Bioimpedance phase angle predicts muscle function, quality of life and clinical outcome in maintenance hemodialysis patients.

BACKGROUND/OBJECTIVES: The association of bioimpedance phase angle (PA), as a measure of nutritional status, with muscle function, health-related quality of life (QoL) and subsequent clinical outcomes in maintenance hemodialysis (MHD) patients. SUBJECTS/METHODS: A 2-year prospective observational study on 250 MHD outpatients (36.8% women) with a mean age of 68.7±13.6 years. Prospective all-cause and cardiovascular (CV) hospitalization and mortality, malnutrition-inflammation score (MIS), handgrip strength (HGS), bioimpedance and short form 36 (SF-36) QoL scores were the study's measurements. RESULTS: Across the three PA tertile groups, HGS was incrementally higher in the higher PA tertiles (P<0.001), maintaining this order in both male (r=0.38, P<0.001) and female patients (r=0.36, P<0.001). Better self-reported QoL was noted with higher PA values. This trend was prominent in total score (P<0.001), mental health (P=0.005) and physical health (P<0.001) dimensions, and in most of the SF-36 scales. For each 1° increase in baseline PA, the first hospitalization hazard ratio (HR) was 0.79 (95% confidence interval (CI), 0.68-0.91) and first CV event HR was 0.70 (95% CI, 0.52-0.95); all-cause death HR was 0.63 (95% CI, 0.48-0.81) and CV death HR was 0.64 (95% CI, 0.44-0.91). Associations between PA and morbidity risk continued to be significant after adjustments for various confounders, but the association between PA and mortality risk was abolished after adding MIS to the multivariable model. CONCLUSIONS: For the MHD population, PA emerged as a useful predictor for impaired muscle function, health-related Qol, upcoming hospitalizations and mortality.

Mesangial cells initiate compensatory tubular cell hypertrophy.

Unilateral nephrectomy results in compensatory renal growth, in which both the size and the functional capacity of the remaining kidney are increased. The functional adaptation to the removal of the contralateral kidney consists mostly of an increase in the glomerular filtration rate of the remaining kidney, and hypertrophy of cells comprising the nephron, mainly of the proximal tubular cells. Although the phenomenon of single kidney hypertrophy has been known for the past thousand years and despite intensive research over the past century, the mechanism of this process still remains unclear. The present article reviews the role of mesangial cells in compensatory renal hypertrophy.

Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine.

Aminoglycoside (AG) antibiotics are associated with several side effects, including a reversible nephrotoxicity and a permanent ototoxicity. Oxidative stress is thought to contribute to the pathophysiology of both conditions. We studied the possible protective effect of the antioxidant N-acetylcysteine (NAC) in gentamicin-induced hearing loss in hemodialysis patients. This study includes 53 hemodialysis patients scheduled to receive gentamicin for dialysis catheter-related bacteremia that were randomized to receive the antibiotic with or without NAC. Hearing function was assessed by the standard technique of pure-tone audiograms over a range of frequencies. Audiometric evaluations were performed at baseline, 1 week and at 6 weeks after the completion of gentamicin therapy. A total of 40 patients completed the study protocol with a mean duration of therapy of almost 15 days. At both 1 and 6 weeks after the completion of antibiotic therapy, there were significantly more patients exhibiting ototoxicity in the control group compared with the group receiving NAC. Additionally, significantly more patients in the control group had bilateral ototoxicity. The greatest otoprotective effect of NAC was noticed in the high audiometric tone frequencies. Taken together, our study suggests that NAC treatment may ameliorate gentamicin-induced ototoxicity in hemodialysis patients.

Dextran 40 (Rheomacrodex) or Polygeline (Haemaccel) as an epidural patch for post dural puncture headache: a neurotoxicity study in a rat model of Dextran 40 and Polygeline injected intrathecally.

BACKGROUND AND OBJECTIVE: Although an epidural autologous blood patch is considered the most effective treatment for post dural puncture headache, which sometimes occurs following spinal or inadvertent spinal anaesthesia, there remains a need for alternative materials for epidural patches. We investigated the potential neurotoxicity of Dextran 40 (Rheomacrodex) and Polygeline (Haemaccel) used for this purpose in a rat model. METHODS: Repeated boluses of 10% Dextran 40, 3.5% Polygeline or 0.9% saline were injected intrathecally over a period of 1 month in three groups of rats. RESULTS: No behavioural or clinical derangements were observed in any of the three groups during this period. After sacrifice of the animals at the end of the experiment, no significant differences in the histopathological appearances of the spinal cords in the three groups were observed. No toxic effects diminishing viability of spinal cord cells were evident. Similarly, viability of renal, hepatic and peripheral blood mononuclear cells remained unaffected (98% +/- 2%). CONCLUSIONS: No deleterious effects, clinical or cellular, were evident in this rat model when Dextran 40 or Polygeline were injected intrathecally. Thus, both substances can be considered as possible alternative materials for epidural patches.

Serum magnesium aberrations in furosemide (frusemide) treated patients with congestive heart failure: pathophysiological correlates and prognostic evaluation.

OBJECTIVES: To determine the prevalence of hypomagnesaemia and hypermagnesaemia, to discern various factors associated with abnormal serum magnesium, and to estimate prognostic significance of serum magnesium aberrations in patients with congestive heart failure. DESIGN: Observational study. SETTING: Medical department of a university hospital (tertiary referral centre). PATIENTS: 404 consecutive patients admitted with congestive heart failure as one of the diagnoses and previously treated with furosemide (frusemide) for at least three months. MAIN OUTCOME MEASURES: Clinical, biochemical, and electrocardiographic variables were analysed with respect to serum magnesium aberrations. Following discharge, mortality rates, including sudden death, were registered. RESULTS: Hypomagnesaemia was found in 50 patients (12.3%) and 20 (4.9%) were hypermagnesaemic. Female sex (p < 0.04), diabetes mellitus (p < 0.006), hypocalcaemia (p = 0.03), hyponatraemia (p < 0.05), malignant disease (p = 0.05), and high fever (p = 0.05) were statistically associated with hypomagnesaemia. Renal failure, severe congestive heart failure, and high dose furosemide treatment (> 80 mg/day) were associated with hypermagnesaemia (p < 0.001, p = 0.05, and p < 0.03, respectively). Hypermagnesaemic patients were older and weighed less. On follow up (median duration 43 months), 169 (41.8%) died, with 22 (13%) sudden deaths. Mortality was highest with hypermagnesaemia, lowest with normomagnesaemia, and intermediate with hypomagnesaemia. After adjustment for renal failure, old age, and severity of congestive heart failure, hypomagnesaemia but not hypermagnesaemia emerged as being significantly associated with shorter survival (p = 0.009). No statistical association was found between sudden death and magnesium concentrations. CONCLUSIONS: While hypermagnesaemia seems to represent a prognostic marker only, hypomagnesaemia appears to have an adverse pathophysiological effect. The subgroup of patients at risk for hypomagnesaemia requires frequent serum magnesium determinations and magnesium replacement for as long as hypomagnesaemia persists.

Zn metabolism affects apoptosis rate and proliferative responsiveness of PBMC from patients on chronic hemodialysis.

Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is not corrected by dialysis. Trace metals, including Zn(2+), are critical for cell differentiation and replication. Zn(2+)also plays important role in cell apoptosis. Both processes are known to be impaired in uremia. The present study was undertaken to evaluate the effect of Zn(2+) supplementation on apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on chronic hemodialysis versus those from healthy control subjects, concomitantly with assessment of mitogen-induced cell proliferation. The results showed that (1) basal total cell-associated Zn(2+) was elevated in uremic PBMC, compared to normal controls (23.9 +/- 5.64 v 10.5 +/- 2.64 micromol/L/mg protein). The gap persisted following incubation in Zn(2+)-enriched medium (63.3 +/- 26.12 v 81.6 +/- 13.4 micromol/L/mg protein, P <.005). (2) Basal proliferative response to phytohemagglutinin (PHA) was significantly decreased in uremic PBMC compared to normal controls (12,000 +/- 1,560 cpm v 16,600 +/- 1,460 cpm, P <.01). Incubation of uremic PBMC in Zn(2+)-enriched medium improved their proliferative response to PHA, yielding counts per minute significantly higher compared to their normal counterparts (37,000 +/- 7,500 cpm v 22,000 +/- 3,000 cpm, P <.001). (3) Basal apoptosis rate in uremic PBMC was significantly elevated compared to normal control cells (7.6% v 2.6%, P <.05). Following incubation in Zn(2+)-enriched medium, apoptosis was increased both in normal and uremic PBMC. Percent apoptosis of uremic PBMC remained significantly elevated compared to control cells (11.7% v 5.7%). We conclude that uremic PBMC are more responsive to exogenous Zn(2+) in culture than their normal counterparts. This, among other abnormalities, might reflect an abnormal regulation of Zn(2+) transport by uremic mononuclear cell membranes. The resultant increase in total cell-associated Zn(2+) content improves poor proliferative responsiveness of uremic PBMC. On the other hand, increased total cell-associated Zn(2+) stimulates enhanced apoptosis in uremic PBMC, which, probably by eliminating defective cells, contributes to the functional capability of the population as a whole. The net effect of the 2 processes is still augmentation of cell proliferation.

Intracellular Ca++/Mg++ homeostasis during postnatal growth of experimental rats. Multiple time-point study.

In most tissues, various cell membrane ion transporting systems are not fully developed and/or maximally active at the prenatal and early postnatal stage. Their progressive development and expression are a function of growth and maturity. We performed a multiple time-point study, in order to investigate the ability of a variety of tissues to maintain appropriate Ca++ and Mg++ homeostasis at different stages of postnatal development. Total intracellular Ca++ in one-week-old rat liver, brain and spinal cord tissues was significantly elevated, compared to mature animals. It increased further through the first three weeks of gestation. Intracellular Ca++ gradually and significantly declined in adult and mature animal groups. Alterations in total intracellular Mg++ of the same tissue samples, although not so profound, paralleled changes in total intracellular Ca++. We conclude that a developmental switch in intracellular Ca++ and Mg++ homeostasis occurs one to three weeks following birth. It might be related to the incomplete development of Ca++ and Mg++ transmembrane transporting systems, previously reported as being only partially expressed at the early postnatal stage. These developmental alterations in total intracellular Ca++ and Mg++ content might serve as a regulatory mechanism, adjusting cell activities to the physiological requirements of the growing and maturing animal.

Red eye syndrome: clinical and experimental experience in a new aspect of diffuse eosinophilic infiltration?

Twenty-two of 24 hemodialysis patients dialyzed simultaneously with a new batch of cellulose acetate dialyzers promptly developed a spectrum of symptoms and physical signs including red eyes, hearing loss, tinnitus, and bone pain, previously described as red eye syndrome. We subsequently injected 4 rabbits with an eluate from a dialyzer of the same or a control batch. Six hours following exposure, the animals developed, in addition to red eyes, diffuse eosinophilic infiltration of various organs as well as myopathic changes and moderate brain edema. On the basis of these data, we suggest that it cannot be concluded whether the underlying pathophysiological mechanisms were toxic, allergic or both and that the occurrence of relevant symptomatology in 2 or more simultaneously dialyzed patients is a strong argument against unnecessary diagnostic or therapeutic procedures. Finally, a second exposure in a given patient should be avoided.

Intrathecal anaesthesia alters intracellular Ca2+/Mg2+ homeostasis in the spinal cord neurones of experimental rats.

BACKGROUND AND OBJECTIVE: The effect of anaesthesia induced by intrathecal injection of 6.3% MgSO4 or 4% lidocaine on intracellular electrolyte homeostasis in spinal cord neurones of a rat model was investigated. METHODS: Intracellular Ca2+, Mg2+, Na+ and K+ concentrations were determined at different times after intrathecal administration of NaCl (saline, a control group), MgSO4 or lidocaine. RESULTS: In both thoracic and lumbar spinal cord segments, Ca2+ concentrations rose significantly 30 min and 2 h after 6.3% MgSO4 injection, and after 24 h were still significantly increased compared with the values obtained from the control group which were subjected to sham 'anaesthesia' by saline injection (172, 121 and 108 ng mg-1 protein vs. control 23 ng mg-1 protein, respectively, in the thoracic segment and 222, 229 and 176 ng mg-1 protein vs. control 43 ng mg-1 protein, respectively, in the lumbar segment). Lidocaine injection also produced a significant increase in intracellular Ca2+ in the thoracic and lumbar spinal cord segments (69, 64 and 53 ng mg-1 protein vs. control 33.4 ng mg-1 protein and 26, 94 and 46 ng mg-1 protein vs. 23 ng mg-1 protein respectively). Only a modest rise in intracellular Mg2+ was observed after intrathecal MgSO4 or lidocaine injection (27 ng mg-1 protein vs. 23 ng mg-1 protein). Na+ and K+ concentrations decreased 24 h after MgSO4 and 1 h after lidocaine injection. CONCLUSION: Intrathecal anaesthesia by MgSO4 or lidocaine alters intracellular electrolyte homeostasis in spinal cord neurones of experimental rats. A possible common mechanism of action via Ca2+ ion channels is discussed.

Vitamin B(6) therapy does not improve hematocrit in hemodialysis patients supplemented with iron and erythropoietin.

BACKGROUND/AIM: Pyridoxine deficiency may be the cause of failure to respond appropriately to iron and erythropoietin (EPO) administration in hemodialysis patients. METHOD: We studied 36 patients on chronic hemodialysis amply supplemented with iron and EPO, who failed to raise hematocrit levels >33%. Patients were divided into three equal groups and evaluated for 6 months as follows: Group A -- no additional therapy; group B -- supplemented with oral pyridoxine 50 mg/day, and group C received 100 mg/day pyridoxine orally. RESULTS: In all our patients, erythrocyte pyridoxine levels were initially within reference range for a healthy population and did not vary significantly during the study period. Likewise, ferritin levels and iron saturation values remained normal and constant. Hemoglobin and/or hematocrit levels remained practically unchanged in all three groups. CONCLUSIONS: The results indicate that in hemodialysis patients with normal pyridoxine status who, despite appropriate supplementation of iron and EPO, fail to reach optimal hematocrit levels, additional pyridoxine treatment does not produce any hematocrit elevation.

Total cell-associated Zn2+ and Cu2+ and proliferative responsiveness of peripheral blood mononuclear cells from patients on chronic hemodialysis.

We investigated total copper (Cu2+) and zinc (Zn2+) content in plasma and peripheral blood mononuclear cells (PBMC) and its impact on proliferative ability of the latter in patients on chronic hemodialysis versus age- and sex-matched healthy volunteers. Plasma levels of Cu2+ and Zn2+ were significantly lower in dialysis patients compared with the control group (83.6 +/- 7.29 v 95.1 +/- 9.63 microg/dL, P <.03 for Cu2+; 71.1 +/- 7.64 v 89.7+/- 12.55 microg/dL, P <.005 for Zn2+). Basal total PBMC-associated Cu2+ content was significantly higher in uremic patients (19.3 +/- 3.59 v 14.6 +/- 2.72 micromol/mg protein, P <.005). Basal PBMC-associated Zn2+ concentration was also significantly elevated in hemodialysis patients compared with their healthy counterparts (23.9 +/- 5.64 v 10.5 +/- 2.64 micromol/mg protein, P <.005). In addition, we incubated PBMC of the uremic patients versus healthy control PBMC in a Zn2+ free versus Zn2+ enriched medium. After a 72-hour incubation, total cell-associated Zn2+ of both normal and uremic cell populations increased significantly compared with the respective baselines (34.6 +/- 22.49 v 4.3 +/- 1.42 and 20.3 +/- 10.71 v 5.8 +/- 2.22 micromol/mg protein, respectively). However, no statistically significant difference was evident between the 2 groups (34.6 +/- 22.49 v 20 +/- 10.7 micromol/mg protein). Total cell Zn2+ content, on the other hand, was significantly increased in uremic PBMC after 72 hours of incubation in Zn2+ enriched medium compared with the control group (63.3 +/- 26.12 v 18.6 +/- 13.42 micromol/mg protein, P <.005). A significant increase in PBMC proliferation evaluated by 3H-thymidine incorporation was evident in the Zn2+ enriched culture (35,559 +/- 4,136 counts per minute [CPM] v 20,497 +/- 7,263 CPM, P <.005). Cu2+ enrichment of the medium, while resulting in a modest elevation of cell-associated Cu2+, did not produce such a proliferative effect.

Proliferative responses of mesangial cells to growth factors during compensatory versus dietary hypertrophy.

While the bulk of renal hypertrophy induced by contralateral nephrectomy or a high-protein diet consists of tubular cell growth, there is some evidence suggesting that mesangial cells play a role in this phenomenon. Previous data suggest that this role of mesangial cells is associated with their proliferation. We, therefore, undertook this investigation to assess the proliferative responses of mesangial cells, originating from single remaining kidneys or from kidneys of rats fed a high-protein diet, to epinephrine, endothelin, arginine vasopressin, neo-synephrine, or epidermal growth factor (EGF). All agents significantly enhanced the proliferation of normal mesangial cells, though the responses to neo-synephrine and EGF were significantly lower as compared with the other growth promoters. The mitogenic effects of the first three agents on single kidney mesangial cells were significant, but blunted as compared with control cells. This blunting was not evident in the case of the latter two mitogens. A significant enhancement of proliferation of mesangial cells originating from protein-fed rats was produced by epinephrine, neo-synephrine, and EGF. These effects were statistically not different from those observed in normal mesangial cells. The proliferative response to each of the mitogens used in the study proved highly specific for each mitogen, since it was abolished by respective specific inhibitors. Mesangial cells may play a role in the activation and later in progressive inhibition of renal hypertrophy in vivo.

Substances used for local and general anaesthesia in major surgery suppress proliferative responsiveness of normal rat peripheral blood mononuclear cells in culture.

We studied the direct effect of intravenous anaesthetics, local anaesthetics and premedication drugs in common use for major surgery, on the spontaneous versus lectin induced proliferation of cultured normal rat peripheral blood mononuclear cells, not exposed to surgical or any other trauma prior to culture. Peripheral blood mononuclear cells were incubated in cell-culture medium in the presence or in the absence of propofol, ketamine, fentanyl, midazolam, thiopental sodium, lidocaine or etomidate. The cells proliferated either spontaneously or under stimulation with a lectin phytohaemagglutinine P for 72 h. The proliferation rate was evaluated by 2H-Thymidine incorporation. Fentanyl, thiopental sodium, lidocaine and etomidate significantly inhibited phytohaemagglutinine P induced 3H-Thymidine incorporation in cultured rat peripheral blood mononuclear cells. Counts per minute of the cultures treated with these drugs were 1667.80 +/- 745.72, 1614.1 +/- 615.00, 1688.0 +/- 615.0 and 1549 +/- 560.41, respectively, compared with the phytohaemagglutinine P stimulated positive control counts per minute, 13488 +/- 4305.6 (P < 0.001 in each comparison). Propofol, ketamine and midazolam inhibited the lectin-induced cell proliferation to levels not statistically different from the baseline. Counts per minute of these cultures were 1361.90 +/- 745.73; 1108.90 +/- 751.33 and 1518.10 +/- 848.88, respectively. Compared either with the baseline 972.57 +/- 356.73 counts per minute or to the positive control culture counts per minute, 13488 +/- 4305.6 the difference was statistically significant (P < 0.001) in each comparison. All the substances tested in this study proved capable of exerting direct inhibitory effect on circulating immunocompetent cells, because the latter were not subjected to any other immunosuppressive factor, be it operative trauma, blood transfusion, malnutrition, drug abuse, prior to culture. The possible theoretical and practical implications are discussed in this study.

Nephrectomy enhances interleukin 6 secretion by interleukin 1-stimulated mesangial cells in vitro.

BACKGROUND: Kidney mesangial cells are capable of producing and responding to interleukin 6 (IL-6) . In experimental glomerulonephritis mesangial cell proliferation correlates with increased IL-6 production. To investigate the involvement of IL-6 in post-nephrectomy compensatory hypertrophy, we studied the capacity of mesangial cells from single remaining kidneys to secrete IL-6 in culture. METHODS: Mesangial cells were obtained from uni-nephrectomized or sham-nephrectomized Charles River rats. Cell cultures were maintained for 8 days in DMEM/FI2HAM medium supplemented with IL-1 of interferon (IFN). IL6 production was measured using an IL-6-dependent B9 human hybridoma cell line. RESULTS: IL-6 production by mesangial cells from normal kidneys was significantly enhanced by IL-1, compared to unstimulated cells (p<0.01), and the increase was significantly greater in mesangial cells from a single remaining kidney (p<0.01). All cultures grown in control medium or with addition of IFN produced similar amounts of IL-6. CONCLUSION: Mesangial cells from single remaining kidneys in culture maintain an exaggerated capacity to produce IL-6 in response to IL-1. IL-6 was reported to enhance or inhibit mesangial cell proliferation in vitro. We suggest that the local over production of IL-6 by a single remaining kidney may play a role in regulating a sequence of physiological events in compensatory renal growth, initially stimulating mesangial cell proliferation and later blunting the process.

High-protein diet or unilateral nephrectomy induces a humoral factor(s) that enhances mesangial cell proliferation in culture.

BACKGROUND: A high-protein diet is one of the maneuvers which produce hypertrophy of kidney mass. The underlying mechanism(s) has not been elucidated. In the present study, we investigated the possibility that a humoral factor may be involved. METHODS: Twenty-eight 3-week-old Charles River rats were studied. Fourteen underwent right nephrectomy and 14 sham operation. Each of these groups was divided into two equal subgroups (n = 7 in each): one maintained on a regular diet (20% protein) and the other on a high-protein diet (60% protein) for 7 days. Following this period the animals were sacrificed. Sera from the animals were added to mesangial cell cultures from kidneys of intact 3-week-old rats, and the thymidine incorporation was assessed. RESULTS: The parameters of kidney mass indicated that the high-protein diet indeed produced kidney hypertrophy. Sera from the sham-nephrectomized animals fed a high-protein diet produced a significantly greater proliferative effect on mesangial cells in culture than sera from the respective animals on a normal-protein diet. Sera from either nephrectomized group or from the high-protein sham-operated group all had similar magnitudes of enhancement of mesangial cell proliferation. CONCLUSION: We conclude that the renal hypertrophy produced by a high-protein diet is mediated, at least in part, by a humoral factor(s).

The proliferative responsiveness of mesangial cells to postnephrectomy serum declines progressively with time elapsing after contralateral nephrectomy.

Postnephrectomy serum has been proved to enhance proliferation of mesangial cells in culture. Studies in offspring to uninephrectomized (UNx) mothers indicate that it remains active for a long period following UNx. On the other hand, postnephrectomy renal compensatory growth in vivo is known to be completed within a short period. In this study we assessed the proliferative responses of mesangial cells from single kidneys of rats which were cultured 48 h or 4 months following contralateral nephrectomy. The proliferative stimulus was provided by different postnephrectomy sera. Proliferation of both experimental cell populations was significantly greater than that of controls. Moreover, the proliferation rate of early postcontralateral nephrectomy mesangial cells was greater than those harvested 4 months after nephrectomy. We, therefore, propose that the early in vivo completion of single kidney compensatory hypertrophy, at least in part, is due to progressive blunting of renal cell responsiveness to the mitotic stimulus of the animal's serum.

Effects of Various Modalities of Oral Furosemide Administration in Mild or Severe Congestive Heart Failure.

BACKGROUND: This study evaluated the optimal formulation (tablet vs solution) and frequency (once vs twice daily) of maintenance oral furosemide in compensated congestive heart failure (CHF). METHODS AND RESULTS: Eighteen patients with mild (group 1) and 18 with severe (group 2) CHF were studied. On 2 consecutive days each patient's individual fixed oral furosemide daily dosage was administered in tablet or solution in a crossover design. In an additional study, 14 patients with severe CHF received the daily dosage in tablet or solution form in two divided doses. Pharmacokinetic data were obtained in six randomly allocated patients of each group, during the once daily administration periods of either formulation. Twenty-four-hour urinary sodium and 12-hour volume were significantly greater in group 1 following furosemide solution versus tablets. In group 2, all parameters were comparable in response to single identical doses in tablets or solution, as well as to once versus twice daily administration of either formulation. These results coincided with a higher C(max) and a shorter t(max) following solution. CONCLUSIONS: A once-daily oral furosemide solution is more effective than the same dosage in tablet form in patients with mild, but not those with severe, CHF. In patients with severe CHF, the natriuretic and diuretic effects are similar whether oral furosemide in tablet or solution is administered in a once or twice daily schedule.