Jason A. Chou

The Obesity Paradox in Kidney Disease: How to Reconcile It With Obesity Management

Obesity, a risk factor for de novo chronic kidney disease (CKD), confers survival advantages in advanced CKD. This so-called obesity paradox is the archetype of the reverse epidemiology of cardiovascular risks, in addition to the lipid, blood pressure, adiponectin, homocysteine, and uric acid paradoxes. These paradoxical phenomena are in sharp contradistinction to the known epidemiology of cardiovascular risks in the general population. In addition to advanced CKD, the obesity paradox has also been observed in heart failure, chronic obstructive lung disease, liver cirrhosis, and metastatic cancer, as well as in elderly individuals. These are populations in whom protein−energy wasting and inflammation are strong predictors of early death. Both larger muscle mass and higher body fat provide longevity in these patients, whereas thinner body habitus and weight loss are associated with higher mortality. Muscle mass appears to be superior to body fat in conferring an even greater survival. The obesity paradox may be the result of a time discrepancy between competing risk factors, that is, overnutrition as the long-term killer versus undernutrition as the short-term killer. Hemodynamic stability of obesity, lipoprotein defense against circulating endotoxins, protective cytokine profiles, toxin sequestration of fat mass, and antioxidation of muscle may play important roles. Despite claims that the obesity paradox is a statistical fallacy and a result of residual confounding, the consistency of data and other causality clues suggest a high biologic plausibility. Examining the causes and consequences of the obesity paradox may help uncover important pathophysiologic mechanisms leading to improved outcomes in patients with CKD.

Incremental Hemodialysis: The University of California Irvine Experience

Incremental hemodialysis has been examined as a viable hemodialysis regimen for selected end‐stage renal disease (ESRD) patients. Preservation of residual kidney function (RKF) has been the driving impetus for this approach given its benefits upon the survival and quality of life of dialysis patients. While clinical practice guidelines recommend an incremental start of dialysis in peritoneal dialysis patients with substantial RKF, there remains little guidance with respect to incremental hemodialysis as an initial renal replacement therapy regimen. Indeed, several large population‐based studies suggest that incremental twice‐weekly vs. conventional thrice‐weekly hemodialysis has favorable impact upon RKF trajectory and survival among patients with adequate renal urea clearance and/or urine output. In this report, we describe a case series of 13 ambulatory incident ESRD patients enrolled in a university‐based centers Incremental Hemodialysis Program over the period of January 2015 to August 2016 and followed through December 2016. Among five patients who maintained a twice‐weekly hemodialysis schedule vs. eight patients who transitioned to thrice‐weekly hemodialysis, we describe and compare patients’ longitudinal case‐mix, laboratory, and dialysis treatment characteristics over time. The University of California Irvine Experience is the first systemically examined twice‐weekly hemodialysis practice in North America. While future studies are needed to refine the optimal approaches and the ideal patient population for implementation of incremental hemodialysis, our case‐series serves as a first report of this innovative management strategy among incident ESRD patients with substantial RKF, and a template for implementation of this regimen.

Association of body weight changes with mortality in incident hemodialysis patients.

Background. Incident hemodialysis patients may experience rapid weight loss in the first few months of starting dialysis. However, trends in weight changes over time and their associations with survival have not yet been characterized in this population. Methods. In a large contemporary US cohort of 58 106 patients who initiated hemodialysis during 1 January 2007–31 December 2011 and survived the first year of dialysis, we observed trends in weight changes during the first year of treatment and then examined the association of post‐dialysis weight changes with all‐cause mortality. Results. Patients’ post‐dialysis weights rapidly decreased and reached a nadir at the 5th month of dialysis with an average decline of 2% from baseline, whereas obese patients (body mass index ≥30 kg/m2) did not reach a nadir and lost ˜3.8% of their weight by the 12th month. Compared with the reference group (−2 to 2% changes in weight), the death hazard ratios (HRs) of patients with −6 to −2% and greater than or equal to −6% weight loss during the first 5 months were 1.08 (95% confidence interval, 1.02–1.14) and 1.14 (1.07–1.22), respectively. Moreover, the death HRs with 2–6% and ≥6% weight gain during the 5th to 12th months were 0.91 (0.85–0.97) and 0.92 (0.86–0.99), respectively. Conclusions. In patients who survive the first year of hemodialysis, a decline in post‐dialysis weight is observed and reaches a nadir at the 5th month. An incrementally larger weight loss during the first 12 months is associated with higher death risk, whereas weight gain is associated with greater survival during the 5th to 12th month but not in the first 5 months of dialysis therapy.

A brief review of intradialytic hypotension with a focus on survival

Intradialytic hypotension (IDH), a common complication of ultrafiltration during hemodialysis therapy, is associated with high mortality and morbidity. IDH, defined as a nadir systolic blood pressure of less than 90 mm Hg on more than 30% of treatments, is a relevant definition and is correlated with mortality. Risk factors for IDH include patient demographics, anti‐hypertensive medication use, larger interdialytic weight gain, and dialysis prescription features as dialysate sodium, high ultrafiltration rate, and dialysate temperature. A high frequency of IDH events carries a substantial death risk. An ultrafiltration rate >10 mL/h/kg, and even more so >13 mL/h/kg, is highly predictive of cardiovascular and all‐cause mortality. Evidence suggests that IDH causes acute reversible segmental myocardial hypoperfusion and contractile dysfunction (myocardial stunning), which can result in long‐term loss of myocardial contractility, leading to premature death. IDH also has negative end‐organ effects on the brain and gut, contributing to mortality through stroke, and endotoxin translocation with associated inflammation and protein‐energy wasting. Given strong association of IDH and dialysis mortality, a paradigm shift to its approach is urgently needed. Randomized controlled trials are required to prospectively test drugs and monitoring devices which may reduce IDH.

Incremental dialysis for preserving residual kidney function-Does one size fit all when initiating dialysis?

While many patients have substantial residual kidney function (RKF) when initiating hemodialysis (HD), most patients with end stage renal disease in the United States are initiated on 3‐times per week conventional HD regimen, with little regard to RKF or patient preference. RKF is associated with many benefits including survival, volume control, solute clearance, and reduced inflammation. Several strategies have been recommended to preserve RKF after HD initiation, including an incremental approach to HD initiation. Incremental HD prescriptions are personalized to achieve adequate volume control and solute clearance with consideration to a patients endogenous renal function. This allows the initial use of less frequent and/or shorter HD treatment sessions. Regular measurement of RKF is important because HD frequency needs to be increased as RKF inevitably declines. We narratively review the results of 12 observational cohort studies of twice‐weekly compared to thrice‐weekly HD. Incremental HD is associated with several benefits including preservation of RKF as well as extending the event‐free life of arteriovenous fistulas and grafts. Patient survival and quality of life, however, has been variably associated with incremental HD. Serious risks must also be considered, including increased hospitalization and mortality perhaps related to fluid and electrolyte shifts after a long interdialytic interval. On the basis of the above literature review, and our clinical experience, we suggest patient characteristics which may predict favorable outcomes with an incremental approach to HD. These include substantial RKF, adequate volume control, lack of significant anemia/electrolyte imbalance, satisfactory health‐related quality of life, low comorbid disease burden, and good nutritional status without evidence of hypercatabolism. Clinicians should engage patients in on‐going conversations to prepare for incremental HD initiation and to ensure a smooth transition to thrice‐weekly HD when needed.

There's no place like home: 35-year patient survival on home hemodialysis

The vast majority of maintenance dialysis patients suffer from poor long‐term survival rates and lower levels of health‐related quality of life. However, home hemodialysis is a historically significant dialysis modality that has been associated with favorable outcomes as well as greater patient autonomy and control, yet only represents a small minority of the total dialysis performed in the United States. Some potential disadvantages of home hemodialysis include vascular access complications, infection‐related hospitalizations, patient fatigue, and attrition. In addition, current barriers and challenges in expanding the utilization of this modality include limited patient and provider education and technical expertise. Here we report a 65‐year old male with end‐stage renal disease due to Alports syndrome who has undergone 35 years of uninterrupted thrice‐weekly home hemodialysis (ie, every Sunday, Tuesday, and Thursday evening, each session lasting 3 to 3¼ hours in length) using a conventional hemodialysis machine who has maintained a high functional status allowing him to work 6‐8 hours per day. The patient has been able to liberalize his dietary and fluid intake while only requiring 3‐4 liters of ultrafiltration per treatment, despite having absence of residual kidney function. Through this case of extraordinary longevity and outcomes after 35 years of dialysis and a review of the literature, we illustrate the history of home hemodialysis, its significant clinical and psychosocial advantages, as well as the barriers that hinder its widespread adaptation.

Introduction to the Critical Balance-Residual Kidney Function and Incremental Transition to Dialysis.

Obsession with dialysis adequacy is the prevailing dogma in the management of patients with endstage renal disease (ESRD) and has overshadowed the needed attention to personalized dialysis treatment and preservation of residual kidney function (RKF). As dialysis therapy emerged in 1960s and early 1970s, a thrice-weekly hemodialysis schedule was laid down by the dialysis pioneers as the “standard of care”—one that would prevent uremic symptoms and offer “the best compromise” by permitting the treatment of many patients with limited resources (1). The rapid (but now stalled) technological progress in hemodialysis therapy has been beneficial, but the many attempts to improve patient outcomes by increasing dialysis dose and frequency have failed to show definite clinical benefits. Recent reports from the Frequent Hemodialysis Network (FHN) Trial group have suggested mixed and even contradictory effects of frequent vs. thrice-weekly in-center hemodialysis on patient survival in that mortality was reduced in the FHN Daily Trial while increased in the FHN Nocturnal Trial (2,3). What might account for such a difference in the effect of dialysis frequency within the same study group? The key may lie in the different characteristics of participants, in particular their RKF. The FHN Daily Trial included mainly long-term hemodialysis patients of whom two-thirds were anuric (3), while the patients recruited for the FHN Nocturnal Trial were relatively new to dialysis with half having urine volumes of 500 ml/day or more (4). Hence, RKF may have obscured the benefit of dialysis dose or frequency (5), considering its pivotal role in maintaining fluid and metabolic homeostasis even at the low levels present in ESRD patients (6). Indeed, residual kidney clearance is more strongly associated with survival among both ESRD patients on hemodialysis and peritoneal dialysis than is dialytic urea clearance (7,8). Interestingly, the above mentioned FHN Nocturnal Trial showed faster RKF decline in the frequent hemodialysis group (9), which may at least partly explain the unexpected higher mortality in this group (10). Frequent hemodialysis also led to worse vascular access outcomes (11). Technological advances have made hemodialysis treatments more efficient, effective, and less costly, allowing for an expansion of the eligibility for dialysis treatment such that the percentage of patients with an estimated GFR of >10 ml/minute/1.73 m at dialysis initiation in the United States has increased from 13% in 1996 to 40% in 2013 (12). The elderly population is also increasing, and almost a quarter of incidence ESRD patients were aged ≥75 years in 2013. Growing heterogeneity in this population clearly warrants individualized treatment, rather than the one-size-fits-all approach. “Personalized dialysis” may offer more favorable clinical outcomes, better quality of life, and yet more cost-savings. To that end, an emerging strategy is incremental dialysis. While an incremental approach has commonly been employed among patients transitioning to peritoneal dialysis, the vast majority of maintenance hemodialysis patients in developed countries are initiated abruptly with thrice-weekly treatments irrespective of their RKF. This is despite the 2006 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggesting less frequent hemodialysis schedules among patients with “substantial” residual renal urea clearance (i.e., Kru ≥ 3.0 ml/minute/1.73 m) (13). This gap between guidelines and clinical practice may be attributed to the misconception that RKF would invariably decline rapidly and quickly become clinically irrelevant after hemodialysis initiation, a belief based on old and inconclusive data from early studies comparing changes in RKF between patients on hemodialysis vs. peritoneal dialysis (14–17). Some— but not all—studies suggest that the current use of biocompatible dialysis membranes have been associated with the slower rate of decline in RKF (18,19). Hemodialysis patients may, contrary to widespread Address correspondence to: Kamyar Kalantar-Zadeh, MD, MPH, PhD, Division of Nephrology and Hypertension, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California Irvine, 101 The City Drive South, City Tower, Suite 400, Orange, CA 92868, Tel.: +1-310-222-2346; Fax: +1-310-222-3839, or e-mail: kkz@uci.edu. Seminars in Dialysis—Vol 30, No 3 (May–June) 2017 pp. 232–234 DOI: 10.1111/sdi.12600

Changes in urine volume and serum albumin in incident hemodialysis patients

Introduction: Hypoalbuminemia is a predictor of poor outcomes in dialysis patients. Among hemodialysis patients, there has not been prior study of whether residual kidney function or decline over time impacts serum albumin levels. We hypothesized that a decline in residual kidney function is associated with an increase in serum albumin levels among incident hemodialysis patients.

Association of Ultrafiltration Rate with Mortality in Incident Hemodialysis Patients

Background/Aims: Ultrafiltration rate (UFR) appears to be associated with mortality in prevalent hemodialysis (HD) patients. However, the association of UFR with mortality in incident HD patients remains unknown. Methods: We examined a US cohort of 110,880 patients who initiated HD from 2007 to 2011. Baseline UFR was divided into 5 groups (<4, 4 to <6, 6 to <8, 8 to <10, and ≥10 mL/h/kg body weight [BW]). We examined predictors of higher baseline UFR using logistic regression and the association of baseline UFR and all-cause and cardiovascular (CV) mortality using Cox proportional hazard models with adjustments for demographics, comorbidities, and markers of malnutrition-inflammation-cachexia syndrome. Results: Patients were 63 ± 15 years, with 43% women, 32% African Americans, and had a mean baseline UFR of 7.5 ± 3.1 mL/h/kg BW. In the fully adjusted logistic regression models, factors associated with higher UFR (≥7.5 mL/h/kg BW) included Hispanic ethnicity, diabetes, and higher dietary protein intake. There was a linear association between UFR and all-cause and CV mortality, where UFR ≥10 mL/h/kg BW (reference UFR 6–<8 mL/h/kg BW) conferred the highest risk in both unadjusted (HR 1.15 [95% CI 1.10–1.19]) and adjusted models (HR 1.23 [95% CI 1.16–1.31]). The linear association with all-cause mortality remained consistent across strata of age, urine volume, and treatment time. Conclusions: Higher UFR is independently associated with higher all-cause and CV mortality in incident HD patients. Clinical trials are warranted to examine the effects of lowering UFR on outcomes.

Volume Balance and Intradialytic Ultrafiltration Rate in the Hemodialysis Patient

Purpose of ReviewVolume management in hemodialysis patients is often challenging. Assessing volume status and deciding how much fluid to remove during hemodialysis, the so-called ultrafiltration rate (UFR), has remained a conundrum.Recent FindingsTo date there is no objective assessment tool to determine the needed UFR during each hemodialysis session. Higher volume overload or higher UFR is associated with poor outcomes including worse mortality and unfavorable clinical outcomes. We suggest combined use of the following criteria to determine UFR or post-dialysis target dry weight: pre-hemodialysis blood pressure and its intradialytic changes, muscle cramps, dyspnea from pulmonary vascular congestion, peripheral edema, tachycardia or palpitation, headache or lightheadedness, perspiration, and post-dialysis fatigue. Restricting fluid and salt intake—and high-dose loop diuretic use in cases of residual kidney function—can be helpful in controlling fluid gains. More frequent and more severe hypotensive episodes are associated with poor outcomes including higher death risk.