Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included.

A method for the estimation of hydration state during hemodialysis using a calf bioimpedance technique.

Although many methods have been utilized to measure degrees of body hydration, and in particular to estimate normal hydration states (dry weight, DW) in hemodialysis (HD) patients, no accurate methods are currently available for clinical use. Biochemcial measurements are not sufficiently precise and vena cava diameter estimation is impractical. Several bioimpedance methods have been suggested to provide information to estimate clinical hydration and nutritional status, such as phase angle measurement and ratio of body fluid compartment volumes to body weight. In this study, we present a calf bioimpedance spectroscopy (cBIS) technique to monitor calf resistance and resistivity continuously during HD. Attainment of DW is defined by two criteria: (1) the primary criterion is flattening of the change in the resistance curve during dialysis so that at DW little further change is observed and (2) normalized resistivity is in the range of observation of healthy subjects. Twenty maintenance HD patients (12 M/8 F) were studied on 220 occasions. After three baseline (BL) measurements, with patients at their DW prescribed on clinical grounds (DW(Clin)), the target post-dialysis weight was gradually decreased in the course of several treatments until the two dry weight criteria outlined above were met (DW(cBIS)). Post-dialysis weight was reduced from 78.3 +/- 28 to 77.1 +/- 27 kg (p < 0.01), normalized resistivity increased from 17.9 +/- 3 to 19.1 +/- 2.3 x 10(-2) Omega m(3) kg(-1) (p < 0.01). The average coefficient of variation (CV) in three repeat measurements of DW(cBIS) was 0.3 +/- 0.2%. The results indicate that cBIS utilizing a dynamic technique continuously during dialysis is an accurate and precise approach to specific end points for the estimation of body hydration status. Since no current techniques have been developed to detect DW as precisely, it is suggested as a standard to be evaluated clinically.

Patient empowerment in the management of hyperphosphatemia.

Despite advances in dialysis technology and an increasing variety of effective phosphate binders (PB) target phosphate levels are achieved in only a minority of ESRD patients. This is only partly explained by insufficient weekly phosphate elimination (2400 - 3000 mg) with traditional 3x 4-5 h dialysis, which is significantly lower than the total amount of phosphorus (iP) accrued from dietary consumption during the same period (about 5000 g). In addition, meal-to-meal and day-to-day variability of dietary iP intake in conjunction with inadequate phosphate binder dosing in relation to meal iP content also may contribute to hyperphosphatemia. It was hypothesized that self-adjusting of PB dose to meal iP content by the patient himself will improve management of hyperphosphatemia. A specific Phosphate-Education-Program (PEP) was developed to train patients to eye-estimate meal iP content by "Phosphate Units" (PU), which categorize food components according to iP content (100 mg iP per serving size = 1 PU). To allow self-adjustment of PB dose to meal iP content, a new prescription concept for PB was required. Phosphate binders are no longer prescribed using a fixed dosing regimen but only in strict relation to meal iP content (#PB per PU). In close collaboration with the patient the PB/PU ratio is then adapted to individual patient needs until serum phosphate targets are met. This new management concept for hyperphosphatemia is the first to establish a direct link between dietary phosphorus intake and PB dose and to empower patients to self-adjust PB dose according to dietary phosphorus intake. Clinical studies are under way to establish the practical value of this new concept for CKD and ESRD patients.

Biosimilars: recent developments.

Biopharmaceuticals are recombinant protein drugs which are produced by biotechnology. The availability of such molecules has revolutionised the way we treat many diseases. However, the patents for many originator biopharmaceuticals are expiring, and a new generation of follow-on molecules, termed "biosimilars", are under development. Health care providers perceive biosimilars to be cheap replacements for originator drugs such as recombinant human erythropoietin and human growth hormone. However, concerns have been raised about the comparability of biosimilars with originator products especially in light of the complex manufacturing process required to produce biopharmaceuticals. The complexity of protein molecules renders it impossible to produce identical copies; this in turn raises questions on the safety of follow-on biosimilar products, particularly with respect to immunogenicity. This review briefly outlines the process of biopharmaceutical production, potential problems that can arise from their long-term use in patients, and the issues facing regulatory bodies as they look to institute guidelines for new biosimilar molecules.

Segment-specific resistivity improves body fluid volume estimates from bioimpedance spectroscopy in hemodialysis patients.

Discrepancies in body fluid estimates between segmental bioimpedance spectroscopy (SBIS) and gold-standard methods may be due to the use of a uniform value of tissue resistivity to compute extracellular fluid volume (ECV) and intracellular fluid volume (ICV). Discrepancies may also arise from the exclusion of fluid volumes of hands, feet, neck, and head from measurements due to electrode positions. The aim of this study was to define the specific resistivity of various body segments and to use those values for computation of ECV and ICV along with a correction for unmeasured fluid volumes. Twenty-nine maintenance hemodialysis patients (16 men) underwent body composition analysis including whole body MRI, whole body potassium (40K) content, deuterium, and sodium bromide dilution, and segmental and wrist-to-ankle bioimpedance spectroscopy, all performed on the same day before a hemodialysis. Segment-specific resistivity was determined from segmental fat-free mass (FFM; by MRI), hydration status of FFM (by deuterium and sodium bromide), tissue resistance (by SBIS), and segment length. Segmental FFM was higher and extracellular hydration of FFM was lower in men compared with women. Segment-specific resistivity values for arm, trunk, and leg all differed from the uniform resistivity used in traditional SBIS algorithms. Estimates for whole body ECV, ICV, and total body water from SBIS using segmental instead of uniform resistivity values and after adjustment for unmeasured fluid volumes of the body did not differ significantly from gold-standard measures. The uniform tissue resistivity values used in traditional SBIS algorithms result in underestimation of ECV, ICV, and total body water. Use of segmental resistivity values combined with adjustment for body volumes that are neglected by traditional SBIS technique significantly improves estimations of body fluid volume in hemodialysis patients.

A Rare Clinical Course of Seronegative Pulmonary-Renal Syndrome.

Purpose. Pulmonary-renal syndrome (PRS) is characterized by diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis mainly due to autoimmune etiologies. Seronegative PRS is a challenging entity to the clinician, since early diagnosis may be missed leading to delayed appropriate treatment. Materials and Methods. We present the clinical course of a 77-year-old patient who was admitted under the suspected diagnosis of pneumogenic sepsis and septic renal failure with fever, dyspnea, and elevated CRP levels. The diagnosis of pulmonary-renal syndrome was initially missed because of the absence of autoantibodies in all serological findings. Results. Despite delayed initiation of immunosuppressive therapy and a prolonged period of dialysis and extracorporeal membrane oxygenation the patient recovered well and was released to a rehabilitation center with nearly normalized creatinine levels. The diagnosis of PRS was established by renal biopsy. Conclusion. This case illustrates the important differential diagnosis of seronegative pulmonary-renal syndrome in patients with pulmonary and renal impairment.

In vivo effects of dialysate flow rate on Kt/V in maintenance hemodialysis patients.

It is generally assumed that hemodialysis adequacy is only minimally affected by increasing the dialysate flow rate (Qd). Recent in vitro studies showed that dialyzer urea clearance (Kd(urea)) may increase substantially more than expected in response to an increase in Qd. Because these studies implied that dialysis efficacy may benefit from greater Qds, we studied in vivo the effects of various Qds on the delivered dose of dialysis in 23 maintenance hemodialysis (MHD) patients. Hemodialysis was performed at Qds of 300, 500, and 800 mL/min for at least 3 weeks each, whereas specific dialysis prescriptions (treatment time, blood flow rate [Qb], ultrafiltration volume, and type and size of dialyzer) were kept constant. Delivered dose of dialysis, assessed by single-pool Kt/V (Kt/V(sp)) and double-pool Kt/V (Kt/ V(dp)), was measured at least three times for each Qd (218 measurements). Mean +/- SEM Kt/V(sp) was 1.19 +/- 0.03 at Qd of 300 mL/min, 1.32 +/- 0.04 at 500 mL/min, and 1.45 +/- 0.04 at 800 mL/min. The relative gains in Kt/V(sp) for increasing Qd from 300 to 500 mL/min and 500 to 800 mL/min were 11.7% +/- 8.7% and 9.9% +/- 5.1%, respectively. Kt/V(dp) increased at a similar percentage (11.2% +/- 8.9% and 10.3% +/- 5.1%, respectively). The observed gain in urea clearance by increasing Qd from 500 to 800 mL/min was significantly greater than the increase in Kd(urea) predicted from mathematical modeling (5.7% +/- 0.4%; P = 0.0008). Removal ratios for creatinine and the high-molecular-weight marker, beta(2)-microglobulin, were not affected by increasing Qd from 500 to 800 mL/min. The proportion of patients not achieving adequacy (Kt/V(sp) >/= 1.2) was reduced from 56% at Qd of 300 mL/min to 30% at 500 mL/min and further to 13% at 800 mL/min. It is concluded that increasing Qd from 500 to 800 mL/min is associated with a significant increase in Kt/V. Hemodialysis with Qd of 800 mL/min should be considered in selected patients not achieving adequacy despite extended treatment times and optimized Qbs.

Heat-preconditioning confers protection from Ca(2+)-mediated cell toxicity in renal tubular epithelial cells (BSC-1).

A rise in intracellular calcium may mediate ischemic damage by phospholipid hydrolysis and proteolysis. Heat shock proteins have been shown to provide protection from various forms of cell stress, but not from models of Ca(2+)-mediated injury. The effect of heat preconditioning in a model of ionomycin-induced injury in cultured renal tubular epithelial cells (BSC-1) was examined. Hsp70-mRNA expression was induced by hyperthermia (HT) (42 degrees C, 60 min). Hsp70 protein accumulation was maximal after 12-18 h and returned to baseline levels by 96 h. Treatment of BSC-1 cells with ionomycin (7.0 microM) produced lethal cell injury characterized by LDH release. Cells examined at 18 h after HT were significantly less damaged than cells studied at 96 h after HT. Our data are the first to demonstrate that heat preconditioning confers protection from Ca(2+)-mediated cell injury. The state of increased tolerance is transient and closely parallels kinetics of Hsp70 expression.

Inhibition of oxidant-induced lipid peroxidation in cultured renal tubular epithelial cells (LLC-PK1) by quercetin.

The protective effect of quercetin against oxidant-induced cell injury (hypoxanthine/xanthine oxidase system) was studied in the renal tubular epithelial cell line LLC-PK1. Pretreatment with quercetin provided protection from structural and functional cell damage in a concentration-dependent manner (10-100 microM). Comparison with structural variants revealed that the protective property of quercetin depends on the number of hydroxyl substituents in the B-ring, the presence of an extended C-ring chromophore, 3-D-planarity and lipophilicity, indicating that membrane affinity is essential for protection. The hypothesis that quercetin exerts its protective effects via inhibition of lipid peroxidation was further examined. Protection by quercetin was found when lipid peroxidation, assessed by the release of malondialdehyde, was initiated by H2O2 or by the combination of 1-chloro-2,4-dinitrobenzene and aminotriazole. In contrast, the bioflavonoid was not protective when oxidative cell damage was induced by menadione and occurred in the absence of lipid peroxidation. These data suggest that cytoprotective effects of quercetin are related to membrane affinity and may be explained by interruption of membrane lipid peroxidation rather than by intracellular scavenging of oxygen free radicals.

New experimental model of acute renal failure and sepsis in rats.

BACKGROUND: A rat model of acute renal failure (ARF) with sepsis (ARF+S) was developed to simulate the clinical syndrome of hypercatabolic illness in patients with ARF. METHODS: Sepsis was created by ligation and needle puncture of the cecum; ARF was created by left renal artery clamping and contralateral nephrectomy. RESULTS: Two studies were performed. In study 1, rats with sham surgery, sepsis, ARF, and ARF+S were examined for 48 hours. During the first 24 hours after surgery, ARF and ARF+S rats displayed increased urea and ammonia nitrogen appearances and abnormal plasma amino acid levels. These abnormalities were exaggerated in ARF+S rats. In study 2, sham, ARF, and ARF+S rats were injected with sodium bicarbonate or normal saline. During the first 24 hours after surgery, the ARF and ARF+S rats showed an increase in urea nitrogen appearance to 210% and 293%, respectively, of sham values, which was greater than the levels that have been previously reported. Sodium bicarbonate treatment did not influence nitrogen output. CONCLUSIONS: Rats with ARF+S may be a useful model for studying catabolic patients with ARF. The lack of effect of sodium bicarbonate on nitrogen balance merits additional study.

Adjustment of dry weight in hemodialysis patients using intradialytic continuous multifrequency bioimpedance of the calf.

BACKGROUND: Current concepts of dry weight (DW) prescription are largely based on clinical symptoms because of the difficulty in assessing extracellular fluid volume (ECV) during dialysis. Intradialytic changes in ECV can be recorded as changes in extracellular resistance [Re] by continuous regional calf multifrequency bioimpedance spectroscopy (BIS). We hypothesized that relative changes in calf Re (Re at time '0' over Re at time 't' [R(e-0)/R(e-t)]) will become very small when ECV is reduced towards normal and individual dry weight is reached. METHOD: Intradialytic continuous calf BIS was recorded repeatedly in 15 hemodialysis (HD) patients. The first measurement was performed at the prevailing clinical dry weight (CDW). Next measurements were made after post-HD body weight was gradually decreased by 0.2-0.3 kg per treatment. This procedure was iterated over several subsequent treatments until a treatment was observed where changes in R(e-0)/R(e-t) were < 1%. The weight at the end of this treatment was defined as "achieved dry weight (ADW)". Each R(e-0)/R(e-t) curve was fitted using a Matlab program (curve fitting toolbox) to obtain the exact weight at 20 min after beginning of the flattening of the R(e-0)/R(e-t) slope ('dry' weight estimated from BIS, DW-BIS). RESULTS: Both mean ADW (80.5 +/- 34.1 kg) and mean DW-BIS (80.6 +/- 34.1) were significantly lower than CDW (81.4 +/- 32.0 kg, p < 0.001), but there was no difference between ADW and DW-BIS. However, the average weight reduction from CDW to ADW (0.80 +/- 0.15 kg) was significantly higher than from CDW to DW-BIS (0.66 +/- 0.14 kg, p < 0.001, paired t-test). When ADW was achieved, pre-dialysis systolic blood pressure (SBP) was lower than at CDW (139.3 +/- 32.5 mmHg, vs. 129.4 +/- 33 mmHg, p < 0.05), post-HD SBP did not differ. The incidence of clinical symptoms of underhydration was similar at CDW (15%) and DW-BIS (15%), but higher at ADW (46%). CONCLUSION: Intradialytic continuous calf BIS allows the assessment of changes in extracellular calf resistance as an indicator of changes in extracellular fluid volume. Recording of a continuous R(e-0)/R(e-t) slope during dialysis appears to be a promising new tool for the prediction of dry weight in hemodialysis patients.

[Malnutrition in hemodialysis patients. Self-assessment, medical evaluation and "verifiable" parameters]. / Malnutrition bei Hämodialysepatienten. Selbsteinschätzung, ärztliche Beurteilung und "objektivierbare" Parameter.

BACKGROUND: Malnutrition in hemodialysis patient is associated with increased mortality and morbidity. Inventions to treat malnutrition are often ineffective. Underestimation by the patients of the importance of dietary interventions might negatively influence any therapeutic outcome. We examined the correlation between nutritional assessment by the patient himself and clinical assessment by the physician. PATIENTS AND METHODS: Subjective global assessment (SGA) was performed in 68 chronic hemodialysis patients Serum concentrations of albumin, prealbumin, transferrin and cholesterin were measured Protein intake was estimated by protein catabolic rate (nPCR). In form of a questionnaire patients were asked to assess then own nutrition. RESULTS: According to SGA-criteria, moderate to severe malnutrition was found in 34% of our patients. In this unauthorized group serum albumin was < 4.0 g/dl in 45% of patients and correlated best with clinical nutritional assessment. Specificity was lower for prealbumin, transferrin, cholesterin, and nPCR. The questionnaire was completed by 85% of patients. Self-assessment of their own nutrition was discrepant to clinical assessment in 84% of malnourished patients. A similar percentage (79%) of malnourished patients considered their own body weight to be adequate, while only 21% indicated desire to gain weight. CONCLUSIONS: Our data indicate that a significant percentage of malnourished hemodialysis patients shows a tendency to overestimate their own nutrition. This may negatively influence patient compliance and should be considered in dietary counseling of malnourished chronic hemodialysis patients.

Metabolic consequences of body size and body composition in hemodialysis patients.

Small body mass index is associated with increased mortality in chronic hemodialysis patients. The reasons for this observation are unclear but may be related to body composition. This study aimed to investigate the body composition in chronic hemodialysis patients. The difference between body mass and the sum of muscle, bone, subcutaneous, and visceral adipose tissue masses, measured by whole body magnetic resonance imaging, was defined as the high metabolic rate compartment representing the visceral mass. Protein catabolic rate was calculated from urea kinetics. Forty chronic hemodialysis patients (mean age 54.7 years; 87.5% African Americans; 45% females) were studied. High metabolic rate compartment expressed in percent of body weight was inversely related to body weight (r=-0.475; P=0.002) and body mass index (r=-0.530; P<0.001). In a multiple linear regression model, protein catabolic rate was significantly correlated only with high metabolic rate compartment (r=0.616; P<0.001). Assuming that protein catabolic rate in addition to protein intake reflects urea and uremic toxin generation, it follows that high metabolic rate compartment is the major compartment involved in their generation. Consequently, uremic toxin production rate may be relatively higher in patients with low body weight and low body mass index as compared to their heavier counterparts. The poorer survival observed in smaller dialysis patients may be related to these relative differences.

Severe valproic acid intoxication is associated with atrial tachycardia: secondary detoxication by hemoperfusion.

Valproic acid is an anticonvulsant drug which is associated with serious toxicity including fatal outcome in case of severe intoxication. Secondary detoxication by hemodialysis or hemoperfusion has been employed successfully in valproic acid intoxication. Cardiac arrhythmias have only been described rarely in valproic acid intoxication in humans. We report on a 15 year-old boy with severe valproic acid intoxication (valproic acid plasma level on admission: 1 150 mg/l) who presented with coma, hypernatremia and atrial tachycardia. The patient was successfully treated with hemoperfusion and intensive supportive care without implementation of a specific antiarrhythmic therapy. We conclude that patients with severe valproic acid intoxication may benefit from secondary detoxication. In addition to generally known symptoms valproic acid intoxication may also be associated with cardiac arrhythmias.

Characterization of threonine transport into a kidney epithelial cell line (BSC-1). Evidence for the presence of Na(+)-independent system asc [corrected].

The transport routes for threonine in a primate kidney epithelial cell line (BSC-1) grown as monolayer in continuous cell culture were studied. We discovered at least four different transport systems for threonine uptake. The Na(+)-dependent route shows biphasic kinetics with a low and high affinity parameter. The apparent kinetic constants for Km1 and Km2 were 0.3 and 36 mM with apparent Vmax values of 6.3 and 90 nmol/mg protein/min, respectively. The high affinity, low Km component resembles system ASC activity, with respect to substrate selectivity. The Na(+)-independent route also exhibits biphasic kinetics. A high affinity component (apparent Km of 1.0 mM, and apparent Vmax of 7.2 nmol/mg protein/min) is sensitive to inhibition by leucine and the aminoendolevo-rotatory isomer of 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid, suggesting participation by system L. The low affinity component (apparent Km of 10.2 mM, and apparent Vmax of 71 nmol/mg protein/min) was specifically inhibited by threonine, serine, and alanine and could be assigned to system asc. The discrimination between system L and asc is based upon differences in pH sensitivity, trans stimulation, and Ki values. In addition, the effects of harmaline, a suspected sodium transport site inhibitor, have been studied. Harmaline noncompetitively inhibited Na(+)-dependent threonine uptake but had no effect on Na(+)-independent transport of threonine. This report is the first to present evidence for the presence of system asc in renal epithelial cells. The physiological and biochemical significance of our findings are discussed.

[Strategies for the use of amino acids. Catabolism and retention]. / Strategien zur Applikation von Aminosäuren. Katabolismus und Retention.

Extensive Catabolism is a hallmark of patients with acute renal failure (ARF) complicating critical illnesses. Catabolism is due to dysregulation of protein metabolism as well as a consequence of diminished renal excretion and renal replacement therapy (RRT). Inadequate nutritional support predisposes patients to malnutrition and increased mortality risk. Since the catabolic rate varies widely in ARF patients and can not be predicted by clinical parameters, direct quantification of the protein catabolic rate should be performed regularly. The urea nitrogen appearance rate (UNA) is a valid and reproducible estimate of nitrogen balance in critically ill patients undergoing continuous RRT. Amino acid losses up to 50 g/day and protein losses up to 15 g/day occur during continuous RRT and need to be compensated for. In order to achieve neutral or positive nitrogen balance a nutritional regimen providing 1.5-2.0 g protein/kg/day and 25-35 kcal/kg/day may be required. Since glutamine losses during continuous RRT may exceed 4 g/day, glutamine supplementation (0.3-0.5 g/kg/day) appears to be recommendable.

Gender-specific differences in dialysis quality (Kt/V): 'big men' are at risk of inadequate haemodialysis treatment.

BACKGROUND: Inadequate dialysis dose is closely related to mortality and morbidity of maintenance haemodialysis (MHD) patients. According to the DOQI guidelines a minimum prescribed dialysis dose of single-pool Kt/V (Kt/Vsp)=1.3, equivalent to equilibrated double pool Kt/V (e-Kt/Vdp)=1.1, is recommended. Knowledge of patient-related risk factors for inadequate delivery of hacmodialysis would be helpful to select patient subgroups for intensive control ofdialysis adequacy. METHODS: A retrospective survey was conducted to assess the prevalence of inadequate dialysis dose according to DOQI criteria during a 7-month period. A total of 320 e-Kt/Vdp measurements in 62 MHD patients were evaluated (mean effective dialysis time 222+/-32 min). Residual renal function (RRF) was expressed as renal weekly Kt/V (r-Kt/Vweek) and included into assessment of total weekly renal and dialytic Kt/V (t-Kt/Vweek). RESULTS: Inadequacy (e-Kt/Vdp<1.10) was prevalent in 37.2% of all measurements and in 22/62 patients (35.5%). In 54% of underdialysed patients r-Kt/Vweek compensated for insufficient dialytic urea removal. Mean weekly Kt/V was inadequate (t-Kt/Vweek<3.30) in 12/62 patients (19.4%) of whom 91.7% (11/12) were male. Body-weight, urea distribution volume (UDV). and body-surface area (BSA) were significantly higher in inadequately is adequately dialysed males. UDV>42.0 litres or BSA>2.0 m2 and a lack of RRF (r-Kt/Vweek<0.3) put 'big men' at increased risk to receive an inadequate dose of dialysis. CONCLUSION: Our data identify patients at risk for inadequate haemodialysis treatment. Special attention should be focused on 'big men' with UDV>42.0 litres or BSA>2.0 m2. In this subset of patients frequent measurements of t-Kt/Vweek and assessment of RRF should be mandatory.

High protein/energy vs. standard protein/energy nutritional regimen in the treatment of malnourished hemodialysis patients.

Although malnutrition is frequently encountered in maintenance hemodialysis (MHD) patients, a clear method of treating this complication is still lacking. Failure of nutritional support regimens may be due to inadequate support of dietary needs. Therefore, a high vs. standard or low protein/energy dietary regimen was studied in malnourished MHD patients. A total of 18 malnourished MHD patients selected according to subjective global assessment (SGA)-scores and biochemical indicators of malnutrition (serum albumin <40 g/l, cholesterol <200 mg/dl, prealbumin <30 mg/dl; two out of three) were assigned to three treatment groups: (A: 45 kcal/kg/d and 1.5 g protein/kg/d; B: 35 kcal/kg/d and 1.2 g protein/kg/d; C: spontaneous intake supplemented with 10% of mean protein and energy intake). A and B received food supplements at appropriate dosing to reach the targeted nutritional intake. During 3-month follow-up nutrient intake was assessed by repeated 4-day dietary diaries. Compliance and tolerance was good in each group. Weight gain (1.2+/-0.4 kg) was observed in group A, but not in B and C. Serum albumin levels increased by 1.0+/-0.5 g/l in group A, but not in B and C. Prealbumin and cholesterol levels were unaffected. Weight change correlated with mean dietary energy intake, but not with mean dietary protein intake. We conclude that prescription of 45 kcal/kg/d and 1.5 g protein/kg/d may be necessary to achieve weight gain and improvement of nutritional indices in malnourished MHD pts. Oral food supplements can be used safely and effectively to increase nutrient intake to high levels in these patients.

Evaluation of renal Kt/V as a marker of renal function in predialysis patients.

BACKGROUND: The use of renal Kt/V (r-Kt/V) as an indicator for the need of dialysis initiation has been recommended in the NKF-DOQI guidelines. In analogy to clinical practice in peritoneal dialysis, a fall of r-Kt/V below a threshold of 2.0 per week may indicate inadequate renal toxin elimination. However, there are no studies linking r-Kt/V with other parameters of glomerular filtration rate (GFR) in predialysis patients, and the validity of r-Kt/V as parameter for timing of dialysis initiation is unknown. METHODS: Renal function was assessed repeatedly in 125 patients (N = 465 measurements). In predialysis patients (r-Kt/V <2.5 per week) r-Kt/V was compared with creatinine [CCr], urea [CUr], averaged creatinine/urea clearance [CCr/Ur], Cockcroft-Gault formula [CCG], and MDRD prediction equation 6 (MDRD6-GFR). The diagnostic performance of r-Kt/V as a parameter for timing the initiation of dialysis was evaluated. RESULTS: Renal Kt/V <2.5 was prevalent in 24.9% of cases (N = 116, mean 1.92 +/- 0.34). In this group mean CCr was 13.8 +/- 4.9, mean CUr 6.7 +/- 1.3, and CCr/Ur 10.2 +/- 2.9 mL/min/1.73 m2. There was no correlation of r-Kt/V with serum creatinine and MDRD6-GFR, but a significantly positive correlation with CCr/Ur (r2 = 0.3382, P < 0.001). Sensitivity of r-Kt/V to detect CCr/Ur < 10.5 mL/min/1.73 m2, defined as the threshold for dialysis initiation, was 73.6% with a specificity of 91.9%. CONCLUSIONS: These results suggest that r-Kt/V is a parameter of acceptable specificity but poor sensitivity for the timing of dialysis initiation. Additional measures of renal function, such as the average of measured creatinine and urea clearance, also should be taken into consideration when deciding on the timing of dialysis initiation prior to the development of clinical signs of uremia and malnutrition.