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.

Hydrochlorothiazide-amiloride causes excessive urinary zinc excretion.

Serum zinc levels and urinary zinc excretion were compared in 15 patients with essential hypertension taking chronically a combination of hydrochlorothiazide and amiloride as monotherapy, eight patients maintained with hydrochlorothiazide alone, and eight control subjects. Serum zinc values were statistically comparable in all three groups. However, urinary zinc excretion was abnormally elevated in the two patient groups. In the dosage used, amiloride did not have a zinc-sparing effect.

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.

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.

Zinc metabolism in patients treated with captopril versus enalapril.

Several zinc parameters were assessed in 13 patients with essential hypertension who were chronically taking only captopril (six subjects) or enalapril (seven subjects), as well as in six untreated hypertensives, and nine healthy controls. Serum zinc levels were comparable in all groups. Twenty-four-hour urinary zinc excretion was significantly increased in the captopril-treated patients compared with the other three groups. The zinc:creatinine ratio in 24-hour urine was significantly increased in both captopril and enalapril groups, but was significantly greater in the former. Although plasma zinc concentrations were comparable in all groups, red blood cell (RBC) zinc values were significantly decreased in the captopril group compared with the other three groups. We conclude that (1) although both captopril and enalapril produce renal zinc loss, this loss is far greater in patients receiving captopril; and (2) captopril administration over 3 months or more generates RBC zinc depletion.

Erythrocyte Na+, K+ and Ca2+, Mg(2+)-ATPase activities in hypertensives on angiotensin-converting enzyme inhibitors.

OBJECTIVE: To investigate erythrocyte membrane Na+, K(+)- and Ca2+, Mg(2+)-ATPase activities in newly diagnosed hypertensive patients before and after 2, 4, and 6 months of treatment with enalapril or captopril as monotherapy. METHODS AND RESULTS: Na+, K(+)-ATPase activity (nmol ATP hydrolysed/min per mg protein) rose by 6 months of treatment in both groups when values were compared in each treated group over time (4.5 +/- 0.8 to 9.9 +/- 1.2; 4.9 +/- 0.8 to 10.5 +/- 1.7, respectively, p < 0.001 for both). When the treated groups were compared with controls at each period of time, Na+, K(+)-ATPase activity was higher at months 4 and 6 (p < 0.001) for both groups, respectively). Ca2+, Mg(2+)-ATPase activity (nmol ATP hydrolyzed/min per milligram protein) in the absence and in the presence of calmodulin increased in the enalapril (6.4 +/- 0.7 to 8.9 +/- 0.95, p < 0.05; 13.4 +/- 1.2 to 17.2 +/- 1.2, p < 0.05, respectively) and captopril (7.0 +/- 0.6 to 8.5 +/- 0.7; 14.4 +/- 1.1 to 16.0 +/- 1.0, p < 0.05, respectively) groups after 6 months of treatment compared within each treated group over time. When patient groups were compared with controls at time 0, 2, 4, and 6 months, the pump activity was higher in the treated groups at 6 months. CONCLUSION: The long-term enhancement of cell membrane Na+, K(+)-and Ca2+, Mg(2+)-ATPase activity associated with enalapril and captopril therapy may represent a specific effect of these agents or alternatively, a nonspecific outcome of blood pressure reduction.

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.

Biopsy proven evolution of post streptococcal glomerulonephritis to rapidly progressive glomerulonephritis of a post infectious type.

A 15 year old boy with chronic impetigo was admitted with severe acute oliguric renal failure requiring temporary dialytic treatment. Renal biopsy revealed typical diffuse and proliferative glomerulonephritis of the poststreptococcal type. Subsequently high temperature developed with flank pains at the biopsy site, concomitantly with deterioration of renal function. On exploration, a sterile perirenal hematoma was found and a wedge renal biopsy revealed crescentic rapidly progressive glomerulonephritis of the post infectious type. Deterioration to end stage renal failure occurred within a few months. Although universally accepted, biopsy proven evolution from diffuse proliferative and exudative glomerulonephritis to crescentic form of post streptococcal glomerulonephritis has been rarely reported.

Replacement of ruptured aneurysm of arteriovenous fistula by segmental frozen venous allograft: a case report.

A ruptured aneurysm of an arteriovenous fistula created for chronic hemodialysis was replaced by a segment of frozen saphenous vein allograft. Fifteen months following the procedure the graft is patent. Frozen vein allografts should be considered as an appropriate option for the reconstruction of disrupted A-V fistulae.

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.

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.

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.

The renotrophic factor, a persistent stimulus that crosses the placenta in mice.

1. Twenty 7-week female mice underwent right nephrectomy and twenty others were sham operated. A week later all animals were made pregnant. Pregnancy was repeated five more times consecutively and various renal parameters were assessed in the pups. 2. Fractional fresh kidney weight (relative to body weight) was significantly increased in the pups of nephrectomized mothers while percentage renal water and protein content expressed as mg/g kidney weight were not statistically different in the two groups of pups. Thus dry kidney weight and amount of protein per kidney were increased in the experimental group. This was true for the newborns of all six pregnancies. 3. Renal morphometric studies performed in newborns of first pregnancies showed that the mean number of glomeruli per microscopic field, mean fractional cumulative glomerular area (relative to microscopic field area) and the mean number of cells per glomerulus were significantly greater in the experimental group. Mean glomerular radius was not statistically different in the two groups. 4. The results indicate that: (1) the renotrophic factor(s) crosses the placenta in mice; (2) its activity in maternal circulation following uninephrectomy is sustained for a relatively long period; and (3) fetal response to enhanced maternal renotrophin stimulation consists of increased renal dry weight and renal protein, formation of super-physiological numbers of glomeruli and cellular hyperplasia of the glomeruli.

Frozen saphenous vein allografts for constructing vascular access for hemodialysis.

Frozen saphenous vein allografts were used in seven patients to construct vascular access for hemodialysis. In five patients the allografts connected the brachial artery to the axillary vein, and in two, the radial artery to the basilic vein. Five allografts functioned for periods varying from 6 to 20 months, one is still functioning after 3 years, and one graft occluded immediately following surgery. The availability of this biological material, the ease of its preparation, the very low cost, and the satisfactory graft survival, call for further evaluation of this method for complex vascular access problems in patients on chronic hemodialysis.

Induction of suppressor cell activity in normal peripheral blood mononuclear cells by sera from predialytic uremic patients.

Normal peripheral blood mononuclear cells (PBMC) were primed with sera from 22 predialytic uremic patients, normal sera, concanavalin A, or both. Their suppressive activity was subsequently tested on fresh phytohemagglutinin-stimulated allogeneic responders (i.e., genetically unrelated to either primed cell or sera donors). Uremic serum induced suppressor cell activity in the normal PBMC. No correlation was found between serum urea/creatinine levels and their effects on suppressor cell activity. The induced activity, expressed as percent suppression, was similar to that induced by concanavalin A. In PBMC primed with both concanavalin A and uremic serum, an additive suppressive effect was evident. The suppressor subset(s) induced by uremic serum proved to belong to adherent cell population. Addition of indomethacin or catalase to responder systems did not abolish the suppressive effects, thus suggesting a mechanism of action other than prostaglandin or hydrogen peroxide release.

Dual challenge for glomerular damage in mice: uninephrectomy and repetitive pregnancies.

We examined the effects of unilateral nephrectomy (UNx) and repetitive pregnancies (RP) on glomerular damage and blood pressure in mice. Four groups of 10 female mice, 7 weeks old, underwent sham nephrectomy (SV) alone, sham nephrectomy and six pregnancies (SP), right nephrectomy alone (NV) and right nephrectomy followed by six repetitive pregnancies (NP). UNx resulted in a significant elevation of serum creatinine up to 11 weeks. In all animals pregnancy was associated with a temporary decrease in serum creatinine except at termination of the 6th pregnancy in group NP. UNx and RP did not result in an increase in protein excretion. UNx in both virgin and pregnant mice resulted in blood pressure elevation without any renal histological abnormalities by the end of the 6th pregnancy. We conclude that at least up to the end of the 3rd pregnancy, gestation was associated with augmentation in function of a single kidney. This effect was lost by the end of the 6th pregnancy. Multiple repetitive pregnancies in uninephrectomized animals entailed renal functional deterioration and a rise in blood pressure without renal histological abnormalities on light microscopy.