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Biomedical subjects

Joel D Kopple

Publications and source records attributed to Joel D Kopple.

At least 19 recordsLinked to original sources
PubMed2006

Association between serum lipids and survival in hemodialysis patients and impact of race.

Despite the enormous cardiovascular disease epidemic among maintenance hemodialysis (MHD) patients, total hypercholesterolemia seems paradoxically to be associated with better survival. It was hypothesized that similar paradoxic associations also exist for serum LDL, HDL, and triglycerides. A 3-yr (July 2001 through June 2004) cohort of 15,859 MHD patients was studied in the United States from DaVita dialysis clinics where lipid profile was measured in at least 50% of all outpatients during a given calendar quarter. Cox proportional hazard models were adjusted for case mix and surrogates of malnutrition-inflammation complex. Both total and LDL hypercholesterolemia showed a paradoxic association with better survival. Hypertriglyceridemia (>200 mg/dl) also showed a similar trend, but serum HDL cholesterol did not have any clear association with survival. The association between a low serum LDL <70 mg/dl, which was prevalent among almost 50% of all MHD patients, and a higher all-cause death risk was robust to multivariate adjustment. In the subgroup analyses, these paradoxic associations persisted among most subgroups, although they tended to be stronger among hypoalbuminemic (<3.8 mg/dl) patients and those with a lower dietary protein intake (<1 g/kg per d). However, in black patients, a high serum LDL (>100 mg/ml) was associated with adjusted cardiovascular death hazard ratio of 1.94 (95% confidence interval 1.12 to 2.38; P = 0.02). Despite inverse associations between hyperlipidemia and survival, black MHD patients with high LDL show almost two-fold increase in cardiovascular death risk. Although these associations may not be causal, they call into question whether specific subgroups of dialysis patients are better targets for cholesterol-lowering therapy.

Aged↗
PubMed2006

Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions.

Muscle atrophy in catabolic illnesses is due largely to accelerated protein degradation. Unfortunately, methods for detecting accelerated muscle proteolysis are cumbersome. The goal of this study was to develop a method for detecting muscle protein breakdown and assess the effectiveness of anticatabolic therapy. In rodent models of catabolic conditions, it was found that accelerated muscle protein degradation is triggered by activation of caspase-3. Caspase-3 cleaves actomyosin/myofibrils to form substrates for the ubiquitin-proteasome system and leaves a characteristic 14-kD actin fragment in the insoluble fraction of a muscle lysate. Muscle biopsies were obtained from normal adults and three groups of patients: 14 who were undergoing hip arthroplasty, 28 hemodialysis patients who were participating in exercise programs, and seven severely burned patients. In muscle of patients who were undergoing hip arthroplasty, the 14-kD actin fragment level was correlated (r = 0.787, P < 0.01) with the fractional rate of protein degradation. In muscle of hemodialysis patients who were undergoing endurance exercise training, the 14-kD actin fragment decreased to values similar to levels in normal adults; strength training did not significantly decrease the actin fragment. Severely burned patients had increased muscle protein degradation and actin fragment levels, but the two measures were not significantly correlated. The experimental results suggest that the 14-kD actin fragment in muscle biopsies is increased in catabolic states and could be used in conjunction with other methods to detect and monitor changes in muscle proteolysis that occur in patients with mild or sustained increases in muscle proteolysis.

Actins↗
PubMed2006

Longitudinal associations between dietary protein intake and survival in hemodialysis patients.

BACKGROUND: Decreased dietary protein intake may be associated with increased mortality risk in individuals with kidney failure undergoing maintenance hemodialysis (MHD). We hypothesized that longitudinal changes in dietary protein intake have independent associations with survival in MHD patients. METHODS: The relation between urea kinetic-based normalized protein nitrogen appearance (nPNA) and all-cause and cardiovascular mortality was examined in a 2-year (July 2001 to June 2003) cohort of 53,933 MHD patients from virtually all DaVita dialysis clinics in the United States, using both conventional and time-dependent (repeated-measure) Cox models to estimate death hazard ratios for quarterly averaged nPNA categories controlled for case-mix, comorbidity, dialysis dose (Kt/V), and available markers of malnutrition-inflammation complex syndrome (MICS). RESULTS: The best survival was associated with nPNA between 1.0 and 1.4 g/kg/d, whereas nPNA less than 0.8 or greater than 1.4 g/kg/d was associated with greater mortality in almost all models. Adjustment for MICS mitigated the associations substantially. A decrease in protein intake during the first 6 months in patients with an nPNA in the 0.8- to 1.2-g/kg/d range was associated incrementally with greater death risks in the subsequent 18 months, whereas an increase in nPNA tended to correlate with reduced death risk. CONCLUSION: Low daily protein intake or decrease in its magnitude over time is associated with increased risk for death in MHD patients. Whether the association between time-varying protein intake and survival is causal or a consequence of anorexia secondary to MICS or other factors needs to be explored further in interventional trials.

Aged↗
PubMed2006

Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study.

BACKGROUND: The long-term effect of a low-protein diet on the progression of chronic kidney disease is unknown. We evaluated effects of protein restriction on kidney failure and all-cause mortality during extended follow-up of the Modification of Diet in Renal Disease Study. METHODS: Study A was a randomized controlled trial from 1989 to 1993 of 585 patients with predominantly nondiabetic kidney disease and a moderate decrease in glomerular filtration rate (25 to 55 mL/min/1.73 m(2) [0.42 to 0.92 mL/s/1.73 m(2)]) assigned to a low- versus usual-protein diet (0.58 versus 1.3 g/kg/d). We used registries to ascertain the development of kidney failure (initiation of dialysis therapy or transplantation) or a composite of kidney failure and all-cause mortality through December 31, 2000. We used Cox regression models and intention-to-treat principles to compute hazard ratios for the low- versus usual-protein diet, adjusted for baseline glomerular filtration rate and other factors previously associated with the rate of decrease in glomerular filtration rate. We estimated hazard ratios for the entire follow-up period and then, in time-dependent analyses, separately for 2 consecutive 6-year periods of follow-up. RESULTS: Kidney failure and the composite outcome occurred in 327 (56%) and 380 patients (65%), respectively. After adjustment for baseline factors, hazard ratios were 0.89 (95% confidence interval [CI], 0.71 to 1.12) and 0.88 (95% CI, 0.71 to 1.08), respectively. Adjusted hazard ratios for both outcomes were lower during the first 6 years (0.68; 95% CI, 0.51 to 0.93 and 0.66; 95% CI, 0.50 to 0.87, respectively) than afterward (1.27; 95% CI, 0.90 to 1.80 and 1.29; 95% CI, 0.94 to 1.78; interaction P = 0.008 and 0.002, respectively). Limitations include lack of data for dietary intake and clinical conditions after conclusion of the trial. CONCLUSION: The efficacy of a 2- to 3-year intervention of dietary protein restriction on progression of nondiabetic kidney disease remains inconclusive. Future studies should include a longer duration of intervention and follow-up.

Blood Pressure↗
PubMed2006

Relationship between serum carnitine, acylcarnitines, and renal function in patients with chronic renal disease.

BACKGROUND: Serum free carnitine is decreased and serum acylcarnitines are increased in maintenance hemodialysis (MHD) patients, and the causes for these abnormalities are not known. This study examined the role of renal failure in the occurrence of low serum carnitine and increased acylcarnitines in patients with advanced chronic kidney disease (CKD) by assessing the relationship between these compounds and renal function in normal individuals and patients with CKD. If these compounds decrease as glomerular filtration rate (GFR) decreases, this suggests that decreased intake or impaired synthesis in kidneys explain the low serum values. If serum compounds increase as GFR decreases, this suggests that impaired excretion may predispose to these values. METHODS: The study, conducted in Lyon, France (part A), and Los Angeles, California (part B), compared serum free carnitine and acylcarnitines to renal function in 20 normal patients, 65 CKD patients, and 29 MHD patients. GFR was measured using inulin (A) and iothalamate (B) clearances. Carnitine compounds were measured by tandem mass spectrometry (A) and electron spray mass spectrometry (B). RESULTS: There was no relationship between serum total carnitine or free carnitine and GFR in the normal subjects and CKD patients. In contrast, serum acylcarnitines were inversely correlated with GFR in these 2 groups. Serum free carnitine was significantly lower in MHD patients than in CKD patients and normal controls in study B, whereas acylcarnitines were significantly greater than controls in studies A and B and than in CKD patients in study A. CONCLUSIONS: Serum free carnitine is not reduced in CKD and decreases in MHD patients. Serum acylcarnitines increase in CKD and MHD patients primarily because of impaired excretory function in the failing kidney.

Adult↗
PubMed2006

Transcriptional levels of growth factors in skeletal muscle of maintenance hemodialysis patients.

This study was performed to assess the mRNA levels in skeletal muscle of maintenance hemodialysis (MHD) patients. Fifty-one sedentary MHD patients and 21 sedentary normal adults of similar age, gender distribution, and racial/ethnic mix as the patients were examined. The subjects had needle muscle biopsy to measure mRNA levels. They were assessed in right vastus lateralis muscle for insulinlike growth factor I (IGF-IEa and IGF-IEc), IGF-II, the IGF-I receptor, the IGF-II receptor, and myostatin. mRNA was measured by real-time polymerase chain reaction amplification of reverse transcribed cDNA. The results showed that in the MHD patients, as compared with the normal control patients, skeletal muscle mRNA levels for IGF-IEa, IGF-II, and the IGF-I receptor were significantly reduced, whereas mRNA for IGF-IEc, IGF-II receptor, and myostatin were not different than normal. We conclude that sedentary MHD patients show reductions in mRNA levels in the right vastus lateralis muscle for certain growth factor proteins, notably IGF-IEa, IGF-II, and the IGF-I receptor. These abnormalities may contribute to the sarcopenia and impaired endurance capacity, strength, and physical performance that occur in MHD patients.

Adult↗
PubMed2006

Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients.

OBJECTIVES: Muscle mass and muscle mRNA levels for certain growth factors are reduced in maintenance hemodialysis (MHD) patients. This study tested the hypothesis that in MHD patients endurance exercise training (EET) increases mRNA levels for insulin-like growth factors and reduces myostatin mRNA. DESIGN: Biopsies of the right vastus lateralis muscle were performed before and at the end of 8.9 +/- 0.9 (SEM) weeks of EET in MHD patients. Muscle tissue was analyzed histologically by electron microscopy and for fiber cross-sectional area, and, in 8 pairs of biopsies, muscle was examined for mRNA levels for the following proteins: myostatin, insulin-like growth factor-I (IGF-I), IGF-I receptor (IGF-IR), IGF binding proteins (IGFBPs)-1, -2, -3, -4, and -5, and IGF-binding protein-related protein-1 (IGFBP-rP1). SETTING: Outpatient MHD centers. PATIENTS: This was a pilot study conducted in sedentary clinically stable MHD patients undergoing EET with no control group. INTERVENTION: EET that was carefully supervised by exercise trainers. MAIN OUTCOME MEASURE: Skeletal muscle mRNA levels, especially myostatin mRNA. RESULTS: With EET, skeletal muscle myostatin mRNA decreased by 51%, mRNA levels increased significantly for IGF-IR (by 41%), IGFBP-2, -4, and -5, and IGFBP-rP1. IGF-I mRNA increased by 35%; this change was not significant. IGFBP-3 mRNA did not change, and IGFBP-1 mRNA was undetectable. There were mild to moderate alterations in skeletal muscle ultrastructure that did not change significantly with EET. Muscle fiber size, measured in 5 patients, did not change. CONCLUSION: In MHD patients who undergo approximately 9 weeks of EET, skeletal muscle mRNA for myostatin decreases and mRNA for IGF-IR, IGFBPs -2, -4, and -5 and IGFBP-rP1 increases. These changes may indicate mechanisms by which EET improves muscle exercise capacity in MHD patients.

Adult↗
PubMed2006

Associations of body fat and its changes over time with quality of life and prospective mortality in hemodialysis patients.

BACKGROUND: In maintenance hemodialysis (MHD) patients, a larger body size is associated with better survival but a worse self-reported quality of life (QoL). It is not clear whether muscle mass or body fat confers the survival advantage. OBJECTIVE: We hypothesized that both a low baseline body fat percentage and a loss of fat over time were independently associated with higher mortality but with a better QoL score. DESIGN: In 535 adult MHD patients, body fat was measured directly with the use of near infrared interactance and QoL was measured with a Short Form 36 questionnaire. The patients were followed for < or =30 mo. RESULTS: Across four 12% increments of body fat at baseline, the reported QoL scores were progressively lower (P < 0.01). After a multivariate adjustment for demographics and surrogates of muscle mass and inflammation (ie, midarm muscle circumference, serum creatinine, and proinflammatory cytokines), 46 patients with body fat of <12% had a death hazard ratio (HR) 4 times that of 199 patients with body fat content between 24% and 36% (HR: 4.01; 95% CI: 1.61, 9.99; P = 0.003). In 411 MHD patients whose body fat was remeasured after 6 mo, a fat loss (< or =-1%) was associated with a death risk 2 times that of patients who gained fat (> or =1%) after a multivariate adjustment (HR: 2.06; 95% CI: 1.05, 4.05; P = 0.04). CONCLUSIONS: A low baseline body fat percentage and fat loss over time are independently associated with higher mortality in MHD patients even after adjustment for demographics and surrogates of muscle mass and inflammation, whereas a tendency toward a worse QoL is reported by MHD patients with a higher body fat percentage. Obesity management in dialysis patients may need reconsideration.

Adipose Tissue↗
PubMed2006

Obesity paradox in patients on maintenance dialysis.

Overweight (body mass index [BMI]=25-30 kg/m2) and obesity (BMI>30 kg/m2) have become mass phenomena with a pronounced upward trend in prevalence in most countries throughout the world and are associated with increased cardiovascular risk and poor survival. In patients with chronic kidney disease (CKD) undergoing maintenance hemodialysis an 'obesity paradox' has been consistently reported, i.e., a high BMI is incrementally associated with better survival. While this 'reverse epidemiology' of obesity is relatively consistent in maintenance hemodialysis patients, studies in peritoneal dialysis patients have yielded mixed results. A similar obesity paradox has been described in patients with chronic heart failure as well as in 20 million members of other distinct medically 'at risk' populations in the USA. Possible causes of the reverse epidemiology of obesity include: (1) time-discrepancies between the competing risks for the adverse events that are associated with overnutrition and undernutrition; (2) sequestration of uremic toxins in adipose tissue; (3) selection of a gene pool favorable to longer survival in dialysis patients during the course of CKD progression, which eliminates over 95% of the CKD population before they commence maintenance dialysis therapy; (4) a more stable hemodynamic status; (5) alterations in circulating cytokines; (6) unique neurohormonal constellations; (7) endotoxin-lipoprotein interactions; and (8) reverse causation. Examining the causes and consequences of the obesity paradox in dialysis patients can improve our understanding of similar paradoxes observed both for other conventional risk factors in chronic dialysis patients, such as blood pressure and serum cholesterol, and in other populations, such as patients with heart failure, cancer or AIDS or geriatric populations.

Humans↗
PubMed2006

Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients.

Although treating anemia of chronic kidney disease by erythropoiesis-stimulating agents (ESA) may improve survival, most studies have examined associations between baseline hemoglobin values and survival and ignored variations in clinical and laboratory measures over time. It is not clear whether longitudinal changes in hemoglobin or administered ESA have meaningful associations with survival after adjustment for time-varying confounders. With the use of time-dependent Cox regression models, longitudinal associations were examined between survival and quarterly (13-wk averaged) hemoglobin values and administered ESA dose in a 2-yr (July 2001 to June 2003) cohort of 58,058 maintenance hemodialysis patients from a large dialysis organization (DaVita) in the United States. After time-dependent and multivariate adjustment for case mix, quarterly varying administered intravenous iron and ESA doses, iron markers, and nutritional status, hemoglobin levels between 12 and 13 g/dl were associated with the greatest survival. Among prevalent patients, the lower range of the recommended Kidney Disease Quality Outcomes Initiative hemoglobin target (11 to 11.5 g/dl) was associated with a higher death risk compared with the 11.5- to 12-g/dl range. A decrease or increase in hemoglobin over time was associated with higher or lower death risk, respectively, independent of baseline hemoglobin. Administration of any dose of ESA was associated with better survival, whereas among those who received ESA, requiring higher doses were surrogates of higher death risk. In this observational study, greater survival was associated with a baseline hemoglobin between 12 and 13 g/dl, treatment with ESA, and rising hemoglobin. Falling hemoglobin and requiring higher ESA doses were associated with decreased survival. Randomized clinical trials are required to examine these associations.

Aged↗
PubMed2005

Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction.

BACKGROUND: Hypoalbuminaemia is a marker of malnutrition-inflammation complex syndrome (MICS) and a strong predictor of cardiovascular (CV) death in maintenance haemodialysis (MHD) patients. However, serum albumin may change over time. Hence, its time-varying associations with outcome may be different. METHODS: Associations between 3-month averaged serum albumin levels, measured in a single laboratory using bromocresol green, and CV mortality were studied longitudinally in a 2-year cohort of 58,058 MHD patients. Mortality predictability of fixed baseline and trimonthly-varying serum albumin concentrations were compared. RESULTS: Hazard ratios (HRs) of CV death strictly increased across decrements of baseline serum albumin, whereas the HR for time-varying serum albumin decrements below 3.8 g/dl did not differ. A drop in serum albumin in the first 6 months was associated with increasing all-cause and CV death risks in the subsequent 18 months, while a rise in serum albumin was a predictor of better survival independent of baseline serum albumin. The multivariate adjusted population-attributable fraction of death due to baseline serum albumin <3.8 g/dl was 19%. CONCLUSIONS: Time-varying hypoalbuminaemia predicts all-cause and CV death differently from fixed measures of serum albumin in MHD patients. An increase in serum albumin over time is associated with better survival independent of baseline serum albumin or other MICS surrogates. If this association is causal, an intervention that could increase serum albumin >3.8 g/dl might reduce the number of MHD deaths in the USA by approximately 10,000 annually. Nutritional interventions examining benefits of increasing serum albumin in MHD patients are urgently needed.

Aged↗
PubMed2005

Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.

BACKGROUND: Endurance training improves cardiopulmonary fitness in maintenance haemodialysis (MHD). Because many MHD patients are profoundly deconditioned and exhibit significant muscle weakness, endurance training may also improve muscle strength and physical performance in these patients. This study assessed this possibility. METHODS: Twelve MHD patients performed incremental and constant work rate cycle exercise tests to determine peak work rate, VO(2)peak and endurance time (ET). Lower extremity strength, power and fatigability, stair-climbing time, 10 m walk time and a timed up-and-go were assessed before and after 8.6+/-2.3 weeks of thrice weekly, progressive, semi-recumbent, leg-cycle training during haemodialysis. Initial training intensity and duration targets were set at 50% peak work rate (WR) and 20 min, respectively, with a goal of progressing to 40 min at the highest WR tolerable. Non-exercising MHD patients and healthy volunteers with similar age, gender and race/ethnicity served as comparison groups. RESULTS: None of the subjects tolerated the initial target intensity. Therefore, WR was reduced to 19+/-9 watts (30% of peak WR) for 19.9 min/session. At end of training, subjects cycled at 29+/-25 watts (46% initial peak WR; P = 0.01) for 38+/-8 min (P<0.001). VO(2)peak and ET improved 22% (P = 0.018) and 144% (P = 0.001), respectively. Quadriceps strength, power and fatigability improved 16% (P = 0.002), 15% (P = 0.115) and 43% (P = 0.029), respectively. The three measures of physical performance improved by 14-17% (P<0.031). Total work performed in training increased by 5.5+/-21.1 kJ/week (17%); a 165% increase during the study period. CONCLUSIONS: Nine weeks of leg-cycling during haemodialysis in MHD patients improves not only cardiopulmonary fitness and endurance but also muscle strength, power, fatigability and physical function. These data underscore the value of endurance training in MHD.

Adult↗
PubMed2005

Growth hormone induces anabolism in malnourished maintenance haemodialysis patients.

BACKGROUND: Growth hormone (GH) promotes anabolism in patients undergoing maintenance haemodialysis (MHD). However, no studies have examined the effects of GH on protein anabolism in MHD patients using full nitrogen-balance techniques. This study tested the hypothesis that recombinant human GH (rhGH) will induce an anabolic response, as assessed by long-term classic nitrogen-balance techniques, in malnourished MHD patients. METHODS: Six adult MHD patients with protein-energy malnutrition underwent nitrogen-balance studies in a general clinical research centre for 28-35 days each. Patients were maintained on a constant dialysis regimen and protein and energy intakes that were similar to their dialysis regimen and diet prior to hospitalization. The first 14-21 hospital days constituted a baseline phase; during the subsequent 8-21 days, patients were given daily subcutaneous injections of rhGH (0.05 mg/kg body weight/day). RESULTS: During treatment with rhGH, serum insulin-like growth factor-I (IGF-I) increased by approximately 225% (P = 0.002), nitrogen balance became strongly positive (+2.35 g/day; P = 0.034 vs baseline) and there was a reduction in serum urea nitrogen (-32%; P = 0.001). Two patients who became acutely ill and had the lowest dietary protein intakes developed a much smaller rise in serum IGF-I levels and increase in nitrogen balance when they received the rhGH treatment. In the remaining four responders, the decrease in nitrogen output was sustained throughout the entire period of treatment with rhGH. There was no change in body weight during the baseline or treatment phases of the study. CONCLUSIONS: Injections of rhGH induce a strong and sustained anabolic effect, as indicated by positive nitrogen balance, in MHD patients with protein-energy malnutrition. This response was attenuated in two patients who were acutely ill with low protein intakes, suggesting that they may have developed partial resistance to GH.

Adult↗