Is malnutrition a determining factor of health-related quality of life in hemodialysis patients? A cross-sectional design examining relationships with a comprehensive assessment of nutritional status.

PURPOSE: To identify relationships between health-related quality of life (HRQOL) and nutritional status in hemodialysis (HD) patients. METHOD: Secondary data from a cross-sectional survey was utilized. HRQOL was assessed for 379 HD patients using the generic Short Form 36 (SF-36) and disease-specific Kidney-Disease Quality of Life-36 (KDQOL-36). Malnutrition was indicated by malnutrition inflammation score (MIS) ≥ 5, and presence of protein-energy wasting (PEW). The individual nutritional parameters included the domains of physical status, serum biomarkers, and dietary intake. Multivariate associations were assessed using the general linear model. RESULTS: MIS ≥ 5 was negatively associated with SF-36 scores of physical functioning (MIS < 5 = 73.4 ± 8.0 SE vs MIS ≥ 5 = 64.6 ± 7.7 SE, P < 0.001), role-limitation-physical (MIS < 5 = 65.3 ± 14.3 SE vs MIS ≥ 5 = 52.9 ± 14.0 SE, P = 0.006), general health (MIS < 5 = 53.7 ± 7.5 SE vs MIS ≥ 5 = 47.0 ± 7.1 SE, P = 0.003), and PCS-36 (MIS < 5 = 40.5 ± 3.3 SE vs MIS ≥ 5 = 35.9 ± 3.1 SE, P < 0.001); and KDQOL-36 score of symptoms/problems (MIS < 5 = 78.9 ± 5.6 SE vs MIS ≥ 5 = 74.8 ± 5.4 SE, P = 0.022), but not with PEW by any tool. Of individual nutritional parameters, underweight (68.1 ± 5.4 SE, P = 0.031), normal weight (63.8 ± 2.8 SE, P = 0.023), and overweight (64.3 ± 2.9 SE, P = 0.003) patients had significantly higher physical functioning scores compared to obese patients (44.8 ± 5.5 SE). Serum albumin levels were positively associated with physical functioning (P = 0.041) score. HGS was also positively associated with physical functioning (P = 0.036), and vitality (P = 0.041) scores. Greater dietary phosphorus intakes were significantly associated with lower scores for role limitation-physical (P = 0.008), bodily pain (P = 0.043), and PCS-36 (P = 0.024). CONCLUSION: Malnutrition diagnosis by MIS, but not PEW, indicated associations with HRQOL in HD patients. Individual nutritional parameters that related to higher HRQOL were BMI < 30 kg/m2, better dietary phosphorus control, greater muscle strength and higher visceral protein pool.

The state of nutrition care in outpatient hemodialysis settings in Malaysia: a nationwide survey.

BACKGROUND: This study aimed to assess the situational capacity for nutrition care delivery in the outpatient hemodialysis (HD) setting in Malaysia by evaluating dietitian accessibility, nutrition practices and patients' outcomes. METHODS: A 17-item questionnaire was developed to assess nutrition practices and administered to dialysis managers of 150 HD centers, identified through the National Renal Registry. Nutritional outcomes of 4362 patients enabled crosscutting comparisons as per dietitian accessibility and center sector. RESULTS: Dedicated dietitian (18%) and visiting/shared dietitian (14.7%) service availability was limited, with greatest accessibility at government centers (82.4%) > non-governmental organization (NGO) centers (26.7%) > private centers (15.1%). Nutritional monitoring varied across HD centers as per albumin (100%) > normalized protein catabolic rate (32.7%) > body mass index (BMI, 30.7%) > dietary intake (6.0%). Both sector and dietitian accessibility was not associated with achieving albumin ≥40 g/L. However, NGO centers were 36% more likely (p = 0.030) to achieve pre-dialysis serum creatinine ≥884 µmol/L compared to government centers, whilst centers with dedicated dietitian service were 29% less likely (p = 0.017) to achieve pre-dialysis serum creatinine ≥884 µmol/L. In terms of BMI, private centers were 32% more likely (p = 0.022) to achieve BMI ≥ 25.0 kg/m2 compared to government centers. Private centers were 62% less likely (p <  0.001) while NGO centers were 56% less likely (p <  0.001) to achieve serum phosphorus control compared to government centers. Patients from centers with a shared/visiting dietitian had 35% lower probability (p <  0.001) to achieve serum phosphorus levels below 1.78 mmol/L compared to centers without access to a dietitian. CONCLUSIONS: There were clear discrepancies in nutritional care in Malaysian HD centers. Changes in stakeholder policy are required to ensure that dietitian service is available in Malaysian HD centers.

Intravenous iron and erythropoiesis-stimulating agents in haemodialysis: A systematic review and meta-analysis.

AIM: Higher dosages of erythropoiesis-stimulating agents (ESAs) have been associated with adverse effects. Intravenous iron is used to optimize ESA response and reduces ESA doses in haemodialysis patients; this meta-analysis evaluates the magnitude of this effect. METHODS: A literature search was performed using MEDLINE, Embase and the Cochrane Collaboration Central Register of Clinical Trials from inception until December 2014, to identify randomized controlled trials of intravenous iron and ESA, in patients undergoing haemodialysis for end-stage kidney disease. Dosing of IV iron in concordance with the Kidney Disease Improving Global Outcomes guidelines was considered optimal iron therapy. RESULTS: Of the 28 randomized controlled trials identified, seven met the criteria for inclusion in the meta-analysis. Results of random-effects meta-analysis show a statistically significant weighted mean (95% CI) difference of -1733 [-3073, -392] units/week in ESA dose for optimal iron versus suboptimal iron. The weighted average change in ESA dose was a reduction of 23% (range -7% to -55%) attributable to appropriate dosing of intravenous iron. A comparison of intravenous iron versus oral iron/no iron (five trials) showed a greater reduction in ESA dose, although this did not reach statistical significance (weighted mean difference, 95% CI: -2,433 [-5183, 318] units/week). The weighted average change in ESA dose across the five trials was a reduction of 31% (range -8% to -55%). CONCLUSION: Significant reductions in ESA dosing may be achieved with optimal intravenous iron usage in the haemodialysis population, and suboptimal iron use may require higher ESA dosing to manage anaemia.

Randomized controlled trial to compare the efficacy and safety of oral paricalcitol with oral calcitriol in dialysis patients with secondary hyperparathyroidism.

AIM: The objective of the study was to compare the efficacy and safety of oral paricalcitol with oral calcitriol for treating secondary hyperparathyroidism. METHODS: We conducted the first multicenter open-labelled parallel group randomized controlled trial in 66 patients on dialysis. Patients were randomized to paricalcitol or calcitriol at a 3:1 dose ratio and adjusted to maintain intact parathyroid hormone (iPTH) level between 150-300 pg/mL, serum calcium ≤2.74 mmol/L and calcium-phosphate product ≤5.63 mmol(2) /L(2). The primary end point was the proportion of patients who achieved >30% reduction in iPTH. RESULTS: At 24 weeks, 22 (61.1%) patients in the paricalcitol and 22 (73.3%) in the calcitriol group had achieved the primary end-point (P-value = 0.29). The cumulative proportion of patients who achieved the end-point at 6 weeks, 12 weeks and 24 weeks were 50%, 80.6% and 86.1%, respectively, in paricalcitol and 53.3%, 86.7% and 86.7%, respectively, in the calcitriol group (P-value = 0.67). Median time to the end-point was 6 weeks in both groups. There were no significant differences in iPTH level at any time during the study. The median reduction in iPTH at 24 weeks was 48.4% in the paricalcitol group and 41.9% in the calcitriol group (P-value = 0.6). The median maximal iPTH reduction was 77.1% (paricalcitol) and 83.7% (calcitriol), P-value = 0.3. Serum calcium and incidence of hypercalcaemia did not differ between groups. 16.7% of patients in both groups had at least one episode of hypercalcaemia (serum calcium >2.74 mmol/L). Other adverse events were similar between groups. CONCLUSION: Our study suggests that oral paricalcitol has similar efficacy and safety to oral calcitriol.

Effectiveness of a Nutritional Mobile Application for Management of Hyperphosphatemia in Patients on Hemodialysis: A Multicenter Open-Label Randomized Clinical Trial.

This study aims to determine the effectiveness of a phosphate mobile app (PMA), MyKidneyDiet-Phosphate Tracker ©2019, on hemodialysis (HD) patients with hyperphosphatemia. A multicenter, open-label, randomized controlled trial design allowed randomization of patients with hyperphosphatemia to either the usual care group (UG; receiving a single dietitian-led session with an education booklet) or the PMA group (PG). Thirty-three patients in each intervention group completed the 12-week study. Post-intervention, serum phosphorus levels were reduced in both groups (PG: −0.25 ± 0.42 mmol/L, p = 0.001; UG: −0.23 ± 0.33 mmol/L, p < 0.001) without any treatment difference (p > 0.05). Patients in both groups increased their phosphate knowledge (PG: 2.18 ± 3.40, p = 0.001; UG: 2.50 ± 4.50, p = 0.003), without any treatment difference (p > 0.05). Dietary phosphorus intake of both groups was reduced (PG: −188.1 ± 161.3 mg/d, p < 0.001; UG: −266.0 ± 193.3 mg/d, p < 0.001), without any treatment difference (p > 0.05). The serum calcium levels of patients in the UG group increased significantly (0.09 ± 0.20 mmol/L, p = 0.013) but not for the PG group (−0.03 ± 0.13 mmol/L, p = 0.386), and the treatment difference was significant (p = 0.007). As per phosphate binder adherence, both groups reported a significant increase in Morisky Medication Adherence Scale scores (PG: 1.1 ± 1.2, p < 0.001; UGa: 0.8 ± 1.5, p = 0.007), without any treatment difference (p > 0.05). HD patients with hyperphosphatemia using the PMA achieved reductions in serum phosphorus levels and dietary phosphorus intakes along with improved phosphate knowledge and phosphate binder adherence that were not significantly different from a one-off dietitian intervention. However, binder dose adjustment with meal phosphate content facilitated by the PMA allowed stability of corrected calcium levels, which was not attained by UC patients whose binder dose was fixed.

A Mobile App for Triangulating Strategies in Phosphate Education Targeting Patients with Chronic Kidney Disease in Malaysia: Development, Validation, and Patient Acceptance.

Hyperphosphatemia afflicts end-stage chronic kidney disease (CKD) patients, contributing to comorbidities and mortality. Management strategies are dialysis, phosphate binder, and limiting dietary phosphate intake, but treatment barriers are poor patient compliance and low health literacy arising from low self-efficacy and lack of educational resources. This study describes developing and validating a phosphate mobile application (PMA). The PMA development based on the seven-stage Precaution Adoption Process Model prioritized titrating dietary phosphate intake with phosphate binder dose supported by educational videography. Experts (n = 13) first evaluated the PMA for knowledge-based accuracy, mobile heuristics, and clinical value. Adult HD patients validated the improved PMA using the seven-point mHealth App Usability Questionnaire (MAUQ). Patient feedback (n = 139) indicated agreement for ease of use (69.2%), interface and satisfaction (69.0%), and usefulness (70.1%), while 72.7% said they would recommend this PMA. The expectation confirmation for 25 PMA features ranged from 92.1% (lifestyle) up to 100.0% (language option); and the utilization rate of each feature varied from 21.6% (goal setting and feature-based log) to 91.4% (information on dietary phosphate and phosphate binder). The Conclusions: MyKidneyDiet-Phosphate Tracker PMA was acceptable to adult Malaysian HD patients as part of clinical phosphate management in low-resource settings.

Circulating fatty acid profiles are associated with protein energy wasting in maintenance hemodialysis patients: a cross-sectional study.

The metabolic impact of circulating fatty acids (FAs) in patients requiring hemodialysis (HD) is unknown. We investigated the associations between plasma triglyceride (TG) FAs and markers of inflammation, insulin resistance, nutritional status and body composition. Plasma TG-FAs were measured using gas chromatography in 341 patients on HD (age = 55.2 ± 14.0 years and 54.3% males). Cross-sectional associations of TG-FAs with 13 markers were examined using multivariate linear regression adjusted for potential confounders. Higher levels of TG saturated fatty acids were associated with greater body mass index (BMI, r = 0.230), waist circumference (r = 0.203), triceps skinfold (r = 0.197), fat tissue index (r = 0.150), serum insulin (r = 0.280), and homeostatic model assessment of insulin resistance (r = 0.276), but lower malnutrition inflammation score (MIS, r = - 0.160). Greater TG monounsaturated fatty acid levels were associated with lower lean tissue index (r = - 0.197) and serum albumin (r = - 0.188), but higher MIS (r = 0.176). Higher levels of TG n-3 polyunsaturated fatty acids (PUFAs) were associated with lower MIS (r = - 0.168) and interleukin-6 concentrations (r = - 0.115). Higher levels of TG n-6 PUFAs were associated with lower BMI (r = - 0.149) but greater serum albumin (r = 0.112). In conclusion, TG monounsaturated fatty acids were associated with poor nutritional status, while TG n-3 PUFAs were associated with good nutritional status. On the other hand, TG saturated fatty acids and TG n-6 PUFAs had both favorable and unfavorable associations with nutritional parameters.

Muscle Status Response to Oral Nutritional Supplementation in Hemodialysis Patients With Protein Energy Wasting: A Multi-Center Randomized, Open Label-Controlled Trial.

Background: Muscle wasting, observed in patients with end-stage kidney disease and protein energy wasting (PEW), is associated with increased mortality for those on hemodialysis (HD). Oral nutritional supplementation (ONS) and nutrition counseling (NC) are treatment options for PEW but research targeting muscle status, as an outcome metric, is limited. Aim: We compared the effects of combined treatment (ONS + NC) vs. NC alone on muscle status and nutritional parameters in HD patients with PEW. Methods: This multi-center randomized, open label-controlled trial, registered under ClinicalTrials.gov (Identifier no. NCT04789031), recruited 56 HD patients identified with PEW using the International Society of Renal Nutrition and Metabolism criteria. Patients were randomly allocated to intervention (ONS + NC, n = 29) and control (NC, n = 27) groups. The ONS + NC received commercial renal-specific ONS providing 475 kcal and 21.7 g of protein daily for 6 months. Both groups also received standard NC during the study period. Differences in quadriceps muscle status assessed using ultrasound (US) imaging, arm muscle area and circumference, bio-impedance spectroscopy (BIS), and handgrip strength (HGS) methods were analyzed using the generalized linear model for repeated measures. Results: Muscle indices as per US metrics indicated significance (p < 0.001) for group × time interaction only in the ONS + NC group, with increases by 8.3 and 7.7% for quadriceps muscle thickness and 4.5% for cross-sectional area (all p < 0.05). This effect was not observed for arm muscle area and circumference, BIS metrics and HGS in both the groups. ONS + NC compared to NC demonstrated increased dry weight (p = 0.039), mid-thigh girth (p = 0.004), serum prealbumin (p = 0.005), normalized protein catabolic rate (p = 0.025), and dietary intakes (p < 0.001), along with lower malnutrition-inflammation score (MIS) (p = 0.041). At the end of the study, lesser patients in the ONS + NC group were diagnosed with PEW (24.1%, p = 0.008) as they had achieved dietary adequacy with ONS provision. Conclusion: Combination of ONS with NC was effective in treating PEW and contributed to a gain in the muscle status as assessed by the US, suggesting that the treatment for PEW requires nutritional optimization via ONS.

Association of dietary patterns with serum phosphorus in maintenance haemodialysis patients: a cross-sectional study.

Sources of dietary phosphate differentially contribute to hyperphosphatemia in maintenance haemodialysis (MHD) patients. This cross-sectional study in Malaysia investigated association between dietary patterns and serum phosphorus in MHD patients. Dietary patterns were derived by principal component analysis, based on 27 food groups shortlisted from 3-day dietary recalls of 435 MHD patients. Associations of serum phosphorus were examined with identified dietary patterns. Three dietary patterns emerged: Home foods (HFdp), Sugar-sweetened beverages (SSBdp), and Eating out noodles (EO-Ndp). The highest tertile of patients in HF (T3-HFdp) pattern significantly associated with higher intakes of total protein (p = 0.002), animal protein (p = 0.001), and animal-based organic phosphate (p < 0.001), whilst T3-SSBdp patients had significantly higher intakes of total energy (p < 0.001), inorganic phosphate (p < 0.001), and phosphate:protein ratio (p = 0.001). T3-EO-Ndp patients had significantly higher intakes of total energy (p = 0.033), total protein (p = 0.003), plant protein (p < 0.001), but lower phosphate:protein ratio (p = 0.009). T3-SSBdp patients had significantly higher serum phosphorus (p = 0.006). The odds ratio of serum phosphorous > 2.00 mmol/l was significantly 2.35 times higher (p = 0.005) with the T3-SSBdp. The SSBdp was associated with greater consumption of inorganic phosphate and higher serum phosphorus levels.

Association of Ultrasound-Derived Metrics of the Quadriceps Muscle with Protein Energy Wasting in Hemodialysis Patients: A Multicenter Cross-Sectional Study.

This study aimed to assess muscle wasting and risk of protein energy wasting (PEW) in hemodialysis (HD) patients using an ultrasound (US) imaging method. PEW was identified using the ISRNM criteria in 351 HD patients. Quadriceps muscle thickness of rectus femoris (RF) and vastus intermedius (VI) muscles and cross-sectional area (CSA) of the RF muscle (RFCSA) were measured using US and compared with other physical measures. Associations of US indices with PEW were determined by logistic regression. Irrespective of gender, PEW vs. non-PEW patients had smaller RF, VI muscles, and RFCSA (all p < 0.001). US muscle sites (all p < 0.001) discriminated PEW from non-PEW patients, but the RFCSA compared to bio-impedance spectroscopy had a greater area under the curve (AUC, 0.686 vs. 0.581), sensitivity (72.8% vs. 65.8%), and specificity (55.6% vs. 53.9%). AUC of the RFCSA was greatest for PEW risk in men (0.74, 95% CI: 0.66-0.82) and women (0.80, 95% CI: 0.70-0.90) (both p < 0.001). Gender-specific RFCSA values (men < 6.00 cm2; women < 4.47 cm2) indicated HD patients with smaller RFCSA were 8 times more likely to have PEW (AOR = 8.63, 95% CI: 4.80-15.50, p < 0.001). The US approach enabled discrimination of muscle wasting in HD patients with PEW. The RFCSA was identified as the best US site with gender-specific RFCSA values to associate with PEW risk, suggesting potential diagnostic criteria for muscle wasting.

Dietary fatty acid intake in hemodialysis patients and associations with circulating fatty acid profiles: A cross-sectional study.

OBJECTIVES: The aims of this study were threefold: first, to assess the dietary fatty acid (FA) intake and blood FA status in Malaysian patients on hemodialysis (HD); second, to examine the association between dietary FA intakes and blood FA profiles in patients on HD; and third, to determine whether blood FAs could serve as a biomarker of dietary fat intake quality in these patients. METHODS: Using 3 d of dietary records, FA intakes of 333 recruited patients were calculated using a food database built from laboratory analyses of commonly consumed Malaysian foods. Plasma triacylglycerol (TG) and erythrocyte FAs were determined by gas chromatography. RESULTS: High dietary saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) consumption trends were observed. Patients on HD also reported low dietary ω-3 and ω-6 polyunsaturated fatty acid (PUFA) consumptions and low levels of TG and erythrocyte FAs. TG and dietary FAs were significantly associated respective to total PUFA, total ω-6 PUFA, 18:2 ω-6, total ω-3 PUFA, 18:3 ω-3, 22:6 ω-3, and trans 18:2 isomers (P < 0.05). Contrarily, only dietary total ω-3 PUFA and 22:6 ω-3 were significantly associated with erythrocyte FAs (P < 0.01). The highest tertile of fish and shellfish consumption reflected a significantly higher proportion of TG 22:6 ω-3. Dietary SFAs were directly associated with TG and erythrocyte MUFA, whereas dietary PUFAs were not. CONCLUSION: TG and erythrocyte FAs serve as biomarkers of dietary PUFA intake in patients on HD. Elevation of circulating MUFA may be attributed to inadequate intake of PUFAs.

Nephrologist-Initiated Peritoneal Dialysis Catheter Insertion Programme: A New Paradigm Shift.

BACKGROUND: The success rate of peritoneal dialysis (PD) catheter insertion is known to vary among different operators and may be influenced by many factors such as patient and various situational factors. Traditionally, surgeons have inserted Tenckhoff catheters by mini-laparotomy or an open technique. However, with recent advances in endoscopic instrumentation and video capabilities, peritoneoscope Tenckhoff catheter insertion has become a viable approach in interventional nephrologist-initiated PD access programmes. SUMMARY: Nephrologist-initiated peritoneoscopic PD access programs have had a positive impact on PD penetration. The technique has been associated with a better primary success rate, superior catheter survival, less postoperative pain, shorter hospital stay, and shorter catheter break-in time compared with the conventional surgical technique. The role of interventional nephrologists in peritoneoscope Tenckhoff catheter placement is still perceived to be a relatively new advance, investigational by some, and many nephrologists and surgeons alike remain sceptical of the value of this recent option. Crucial questions often raised are how many procedures one needs to perform before being considered competent and who should be credentialed to perform the procedure or supervise trainees performing it. The evaluation of technical proficiency in a specific operation is difficult and complex. Cumulative summation (CUSUM) analysis is one option for tracking the success and failure of technical skill and examining trends over time. Key Messages: The author's facility has had good outcomes with a nephrologist-initiated peritoneoscopic PD access programme. Quality control of PD catheter insertion can be performed using CUSUM charting to monitor for primary catheter dysfunction, primary leak, and primary peritonitis.

A randomized, multicenter, open-label trial to determine peritonitis rate, product defect, and technique survival between ANDY-Disc and UltraBag in patients on CAPD.

BACKGROUND: With the various twin-bag systems available on the market, we decided to conduct a therapeutic equivalence study comparing ANDY-Disc (Fresenius Medical Care, Bad Homburg, Germany) with UltraBag (Baxter, Deerfield, IL) in patients on continuous ambulatory peritoneal dialysis (CAPD) therapy. METHODS: This multicenter, open-label, parallel-group, randomized trial is designed to show the therapeutic equivalence of ANDY-Disc with UltraBag. All CAPD patients from the 6 participating centers who met inclusion/exclusion criteria were enrolled into the trial. They were randomly assigned and converted from the Y-disconnect system (Ultraset; Baxter) to the twin-bag systems. The primary outcome variable is peritonitis, and secondary outcome parameters are technique failure or product defect. RESULTS: From April 2002 to May 2003, a total of 270 patients were recruited for this study. Overall peritonitis rates were 22.9 patient-months/episode for ANDY-Disc and 35.0 patient-months/episode for UltraBag. The overall peritonitis rate for ANDY-Disc was 53% greater compared with UltraBag, but the 95% confidence interval overlaps the prespecified margin of equivalence. There were more product defects reported with ANDY-Disc; 236 product defects compared with 17 with UltraBag. The time series of the number of product defects and peritonitis count on the ANDY-Disc arm suggests a possible cause-and-effect relationship. CONCLUSION: Therapeutic equivalence of ANDY-Disc to UltraBag could not be established with respect to peritonitis. There is a trend toward greater risk for peritonitis on the Andy-Disc arm. There also is a suggestive cause-and-effect relation between the occurrence of product defect and peritonitis on the ANDY-Disc arm during the early part of the trial.

Randomized trial on the therapeutic equivalence between Eprex and GerEPO in patients on haemodialysis.

AIM: Treatment of renal anaemia with epoetin is well established. However, epoetin is expensive. Biogeneric epoetin with proven efficacy would reduce cost and improve access to therapy. We conducted this first ever comparative study of a biogeneric and the original product. METHODS: Stable haemodialysis patients with haemoglobin (Hb) of at least 9 g/dL and receiving the human recombinant erythropoietin Eprex were randomized to continue Eprex or convert to GerEPO, a biogeneric epoetin, for 12 weeks. The primary efficacy variable was a change in Hb from baseline. RESULTS: Ninety-three subjects were randomized to each arm. Ninety-two and 87 subjects on the Eprex and GerEPO arms, respectively, completed the trial. Mean Hb in both groups declined over time. The mean decline in Hb was -0.47 g/dL in the Eprex group and -0.45 g/dL in the GerEPO group. The mean difference in the change in Hb from baseline to week 12 between the two groups was 0.02. The 95% confidence interval was -0.42 to 0.46, which lies within the margin of equivalence (+/-0.5 g/dL). The results of intention-to-treat analysis were similar. There were no significant differences in the epoetin dose, iron therapy or iron stores between the groups. Patients receiving GerEPO reported more adverse events. CONCLUSION: GerEPO was therapeutically equivalent to Eprex with respect to Hb response for patients with Hb in the subtherapeutic target range as is common in this study population. The trial duration was insufficient for safety evaluation, which must await further investigation. More biogeneric products should be subjected to rigorous evaluation.