration and frequency, the choice of dialyzer, and the specifics of the dialysate composition. It is imperative that the nephrologist understand how to deliver the most optimal treatment that is additionally the most cost effective. In short, hemodialysis is the process by which a patient's blood can be chemically modified by driving it through a device (dialyzer) that allows for the removal of substances (blood solutes) as well as the gain of substances (dialysate solutes) with the additional option of the simultaneous removal of plasma water. It has evolved for almost a century but remains dependent on the chemical properties of a semipermeable membrane that is selective to the movement of solute and resistive to the movement of solvent. The primary purpose of dialysis is to eliminate uremic poisons in patients with end-stage renal disease and to modify serum electrolytes so as to mimic the appropriate serum composition of healthy individuals. A dialyzer can be classified based on properties of the chemical composition of its membrane or based on its properties of solute removal (most commonly urea removal) and solvent permeability (most commonly water, termed hydraulic permeability) under specific operating conditions (blood flow rate [QB in mL/min] and dialysate flow rate [QD in mL/min]). Some dialyzers are more efficient at solute removal and are termed high-efficiency, whereas other dialyzers have lesser resistance to water movement and are termed high-flux. Dialyzer membrane properties have been recently reviewed.1 in which the dialyzer's ability to remove a solute K is proportional to the product of the mass transfer coefficient of that dialyzer's membrane (Ko) and the membrane surface area (A). KoA is specific to a particular solute (such as urea) and is independent of QB and QD (assumption of the model). The KoA of a particular dialyzer is provided by the manufacturer, is determined in vitro in aqueous solutions, and usually overestimates by about 20% when compared with in vivo blood-based solutions containing proteins and red blood cells. It is difficult to fully appreciate the relationships among KoA, QB, and QD. Figure 1 presents these relationships graphically, depicting urea clearance K as a function of QB for a dialyzer KoA of 1,000 and three separate QDs of 1,000, 500, and 400 mL/min (from the top curve down). Dialysis clearance equation. K versus QB for QD = 1,000, 500, 400 [KoA = 1,000]. At lower QBs, the clearance (K) is linear with QD, but as QB increases closer to QD, there is a diminishing benefit of increasing QB further (as QD becomes clearance limiting). Many insights can be obtained by an analysis of the clearance equation. Table I illustrates the effects on the overall clearance of urea of changing a number of parameters. The first observation is that the overall clearance is simply determined by the lowest of the three parameters KoA, QB, and QD. Most high-efficiency, high-flux dialyzers have a KoA for urea of 1,000–2,000. Since QDs are typically in the range of 600–800 mL/min Dialyzer membrane properties have it is the lowest parameter, QB (typically in the range of 400–500 mL/min) that determines the overall clearance K. In fact, the more general observation is that clearance becomes limited as QB approaches either QD or KoA. Additionally, if the magnitude of both QD and KoA are close to QB, QB is even further diminished. There are practical ramifications of these observations. One lesson is that in this current era of bundling and small financial margins, it makes sense not to spend resources on dialyzers that have excessively high KoAs in that their benefit will be minimized by the QB, which is, in turn, limited by access flow and needle resistance limitations. In general, KoAs in excess of 1,000 are of marginal benefit. An additional lesson is that with daily hemodialysis methodologies that have reduced QDs of 150 mL/min (for example, NxStage) or continuous veno-venous hemodialysis (CVVHD) techniques with QDs of 50–100 mL/min, there is no reason to employ higher QBs or to use large dialyzers, as K will be limited by QD. Another example of an even greater waste of financial resources is the use of two dialyzers simultaneously, combined either in-parallel (Figure 2A) or in-series (Figure 2B) to effectively increase KoA. A) Operational configuration of 2 dialyzers placed in-parallel; B) Operational configuration of 2 dialyzers placed in-series. Reprinted from AJKD (reference 7), copyright 2003, with permission from Elsevier. Table II illustrates the overall effect on clearance by use of these configurations. Although a theoretical added clearance of about 14–15% can be achieved, the total dialysis treatment “dose” can often be obtained more cost effectively by simply extending the dialysis treatment time using a single dialyzer by an additional 15–30 minutes with a minimal added cost of dialysate consumption! To employ the other configurations, additional connectors must also be purchased, increasing the costs associated with the treatment. Additionally, these configurations also result in greater dialysis disequilibrium (faster rate of solute removal, which is proportional to K/V); depending on the methodology of the urea kinetic modeling utilized, this can lead to greater overestimation of solute removal and a false sense of security that enough dialysis is being performed. The sigma (σ) relates to the permeability of the dialysis membrane to a particular solute. This equation is the equation of a straight line, and if one experimentally measures the clearance of a molecule as a function of ultrafiltration rate, QF in mL/min, the σ and KoA can be determined from the slope (1 − σ)and the intercept (KoA).3 Doing this for the clearance of vancomycin (molecular weight of 1,486) for a specific dialyzer (Fresenius F80) results in the determination of σ of 0.9 and a KoA of 20. Graphing the clearance (here defined as D′) of vancomycin as a function of QB and QF (Figure 3) demonstrates that it is removed more effectively with lower QBs and higher QFs. K vs QB [QF = 20 − 100] [σ = 0.9, K0A = 20, QD = 500]. From reference 3. For larger solutes cleared by convection, the greater the time of the dialysis membrane exposure (slower QB) and the greater the pressure gradient across the dialyzer membrane (higher QF), the greater the clearance. The opposite of this is true as well. For example, to minimize vancomycin clearance, faster QBs and smaller QFs will clear less of the antibiotic for a given dialysis prescription. As a result of dialysis being performed in a in-parallel fashion, there is the generation of both an access recirculation (AR) and a cardiopulmonary recirculation (CPR). The dialyzer operating in-parallel with the peripheral access results in AR, and the peripheral access operating in-parallel with the systemic venous circulation results in CPR (Figure 4). Origin of AR and CPR as depicted by parallel blood flows from dialyzer to access, and access to the systemic circulation. AR and CPR effectively prevent the dialyzer from actually receiving blood with systemic concentrations of solute; instead, a “diluted” sampling of systemic venous blood with solute cleared blood is received (Figure 5). (The extraction efficiency of a dialyzer is proportional to the incident concentration of the solute to be removed). The mathematics of these effects has been worked out by Schneditz et al.4 As a consequence, the actual removal of solute is not only based on the dialysis treatment prescription but is also dependent on patient specific parameters that include cardiac output and venous flow through the peripheral access. Reduced efficiency from AR adn CPR results from blood effectively cleared of urea nitrogen by dialysis being mixed with blood with high urea nitrogen from its primary source (skeletal muscle tissue). This mixing reduces the concentration of urea nitrogen returning back to the central venous compartment and leads to reduced urea nitrogen concentration in the blood incident to the dialyzer. Another barrier to our effectively eliminating urea from a patient's body results from the fact that the storage of urea occurs primarily in the skeletal muscle and its removal may depend on the vascular “communication” of this compartment with the central venous system. This provides one theory of why exercise during dialysis improves the quality of urea removal: it allows for greater vascular flow (improved communication) with the skeletal compartment and a subsequent higher central venous concentration of urea. Table III illustrates a comparison between two patients with an identical extracorporeal dialysis treatment prescription but different cardiac output and access flows. Patient A is relatively healthy with a normal cardiac output and no significant access pathology. Patient B has mild anemia, a cardiomyopathy, and poorly functioning access flow. Ultimately, patient B receives 30% less dialysis in spite of having the same identical treatment prescription. The lesson here is that the actual delivered amount of dialysis can be significantly less than the theoretically prescribed dialysis. Flow recirculations (AR and CPR) and a patient's individual physiology (urea trapping in skeletal muscle and cardiac output) and access health result in a delivered clearance dependent on factors out of our prescriptive control. Careful consideration of a patient's cardiac status and access health may indicate a need for additional clearance beyond that predicted by an a simple analysis of his or her urea kinetic modeling. Dialysis machines employ a proportioning system that mixes an acid concentrate with a bicarbonate concentrate and purified water. This allows for the generation of a dialysate with a physiologic pH and minimizes the possibility of forming a precipitate between bicarbonate containing alkaline solutions and calcium. The acid concentrate contains dextrose and is the source of electrolytes including potassium, calcium, magnesium, and acetic (or citric) acid. The bicarbonate concentrate may contain sodium chloride as well as sodium bicarbonate (36.83 × ) or may contain only sodium bicarbonate (35 × /45 × ). The nomenclature of the commonly used Fresenius 45x system is derived from the fact that the proportioning system mixes 1 part acid concentrate to 1.72 parts bicarbonate concentrate to 42.28 parts water, which adds up to 45 “parts.” It is important to understand that modifying the prescription for sodium or bicarbonate in real time during rounding will alter all electrolyte concentrations of the dialysate solution. Most current equipment will show the effects of changing the dialysate proportioning in real time. It is also of importance that the total buffer in this system include bicarbonate as well as acetate (or citrate), which can add an additional 2.0–8.0 mEq/L buffer. If one prescribes a dialysate bicarbonate delivery of 35 mEq/L, the total delivered buffer will be the sum of the bicarbonate and the acetate (or citrate) from the acid concentrate (which is metabolized to bicarbonate in the liver). Therefore, the total delivered base (TDB) to a patient has to include consideration of both bicarbonate and acetate (or citrate) buffers. Consequently, on longer dialysis treatments using high bicarbonate concentrations (40 mEq/L), we can induce a chronic metabolic alkalosis, which can have adverse effects on patient mortality (based on mortality data obtained by several large dialysis providers). High dialysate sodium concentrations can lead to sodium loading, increased thirst, and subsequent high weight gains and hypertension. A chronic state of volume overload and hypertension ultimately leads to left ventricular hypertrophy and cardiac dysfunction. Sodium is removed from the patient both by ultrafiltration (for patients with large weight gains) and by diffusion. Consequently, the total fluid removed as well as the sodium gradient between the patient and the dialysate at the initiation of the treatment are both critical factors. It has been suggested that individualizing the dialysis sodium concentration to be slightly less than a patient's historic sodium concentration may be the best way to prevent sodium loading.5 Much controversy exists over the optimal calcium concentrations in dialysate. A concern exists that calcium loading may be harmful to patients and that many hemodialysis patients are constantly exposed to a state of positive calcium balance between the oral ingestion of calcium in foods and binders as well as from a positive calcium influx from the dialysate. This positive calcium balance may contribute to calcium deposition in arterial vessels and heart valves. A recent mathematical analysis of this issue by Gotch et al.6 suggests that dialysate concentrations below 2.5 mEq/L may be necessary to limit calcium influx from the dialysate. One assumes that if the hemodialysis machine is set appropriately with the correct concentrates, then the dialysate composition delivered to each dialyzer is exactly as prescribed. Unfortunately, a number of variables can affect the proportioning system, one being the inlet pressure of the dialysis concentrates and water entering into the dialysis machine. Depending on the open or closed loop nature of the distribution system, inlet pressures to the machines can significantly vary even by position within the loop. To promote a more consistent pressure, a gravity feed system is often utilized. Perhaps one of the most significant aspects of the quality assessment of each dialysis facility is to ensure the correct dialysate delivery to each patient's dialyzer by sampling dialysate at the first and last chair of each distribution loop. Most dialysis specialty labs can measure electrolytes on non-blood samples and provide this as a safety check.

Citation: Vincenti F, Blancho G, Durrbach A, et al. Five-year safety and efficacy of belatacept in renal transplantation. J Am Soc Nephrol. 2010;21: 1587–1596. Analysis: Belatacept is a co-stimulation blocker that binds CD80/CD86 on antigen-presenting cells preventing T-cell activation, a new class of therapeutic agents in transplantation immunosuppression that differs from existing immunosuppressive agents. It is a recombinant soluble fusion protein consisting of the extracellular domain of human CTLA-4 and a fragment (hinge–CH2–CH3 domains) of a modified Fc domain of human IgG1. It is given intravenously.1 The primary aim of the current study was to assess the safety and tolerability of long-term belatacept administration in kidney transplant patients. The secondary aim was to assess the efficacy of belatacept as a long-term maintenance immunosuppressant. Pharmacokinetic and pharmacodynamic properties of the belatacept and anti-belatacept antibody generation were also investigated. The current study extends the observations reported from a randomized multicenter Phase 2 clinical study of 218 patients conducted in the U.S., Canada, and Europe that demonstrated non-inferiority of belatacept for safety and efficacy (allograft preservation) with better preservation of the glomerular filtration rate (GFR) at 12 months when compared with cyclosporine (CsA).2 In the original study, patients were randomly assigned in equal numbers of three groups to receive a more intensive or less intensive regimen of belatacept, or CsA. All patients received induction therapy with basiliximab and adjuvant therapy with mycophenolate mofetil and corticosteroids for 12 months after transplant. This paper by Vincenti and colleagues reports on the results of the extension of the first randomized clinical trials to assess long-term safety and efficacy of belatacept over 5 years compared with conventional therapy with CsA. The data cutoff date occurred 6 years and 7 months after the initiation of the original trial. One-hundred twentyeight patients consented to continue in the extension trial and were kept on the original maintenance treatment arms: CsA or belatacept (5 mg/kg at 4- or 8-week intervals); 56 belacept recipients received 4-week dosing, and 46 received 8-week dosing; 78 of 102 patients receiving belatacept and 16 of 26 receiving CsA completed the 5 year extension of the trial. Renal function was stable in belatacept patients with average calculated GFR was 75.8 ml/min per 1.73 m2 at 12 months and 77.2 ml/min per 1.73 m2 at 60 months post-transplantation. GFR was similar for patients on either 4- or 8-week belatacept dosing. In the CsA group, GFR decreased significantly from 74.4 ml/min per 1.73 m2 at 12 months to 59.3 ml/min per 1.73 m2 at 60 months post-transplantation. Incidences of graft loss or death were low. There were 6 cases of biopsyproven acute rejection (BPAR) in the belatacept group (2 cases in 4-week dosing during year 2, and 4 cases in 8-week dosing in years 2, 3, 4, and 5). In the CsA extension arm there were no BPAR cases, however, 3 cases were treated for acute rejection (AR) on the basis of clinical findings. Overall, BPAR was uncommon in the years following the initial RCT and no BPAR cases in the belatacept group led to graft loss. At 60 months post-transplant, 86% of patients in the belatacept group and 89% in the CsA group required antihypertensives, and 52% of the belatacept group and 72% of the CsA required lipid-lowering agents. Serious infections were seen in 16% of the belatacept group and 27% in the CsA group. Cytomegalovirus (CMV) and BK polyomavirus infection were rare in both groups. The frequencies for CMV infection were 1% in the belatacept and 4% in the CsA group. Two percent of the belatacept recipients but no CsA recipients developed BK polyomavirus infection. During the extension of the original RCT, no patient in the belatacept group but 1 patient in the CsA group developed post-transplantation lymphoproliferative disorder (PTLD). Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic studies from a subset of belatacept study subjects showed consistent exposure to belatacept over time. Safety and efficacy were similar between the 4- and 8-week dosing groups, except for a higher incidence of AR with the 8- week dosing schedule. Mean half-life of belatacept was 8 days with a predictable decline in the levels over time and little inter-patient variability. Two belatacept-treated patients developed neutralizing antibodies. CD86 receptor saturation was higher in the 4-week schedule than the 8-week schedule patients (74% versus 56%). Validity and threats to validity: This study is an extension of open label RCT, prospectively randomized (with masked allocation) multicenter clinical study in which bias and threats to validity were addressed by the randomization procedure, masked allocation and masked adjudication of outcomes. The patients, however, who entered the long-term extension trial were selfselected and were generally those who did particularly well during the RCT phase of the study prior to entrance into the long-term extension study. The average GFR of the study subjects continuing into the extended phase trial at the time of extension study entrance was higher than that observed in patients who did not enter the long-term extension phase; 75.8 versus 69.5 ml/min per 1.73 m2 for belatacept and 74.4 versus 67.4 ml/min per 1.73 m2 for CsA. In addition, a higher percentage of belatacept recipients remained in the long-term extension trial (76% versus 62% for CsA). Both of these potentially introduce a selection bias into the study and may have distorted the results of the extension phase trial. The limitation of the study also includes small sample size and relatively “short” duration of follow-up (5 years). This follow-up period is not long enough to observe the full longterm effects of belatacept on the occurrence of chronic allograft nephropathy. Another potential limitation is that this study used CsA rather than tacrolimus as the primary calcineurin inhibitor for comparison to belatacept where the latter is now the preferred calcineurin inhibitor in many centers. Clinical bottom line: Belatacept may be an alternative to calcineurin inhibitors because of the observed superior preservation renal function, and possible improvement of long-term outcomes. Calcineurin inhibitors are associated with non-immunologic untoward side effects including worsening of hypertension, diabetes, and dyslipidemia that can negatively impact on cardiovascular morbidity and allograft function where these untoward side effects might be avoided with the use of belatacept. On the downside, belatacept requires intravenous administration which may be difficult long-term in many ESRD patients. The current long-term extension trial demonstrated high patient adherence with intravenous belatacept, providing stable renal function, predictable pharmacokinetics, in addition to similar efficacy and safety to CsA over 5 years.3, 4 These extend the findings reported after shorter periods of followup in the Phase 3 studies.These Phase 3 studies (the BENEFIT Study3 and the BENEFIT-EXT Study)4 have shown similar results, namely, that belataceptbased regimens sustained better renal function, similar patient/graft survival, and improved cardiovascular and metabolic risk profiles at 2 years when compared with CsA. Additionally, belatacept (BENEFIT-EXT Study) appears to be safe and effective for ECD kidney transplant recipients. Citation: Franz S, Regeniter A, Hopfer H, Mihatsch M, Dickenmann M. Tubular toxicity in sirolimus- and cyclosporinebased transplant immunosuppression strategies: an ancillary study from a randomized controlled trial. Am J Kidney Dis. 2010;55:335–343. Analysis: Cyclosporine has been a mainstay of immunosuppressive therapy for more than 30 years, but the side effects of renal vasoconstriction, increased risk of cardiovascular disease and malignancies, and chronic allograft nephropathy have prompted the continuing search for better alternatives.5 Sirolimus, which acts at a later step in the T-cell signaling pathway, has been promoted over the last decade as both a calcineurin sparing agent6 and as an alternative for the prevention of acute and chronic rejections.7 Recently, however, several studies have focused on the tubular toxicity of sirolimus, particularly with respect to the development of delayed graft function and proteinuria.8, 9 In this randomized, prospective trial by Franz and colleagues, a sirolimus-based regimen for incident transplant patients was compared to that of a more traditional cyclosporine regimen. The study enrolled 127 patients, excluding high and low risk patients, who were all treated with mycophenolate mofetil and prednisone and randomized to receive either cyclosporine or sirolimus. Patients were followed for 6 months and comparisons were made with respect to overall kidney function, patient and graft survival, number of rejection episodes, and for biomarkers of glomerular and tubular injury. The results demonstrate no difference in kidney function or graft survival, but do show greater tubular and glomerular damage in the sirolimus group. Validity and threats to validity: Strengths of the study include masked randomization, prospective allocation, predefined inclusion and exclusion criteria, and clinically important predefined primary and secondary outcomes. There was nearly complete follow-up with 2 patients being lost to death and 2 to primary non-functioning grafts. While specifics of how the randomization was carried out (block randomization, stratification, etc.) are not detailed in this paper, the baseline characteristics of both groups are similar. The data was rigorously analyzed, and the tables indicate that the analysis was performed by intention-to-treat. Several factors, however, must be considered when interpreting the results. First, nearly half of the sirolimus arm and one-quarter of the cyclosporine arm patients were withdrawn from the protocol before the 6-month follow-up. Such high numbers lost to follow-up and possible unknown secondary interventions/protocol deviations, introduce a significant degree of uncertainty into the findings and reduce the strength of any conclusions arising from this study about hard outcomes. Also, while the total number of rejections was similar between the groups, 18 patients were withdrawn from the sirolimus group due to severe or repeated rejections, versus only 10 patients in the cyclosporine arm. A per-protocol analysis may be beneficial in this situation to help determine whether the increased markers of glomerular and tubular dysfunction were related to the higher number of severe rejections in the sirolimus subjects or to direct toxicity from sirolimus. It is likely that the differential drop-out rate will have distorted the results but if so, the direction of distortion is likely to have demonstrated a more favorable outcome with sirolimus than truly exists. An unfavorable outcome for the subjects on sirolimus was demonstrated so the expected distortion will most likely act to lessen the magnitude of the adverse effects and reduced the power of this study to demonstrate important patient centered adverse clinical outcomes. Additionally, markers of injury declined in both groups over time. While the ratios were unchanged between the groups, there was a steady decline over the 6-month period. Whether the difference in tubular injury markers would remain significant or whether patientcentered outcomes such as mortality and graft survival would be differentially affected after a longer follow-up period is unaddressed by this study. Clinical bottom line: While the current study demonstrates that markers of tubular and glomerular injury are worse in patients on sirolimus, this intention-to-treat analysis may produce significantly skewed results because of the differential and high drop-out rate and protocol deviations, particularly in the sirolimus arm of the study where protocol deviations occurred in nearly 50% of the patients. An additional potentially important observation reported from this study is the high rate of severe rejection episodes (29% in the sirolimus group), a rate much higher than previously reported.7, 10 This study does add concern to the growing evidence of potential tubulotoxic or proteinuric effects of sirolimus, but at this point, the data are insufficient to address whether the evidence of tubular injury translates into additional adverse long-term patient-centered outcomes. Citation: Van Leeuwen MT, Webster AC, McCredie MR, et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ. 2010;340:c570. Analysis: Van Leeuwen and colleagues exploit two robust, independently assembled, relatively complete and linkable registries (the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry (Australian participants) and the Australian National Cancer Statistics Clearing House registry) to estimate the risk of various types of cancer during immunosuppression for renal transplantation and after immunosuppression is discontinued for those individuals who have a failed transplant and return to dialysis. The authors use the time of return to dialysis as a means of estimating the date of discontinuation of immunosuppression therapies. In this study, the authors confirm the previously reported observation that risk for a broad range of cancers is increased with immunosuppression, including those that are, in part, thought to be related to concurrent viral infections including Kaposi's sarcoma, non-Hodgkins lymphoma and anogenital cancers. The novel finding from this study is the observation that cancer risk compared to age- and gender-matched healthy individuals in the general population changes for certain types of cancer when immunosuppression is discontinued—that the cancer risk for certain types of cancers is rapidly reversible once immunosuppression is discontinued. This finding is particularly evident for Kaposi's sarcoma, non-Hodgkin's lymphoma, melanoma, and lip cancers. For cancers that are more strongly associated with ESRD such as kidney, urinary tract and thyroid cancers and for lung cancer, leukemia, no such reversibility is seen in individuals who return to dialysis off of immunosuppression medications. In this epidemiologic analysis, colon, breast and prostate cancer risks were not increased in patients with transplantation or those in the on dialysis when compared with the general population. Validity and threats to validity: This study reports on cancer risk in transplant recipients and the changes in cancer risk when immunuosuppression is discontinued. A robust way of evaluating this question is to measure cancer risk in a prospective cohort. The ANZDATA registry represents such a prospective cohort. Data regarding transplant type and duration and the data of return to dialysis are prospectively recorded and the data is complete for the population (except for the very small number of individuals who migrate from Australia). In this study, individuals were censored from the data when they died, where death from a non-cancerous cause represents a competing outcome for the development of cancer. A composite outcome, cancer or death was not evaluated and therefore, competing outcomes might have distorted somewhat the risk profiles. Only cancers occurring more than 3 months after change in immunosuppression status were included in an attempt to evaluate cancers likely to have been influenced by treatment status. Outcomes (i.e., cancer diagnosis) were obtained from the national cancer registry, where data were collected prospectively on a national level and independently of transplant status. It is unlikely that there was a significant rate of misclassification of individuals included in the registry related to transplant status. It is uncertain, however, if any individuals with cancer were not captured in this registry where this ascertainment of outcomes might be different depending on transplant status. It is likely that nearly everyone with a functioning transplant was identified if and when they developed a cancer. The added surveillance for cancer in patients followed in a transplant specialty clinic might have resulted in the identification of cancers at an earlier stage. It is also possible that individuals with a failed transplant back on dialysis might choose not to have suspicious symptoms evaluated thereby leading to an under diagnosis of cancers in individuals on dialysis. The influence of any potential ascertainment bias on the results can not be determined. It seems unlikely that this bias was large given that not all cancer risks changed similarly with changes in immunosuppression status. It seems reasonable to equate dialysis or functioning transplant with immunosuppression therapy status especially if the customary practice in Australia is to discontinue immunosuppressive medications promptly upon resumption of chronic dialysis therapy. It is also possible that some patients were not taken off of their immunosuppression medications promptly on the return to dialysis and this would represent a potential, albeit likely small, misclassification of exposure bias. The study was underpowered to evaluate risk for certain rare types of malignancies and either a larger prospective cohort study of longer duration or a carefully crafted case-control study, nested within a much larger cohort, will be required to evaluate for any incremental risk for rare or uncommon cancers. Clinical bottom line: This study supports the view that the excess risk observed for certain cancers amongst individuals on immunusuppression therapy after renal transplantation can be reversed rapidly with cessation of the immunosuppressive medications. For certain other types of cancers, however, changes in immunosuppression medication status does not seem to alter risk. These findings may provide clinicians and patients with a better understanding of cancer risk and the contribution from immunosuppresion therapy to this risk, a clearer appreciation that this risk is rapidly reversible for some but not all cancers, and a better understanding of whether judicious changes in therapy might alter risk for some patients. This study provides support for the strategy of relatively promptly discontinuing immunosuppression therapy once an individual's kidney transplant fails and they are required to return to dialysis.

Post-transplant lymphoproliferative disease (PTLD) is a rare but potentially fatal complication of organ transplanta-tion. Most cases of PTLD represent Epstein Barr virus (EBV)-related B-cell disease in a setting of pharmacological immunosuppression. Post-transplant plasma cell dyscrasia is very rare, and post-transplant plasma cell dyscrasia with extramedullary plasmacytoma is extremely rare. We report here a case of the latter, which to our knowledge is the fourth such reported case in the English literature. A 22-year-old man developed post-transplant plasma cell dyscrasia 20 years after a renal transplant while on immunosuppression. His presentation included retroperitoneal plasmacytoma, which is very rare and is probably the first case in a renal transplant patient. The patient is in complete remission 1 year after receiving five cycles of bortezomib and dexamethasone.

Now that the dialysis industry has been able to get acquainted with the first phase of the new bundled prospective payment system (PPS), it is time to prepare for the next phase of implementation, the quality incentive program (QIP). After a brief review of the PPS, specifics of the 2012 QIP will be presented, and, using historical performance projections, I will discuss the possible impact of the 2012 QIP on the hemodialysis industry. H.R. 6331, the Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) mandated that the Centers for Medicare & Medicaid Services (CMS) implement a bundled rate payment system to replace the historical fee-for-service payment system.1 Instead of the government paying separately for the individual components of a dialysis treatment, reimbursement will be a flat rate based on several patient metrics and a geographic wage component to account for cost of living variances. The positive financial incentives for providing more profitable drugs and services in the old fee-for-service model are now reversed, with all intravenous drugs now included, or “bundled,” into a single payment. Bundling has led to an expected decrease in drug utilization, particularly the most expensive injectable drug, erythropoietin (EPO). In the last year, Fresenius Medical Services has experienced over a 20% decline in EPO usage. With both the Government Accountability Office (GAO) and CMS having concerns with patients obtaining less medication and subsequently developing severe anemia, CMS proposed a QIP that incorporates penalties for poor anemia management. Beginning January 1, 2012, the first mandated QIP will impact dialysis facilities based on three quality metrics. All facilities that treat Medicare patients must obtain 2% or less of patients with average hemoglobin levels <10 g/dL, 26% or less of patients with average hemoglobin levels >12 g/dL, and 96% or more of patients with average urea reduction ratio (URR) of >65%. Failure to meet these goals will result in a facility payment withhold for the subsequent year.2 The three metrics (Hgb < 10, Hgb > 12, and URR > 65%) will have weightings of 50%, 25%, and 25%, respectively.2 A greater weighting was given to Hgb < 10 to help ensure that patients will not be given too little EPO, which places the patient at risk for needing blood transfusions. For each 1% worse than the national average, the respective quality metric will lose one point out of ten.2 Ultimately, summing the score for all three metrics leads to a score out of a possible thirty, which will determine if the facility will receive a 0-2% Medicare payment penalty (in half percent increments).2 Based on the historical performances of dialysis facilities from 2007 utilizing the new scoring system, it is possible to estimate the projected financial impacts of the proposed QIPs on the industry and individual facilities for 2012. Using the most recent dialysis facility compare data provided by CMS, one can estimate a financial loss of about $55.5M in 2012.3 (Please be aware that drug utilization, facilities, patients, and patient outcomes have most assuredly changed since 2007, so these numbers are our best estimates at this moment.) This was forecasted by estimating 2012's industry average expected bundled rate of $267 revenue per treatment, a 1.9% increase from CMS's recently released 2012 End-Stage Renal Disease (ESRD) Proposed Rule over 2011's estimated $264 revenue per treatment with 0.0% transition adjuster reduction, and multiplied by 144 expected hemodialysis treatments per patient per year. Lastly, each facility's corresponding QIP penalty and patient volumes were included. (This includes CMS's allowed three-quarter year add-back of the 3.1% transition adjuster starting April 1, 2011 from CMS's reported 2010 proposed bundle rule data showing $256 industry average revenue per treatment rate.) Of the 4,713 facilities reporting all three quality metrics in 2007, this analysis suggests an average $12,000 reduction in Medicare payments per facility. Since 46.1% of facilities would have received no penalty based on their metrics, for those facilities that actually qualified for a reduction, the average penalty is closer to a $22,000 reduction in Medicare payments per facility. Alternatively, this equates to an overall $1.45 per patient per treatment reduction in Medicare payments over all facilities or a $2.65 reduction per patient per treatment penalty for the 53.9% of facilities that will actually qualify for a QIP penalty. Table I further breaks out the number of dollars, patients, and facilities that are tied to each penalty group. As expected, the higher the percent QIP penalty, the lower the number of patients, treatments, and facilities in each penalty category; also, the higher the percent QIP penalty, the larger the financial penalty with the exception of the giant 0.5% penalty group. The two largest providers, DaVita and Fresenius Medical Care (FMC), are responsible for less than half of the total QIP penalty, at approximately $26.5M, but represent over half of the industry's Medicare patients, with approximately 146,000 patients. This means that the QIP may put an increased burden on those smaller or individually owned facilities that cannot obtain large company efficiencies. Smaller providers absorbing a disproportionate negative financial bundle impact could lead to further and accelerated consolidation in the dialysis industry. Further analysis of the facilities by each specific metric demonstrates that the Hgb < 10 is the largest contributor to the QIP penalty estimate based on the 2007 data (Table II). This is not surprising, as CMS doubled the weighting of the Hgb < 10 (50%) with respect to the Hgb > 12 (25%) and URR > 65 (25%) metrics. Table III expresses what would happen if all three quality metrics were weighted equally (33% each). Even with equal weighting of all three metrics, the Hgb < 10 metric remains the greatest contributor to the projected penalty. With CMS weighting the severe anemia metric more aggressively, this might be an effort to minimize costly blood transfusions. On the high hematocrit side of the penalty range, Hgb > 12, the bundle's impact of curtailing the use of ESAs by 20% is additive to the financial savings already afforded by promoting an additional penalty. This inherent double penalty due to the bundle and QIP should be reconsidered. Fortunately, CMS has stated that they will be open minded in regard to adding to or modifying the QIP in 2013 and 2014. In CMS's 2012 ESRD Proposed Rule, CMS outlines the potential QIP for 2013 and 2014, with some major changes. In 2013, the QIP will remove the Hgb < 10 metric completely and weight the remaining two, Hgb > 12 and URR > 65, at 50% each based on 2011 facility performance.4 Removal of this metric was primarily because of CMS's inability to find a comfortable lower bound that was safe for all patients. While I agree with this stance, it seems that it would also be hard to justify an upper bound Hgb > 12 using the same logic; different patients have different needs. CMS has acknowledged this and is asking for public feedback on the Hgb > 12 metric for 2013. The most dramatic change to the QIP will happen in 2014. The potential metrics released in the 2012 proposed rule for 2014's QIP may include a Kt/V metric, vascular access metrics, standardized hospitalization ratio (SHR) admission metric, a patient well-being metric, a bone mineral metabolism metric, blood stream infection metric, iron metric, and potentially others.4 Unfortunately, we will have to wait for future rulings and data on what new quality metrics CMS will actually pick to see what the financial impacts may be. The dialysis industry has enjoyed a high degree of government collaboration, which no other industry has achieved. While we have some basic outlines on what to expect in 2013 and 2014, future QIPs could see additional, fewer, or changed quality metrics depending on its success or failure in promoting quality in 2012 and future years. Whether QIP is perfect or not, hopefully we can learn from it through experience and improve upon it, thus improving patients' lives and health. Given the uncertainty about the 2014's QIP, my recommendation is to do what most, if not all, physicians already do: what is in the best interest of the patient. That way, if CMS chooses to add another quality metric, you will have the best chance for coming out ahead.

Background: Acute kidney injury is a frequent problem among many critically ill patients, commonly in the context of multiple organ failure and decreased renal perfusion. Its presence conveys a poor prognosis. Currently, effective therapeutic interventions are limited and dopaminergic agonists have been suggested as an option to prevent further damage. Methods: We performed a randomized, double-blinded, prospective crossover study in 17 patients admitted to our trauma intensive care unit (ICU) with evidence of impaired renal function. Patients were randomized to a 24-h intravenous infusion of low-dose fenoldopam or placebo. When the infusion of fenoldopam or placebo was completed, patients underwent a 24-h "washout" period in which no study intervention was performed. This sequence was repeated in each patient with the opposite agent, so each patient served as his own control. Four-hour creatinine collections were taken during the last 4 h of each infusion and washout periods to determine creatinine clearance changes during and after the administration of the study drug. Results: The creatinine clearance was higher with fenoldopam infusion than with placebo infusion (P = 0.045). The FENa was not significantly different. Conclusions: Our study showed that low-dose Fenoldopam increases creatinine clearance in the critically ill with renal insufficiency. Fenoldopam may be a useful drug in ICU patients with early renal dysfunction.

Patients undergoing hemodialysis are subject to recurrent acid-base perturbations. Prior to each dialysis treatment, they are relatively acidemic, which is corrected rapidly during dialysis. We report a patient with obesity, obstructive lung disease, and pneumonia who developed acute respiratory failure triggered by an influx of high bicarbonate during dialysis. This case emphasizes that in patients with severely compromised respiratory reserve, a large amount of bicarbonate influx during hemodialysis may cause acute CO(2) accumulation and ventilatory distress. An individualized approach with judicious adjustment of the dialysate bicarbonate concentration may be necessary.

I was pleased to hear that the paper “The Hemodialysis Product (HDP): A better Index of Dialysis Adequacy than Kt/V,” which I co-authored with the late Professor Belding Scribner, was elected as one of D&T's most-read papers. Since then, there have been the results of the HEMO Study, which did not confirm that increasing the dialysis time/dose would lead to clinical improvement. This contradicted the experience of many investigators that more frequent and longer sessions (such as nocturnal dialysis) would provide better results. After all, normal kidneys work seven days a week for 24 hours a day. With new studies and a renewed interest among American nephrologists in more frequent (daily) dialysis of shorter duration and nocturnal dialysis, and the improved results reported for slow nocturnal (overnight) dialysis, I believe that Dr. Scribner's position will be vindicated, and that we are entering a new era of dialysis for our patients. It was a great honor to serve as co-author with one of the giants of our specialty of nephrology, on what became one of his final papers. Congratulations to D&T.

I have worked as a certified hemodialysis technologist/technician (CHT) for about 12 years, and have been in the medical field for almost 20. I've worked with many extraordinary patients over the years, but I have one particular patient who was very special to me—my dad. Dad went into the hospital to have an aneurysm on his aorta removed. It had been there for years, and we all knew it. It was a triple “A” surgery (abdominal aortic aneurysm) that ended up with a fourth aneurysm found in his groin area that exploded throughout his left leg. To make a long story short, Dad lost circulation in his left leg which then had to be removed below the knee. Then what I thought was my worst nightmare occurred—his kidneys shut down. We had to make another traumatic decision, to start dialysis right away. I helped set up the machine, and while stringing it I took measures and precautions beyond those I typically do with patients to ensure sterilization because, after all, this was my dad. The catheter placement wasn't the best, but I helped get the dialysis going and, as I sat there watching him, I knew Dad wouldn't want to live like that. But, I took every measure I could to make him comfortable, telling myself it was just an acute setting and that he would bounce back. During this time that my father was ill, the company I work for had offered me a biomedical position—a job that would take me away from direct patient care—which I was considering. My dad and I were always close, and he was always my hero. He always listened to me and helped me make decisions about different things in my life, and I always went to him for advice. Sitting there with my dad in the hospital, I started to think about all of the patients in my dialysis facility—how they feel, all they go through as dialysis patients, and all of the tough decisions they have to make. Sitting there with my dad in the hospital, I started to think about all of my patients— how they feel, all they go through, and all of the tough decisions they have to make. As I had in the past, I took this time talked to my dad about the opportunity, even though I wasn't sure he couldn't hear me as he lay there in the hospital bed. I told him about the offer and, even though he could not talk because of his ventilator, he raised his arm, put his hand on mine, and shook his head “no.” I said, “Dad, do you want me to stay with the patients?” And he nodded his head “yes.”. This was a very moving moment for me, and I immediately decided to decline my company's offer and stay with patient care. When you set up patients every day, it's easy to become mechanical and just go through the motions. But I now look at every patient as if he or she is my dad, and am careful to string a machine and hook up every patient with the same care and precision as if my dad was in that chair. My father passed away three years ago. I loved him very much, and I miss him terribly, but he helped me make a decision I've never been sorry for. Thank you, Dad. You were my favorite patient. Love, your son, John.

On June 24 the U.S. Food and Drug Administration (FDA) made a major modification to the erythropoiesis stimulating agent (ESA) label, recommending fundamental changes to how ESAs are used to manage chronic kidney disease (CKD) anemia (Table I).1 The FDA emphasized there should be a paradigm shift from aiming for a hemoglobin (Hgb) target range of 10 to 12 g/dL to using the lowest possible dose of ESA to prevent a blood transfusion. Treatment of CKD anemia with ESA therapy should be individualized and, the FDA pointed out, no Hgb target level or ESA dosing strategy should be considered without adverse risk. The FDA has gone further than many would have predicted, but the important issue is how clinicians are going to respond to these label changes in altering their clinical practice. In this article, I will evaluate how these guidelines can be applied to clinical case scenarios that are common in clinical practice. A more detailed discussion of the evidence is published elsewhere.2, 3 A 66-year-old man on chronic hemodialysis with a stable Hgb level in the 11-to-12.5 g/dL range is iron replete and being treated using an anemia protocol. His current dose of epoetin-alfa is 27,000 units/week intravenously. What should you do? This patient's Hgb concentration is outside of the recommended guidance by the FDA. The patient's Epogen should be held until the Hgb level falls into the 10-to-11 g/dL range. Some might view this as controversial and argue instead that a reduction in dose would be a better approach because there might be a precipitous drop in the Hgb level. This is an assumption unsupported by the evidence.4 Epogen dosing should be resumed at 50% of the previous dose and then calibrated to maintain the Hgb level between 9 to 11 g/dL. The patient should be informed of the risk of ESA therapy, as per the REMS guidance from the FDA, and provided educational material germane to this risk.5 The dialysis unit should abandon use of an anemia protocol that mandates Epogen dose changes based on Hgb concentration. Further, the anemia protocol is now outdated, and the focus should be individualizing anemia management. An 82-year-old patient on dialysis has a Hgb concentration that, over a 3-month period, ranges from 10.1 to 11.2 g/dL. The patient complains of fatigue whenever her Hgb concentration falls below 11 g/dL. She is iron replete. What should you do? The FDA has determined that the primary indication for ESA therapy is to prevent the need for blood transfusion. Therefore, the first step should be to determine the Hgb level at which one would administer a blood transfusion to this patient (“the hemoglobin trigger”). Most young patients can tolerate Hgb concentrations in the 8-to-9 g/dL range without experiencing symptoms, but older patients with other co-morbidities may be less tolerant. While the FDA has removed an improvement in quality of life as a benefit of ESA treatment of CKD anemia, several trials demonstrate that there is a benefit, albeit perhaps modest.6-9 Furthermore, the instruments used to evaluate quality of life may not be sufficiently sensitive to improvements in quality of life in this patient population. Since the FDA emphasizes the importance of individualizing ESA therapy, and no Hgb level has been demonstrated to be free of risk, the treatment approach for this patient should be to counsel her on the risk of ESA therapy, and to manage her at a Hgb concentration that allows her to be functional. Maximizing her quality of life with ESA therapy is reasonable, as long as she understands the risks and reward of this strategy. A 72-year-old man on chronic hemodialysis is recently diagnosed with prostate cancer. Radiation therapy is recommended. His average Hgb concentration is in the 12.2-to-13.1 g/dL range while receiving 15,000 units of Epogen each week. What should you do? This patient has an active malignancy. While there is no evidence to indicate that exposure to ESA worsens outcomes or results in progression of prostate cancer specifically, evidence from patients exposed to ESAs who have other cancers suggests that ESAs do result in worse outcomes.10, 11 It is possible that this is due to the dual risk of heightened thromboembolic risk that accrues from the cancer itself and from exposure to ESA. The goal should be to minimize exposure to ESA. The ESA should be discontinued in this patient and the Hgb concentration allowed to gradually drift down to between 9 and 10 g/dL. A combination of low-dose ESA and intermittent blood transfusion should be used to keep the patient's Hgb concentration in this range. A 42-year-old female patient experienced a failed kidney transplantation 2 months prior and is now back undergoing chronic hemodialysis. She has some mild tenderness over her allograft. The patient denies fatigue. She is being treated with prednisone 10 mg, among several other medications. She has a Hgb concentration of 9.2 g/dL. The patient has a Tsat of 19% and a serum ferritin level of 800 ng/mL. She is currently receiving 32,000 units of Epogen each week. What should you do? This patient has anemia due to both kidney failure and inflammation. The inflammation is causing her to have ESA resistance. The inflammation may also be causing a block in iron mobilization, and the patient has functional iron deficiency. Instead of treating with progressively higher doses of ESA, evidence from a secondary analysis of the TREAT study and now guidance from the FDA points to the futility of this approach.12, 1 This patient is demonstrating hypo-responsiveness to ESA. A lower-risk strategy would be to administer intravenous iron to overcome the block in iron mobilization from stores. Evidence from the DRIVE study supports such an approach. DRIVE demonstrated the efficacy of intravenous iron among anemic dialysis patients with high ferrtin levels.13 Further, secondary analysis from DRIVE indicated the conventional measures of iron deficiency have limited value in predicting the response to intravenous iron.14 Further, in patients who are ESA resistant and on high doses of ESA, treatment with intravenous iron reduces epoetin requirements.15 Additionally, consideration should be given to removing the allograft as it is the likeliest source of inflammation in this patient. Establish the Hgb trigger for your patient. This is the Hgb concentration at which intervention—ESA therapy, iron therapy, blood transfusion, or a combination—is necessary. Determine what the risk-reward ratio is for your patient. This will depend on the patient's underlying history and what the benefits of therapy might be. For a young patient awaiting kidney transplantation, symptomatic anemia will necessitate ESA therapy and the goal should be to avoid blood transfusion if possible, in order to avoid allo-sensitization. For a dialysis patient who is not a transplant candidate, a reasonable strategy might be the use of low doses of ESA aiming for a Hgb of 9 to 11 g/dL with the occasional blood transfusion if necessary. For the patient with an active cancer or a patient with a history of prior stroke, avoiding ESA or at minimum using very low dosage of ESA coupled with blood transfusion would be the right approach. Recognize that the Hgb concentration is a flawed surrogate marker for outcome—don't chase it if therapy doesn't result in a change. Focus on the patient's symptoms, not on the Hgb level per se. Lack of responsiveness may reflect underlying inflammation or an acute medical illness, such as a gastrointestinal bleed. Progressive increases in ESA dose or repeated blood transfusion will only heighten risk but not improve outcome. Looking for the underlying cause for non-responsiveness is key. The author was Principal Investigator of the CHOIR study, and a member of the Executive Committee for the TREAT study. He presented to the FDA Cardiovascular Disease and Renal Advisory Committee (CDRAC) September 2007 and 2010 and to the U.S. Congress House of Representatives, Ways and Means Committee in December 2006 and June 2007. He is a member of the Medicare Evidence Development & Coverage Advisory Committee, and provides evidence to the committee. He reports receiving consulting income from Johnson and Johnson, Rockwell, ConCert, and Sandoz. The author of this review received an honorarium from the publisher for his time and expertise in preparing this article. The publisher had no input on the article; all data and composition is the work of the author.

I had never felt more alive and inspired as I did the beautiful morning of January 1, 2011 when the Donate Life float made a right-hand turn onto Colorado Boulevard in Pasadena, Calif., for the 2011 Rose Parade. As I waived to the 51.9 million Americans watching on TV, millions of international viewers in 220 territories around the world, and the more than 700,000 people lining the streets, I was loving life and was so grateful to have the opportunity to show the country that organ donation is vital, that transplantation works, and the resilience and beauty of life. I was encouraging organ and tissue donation! I felt free, invincible and didn't have a care in the world. I haven't had many moments in life like this—where I didn't have a care in the world. I feel as if I have an old soul and definitely had to grow up faster than most. My earliest memory as a little girl is from the age of five, when I had my first grand mal seizure. At ten years old, I had sky-high blood pressure of 160/140 and was diagnosed with one of the most common lifethreatening genetic diseases, polycystic kidney disease (PKD). I missed the first half of my eighth grade year because of scoliosis surgery: two Harrington rods were placed on either side of my spine. I battled cyst bleeds and onand-off hospital stays throughout high school. Two months into college, I had the worst cyst bleeding ever, which put me in the hospital for 11 months. During this time, the difficult decision was made to remove both of my kidneys (at 19 years old), and I was put on daily dialysis. In addition to all of this, I had a six-month bout of pancreatitis, more than 70 blood transfusions, 40 inches of scars, and emergency stomach surgery for a bleeding vessel and four bleeding ulcers. There was a point where my family was called down to Johns Hopkins because the doctors did not think I would make it through the next emergency surgery. If only we knew how beautiful and rewarding my life would be. I pulled through that emergency surgery and my body held on for the next few months until I received just what I needed to survive, the gift of life from a dear family friend, Sally Robertson. All of my health challenges and my transplant taught me that our bodies are stronger than we sometimes give them credit for, that when one embraces the journey one can surpass the boundaries of mind, body, and spirit, and that transplantation does not limit us; instead, it lets us live the most rewarding life possible. Transplantation has a life-changing, domino effect on so many people, aside from the recipient. I love my transplanted kidney because it has given me life and the opportunity to help others improve their lives. In 2008, my award-winning biography, titled “My Favorite American,” was published. It's opened doors and enabled me to help educate the world about PKD and organ transplantation. Valen (right) with her living kidney donor and family friend, Sally Robinson. Valen on the Donate Life float in the 2011 Rose Parade in Pasadena, Calif. Photo courtesy Scott Weersing. After my transplant, I developed a passion to raise awareness of PKD and organ donation. In 2004, I founded the South Central Pennsylvania Chapter of the PKD Foundation. In addition to working full time, I held monthly meetings, organized annual fundraising walks and educational seminars, spoke at PKD conventions, raised funds to support PKD research, and helped raise awareness on the local, state, and federal levels. I've shared my message of hope at more than 70 events and with more than 5,000 people across North America. This new lease on life has fueled me to live every day with purpose: to make my parents proud, and my donor proud of the decision she made to donate her kidney to me. I hope my positive story of transplantation encourages other transplant recipients to embrace their transplant, because it shows how much one can accomplish after a transplant and encourages everyone to be organ donors. I believe with all my heart I was given this gift and I am still alive today to share with the world my story and the lessons this gift has taught me. In 2010, my fiancé and I embarked on a cross-country adventure by moving from Pennsylvania to California. For me, this move is a powerful statement that one can live a fulfilling life after transplant, and with an incurable disease like PKD. embrace life; believe that anything is possible; believe in myself; never lose hope; and be the change you wish to see in the world. I feel as though all the difficult days my family and I have had to endure due to my health issues are one by one being erased and replaced with beautiful life-changing moments, like the lives I have touched through my volunteer efforts and most recently, thanks to Astellas, being selected as a winner of their “Ride of a Lifetime” contest. The friendships I made and the experience as a whole will be something I will always treasure. It is overwhelming what joy can come from pain when one embraces life.

Azilsartan medoxomil (Edarbi) tablets have been approved by the Food and Drug Administration (FDA) for treating hypertension.1 Compared with olmesartan and valsartan, the 80-mg dose had greater 24-hour blood pressure-lowering effects, in Phase 3 clinical trials.2 It is available in 40-mg and 80-mg tablets. In addition, a new drug application (NDA) was recently filed for a tablet that combines both azilsartan and chlorthalidone. In a clinical trial presented at the American Society of Hypertension's 2010 meeting, the combination of azilsartan/chlorthalidone had better blood pressure-lowering effects than the combination of azilsartan and hydrochlorothiazide (HCTZ). After all this waiting, belimumab (Benlysta) was finally FDA-approved for treating systemic lupus erythematosus (SLE) in March 2011.3 It is a monoclonal antibody that targets B-lymphocyte stimulator protein, also known as BLyS. It is dosed via an intravenous (IV) infusion of 10 mg/kg every 2 weeks for three doses, followed by every 4-week dosing thereafter. Patients in clinical trials only had modest improvement in symptoms with the agent, but its effectiveness was significantly better than placebo. One-year response rates were 43% for belimumab-treated patients and 32% for placebo-treated patients. The drug should not be administered along with live vaccines. A medication guide will be distributed to all patients who receive this agent to inform them of the treatment risks. The last agent to be FDA-approved to treat SLE was hydroxychloroquine, in 1955. For patients with CrCl > 30 mL/min, take 150 mg orally, twice daily For patients with CrCl 15-30 mL/min, take 75 mg orally, twice daily. At a recent guideline committee meeting of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society, the committee recommended that dabigatran be used as an alternative to warfarin in patients with atrial fibrillation who do not have significant heart valve disease, do not have a prosthetic heart valve, and/or do not have advanced hepatic disease, and/or do not have severe renal failure to reduce their clot risk.6 Other similar agents are currently in the FDA pipeline for this and other similar uses.7 The QMS Everolimus Immunoassay was recently FDA-approved as the first test to monitor everolimus blood levels in renal transplant patients.8 Similar blood level tests are already available to monitor transplant patients receiving cyclosporine, tacrolimus, and/or sirolimus. The test is manufactured by Thermo Fisher Scientific (Waltham, Mass.). Voriconazole tablets were FDA-approved as a generic of Vfend in February of 2011.9 The company has 180 days of market exclusivity before other generics will be available. The liquid and IV versions of the drug are covered under a separate patent. Calcitonin, recombinant salmon oral, is currently in Phase 3 clinical trials for the treatment of postmenopausal osteoporosis.10 It was compared with synthetic salmon calcitonin nasal spray and placebo in 565 women, in a Phase 3 clinical trial. At 1 year, the recombinant oral calcitonin product was statistically significantly non-inferior to placebo and nasal calcitonin in increasing bone mineral density. CTAP101 is currently in Phase 2b clinical trials.11 It is an oral, non-hormonal, treatment for vitamin D insufficiency in patients with secondary hyperparathyroidism and stage 3 chronic kidney disease (CKD). It is currently undergoing clinical trials to evaluate its efficacy, safety, pharmacokinetics, pharmacodynamics, and tolerability. Dapagliflozin has had its NDA accepted by the FDA and the European Medicines Agency (EMA) as a new antidiabetic agent in a potentially new medication class.12 The new class is that of sodium-glucose co-transporter-2 (SGLT2) inhibitors, which target a specific location in the kidney, controlling glycemia independent of insulin pathways.12 Presently, there is limited information on using this agent in patients with renal disease. The FDA's Prescription Drug User Fee Act (PDUFA) goal date for this agent is October 28, 2011. Exenatide extended-release (Bydureon) failed to reduce average blood glucose levels in type 2 diabetics compared with liraglutide in a Phase 3 head-to-head trial known as DURATION-6.13 The fate of this agent is not yet known. The FDA declined its approval in October 2010, requesting additional data on its effect on heart rates. It is expected that Eli Lilly/Amylin will respond to the FDA's letter in the second half of this year. Lixisenatide, a once-daily glucagon-like peptide-1 (GLP-1) agonist, was shown to be as effective as twice daily exenatide in lowering HbA1c levels from baseline in type 2 diabetic patients in the 24-week GetGoal-X trial.14, 15 Additionally, lixisenatide-treated patients exhibited fewer symptomatic hypoglycemic reactions compared with exenatide-treated patients (2.5% vs. 7.9%, p < 0.05), and sixfold fewer hypoglycemic events were observed with the investigational agent compared with the FDA-approved agent (8 vs. 48 events). Patients received stepwise dose increases up to a maximum of 20 µm.

Available data are suggesting that insertion of the hemodialysis needles in exactly the same spot for consecutive dialyses (the “buttonhole” method) may be associated with fewer complications as compared with using different needle insertion sites for each dialysis. The buttonhole method is becoming popular among home hemodialysis patients. This paper will describe the origin of the method, early results, and the reasons why the method has not gained widespread popularity in U.S. hemodialysis centers. Dial. Transplant. © 2011 Wiley Periodicals, Inc.

n a recent issue of this journal, Dr. Peter Blake and others commented on the ADEMEX (Adequacy of Peritoneal Dialysis in Mexico) study, a brilliantly planned and conducted study on the influence of increases in Kt/V on the outcome of anuric continuous ambulatory peritoneal dialysis (CAPD) patients in Mexico. This prospective, controlled study was presented at the recent meeting of the International Society for Peritoneal Dialysis (Montreal, June 2001), but has not yet been published. The results were clear-cut and highly significant. Specifically, they demonstrated that increasing the dose of CAPD—as measured by Kt/V and weekly creatinine clearance— among anuric CAPD patients had no effect on patient survival when compared to a control group on a lower dose of dialysis. This result provides additional evidence that Kt/V is a flawed concept upon which to base the dose of dialysis in general. The prime example that Kt/V is flawed is that it fosters short hemodialysis, which is inefficient in removing toxic middle molecules. Short hemodialysis may give a false impression of highly efficient hemodialysis by removing fast-diffusing urea and, thus, resulting in a high Kt/V. However, removal of toxic middle molecules and PO4, which dialyzes like a middle molecule, is reduced because of the shortened time. Short hemodialysis sessions have great appeal only to the uninformed dialysis patient and to for-profit dialysis centers. For the last three decades worldwide, but especially in the U.S.A., belief among the hemodialysis community in the reliability of Kt/V, combined with the natural desire of the patient to have the shortest possible time on dialysis, has resulted in the underdialysis of the vast majority of hemodialysis patients.