Effects of diet and exercise on adipocytokine levels in patients with moderate to severe chronic kidney disease.

BACKGROUND AND AIMS: Obesity is a pro-inflammatory risk factor for progression of CKD and cardiovascular disease. We hypothesized that implementation of caloric restriction and endurance exercise would improve adipocytokine profiles in patients with moderate to severe CKD. METHODS AND RESULTS: We enrolled patients with moderate to severe CKD through a multi-center pilot randomized trial of diet and exercise in a 4-arm design (dietary restriction of 10%-15% reduction in caloric intake, exercise three times/week, combined diet and exercise, and control) (NCT01150851). Adipocytokines (adiponectin and leptin) were measured at the beginning and end of the study period as secondary outcomes. Treatment effect was analyzed in a multivariable model adjusted for baseline outcome values, age, gender, site and diabetes. A total of 122 participants were consented, 111 were randomized (42% female, 25% diabetic, and 91% hypertensive), 104 started intervention and 92 completed the study (Figure 1). Plasma adiponectin levels increased significantly in response to diet by 23% (95% CI: 0.2%, 49.8%, p = 0.048) among participants randomized to the caloric restriction and usual activity arm but not to exercise, whereas circulating leptin did not change by either treatment. CONCLUSION: Our data suggest that dietary caloric restriction increases plasma adiponectin levels in stage 3-4 CKD patients, with limited effect on leptin levels. These findings suggest the potential for improving the metabolic milieu of CKD with moderate calorie restriction.

Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis.

BACKGROUND AND AIMS: Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD. METHODS AND RESULTS: HDL was isolated at the starting point (pre) and 3-6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA. CONCLUSION: Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease.

Higher protein intake is associated with increased risk for incident end-stage renal disease among blacks with diabetes in the Southern Community Cohort Study.

BACKGROUND AND AIMS: Diabetes, a risk factor for end-stage renal disease (ESRD), is associated with impaired protein metabolism. We investigated whether protein intake is associated with ESRD and whether the risk is higher among blacks with diabetes. METHODS AND RESULTS: We conducted a nested case-control study of ESRD within the Southern Community Cohort Study, a prospective study of low-income blacks and whites in the southeastern US (2002-2009). Through 2012, 1057 incident ESRD cases were identified by linkage with the United States Renal Data System and matched to 3198 controls by age, sex, and race. Dietary intakes were assessed from a validated food frequency questionnaire at baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models that included matching variables, BMI, education, income, hypertension, total energy intake, and percent energy from saturated and polyunsaturated fatty acids. Mean (±SD) daily energy intake from protein was higher among ESRD cases than controls (15.7 ± 3.3 vs. 15.1 ± 3.1%, P < 0.0001). For a 1% increase in percent energy intake from protein, the adjusted ORs (95% CIs) for ESRD were 1.06 (1.02-1.10) for blacks with diabetes, 1.02 (0.98-1.06) for blacks without diabetes, 0.99 (0.90-1.09) for whites with diabetes and 0.94 (0.84-1.06) for whites without diabetes. Protein intake in g/kg/day was also associated with ESRD (4th vs. 1st quartile OR = 1.76; 95% CI: 1.17-2.65). CONCLUSION: Our results raise the possibility that among blacks with diabetes, increased dietary protein is associated with increased incidence of ESRD. Studies on how protein intake and metabolism affect ESRD are needed.

A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease.

The recent research findings concerning syndromes of muscle wasting, malnutrition, and inflammation in individuals with chronic kidney disease (CKD) or acute kidney injury (AKI) have led to a need for new terminology. To address this need, the International Society of Renal Nutrition and Metabolism (ISRNM) convened an expert panel to review and develop standard terminologies and definitions related to wasting, cachexia, malnutrition, and inflammation in CKD and AKI. The ISRNM expert panel recommends the term 'protein-energy wasting' for loss of body protein mass and fuel reserves. 'Kidney disease wasting' refers to the occurrence of protein-energy wasting in CKD or AKI regardless of the cause. Cachexia is a severe form of protein-energy wasting that occurs infrequently in kidney disease. Protein-energy wasting is diagnosed if three characteristics are present (low serum levels of albumin, transthyretin, or cholesterol), reduced body mass (low or reduced body or fat mass or weight loss with reduced intake of protein and energy), and reduced muscle mass (muscle wasting or sarcopenia, reduced mid-arm muscle circumference). The kidney disease wasting is divided into two main categories of CKD- and AKI-associated protein-energy wasting. Measures of chronic inflammation or other developing tests can be useful clues for the existence of protein-energy wasting but do not define protein-energy wasting. Clinical staging and potential treatment strategies for protein-energy wasting are to be developed in the future.

Exercise improves albumin fractional synthetic rate in chronic hemodialysis patients.

OBJECTIVE: To determine whether exercise augments the improvements in fractional synthetic rate (FSR) of albumin observed with nutrition alone. DESIGN: Randomized crossover study. Each patient randomly participated in two protein metabolism kinetic studies using primed-constant infusion of (13C) leucine 2 h before, during and 2 h after hemodialysis. Plasma enrichments of (13C) leucine and (13C) ketoisocaproate were examined to determine the FSR of albumin. SETTING: General Clinical Research Center at Vanderbilt University Medical Center. SUBJECTS: Five chronic hemodialysis (CHD) patients. INTERVENTIONS: Intra-dialytic parenteral nutrition (IDPN) with or without exercise. RESULTS: Exercise performance during hemodialysis significantly improves the FSR of albumin beyond what is observed with IDPN alone (26.2+/-3.1% per day versus 17.7+/-1.9% per day, P<0.05). CONCLUSION: Exercise improves albumin fractional synthetic rate beyond what is observed with IDPN alone in the acute setting in CHD patients.

Adiponectin level is reduced and inversely correlated with the degree of proteinuria in type 2 diabetic patients.

AIMS: Adiponectin seems to be an important modulator for metabolic and vascular diseases. We aimed to measure plasma adiponectin levels in type 2 diabetic patients and investigate any association with the severity of proteinuria. METHODS: 80 patients (mean age, 46.9 +/- 5.1 years; body mass index (BMI), 25.8 +/- 1.98 kg/m2) and 47 healthy volunteers (mean age, 46.1 +/- 5.5 years; BMI 26.74 +/- 2.23 kg/m2) were included. Plasma adiponectin concentration, insulin levels, homeostasis model assessment (HOMA) indices, calculated glomerular filtration rate (GFR), high sensitive C reactive protein (hsCRP) and biochemistry panel were determined in all subjects. The association between adiponectin concentration and proteinuria was evaluated. Additionally, the relationship between adiponectin and hsCRP and calculated GFR were also investigated. RESULTS: Adiponectin levels in patients were significantly lower than those of controls (n = 80; 8.76 +/- 4.50 microg/ml for patients, n = 47; 24.27 +/- 5.59 microg/ml for controls, p < 0.001). Plasma adiponectin levels in patients with proteinuria were significantly lower than those without proteinuria (n = 43; 6.81 +/- 2.82 microg/ml for proteinuria, n = 37; 11.98 +/- 3.32 microg/ml for no proteinuria, p < 0.001). There was a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r = -0.433, p < 0.001). There were also significant negative correlations between adiponectin concentrations and insulin levels as well as HOMA index in the patient group (r = -0.322, p = 0.004; r = -0.301, p = 0.032). Additionally there was a significant negative correlation between adiponectin and hsCRP levels in the patient group (r = -0.872, p < 0.001). CONCLUSION: The results show that adiponectin is lower in patients with type 2 diabetes and the levels are negatively correlated with the severity of proteinuria.

Intradialytic serial vascular access flow measurements.

Hemodialysis vascular access failure represents a major source of morbidity and mortality in chronic hemodialysis (CHD) patients. Serial vascular access blood flow (VABF) measurements are being used as a screening method at an increasing rate. There are limited data on the changes in VABF throughout the hemodialysis session, which may potentially affect the validity of VABF measurement. This study is performed to evaluate the trend in VABF during a given hemodialysis session by serial VABF measurements, along with potential factors that may affect VABF. Thirty-two CHD patients had serial VABF measurements performed during a hemodialysis session. Each patient had three serial VABF measurements during a hemodiaysis treatment (within 30, 90, and 150 minutes from the start of hemodialysis). Mean arterial blood pressure (MAP), ultrafiltration rate, and patient symptoms were recorded simultaneously. The mean VABF was 1,344 +/- 486 mL/min within 30 minutes of hemodialysis and decreased to 1,308 +/- 532 and 1,250 +/- 552 mL/min after 90 and 150 minutes, respectively. This trend was statistically significant (P = 0.03). There was a strong correlation between VABF measurements and MAP, which was more pronounced after 90 minutes of initiation of hemodialysis (r = 0.68; P < 0.001). Using multivariate analysis, it can be predicted that after 90 minutes of hemodialysis, each 10% decrease in MAP would result in an expected decrease of 8% in VABF. There was no effect of type of vascular access, baseline VABF, or amount of ultrafiltration on VABF changes. In conclusion, VABF measurements can be performed up to 2 to 2(1/2) hours from the start of hemodialysis in the majority of patients. The major determinant of VABF changes is MAP. In a subset of patients with a decrease MAP greater than 15%, it is advisable to perform VABF measurement either at the first 90 minutes of hemodialysis or postpone it to another treatment session, when MAP is more stable.

Prescribed versus delivered dialysis in acute renal failure patients.

The current study was designed first to determine separately the prescribed and delivered dose of dialysis and, second, to determine what factors lead to failure to deliver the prescribed dose of dialysis in patients with acute renal failure (ARF). Forty patients, who collectively underwent 136 dialysis treatments, were studied prospectively at two institutions. The results showed that almost half the prescriptions (49%) were for a Kt/V less than 1.2 and, more importantly, nearly 70% of the treatments delivered a Kt/V less than 1.2, the minimally acceptable dose defined in the Dialysis Outcomes Quality Initiative (DOQI) guidelines for chronic hemodialysis (CHD) patients. Patient predialysis weight was the most important variable associated with a low prescribed and delivered dose of dialysis, as well as lack of delivery of the prescribed dose of dialysis. From the statistical model, it is estimated that for every 10-kg increase in predialysis weight, the chance of prescribing or delivering a Kt/V less than 1.2 increased 4.6- and 1.95-fold, respectively. The lower than prescribed blood flow achieved by the temporary catheters and patients not receiving anticoagulation were variables also associated with not receiving the prescribed Kt/V. It is concluded that patients with ARF are prescribed and receive a dose of dialysis that would be considered inadequate for CHD patients. Until the association between dose of dialysis and outcome is better defined, it would be prudent that both the dialysis prescription and the delivery of dialysis to patients with ARF should be performed with the same care and goals as that currently received by patients with end-stage renal disease (ESRD).

Adequacy of dialysis.

Despite improvements in the delivery of dialysis, morbidity and mortality remain excessively high in end-stage renal disease patients. Multiple lines of evidence suggest that inadequate dialysis is responsible these trends. The limits of our understanding of the influence of dialysis dose on mortality and morbidity are discussed. In that context, the relationship between dialysis dose and nutritional status of dialysis patients is also reviewed. The best marker for adequacy of dialysis is yet to be determined. However, urea as a surrogate for small molecular weight solute clearance, has been demonstrated by many studies to be a parameter of adequacy, both in hemodialysis and peritoneal dialysis populations. The application of kinetic modeling of urea is discussed for hemodialysis. The new insights that will be forthcoming at the conclusion of the National Institute of Health HEMO study should help to define an optimal dose of dialysis.

Nitrogen balance in hospitalized chronic hemodialysis patients.

Malnutrition is an important factor in the increased morbidity and mortality of chronic hemodialysis (CHD) patients. Dietary protein intake necessary to maintain neutral nitrogen balance appears to be higher in CHD patients due to various catabolic effects of the hemodialysis procedure, including nutrient losses and increased energy expenditure. Dietary intake may be further decreased in hospitalized CHD patients. We examined this issue in 18 CHD patients (9 male, 9 female) who were admitted to a regular ward. Daily protein intake (DPI) and daily caloric intake were measured for each patient. In addition, protein catabolic rate (PCR) calculated from interdialytic changes in BUN were calculated. Our results showed that mean (+/- SD) DPI was 0.79 +/- 0.41 g/kg/day, while PCR was 0.93 +/- 0.38 g/kg/day. Dietary protein and energy intake were 66% and 50% of suggested values, respectively, and DPI accounted for only 85% of PCR. Mean nitrogen balance was negative by -2.11 +/- 2.77 g of nitrogen/day (range -9.91 g of nitrogen/day to +3.89 g of nitrogen/day). Biochemical nutritional parameters such as serum albumin, cholesterol, prealbumin and transferrin obtained one week following admission were also indicative of undernutrition (3.16 +/- 0.39 g/dl, 132 +/- 30 mg/dl, 20 +/- 7.4 mg/dl, 154 +/- 49 mg/dl, respectively). We conclude that hospitalized CHD patients have inadequate protein and energy intake and this is evidenced by a significant deterioration in nutritional parameters during hospitalization. More aggressive nutritional interventions may be needed for this group of patients to prevent the adverse effects of hospitalization on nutritional status.

Plasma F2-isoprostane levels are elevated in chronic hemodialysis patients.

AIMS: Cardiovascular mortality has been reported to be 10- to 20-fold higher in chronic dialysis patients than in the age-matched general population. It has been suggested that increased oxidant stress and resulting vascular wall injury due to uremia and the hemodialysis procedure may be one of the mechanisms predisposing to these cardiovascular complications. Further, hemodialysis membrane bioincompatibility can contribute to increased oxidative stress and prevalence of inflammation. MATERIALS: We studied 18 chronic hemodialysis (CHD) patients (age 62.8 +/- 14.7 years, 39% male, 61% African-American, 44% insulin-dependent diabetic, 61% smokers, 61% with documented coronary artery disease) during hemodialysis with 2 membranes with different flux and complement activating properties. METHODS: We have measured free and phospholipid-bound F2-isoprostane (F2-IsoP) levels, a sensitive marker of oxidative stress, in CHD patients and compared them to levels in healthy subjects. We have also examined the acute effects of the hemodialysis procedure using both biocompatible and bioincompatible membranes on F2-IsoP levels. RESULTS: The results indicated that, compared to controls, both free (96.2 +/- 48.8 pg/ml versus 37.6 +/- 17.2 pg/ml) and bound F2-IsoP (220.4 +/- 154.8 pg/ml versus 146.8 +/- 58.4 pg/ml) levels were significantly higher (p < 0.05 for both). There was a statistically significant decrease in free F2-IsoP concentrations at 15 and 30 minutes of HD, which rebounded to baseline levels at the completion of the procedure. There were no significant differences in F2-IsoP concentrations between the 2 study dialyzers at any time point. Age, smoking status, diabetes mellitus and presence of cardiovascular disease were also not correlated with F2-IsoP levels in this patient population. There was a significant association between predialysis F2-IsoP and C-reactive protein concentrations. CONCLUSION: Using a sensitive and specific assay for the measurement of F2-IsoP, we demonstrated that CHD patients are under increased oxidative stress. During a single hemodialysis treatment, the hemodialysis membrane appears to have no discernable effect on oxidative stress status. Measurement of F2-isoprostanes may be a useful biomarker of oxidative stress status as well as in developing new therapeutic strategies to ameliorate inflammatory and oxidative injury in this patient population.

Malnutrition in peritoneal dialysis patients: etiologic factors and treatment options.

It is clear that malnutrition is common in chronic dialysis patients and is associated with increased morbidity and mortality. Evidence is accumulating that several measures can be taken to improve the nutritional status of these patients. An early start of dialysis, an increase in dialysis dose, the use of biocompatible membranes or dialysis solutions, and intensive nutritional counseling should be applied when necessary. If these measures fail, additional interventions, such as parenteral or enteral nutritional supplements, rhGH, and rhIGF-1, alone or in combination, should be tried.

Acute kidney injury: changing lexicography, definitions, and epidemiology.

In recent years, there have been numerous advances in understanding the molecular determinants of functional kidney injury after ischemic and/or toxic exposure. However, translation of successful novel therapies designed to attenuate kidney functional injury from animal models to the clinical sphere has had modest results. This lack of translatability is at least in part due to lack of sufficient standardization in definitions and classification of cases of acute kidney injury (AKI), an incomplete understanding of the natural history of human AKI, and a limited understanding of how kidney injury interacts with other organ system failure in the context of systemic metabolic abnormalities. A concerted effort is now being made by nephrologists and intensivists to arrive at standardized terminology and classification of AKI. There have also been dramatic advances in our understanding of the epidemiology and natural history of AKI, particularly in the hospital and intensive care unit setting. Promising strategies are now being developed which may ultimately lead to improved outcomes for patients at risk for or who have developed AKI, which should be readily testable in the coming decade.

Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients.

Deranged protein metabolism is known to complicate uremia. Insulin resistance is evident in chronic hemodialysis (CHD) patients. We hypothesized that the degree of insulin resistance would predict protein catabolism in non-diabetic CHD patients. We examined the relationship between Homeostasis Model Assessment (HOMA) and fasting whole-body and skeletal muscle protein turnover in 18 non-diabetic CHD patients using primed-constant infusions of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine. Mean+/-s.d. fasting glucose and body mass index were 80.6+/-9.8 mg/dl and 25.4+/-4.4 kg/m(2), respectively. Median (interquartile range) HOMA was 1.6 (1.4, 3.9). Mean+/-s.e.m. skeletal muscle protein synthesis, breakdown, and net balance were 89.57+/-11.67, 97.02+/-13.3, and -7.44+/-7.14 microg/100 ml/min, respectively. Using linear regression, a positive correlation was observed between HOMA and skeletal muscle protein synthesis (R(2)=0.28; P=0.024), and breakdown (R(2)=0.49; P=0.001). An inverse association between net skeletal muscle protein balance and HOMA was also noted (R(2)=0.20; P=0.066). After adjustment for C-reactive protein, only the relationship between HOMA and skeletal muscle protein breakdown persisted (R(2)=0.49; P=0.006). There were no significant associations between components of whole-body protein turnover and HOMA. This study demonstrates that insulin resistance is evident in non-diabetic dialysis patients, is associated with skeletal muscle protein breakdown, and represents a novel target for intervention in uremic wasting.

Mortality after acute renal failure: models for prognostic stratification and risk adjustment.

To adjust adequately for comorbidity and severity of illness in quality improvement efforts and prospective clinical trials, predictors of death after acute renal failure (ARF) must be accurately identified. Most epidemiological studies of ARF in the critically ill have been based at single centers, or have examined exposures at single time points using discrete outcomes (e.g., in-hospital mortality). We analyzed data from the Program to Improve Care in Acute Renal Disease (PICARD), a multi-center observational study of ARF. We determined correlates of mortality in 618 patients with ARF in intensive care units using three distinct analytic approaches. The predictive power of models using information obtained on the day of ARF diagnosis was extremely low. At the time of consultation, advanced age, oliguria, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality. Upon initiation of dialysis for ARF, advanced age, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality; higher blood urea nitrogen and lower serum creatinine were also associated with mortality in logistic regression models. Models incorporating time-varying covariates enhanced predictive power by reducing misclassification and incorporating day-to-day changes in extra-renal organ system failure and the provision of dialysis during the course of ARF. Using data from the PICARD multi-center cohort study of ARF in critically ill patients, we developed several predictive models for prognostic stratification and risk-adjustment. By incorporating exposures over time, the discriminatory power of predictive models in ARF can be significantly improved.

Nutrition in end-stage renal disease.

In summary, it is evident that malnutrition is highly prevalent in ESRD patients. This is clearly related to multiple factors encountered during the pre-dialysis stage, as well as during maintenance dialysis therapy. A body of evidence highlights the existence of relationship between malnutrition and outcome in this patient population. Several preliminary studies suggest that interventions to improve the poor nutritional status of the ESRD patients may actually improve the expected outcome in these patients, although their long-term efficacy is not well established. It is therefore important to emphasize that malnutrition is a major co-morbid condition in the ESRD population and that the nutritional status and the treatment parameters of these patients should be altered to improve not only the mortality outcome of ESRD patients but also their quality of life.

Quantitating urea removal in patients with acute renal failure: lost art or forgotten science?

A 67-year-old woman is admitted to the surgical service with a high fever, a painful and distended abdomen, jaundice, and almost complete anuria. A urinalysis revealed dark red-brown urine notable for albuminuria, erythrocytes, leukocytes, and casts. The patient was treated with antibiotics, but continued to have oligoanuria. On the eighth day of hospitalization, the following laboratory tests were obtained: serum potassium, 13.7 mEq/L; BUN, 396 mg/dl. At this time the patient was noted to be encephalopathic with deteriorating clinical condition. Renal replacement therapy was initiated. The characteristics of the initial dialysis treatment are described in Table 1. After the initial dialysis treatment, the patient went on to become nonoliguric, followed by gradual recovery of urea clearance. She survived her acute illness, left the hospital, and at 7 months posthospitalization was doing quite well.

Nutrition in acute renal failure patients.

The care of patients with acute renal failure remains a challenge for the nephrologist, with unacceptably high mortality rates. Among many other contributing factors, protein-calorie malnutrition has been suggested as an important predictor of outcome. Protein-calorie malnutrition is highly prevalent in acute renal failure (ARF) patients, and extensive catabolism is a hallmark of these patients. Hypercatabolism can be related to abnormal protein metabolism as well as be a consequence of renal replacement therapy. Inadequate nutritional supplementation also predisposes acute renal failure patients to poor nutritional status. Although multiple studies have evaluated the effects of aggressive nutritional supplementation to reverse malnutrition and improve the outcome in ARF patients, the complexity of the disease process has precluded obtaining meaningful and clear-cut results from these clinical studies. Nevertheless, there is a great need as well as potential to study the actual importance of nutritional aspects in complicated ARF patients.