Effect of D-alpha-tocopherol on tubular nephron acidification by rats with induced diabetes mellitus.

The objective of the present study was to determine if treatment of diabetic rats with D-alpha-tocopherol could prevent the changes in glomerular and tubular function commonly observed in this disease. Sixty male Wistar rats divided into four groups were studied: control (C), control treated with D-alpha-tocopherol (C + T), diabetic (D), and diabetic treated with D-alpha-tocopherol (D + T). Treatment with D-alpha-tocopherol (40 mg/kg every other day, ip) was started three days after diabetes induction with streptozotocin (60 mg/kg, ip). Renal function studies and microperfusion measurements were performed 30 days after diabetes induction and the kidneys were removed for morphometric analyses. Data are reported as means +/- SEM. Glomerular filtration rate increased in D rats but decreased in D + T rats (C: 6.43 +/- 0.21; D: 7.74 +/- 0.45; D + T: 3.86 +/- 0.18 ml min-1 kg-1). Alterations of tubular acidification observed in bicarbonate absorption flux (JHCO3) and in acidification half-time (t/2) in group D were reversed in group D + T (JHCO3, C: 2.30 +/- 0.10; D: 3.28 +/- 0.22; D + T: 1.87 +/- 0.08 nmol cm-2 s-1; t/2, C: 4.75 +/- 0.20; D: 3.52 +/- 0.15; D + T: 5.92 +/- 0.19 s). Glomerular area was significantly increased in D, while D + T rats exhibited values similar to C, suggesting that the vitamin prevented the hypertrophic effect of hyperglycemia (C: 8334.21 +/- 112.05; D: 10,217.55 +/- 100.66; D + T: 8478.21 +/- 119.81 microm(2)). These results suggest that D-alpha-tocopherol is able to protect rats, at least in part, from the harmful effects of diabetes on renal function.

Aminoglycosides and renal acid excretion.

The effect of three aminoglycosides, gentamicin, netilmicin and amikacin, on renal acid excretion was studied in rats treated with doses equivalent to 10 times those used clinically. The gentamicin and amikacin groups showed a marked decrease (P less than 0.05), in glomerular filtration rate (GFR), U/P inulin ratio and renal plasma flow (RPF), while in the normal acid-base state. Under acidotic conditions, only gentamicin promoted significant alterations in GFR and RPF. Net acid excretion as measured by the acid balance (BH) was calculated as the sum of ammonium excretion (NH4+) and titratable acidity (AT) minus the amount of excreted bicarbonate (CHCO3-). Under normal conditions, netilmicin promoted a considerable fall in both NH4+ and AT, which led to a significant decrease in BH, whereas no changes were observed in these parameters with the other two drugs. In contrast, during acute metabolic acidosis, all tested antibiotics promoted a marked fall in BH, particularly due to a significant decrease in NH4+ and AT. These data suggest that the effects of aminoglycoside treatment during acute metabolic acidosis in clinical practice deserve further study in view of possible deleterious effects on the clinical state.

The renal effects of kainic acid.

The effect of kainic acid (KA), a potent neurotoxic agent, on the renal function of rats was investigated. Intrahippocampal and intraperitoneal KA injections (2.5 micrograms and 8 mg/kg, respectively) led to a decrease in glomerular filtration rate and U/P inulin ratio with a concomitant increase in the amount of excreted Na+. However, acid excretion was maintained. These findings support the idea of a straight connection between neurohormonal secretion and renal function and may provide an interesting model to study renal hemodynamic changes induced by neurological disturbances.

Effect of thyroparathyroidectomy on urinary acidification in diabetic rats.

In previous studies we have shown stimulation of renal acid excretion in the proximal tubules of rats with diabetes of short duration, with no important alterations in glomerular hemodynamics; on the other hand, in thyroparathyroidectomized rats (TPTX model), a significant decrease in renal acid excretion, glomerular filtration rate (GFR) and renal plasma flow (RPF) was detected. Since important changes in the parathyroid hormone-vitamin D-Ca axis are observed in the diabetic state, the present study was undertaken to investigate the renal repercussions of thyroparathyroidectomy in rats previously made diabetic by streptozotocin (45 mg/kg). Four to 6 days after the induction of diabetes (DM), a group of rats were thyroparathyroidectomized (DM + TPTX). Renal functional parameters were evaluated by measuring the inulin and sodium para-aminohippurate clearance on the tenth day. The decrease in the GFR and RPF observed in TPTX was not reversed by diabetes since the same alterations were observed in DM + TPTX. Net acid (NA) excretion was unchanged in DM (6.19 +/- 0.54), decreased in TPTX (3.76 +/- 0.25) and returned to normal levels in DM + TPTX (5.54 +/- 0.72) when compared to the control group (6.34 +/- 0.14 mumol min-1 kg-1). The results suggest that PTH plays an important vasodilator role regarding glomerular hemodynamics, since in its absence the impairment in GFR and RPF was not reversed by the diabetic state. However, with respect to acid excretion, the presence of diabetes was able to overcome the negative stimulus represented by TPTX.

Effect of aluminium on urinary acidification in the rat: influence of parathyroid hormone.

1. The influence of thyroparathyroidectomy and/or acidosis on renal function and specifically on acid excretion was studied in rats treated with a cumulative dose of 2 mg of aluminium. 2. Aluminium-treated and non-treated thyroparathyroidectomized rats showed a significant decrease in glomerular filtration rate and in the urinary/plasma inulin ratio without alteration in net acid excretion. 3. Non-treated thyroparathyroidectomized acidotic rats showed a significant fall in the amount of ammonium excreted and in overall acid excretion, suggesting that parathyroid hormone participates in an important way in the defence against metabolic acidosis. 4. The effects of acidosis, thyroparathyroidectomy and aluminium treatment on renal function parameters were not additive, suggesting a common final mechanism. In normal or acidotic aluminium-treated rats, thyroparathyroidectomy had no effect on renal acid excretion, suggesting that aluminium even in low doses inhibited the action of PTH on the renal tubule. 5. After exposure to aluminium, the relative inhibition of PTH on the renal tubule may become an additional factor that could contribute to the worsening of clinical conditions in which an inappropriate retention of acid loads can occur.

Effect of gentamicin on urinary acidification in the rat.

The effect of gentamicin, an aminoglycoside antibiotic, on renal function and especially on acid excretion was studied in normal and acidotic rats. The doses used were 1 (G4) and 10 (G40) times the suggested human therapeutic dose on a weight basis. After 10 days of each treatment, the glomerular filtration rate (GFR) was unchanged in G4 but fell significantly (p less than 0.05) in G40. In the acidotic groups (AG4 and AG40) there was an accentuated reduction in GFR, renal plasma flow and urine/plasma insulin ratio. Normal rats showed a normal acid excretion even with the high-dose treatment but, in the acidotic group, there was a significant decrease in ammonia excretion. The amount of bicarbonate excretion was significantly elevated in those groups, leading to a greater urinary pH. These results indicate that acute metabolic acidosis enhanced the nephrotoxic effects of gentamicin and impaired the excretion of an acid overload.

Effects of parathyroid hormone and calcium and their interrelationship on urinary acidification in the rat.

1. The influence of thyroparathyroidectomy on renal function and specifically on acid excretion was studied in rats with or without oral supplementation of calcium. 2. Thyroparathyroidectomy caused a significant decrease in glomerular filtration rate, in the urinary/plasma inulin ratio and in overall acid excretion. These changes were not corrected by calcium supplementation. 3. Rates of proximal tubular acidification were studied by means of double-barrelled resin/reference microelectrodes. Acidification half-time was significantly increased in both thyroparathyroidectomized and calcium-supplemented thyroparathyroidectomized rats (8.38 s and 7.40 s, respectively) compared with control rats (5.44 s). 4. When 10(-6) mol/l A23187, a calcium ionophore, was added to the luminal bicarbonate solution, the acidification half-time returned to 3.97 s in the thyroparathyroidectomized rats, whereas no significant changes were detected in the properties of acidification in the control rats. 5. These data show that parathyroid hormone and cellular calcium are important factors involved in proximal tubular H+ secretion, which appears to be largely dependent on a well-defined concentration range of these agents.

Aminoglycoside and nephrotoxicity.

The effect of three aminoglycosides--gentamicin, netilmicin and amikacin--on renal acid excretion was studied in male rats treated with doses equivalent to those clinically used. The amikacin and netilmicin groups showed no important changes in the values of glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and U/P inulin ratio during normal and acidotic conditions. The gentamicin group, however, showed a clear tendency to decreases in these functional parameters even in normal conditions, a finding that reinforces the concept that gentamicin is more nephrotoxic than other aminoglycosides. During normal conditions net acid excretion (BH) did not change with any of the three tested drugs. However, after an acute acid load BH markedly fell regardless of the antibiotic used. The capacity to elevate the urine-blood pCO2 was preserved after an alcaline overload, suggesting that the distal tubule was not significantly affected by aminoglycoside treatment. These data suggest that the clinical use of aminoglycosides during metabolic acidosis deserves close attention due to the possible deleterious effect that can emerge as the result of an inappropriate retention of acid loads.

Influence of parathyroidectomy and calcium on rat renal function.

Parathyroid hormone (PTH) has multiple effects on water and electrolyte transport along the nephron. However, the influences of PTH and calcium on the urinary concentration ability are not fully understood. In this study, clearance and microperfusion studies were performed in thyroparathyroidectomized (TPTX) rats either supplemented (TPTX+Ca(2+)) or not with calcium added to the ingested food as CaCl(2) (1.6 g/100 g). Acid-base data and renal functional parameters were measured in TPTX and TPTX+Ca(2+) rats. Additional studies were performed in the isolated inner medullary collecting tubules of intact and TPTX rats to evaluate the osmotic permeability of this segment in the presence of 10(-6) M PTH added to the bath. In these experiments the possible influence of PTH on antidiuretic hormone induced changes of the osmotic permeability in TPTX and TPTX+Ca(2+) rats was also investigated. In the TPTX+Ca(+) group, the glomerular filtration rate increased significantly when compared to the TPTX group (6.04 +/- 0.42 vs. 4.88 +/- 0.20 ml.min(-1).kg(-1); p < 0.05), but the U/P inulin ratio remained lower than control values (30.8 +/- 1.48 vs. 54.0 +/- 3.5; p < 0.05), which suggests that normal levels of PTH are necessary to maintain the concentrating ability. In a group of TPTX rats, an acute infusion of PTH (0.5 microg.min(-1).kg(-1)) significantly decreased the urinary flow and increased the renal plasma flow, results that agree with the vasomodulator action of this hormone on the renal vasculature. A significant increase in the fractional K(+) excretion observed in the TPTX+Ca(2+) group as compared with both control and TPTX, groups suggests that the excreted load of Ca(2+) may interfere with tubular K(+) handling in the absence of PTH. PTH (10(-6) M) added to the bath of the isolated inner medullary collecting tubules did not change the osmotic permeability, of intact, TPTX, and TPTX+Ca(2+) rats. Furthermore, it did not modify the antidiuretic hormone induced changes in the osmotic permeability. These results suggest that this segment of the nephron is PTH insensitive as far as water and ion transport are concerned.

Effect of D-alpha-tocopherol on tubular nephron acidification by rats with induced diabetes mellitus

The objective of the present study was to determine if treatment of diabetic rats with D-alpha-tocopherol could prevent the changes in glomerular and tubular function commonly observed in this disease. Sixty male Wistar rats divided into four groups were studied: control (C), control treated with D-alpha-tocopherol (C + T), diabetic (D), and diabetic treated with D-alpha-tocopherol (D + T). Treatment with D-alpha-tocopherol (40 mg/kg every other day, ip) was started three days after diabetes induction with streptozotocin (60 mg/kg, ip). Renal function studies and microperfusion measurements were performed 30 days after diabetes induction and the kidneys were removed for morphometric analyses. Data are reported as means ± SEM. Glomerular filtration rate increased in D rats but decreased in D + T rats (C: 6.43 ± 0.21; D: 7.74 ± 0.45; D + T: 3.86 ± 0.18 ml min-1 kg-1). Alterations of tubular acidification observed in bicarbonate absorption flux (JHCO3) and in acidification half-time (t/2) in group D were reversed in group D + T (JHCO3, C: 2.30 ± 0.10; D: 3.28 ± 0.22; D + T: 1.87 ± 0.08 nmol cm-2 s-1; t/2, C: 4.75 ± 0.20; D: 3.52 ± 0.15; D + T: 5.92 ± 0.19 s). Glomerular area was significantly increased in D, while D + T rats exhibited values similar to C, suggesting that the vitamin prevented the hypertrophic effect of hyperglycemia (C: 8334.21 ± 112.05; D: 10,217.55 ± 100.66; D + T: 8478.21 ± 119.81æm²). These results suggest that D-alpha-tocopherol is able to protect rats, at least in part, from the harmful effects of diabetes on renal function.

Effect of thyroparathyroidectomy on urinary acidification in diabetic rats

In previous studies we have shown stimulation of renal acid excretion in the proximal tubules of rats with diabetes of short duration, with no important alterations in glomerular hemodynamics; on the other hand, in thyroparathyroidectomized rats (TPTX model), a significant decrease in renal acid excretion, glomerular filtration rate (GFR) and renal plasma flow (RPF) was detected. Since important changes in the parathyroid hormone-vitamin D-Ca axis are observed in the diabetic state, the present study was undertaken to investigate the renal repercussions of thyroparathyroidectomy in rats previously made diabetic by streptozotocin (45 mg/kg). Four to 6 days after the induction of diabetes (DM), a group of rats were thyroparathyroidectomized (DM + TPTX). Renal functional parameters were evaluated by measuring the inulin and sodium para-aminohippurate clearance on the tenth day. The decrease in the GFR and RPF observed in TPTX was not reversed by diabetes since the same alterations were observed in DM + TPTX. Net acid (NA) excretion was unchanged in DM (6.19 ± 0.54), decreased in TPTX (3.76 ± 0.25) and returned to normal levels in DM + TPTX (5.54 ± 0.72) when compared to the control group (6.34 ± 0.14 µmol min-1 kg-1). The results suggest that PTH plays an important vasodilator role regarding glomerular hemodynamics, since in its absence the impairment in GFR and RPF was not reversed by the diabetic state. However, with respect to acid excretion, the presence of diabetes was able to overcome the negative stimulus represented by TPTX

The renal effects of kainic acid

the respone of juvenile cultivated Piaractus mesopotamicus to handling stress, whthout anesthesia, was determined over 3-5 min (T1), 1 h (T2) and 6 h (T3) afeter capture. Plasma cortisol, glucose and total cholesterol were measured. Hyperglycemia present at T2 continued to rise until T3 while plasma cortisol levels increased but were similar at T2 and T3. Total plasma cholesterol was altered only at T3. Hyperglycemic changes were greater in fish without than stomach contents during the T2-T3 period. These differences in hyperglycemic changes may reflect the role of hormones other than cortisol in the regulation of glucose release in these fish

Malnutrition as an additional risk factor to gentamicin nephrotoxicity / Desnutrição como um fator de risco adicional na nefrotoxidade à gentamicina

A relação entre a desnutrição e as doenças infecciosas tem sido descrita há algum tempo. A gentamicina é um antibiótico aminoglicosídeo muito utilizado no tratamento de infecções graves por gram-negativos, apesar de sua nefrotoxidade. Estudos experimentais e clínicos também mostraram alterações importantes na função renal durante a desnutrição. Assim sendo, o objetivo do presente estudo foi verificar se o uso da gentamicina (G) em ratos submetidos à restrição alimentar (R) pode interferir no desenvolvimento da nefrotoxidade à gentamicina. Ratos Wistar machos com dois meses de idade foram submetidos à restrição alimentar (50 porcento) durante 30 dias. Nos 10 últimos dias, eles foram tratados com soro fisiológico ou gentamicina (40mg/kg/dia intraperitoneal). Os grupos estudados foram: C)- ratos com alimentação ad libitum + soro fisiológico, G)- alimentação ad libitum + gentamicina, R)- restrição alimentar + soro fisiológico, RG)- restrição alimentar + gentamicina. Uma queda significativa na taxa de filtração glomerular (TFG) foi observada nos grupos R (5,69 ± 0,22) e G (5,31 ± 0,27) se comparados ao grupo C (7,17 ± 0,42 ml.min kg). No grupo RG, a diminuição a TFG foi mais evidente do que nos grupos G ou R, (4,42 ± 0,24 ml.min-1.kg-1). Em todos os grupos experimentais, a diminuição da TFG ocorreu paralelamente à diminuição do fluxo plasmático renal (FPR), de modo que a fração de filtração (FF porcento) foi mantida. Um declínio na proporção inulina urina/plasma foi observado em ambos os grupos tratados com gentamicina e também no grupo com restrição alimentar. Apesar de G e R "per se" causarem um aumento na excreção de Na elevado a +, os valores mais altos foram obtidos no grupo RG. Apesar do nosso estudo ter sido realizado num modelo experimental, se extrapolado a protocolos humanos pode-se sugerir que o uso de antibióticos aminoglicosídeos nos pacientes desnutridos deve ser feito com cautela, especialmente devido a função renal e considerando o risco aumentado potencial exibido por estes pacientes.