Allon N. Friedman

Reassessment of Albumin as a Nutritional Marker in Kidney Disease

The decision by nephrologists, renal dietitians, federal agencies, health care payers, large dialysis organizations, and the research community to embrace serum albumin as an important index of nutrition and clinical performance is based on numerous misconceptions. Patients with analbuminemia are not malnourished and individuals with simple malnutrition are rarely hypoalbuminemic. With the possible exception of kwashiorkor, a rare nutritional state, serum albumin is an unreliable marker of nutritional status. Furthermore, nutritional supplementation has not been clearly shown to raise levels of serum albumin. The use of serum albumin as a quality care index is also problematic. It has encouraged a reflexive reliance on expensive and unproven interventions such as dietary supplements and may lead to adverse selection of healthier patients by health care providers. The authors offer a rationale for considering albumin as a marker of illness rather than nutrition. Viewed in this manner, hypoalbuminemia may offer an opportunity to improve patient well-being by identifying and treating the underlying disorder.

Review of the Effects of Omega-3 Supplementation in Dialysis Patients

Chronic dialysis patients experience a host of conditions that limit quality and length of life, and recent therapeutic strategies have had only modest success in ameliorating many of these problems. By mediating cell membrane function and structure and the synthesis of lipid mediators such as eicosanoids, omega-3 fatty acids may offer dialysis patients a host of therapeutic benefits. Omega-3 fatty acids are derived primarily from dietary sources, and cold-water fish is the main source of eicosapentanoic and docosahexanoic acids, the two major bioactive omega-3 fatty acids. Studies of omega-3 supplementation in dialysis patients describe salutary effects on triglyceride levels, dialysis access patency, and perhaps uremic pruritus and oxidative stress. In contrast, the putative hematologic, antihypertensive, anti-inflammatory, and antiarrhythmic effects are not as well documented. Adverse effects generally have been limited to gastrointestinal complaints. Unfortunately, the preponderance of published studies are characterized by suboptimal study design, small sample sizes, supraphysiologic omega-3 doses that may be difficult to consume for extended periods, little long-term follow-up, and a lack of confirmation of compliance. Not surprising, the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients recommend further research in this field. In summary, although preliminary data suggest that omega-3 fatty acids may have clinical benefits, formal recommendations encouraging omega-3 supplementation of dialysis patients are premature until long-term and adverse effects are better defined.

Comparative Effects of Low-Carbohydrate High-Protein Versus Low-Fat Diets on the Kidney

BACKGROUND AND OBJECTIVES Concerns exist about deleterious renal effects of low-carbohydrate high-protein weight loss diets. This issue was addressed in a secondary analysis of a parallel randomized, controlled long-term trial. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS Between 2003 and 2007, 307 obese adults without serious medical illnesses at three United States academic centers were randomly assigned to a low-carbohydrate high-protein or a low-fat weight-loss diet for 24 months. Main outcomes included renal filtration (GFR) indices (serum creatinine, cystatin C, creatinine clearance); 24-hour urinary volume; albumin; calcium excretion; and serum solutes at 3, 12, and 24 months. RESULTS Compared with the low-fat diet, low-carbohydrate high-protein consumption was associated with minor reductions in serum creatinine (relative difference, -4.2%) and cystatin C (-8.4%) at 3 months and relative increases in creatinine clearance at 3 (15.8 ml/min) and 12 (20.8 ml/min) months; serum urea at 3 (14.4%), 12 (9.0%), and 24 (8.2%) months; and 24-hour urinary volume at 12 (438 ml) and 24 (268 ml) months. Urinary calcium excretion increased at 3 (36.1%) and 12 (35.7%) months without changes in bone density or clinical presentations of new kidney stones. CONCLUSIONS In healthy obese individuals, a low-carbohydrate high-protein weight-loss diet over 2 years was not associated with noticeably harmful effects on GFR, albuminuria, or fluid and electrolyte balance compared with a low-fat diet. Further follow-up is needed to determine even longer-term effects on kidney function.

Omega-3 Fatty Acid Supplementation in Advanced Kidney Disease

Long‐chain polyunsaturated omega‐3 fatty acids (n‐3 PUFA), which are obtained primarily from dietary sources such as coldwater fish, have diverse and potent mediating effects on the immune, inflammatory, and metabolic pathways, signal transduction, and cell membrane physiology. N‐3 PUFA are increasingly being studied for their clinical benefits in a variety of medical conditions, some of which are relevant to individuals with advanced chronic kidney disease (CKD). These include, among others, renoprotection in IgA nephropathy, cardioprotective effects via a variety of mechanisms including blood pressure and triglyceride reduction, maintenance of dialysis access patency, sparing of inflammation‐associated muscle loss, and even mortality. However, further confirmatory work needs to be performed before establishing formal intake recommendations and dosing goals for advanced CKD patients. In the meantime, the current American Heart Association n‐3 PUFA intake guidelines can be applied to CKD patients, especially given n‐3 PUFA’s potential benefits and negligible risk profile. Over time, it will be incumbent upon the nephrology community to more clearly define the utility and optimal dosing of n‐3 PUFA in CKD patients with advanced disease via randomized clinical trials.

Predicting the Glomerular Filtration Rate in Bariatric Surgery Patients

Background/Aims: Identifying the best method to estimate the glomerular filtration rate (GFR) in bariatric surgery patients has important implications for the clinical care of obese patients and research into the impact of obesity and weight reduction on kidney health. We therefore performed such an analysis in patients before and after surgical weight loss. Methods: Fasting measured GFR (mGFR) by plasma iohexol clearance before and after bariatric surgery was obtained in 36 severely obese individuals. Estimated GFR was calculated using the Modification of Diet in Renal Disease equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using serum creatinine only, the CKD-EPI equation using serum cystatin C only and a recently derived equation that uses both serum creatinine and cystatin C (CKD-EPIcreat-cystC) and then compared to mGFR. Results: Participants were primarily middle-aged white females with a mean baseline body mass index of 46 ± 9, serum creatinine of 0.81 ± 0.24 mg/dl and mGFR of 117 ± 40 ml/min. mGFR had a stronger linear relationship with inverse cystatin C before (r = 0.28, p = 0.09) and after (r = 0.38, p = 0.02) surgery compared to the inverse of creatinine (before: r = 0.26, p = 0.13; after: r = 0.11, p = 0.51). mGFR fell by 17 ± 35 ml/min (p = 0.007) following surgery. The CKD-EPIcreat-cystC was unquestionably the best overall performing estimating equation before and after surgery, revealing very little bias and a capacity to estimate mGFR within 30% of its true value over 80% of the time. This was true whether or not mGFR was indexed for body surface area. Conclusions: In severely obese bariatric surgery patients with normal kidney function, cystatin C is more strongly associated with mGFR than is serum creatinine. The CKD-EPIcreat-cystC equation best predicted mGFR both before and after surgery.

Is bariatric surgery an effective treatment for type II diabetic kidney disease

Type II diabetic kidney disease is devastating to patients and society alike. This review will evaluate bariatric surgery as a treatment for diabetic kidney disease primarily through its ability to induce and maintain regression of type II diabetes. The review begins by outlining the global challenge of diabetic kidney disease, its link to obesity, and the comparative benefits of bariatric surgery on weight and type II diabetes. It then surveys comprehensively the relevant literature, which reports that although bariatric surgery is associated with reductions in albuminuria, its effect on harder clinical end points like progression of diabetic kidney disease is not known. The review also includes a critical assessment of the risks and costs of bariatric surgery and concludes by acknowledging the major knowledge gaps in the field and providing research strategies to overcome them. Until these knowledge gaps are filled, clinicians will be forced to rely on their own subjective judgment in determining the benefit-risk ratio of bariatric surgery for patients with diabetic kidney disease.

Measuring the glomerular filtration rate in obese individuals without overt kidney disease.

Background: Identifying methods to accurately measure the glomerular filtration rate (GFR) in obese individuals without kidney overt kidney disease is necessary to understanding the pathophysiology and natural history of obesity-related kidney disease. Methods: Using a cross-sectional design, iohexol clearance and disposition was measured, an optimal sampling schedule was identified, and the reliability of GFR-estimating methods was described in 29 obese individuals with normal serum creatinine levels. Iohexol disposition was measured using population pharmacokinetics. The agreement with GFR-estimating equations was assessed by intraclass coefficients. Results: Mean age was 44 ± 10 years, body mass index 45 ± 10, creatinine 0.7 ± 0.2 mg/dl (62 ± 18 µmol/l) , and cystatin C 0.83 ± 0.18 mg/dl (8.3 ± 1.8 mg/l). Iohexol disposition fit a two-compartment model and 5 sampling windows were identified over a 4-hour period to optimize model accuracy and minimize blood draws. Precision was not compromised with this sampling design. Neither creatinine nor cystatin C were linearly correlated with the measured GFR though cystatin C was independent of body composition. Agreement was fair to poor between the measured GFR and GFR-estimating equations. Conclusion: This study offers a rigorous method to study obesity-related kidney disease and improve upon suboptimal GFR-estimating methods.

Inverse relationship between long-chain n-3 fatty acids and risk of sudden cardiac death in patients starting hemodialysis

Experimental and clinical evidence suggests that long chain n-3 fatty acids may protect against sudden cardiac death, the leading cause of mortality in hemodialysis patients. Here we investigated whether long chain n-3 fatty acids have a protective relationship with sudden cardiac death in 100 patients who died of sudden cardiac death during the first year of starting hemodialysis and 300 patients who survived. Individuals were selected from a nationally representative cohort of over 1000 U.S. hemodialysis units in 2004–2005. The odds of sudden cardiac death were calculated by quartile of long chain n-3 fatty acids levels over the first year. There was a significant inverse relationship between long chain n-3 fatty acids and the risk of sudden cardiac death even after adjusting for relevant co-morbid conditions, biochemical values, and dietary fats. The odds of sudden cardiac death at 1 year for the second, third, and fourth quartile groups of long chain n-3 fatty acids were 0.37, 0.22, and 0.20, respectively, compared to the lowest quartile. This significant inverse relationship was maintained even during the highest-risk first few months on hemodialysis. Thus, long chain n-3 fatty acids are strongly and independently associated with a lower risk of sudden cardiac death in hemodialysis patients throughout the first year of hemodialysis.

Feasibility Study of Erythrocyte Long-Chain Omega-3 Polyunsaturated Fatty Acid Content and Mortality Risk in Hemodialysis Patients

OBJECTIVE Long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) are increasingly believed to be cardioprotective. We tested the hypothesis that erythrocyte n-3 PUFA levels, as measured by the omega-3 index (O3I), are inversely related to mortality in hemodialysis patients. DESIGN AND STUDY POPULATION This was a retrospective study of 93 prevalent urban American hemodialysis patients with baseline n-3 PUFA blood levels. MAIN OUTCOME MEASURE The mortality rate was measured over a median period of 755 days. RESULTS The median omega-3 index was 4.69 mean weight %. During follow-up, 19 patients died, and 8 underwent renal transplantation. The probability of survival was significantly greater in patients with an O3I above the median (P = .025). Univariate analyses found that increasing age and a higher Charlson Comorbidity Index were associated with reduced survival, whereas a higher O3I and black race were linked with greater survival. In a multivariate model, only the Charlson Comorbidity Index score clearly predicted mortality (hazard ratio, 1.31; 95% confidence interval, 1.06 to 1.62), though a protective trend was observed with an O3I above the median (hazard ratio, 2.48; 95% confidence interval, 0.88 to 6.95). CONCLUSION Though this modest-sized study did not find a statistically significant relationship between erythrocyte n-3 PUFA levels and mortality, an inverse association was suggested. The existence of such a relationship will need to be confirmed in cohorts with greater statistical power.

Value of urinary albumin-to-creatinine ratio as a predictor of type 2 diabetes in pre-diabetic individuals

OBJECTIVE—The albumin-to-creatinine ratio (ACR) reflects urinary albumin excretion and is increasingly being accepted as an important clinical outcome predictor. Because of the great public health need for a simple and inexpensive test to identify individuals at high risk for developing type 2 diabetes, it has been suggested that the ACR might serve this purpose. We therefore determined whether the ACR could predict incident diabetes in a well-characterized cohort of pre-diabetic Americans. RESEARCH DESIGN AND METHODS—A total of 3,188 Diabetes Prevention Program (DPP) participants with a mean BMI of 34 kg/m2 and elevated fasting glucose, impaired glucose tolerance, and baseline urinary albumin excretion measurements were followed for incident diabetes over a mean of 3.2 years. RESULTS—Of the participants, 94% manifested ACR levels below the microalbuminuria range and 21% ultimately developed diabetes during follow-up. Quartiles of ACR (median [range] within quartiles: 1, 3.0 [0.7–3.7]; 2, 4.6 [3.7–5.5]; 3, 7.1 [5.5–9.7]; and 4, 16.5 [9.7–1,578]) were positively associated with age, markers of adiposity and insulin secretion and resistance, blood pressure, and use of antihypertensive agents with antiproteinuric effects and inversely related to male sex and serum creatinine. An elevated hazard rate for developing diabetes with doubling of ACR disappeared after adjustment for covariates. Within the DPP intervention groups (placebo, lifestyle, and metformin), we found no consistent trend in incident diabetes by quartile or decile of ACR. CONCLUSIONS—An ACR at levels below the microalbuminuria range does not independently predict incident diabetes in adults at high risk of developing type 2 diabetes.