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Background: Health-Related Quality of Life (HRQoL) assessment after kidney transplantation has become an important tool in evaluating outcomes. This study aims to identify the associated factors with HRQoL among a representative sample size of Kidney Transplant Recipients (KTR) at the time of their inclusion in the study., Methods: Data of this cross-sectional design is retrieved from a longitudinal study conducted in five French kidney transplant centers in 2011, and included KTR aged 18 years with a functioning graft for at least 1 year. Measures include demographic, psycho-social and clinical characteristics. To evaluate HRQoL, the Short Form-36 Health Survey (SF-36) and a HRQoL instrument for KTR (ReTransQol) were administered. Multivariate linear regression models were performed., Results: A total of 1424 patients were included, with 61.4% males, and a mean age of 55.7 years (±13.1). Demographic and clinical characteristics were associated with low HRQoL scores for both questionnaires. New variables were found in our study: perceived poor social support and being treated by antidepressants were associated with low scores of Quality of Life (QoL), while internet access was associated with high QoL scores., Conclusion: The originality of our study's findings was that psycho-social variables, particularly KTR treated by antidepressants and having felt unmet needs for any social support, have a negative effect on their QoL. It may be useful to organize a psychological support specifically adapted for patients after kidney transplantation.

Objective: LN is a severe complication of SLE. Non-invasive biomarkers are needed for identifying patients at risk of a renal flare, for differentiating proliferative from non-proliferative forms and for assessing prognoses for LN., Methods: We assessed the link between blood transcriptional signatures and LN using blood samples from patients with biopsy-proven LN, extra-renal SLE flares or quiescent SLE. Healthy controls, and control patients with glomerular diseases or bacterial sepsis were included. Modular repertoire analyses from microarray data were confirmed by PCR., Results: A modular neutrophil signature (upregulation of module M5.15) was present in 65% of SLE patients and was strongly associated with LN. M5.15 activity was stronger in LN than in extra-renal flares (88 vs 17%). M5.15 was neither correlated to IFN modules, nor to SLEDAI or anti-dsDNA antibodies, but moderately to CS dose. M5.15 activity was associated with severity of LN, was stronger when proliferative, and decreased in patients responding to treatment. M5.15 activation was not caused by higher CS dose because it correlated only moderately to neutrophil count and was also observed among quiescent patients. Among quiescent patients, those with a past history of LN had higher M5.15 activity (50 vs 8%). M5.15 activation was present in patients with bacterial sepsis or ANCA-associated vasculitis, but not in patients with other glomerular diseases. Overall, M5.15 activation was associated with past, present or future flares of LN., Conclusion: Modular neutrophil signature could be a biomarker for stratifying LN risk and for monitoring its response to treatment., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00920114., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background and Objectives: Monoclonal gammopathies (MGs) with renal involvement can lead to ESRD caused by myeloma cast nephropathy (MCN), immunoglobulin light chain amyloidosis (ALA), or light-chain deposition disease (LCDD). Few studies have focused on the prognosis of patients with MG on chronic dialysis. We evaluated the outcomes of patients with MG incident on chronic dialysis in France., Design, Setting, Participants, & Measurements: All incident patients registered in the Renal Epidemiology and Information Network Registry between 2002 and 2011 with ESRD caused by ALA, LCDD, or MCN were included. Patient's survival, censored for renal transplantation, renal recovery, and loss to follow-up, as well as renal outcomes were analyzed and compared with a control group. Risk factors and causes of death were analyzed., Results: We included 1459 patients, comprising 265 (18%) patients with ALA, 334 (23%) patients with LCDD, and 861 (59%) patients with MCN. Median age was 72 years, and 56% were men. Median follow-up was 13.1 months. Renal recovery was observed in 9.1% of patients and more frequent after 2006. Kidney transplantation was rare in this population (2.3%). Among 1272 patients who remained on dialysis, 67% died. Median survival on dialysis was 18.3 months. Main causes of death were malignancies (34.4%), cardiovascular diseases (18%), infections (13.3%), and cachexia (5.2%). Independent risk factors of death were age (hazard ratio [HR], 1.03 per year increase; 95% confidence interval [95% CI], 1.02 to 1.03), frailty (HR, 1.93; 95% CI, 1.58 to 2.36), congestive heart failure (HR, 1.54; 95% CI, 1.23 to 1.93), and dialysis initiation on a central catheter (HR, 1.40; 95% CI, 1.11 to 1.75). Factors associated with a lower risk of death were year of dialysis initiation (HR, 0.95 per year increase; 95% CI, 0.91 to 0.99) and high BP (HR, 0.80; 95% CI, 0.67 to 0.97)., Conclusions: Survival of patients with ALA, LCDD, or MCN on chronic dialysis is poor but has improved over time. Progressive malignancy is the main cause of death in this population. Renal recovery has increased since 2006., (Copyright © 2016 by the American Society of Nephrology.)

Background: The Epidemiology Network and Nephrology Information provides since 2001 the epidemiological monitoring of end stage renal disease (ESRD) in France. Two cross-sectional studies to estimate the level of quality of life in ESRD patients were performed in 2005 and 2007 and repeated in 2011. The main objective is to analyze the evolution of the quality of life of ESRD between these two surveys., Methods: The studies were conducted on a representative sample of subjects aged 18 and over, prevalent dialysis or holders of a functioning kidney transplant last year, followed in center dialysis and/or transplantation in one of the eight French regions selected. The quality of life was measured by a generic questionnaire, and two specifics questionnaires., Results: The evolution of the quality of life deteriorated slightly between 2005-2007 and 2011. There is however few dimensions affected. The variation in scores is not meaningful in general, with maximum decreases less than 4 points according to the statistical methods used. This diminution is not clinically significant., Discussion: The quality of life in dialysis patients or transplant did not evolve between 2005-2007 and 2011. Currently, it is difficult to assess the benefits of the national plan for improving the quality of life of people with chronic diseases because the last data are too close to the end of the plan., (Copyright © 2014 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Background: This study aims to identify factors associated with health related quality of life (HRQOL) through a comprehensive analysis of sociodemographic and clinical variables among a representative sample size of renal transplant recipients (RTR) in France., Methods: A cross-sectional multicenter study was carried out in 2008. All RTR over 18 years old with a functioning graft for at least one year were included. Data included socio-demographic, health status, and treatment characteristics. To evaluate HRQOL, the Short Form-36 Health Survey (SF-36) and a HRQOL instrument for RTR (ReTransQol) were administered. Multivariate linear regression models were performed., Results: A total of 1061 RTR were included, with a return rate of 72.5%. The variance explained in regression models of SF-36 ranges from 20% to 40% and from 9% to 33% for ReTransQol., Conclusions: The originality of our study's findings was that novel variables, particularly treatment side effects and unemployment, have a negative effect on quality of life of RTR. The French Biomedicine Agency and the National Health Institute for Public Health Surveillance conduct specific actions for professional reintegration and therapeutic education programs in the national plan to improve the HRQOL of people living with chronic diseases.

Background: Anti-Xa activity is used as a clinical guide to anticoagulation with heparin, but heparin dosing regimens for hemodialysis were established before anti-Xa assays were developed; thus, the optimal regimen for heparin dosing was not determined. The aim is to confirm the interesting characteristics of unfractionated heparin pharmacokinetics for hemodialysis anticoagulation, provide insight into the hemorrhagic risk of hemodialysis patients, and determine the dose of unfractionated heparin and its adequate mode of administration., Study Design: Cross-sectional study of the pharmacokinetics of unfractionated heparin performed during and after a 4-hour midweek hemodialysis session., Setting & Participants: 35 long-term hemodialysis patients at the Sainte-Marguerite Unit of the Marseille University Hospital, Marseille, France., Predictor: Hemodialysis anticoagulation with continuous unfractionated heparin infusion at a dose of 50 IU/kg/session (25 IU/kg/h during the first hour, 12.5 IU/kg during the second and third hours, and stop during the last hour)., Outcome & Measurements: Anti-Xa activity was monitored during the 10 hours after the beginning of the hemodialysis session. Levels of 0.3 to 0.7 IU/mL are considered sufficient for anticoagulation. Pharmacokinetics was determined by using a population approach (nonlinear mixed-effects modeling). The final model and corresponding parameter values (including interindividual and residual variability) were used to simulate 1,000 replicates., Results: No case of clotting was recorded. A pharmacokinetic model with 1 compartment and first-order elimination best fitted the data. Terminal half-life was 54 minutes. Median anti-Xa activities were 0.55 IU/mL at peak, 0.25 IU/mL at end of the 4-hour session, and less than 0.1 IU/mL at 90 minutes after the session. We simulated a continuous infusion of the dose of 50 IU/kg for 1, 2, 3, and 4 hours. Peak values were 1.1, 0.8, 0.6, and 0.5 IU/mL, respectively. Values at the end of the session were 0.12, 0.18, 0.3, and 0.5 IU/mL, respectively. Values became less than 0.1 IU/mL at 15, 60, 105, and 120 minutes after the session, respectively., Limitations: Interindividual variability in unfractionated heparin pharmacokinetics., Conclusions: Unfractionated heparin administered by means of a 3-hour continuous infusion for hemodialysis anticoagulation provided an efficient and safe effect that quickly disappeared after the end of the session.

Background: Haemodialysis (HD) sometimes accelerates left ventricular failure (LVF). As adenosine (ADO) is strongly implicated in cardiovascular functions, particularly via A(2A) receptor activation and as changes of peripheral A(2A) receptors mirror changes occurring in the cardiovascular system, we examined the influence of HD and LVF on both ADO plasma concentration and the expression of A(2A) receptors (i.e. Bmax, K(D) and mRNA amount) of peripheral blood mononuclear cells., Methods: This cross-sectional study included 61 chronic renal failure (CRF) patients: 41 without LVF (24 haemodialysed and 17 undialysed) and 20 with LVF (9 haemodialysed and 11 undialysed). Ten LVF patients without CRF and 10 healthy subjects were also examined., Results: (i) Bmax values of CRF patients without LVF were significantly decreased in undialysed patients compared with haemodialysed patients, and compared with controls (69 +/- 25 vs 98 +/- 33 vs 180 +/- 60 fmol/mg of protein, P < 0.05). Bmax values of CRF patients with LVF were lower in undialysed patients than in haemodialysed patients (60 +/- 27 vs 101 +/- 27 fmol/mg of protein, P < 0.05). Bmax values of LVF patients without CRF were lower than in controls (51 +/- 19 vs 180 +/- 60 fmol/mg of protein). (ii) A(2A) mRNA expression was increased in haemodialysed patients compared with controls (20.2 +/- 0.75 vs 17.6 +/- 1.3, P < 0.05). (iii) ADO plasma levels were high in haemodialysed patients and further increased during the HD sessions., Conclusion: The number of A(2A) receptors was decreased by CRF with or without LVF. However, this decrease was less important in haemodialysed patients. The changes in peripheral A(2A) receptor expression suggest a significant inflammatory response to HD and heart or kidney failure. Whether these changes do reflect alterations in cardiomyocytes needs further investigation.

Background: Contrast nephropathy (CN) is a common cause of renal dysfunction that may be prevented by saline hydration and by drugs such as theophylline or furosemide. Whether oral saline hydration is as efficient as intravenous saline hydration is unknown. The preventive efficacy of theophylline and furosemide for CN remains controversial. The purpose of the current study was to evaluate the efficacy of oral saline hydration and of intravenous saline hydration plus theophylline or furosemide for the prevention of CN., Methods: We prospectively studied 312 patients with chronic renal failure (serum creatinine 201+/-81 micromol/l, Cockcroft clearance 37+/-12 ml/min/1.73 m(2)), who were undergoing various radiological procedures with a non-ionic, low osmolality contrast agent. Patients were randomly assigned to four arms. In arm A, patients received 1 g/10 kg of body weight/day of sodium chloride per os for 2 days before the procedure. In arm B, patients received 0.9% saline intravenously at a rate of 15 ml/kg for 6 h before the procedure. In arm C, patients received the same saline hydration as in arm B plus 5 mg/kg theophylline per os in one dose 1 h before the procedure. In arm D, patients received the same saline hydration as in arm B plus 3 mg/kg of furosemide intravenously just after the procedure., Results: Patients were well-matched with no significant differences at baseline in any measured parameters. Acute renal failure, defined as an increase in serum creatinine of 44 micromol/l (0.5 mg/dl), occurred in 27 out of 312 patients (8.7%). There was no significant difference between the rate of renal failure in the different arms of the study: five out of 76 (6.6%) in arm A, four out of 77 (5.2%) in arm B, six out of 80 (7.5%) in arm C and 12 out of 79 (15.2%) in arm D. No patient had fluid overload or a significant increase in blood pressure in the 2 days following the radiological procedure. The independent predictors of CN were diabetes mellitus, high baseline serum creatinine and high systolic blood pressure., Conclusions: Oral saline hydration was as efficient as intravenous saline hydration for the prevention of CN in patients with stage 3 renal diseases. Furosemide and theophylline were not protective.

Objectives: To determine the pharmacokinetic parameters of ceftriaxone following an infusion in haemodialysed outpatients and to use these parameters for an optimisation of dosing based on pharmacodynamic indices., Methods: Fifty haemodialysed patients were enrolled in a single-centre, prospective, open-label study. They received short intravenous infusions of ceftriaxone 1 or 2 g every 48 hours for bronchopneumonia immediately after the dialysis session. Total plasma concentrations of ceftriaxone were analysed with a population pharmacokinetic approach using nonlinear mixed-effects modelling. Free drug concentrations were derived from published binding parameters in order to estimate the time when they exceed the minimum inhibitory concentration (MIC)., Results: The pharmacokinetics were best described by a two-compartment model. None of the covariates tested (age, bodyweight, height, sex, body mass index, albumin) influenced the pharmacokinetic parameters. The estimated population pharmacokinetic parameters (interindividual variability [percentage of coefficient of variation]) were clearance 0.36 L/h (48%), volume of distribution of the central compartment 4.53 L (47%), intercompartmental clearance 10.8 L/h and volume of distribution of the peripheral compartment 9.54 L (63%). The terminal elimination half-life (t(1/2)beta) from plasma was 27.5 hours. The mean (range) times when the free drug concentration exceeded the MIC (T>MIC) following ceftriaxone 1 g infusion were 60.3 (53.0-67.7) hours and 2.5 (1.0-3.9) hours for the breakpoints 1 and 8 mg/L (based on free drug concentration), respectively. After administration of ceftriaxone 2 g, the T>MIC was 88.5 (78.8-98.3) hours and 17.7 (13.3-22.0) hours for the breakpoints 1 and 8 mg/L, respectively. The simulated free drug concentrations (median, first and third quartile) for 48 and 72 hours following the first dose of ceftriaxone 1g were 1.11, 0.63 and 1.89 mg/L, and 0.63, 0.28 and 1.18 mg/L, respectively. For ceftriaxone 2g infusion, the simulated free concentrations (median, first and third quartile) at 48 and 72 hours were 2.50, 1.40 and 4.52 mg/L, and 1.37, 0.60 and 2.70 mg/L, respectively., Conclusions: On the basis of decreased clearance in haemodialysed patients, it can be argued that the dose of ceftriaxone should be decreased or the delay between doses should be increased. However, taking into account pharmacodynamic considerations, this study showed that following intravenous administration of ceftriaxone 1 g after each dialysis session, some patients were at risk of achieving a concentration below the MIC (1 mg/L), particularly if the second administration occurred 72 hours after the first dosing. Thus, a dose of ceftriaxone 2 g intravenously is recommended immediately following dialysis, particularly in patients with severe infections or when the dosing interval will be higher than 48 hours.

Background: Loop diuretics are the drugs of choice for the treatment of hypertension in chronic renal failure patients. However, the adaptive changes in the distal nephron and the short half-life of these drugs may decrease their long-term efficacy. Thiazides are not believed to be efficient in advanced renal failure, but this is debated., Methods: We compared the efficacy of long-acting furosemide (60 mg/day) and hydrochlorothiazide (25 mg/day) in a double-blind, randomized crossover trial in seven patients with severe renal failure and hypertension (seven men, 54+/-10 years old). The primary end-points were sodium and chloride fractional excretions after 1 month of each diuretic and then after their combination. During the trial, other treatments and the diet were controlled., Results: A trend towards an increase in the fractional excretion of sodium and of chloride was observed with furosemide, but the difference did not reach the level of statistical significance (P = NS). Hydrochlorothiazide significantly increased fractional excretion of sodium and chloride from 3.7+/-0.9 to 5.5+/-0.3 and from 3.9+/-0.19 to 6.5+/-0.3, respectively (P<0.05). The combination of the two diuretics had no additional effect on the increase in sodium and chloride fractional excretion. Furosemide, hydrochlorothiazide and the combination of the two diuretics decreased mean arterial blood pressure by the same extent from 112 to 97, 99 and 97 mmHg, respectively (P<0.05)., Conclusions: Hydrochlorothiazide increased the fractional excretion of sodium and chloride more than furosemide did in hypertensive severe renal failure patients. Mean arterial blood pressure decreased by the same amount with both diuretics. Combining furosemide and hydrochlorothiazide did not increase the efficacy of hydrochlorothiazide.

Background: We previously showed that high intralymphocytic adenosine (Ado) concentrations are found in hemodialyzed patients due to the reduced activity of mononuclear cell adenosine deaminase (MCADA). These abnormalities contribute to the immune defect observed in HD patients. The kinetics of these abnormalities and the causes of the low MCADA activity, however, have not been investigated. Here, we addressed this question. Since interferon gamma (IFNgamma) partially modulates MCADA, we also evaluated the effect of IFNgamma on MCADA activity in vitro., Methods and Results: The study included 12 patients (eight men and four women) who were observed from the first to the 36th hemodialysis (HD) session, and eight healthy subjects (controls). MCADA activity and Ado concentrations were normal before the first HD session. Ado concentrations progressively increased from the first (10.5 +/- 3.1 pmol/10(7) cells) to the fourth session (26.7 +/- 3 pmol/10(7) cells), before stabilizing at a high level. MCADA activity increased transiently until the second session (2.2 +/- 0.5 IU/10(7) cells before HD vs. 2.8 +/- 0.6 IU/10(7)cells), and then decreased and stabilized at a low level (1.0 +/- 0.5 IU/10(7)cells). The amount of MCADA mRNA transiently increased until the third session (mRNA MCADA/mRNA beta-actin: 0.6 +/- 0.2 vs. 0.8 +/- 0.2), and then decreased to 0.3 +/- 0.1 at the 36th session. MCADA activity underwent a dose-dependent increase after IFNgamma stimulation., Conclusion: HD affects the transcription of the gene encoding MCADA after just three HD sessions, leading to decreased MCADA activity and increased plasma concentration of Ado.

Background: The aims of the present study were to determine the prevalence of inducible myocardial ischemia (IMI) in renal transplant recipients (RTR) more than 50 years old, to identify predictors of IMI, and to search for its prognostic value., Methods: Among the 377 renal transplantations performed between 1989 and 1998 in a single institution, 120 were done in patients > or =50 years old, and 97 were recruited for the study. During the last quarter of 1998, all of them underwent an exercise test (EST), an exercise-thallium 201 single photon emission computed tomography coupled with dipyridamole (SPECT), and 81% of them had a dobutamine stress echocardiography (DSE). Patients with IMI subsequently underwent coronary angiography to detect coronary stenosis., Results: IMI was present in 12 of the 97 patients (10%). The diagnosis was evidenced by EST in four cases, by SPECT in 11 cases, and DSE in three cases. Five of these 12 patients (42%) had significant coronary artery stenosis (> or =50%). Multivariate analysis of several pre- and post-transplant variables evidenced acute rejection and left ventricular hypertrophy as significant correlates of IMI (both P < 0.03). Patients were prospectively followed-up for 48 months for the occurrence of major cardiovascular events. Kaplan-Meier analysis revealed a significant increase in cardiovascular events in the IMI group (P < 0.0001). In addition, the Cox proportional hazards model revealed that IMI and diabetes mellitus had an independent significant effect on the occurrence of major cardiovascular events., Conclusion: IMI was present in 10% of RTR aged > or =50 years, and was predicted by acute rejection and left ventricular hypertrophy. IMI had a strong effect on major cardiovascular events in this population.

Health related quality of life (HRQOL) indicators take into account the personal perception of health, and are proposed as an alternative for efficacy indicators in medical and therapeutic decision making. They provide, due to elaboration and validation of a questionnaire, a standardised assessment of the health status perception. This paper provides a review of a variety of HRQOL instruments developed for patients suffering end-stage renal disease (ESRD). Generic instruments are designed to be applicable in general population and disease-targeted instrument are potentially more sensitive to the characteristics of a specific population. Among HRQOL instruments, we found 4 generic questionnaires (the Sickness Impact Profile, the SF 36, the Nottingham Health Profile and the EQ-5D), 3 disease-targeted questionnaires developed for ESRD patient undergoing dialysis (the Kidney Disease Quality of Life instrument, the Kidney Disease Questionnaire and the Choice Health Experience Questionnaire), 1 questionnaire specific for ESRD patients (the HRQOL questionnaire), and 2 specific disease-targeted instruments for renal transplant (the Kidney Transplant Questionnaire and the ESRD Symptom Checklist-Transplantation Module). In France, very few studies on the quality of life of ESRD patients were published; no specific questionnaire validated in French is yet published.

To assess the influence of the timing of nephrology referral on the short- and long-term outcome of hemodialysis patients, we retrospectively studied 309 patients who had end-stage renal failure and entered the chronic hemodialysis program in Sainte-Marguerite University Hospital between January 1, 1989, and December 31, 1996. We excluded from the analysis five patients without available data on referral pattern and 34 patients with irreversible acute renal failure. Of the remaining 270 patients, 177 patients (58%) had an early referral (ER) 16 or more weeks before the start of dialysis, and 93 patients (31%) had a late referral (LR) of less than 16 weeks before dialysis. Short-time morbidity (initial emergent dialysis, pulmonary edema, severe hypertension, temporary vascular access placement for first dialysis, prolonged initial hospitalization) was significantly more frequent in LR patients. Long-term evolution (mean follow-up, 26.5 +/- 26 months) did not differ between the two groups. The number of days of hospitalization per patient-year at risk beyond the third month was 21.5 +/- 33.7 days for ER and 21.1 +/- 36 days for LR patients. Survival analysis showed no difference between the two groups: 3-month survival rates were 96% in both groups, 1-year survival rates were 90% in the ER and 89% in the LR group, and 5-year survival rates were 52% in the ER and 56% in the LR group. In a Cox hazards regression model, referral pattern was not associated with a greater risk for death. In conclusion, delayed nephrology referral generated strikingly greater initial morbidity, but long-term outcome of hemodialysis patients was not modified by delayed nephrological care.

A transmembrane passage of endotoxins may account for the dysfunction of cytokine production which has been often reported in haemodialysis. We developed an assay based on the ability of patient serum to stimulate tumour necrosis factor alpha (TNF alpha) secretion in normal peripheral blood mononuclear cells. Three groups of subjects were investigated: normal controls (n = 14), patients with chronic renal failure, CRF (n = 15), and patients dialysed with polyacrylonitrile (n = 7), polysulphone (n = 8), and cellulose acetate (n = 7). Sera from dialysed patients displayed a significantly higher TNF alpha-inducing activity than those of controls and CRF patients. The ability of serum to elicit TNF alpha secretion was neither modified during the dialysis session nor influenced by the type of haemodialysis membrane. TNF alpha-inducing activity in serum was not inhibited by polymyxin B, known to impair endotoxin-dependent cell responses, thus suggesting that it was not related to circulating endotoxins. We conclude that non-endotoxinic factors are present in serum from dialysed patients and are able to induce cytokine secretion.

We report two cases of tuberculosis in patients undergoing maintenance dialysis. In both cases Mycobacterium tuberculosis was not isolated in spite of multiple localizations and diagnosis was made with delay. Severe hypocalcemia was the main symptom in one patient, who had pulmonary, genito-urinary and spinal tuberculosis. The other patient had tuberculous lymphadenitis. The two patients survived their disease on antituberculous therapy. From the literature the authors give the actuarial data of tuberculosis occurring in patients undergoing hemodialysis.

Muscular disorders are usual in hypothyroidism, but hypothyroid myopathy is most often limited to myalgias, muscle stiffness and cramps with sometimes elevated levels of muscle enzymes. We report a case of acute renal failure related to rhabdomyolysis, which complicated hypothyroïd myopathy. Thyroid hormone replacement therapy improved thyroid and renal function, and reversal rhabdomyolysis. Hypothyroidism appears to be an authentic cause of rhabdomyolysis and should be eliminated in all patients with serum muscle enzyme increase.