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Aim: The therapeutic expediency of cisplatin was limited due to its nephrotoxic side effects, so this study planned to assess the nephrotic and neuroprotective impact of metformin (MET) and low-dose radiation (LDR) in cisplatin-prompted kidney injury and uremic encephalopathy (UE)., Methods: The effect of the 10-day MET treatment (200 mg/kg, orally) and/or fractionated LDR (0.25 Gy, of the total dose of 0.5 Gy, 1st and 7th day, respectively) on (5 mg/kg, intraperitoneally) cisplatin as a single dose was administered at the 5th day. Serum urea, creatinine and renal kidney injury molecule-1 were measured for the assessment of kidney function. Furthermore, the antioxidant potential in the renal and brain tissues was evaluated through, malondialdehyde and reduced glutathione estimation. Moreover, renal apoptotic markers: AMP-activated protein kinase, lipocalin, B-cell lymphoma 2 associated X protein, B-cell lymphoma 2, P53 and beclin 1 were estimated. UE was evaluated through the determination of serum inflammatory markers: nuclear factor kappa B, tumor-necrosis factor-α and interleukin 1 beta likewise, the cognitive deficits were assessed via forced swimming test, gamma-aminobutyric acid, n-methyl-d-aspartate and neuronal nitric oxide synthases besides AMP-activated protein kinase, light chain 3 and caspase3 levels in rats' cerebella., Key Findings: The obtained results revealed a noticeable improvement in the previously mentioned biochemical factors and behavioral tasks that was reinforced by histopathological examination when using the present remedy., Significance: metformin and low doses of radiation afforded renoprotection and neuroprotection against cisplatin-induced acute uremic encephalopathy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chronic kidney disease-mineral bone disorders (CKD-MBD) exhibit abnormalities in the circulating mineral levels, vitamin D metabolism, and parathyroid function that contribute to the formation of a bone lesion. The uremic toxin, indoxyl sulfate (IS), accumulates in the blood in cases of renal failure and leads to bone loss. The bone and renal responses to the action of the parathyroid hormone (PTH) are progressively decreased in CKD in spite of increasing PTH levels, a condition commonly called PTH resistance. There is a high prevalence of low bone turnover or adynamic bone disease in the early stages of CKD. This could be due to the inhibition of bone turnover, such as in PTH resistance, reduced active vitamin D levels, diabetes, aluminum, and, increased IS. With an increase in IS, there is a decrease in the osteoblast Wnt/b-catenin signaling and increase in the expression of Wnt signaling inhibitors, such as sclerostin and Dickkopf-1 (DKK1). Thus, a majority of early CKD patients exhibit deterioration of bone quality owing to the action of IS, this scenario could be termed uremic osteoporosis. However, this mechanism is complicated and not fully understood. With progressive deterioration in the renal function, IS accumulates along with persistent PTH secretion, potentially leading to high-turnover bone disease because high serum PTH levels have the ability of overriding peripheral PTH resistance and other inhibitory factors of bone formation. Finally, it leads to deterioration in bone quantity with prominent bone resorption in end stage renal disease. Uremic toxins adsorbents may decelerate oxidative stress and improve bone health in CKD patients. This review article focuses on IS and bone loss in CKD patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Periodate salts are being developed as potential replacements for perchlorate due to potential health hazards associated with exposure to perchlorate. The aim of this study was to investigate acute and subacute effects of periodate salts in rats. Acute oral toxicity of potassium and sodium periodate was determined using the Sequential Stage-Wise Probit method. The LD 50 for potassium periodate was 732 (95% CI = 539-838, slope = 13.4) and 685 mg/kg (95% CI = 580-809, slope = 10.6) for females and males, respectively. The LD 50 for sodium periodate was 318 (95% CI = 292-347, slope = 24.3) and 741 mg/kg (95% CI = 704-779, slope = 31.2) for females and males, respectively. In the subacute study, rats were administered sodium periodate at five doses (1/16 LD 50 up to LD 50 ) or distilled water for 14-days via oral gavage. Female rats in the 318 mg/kg-day group and male rats in the 185, 370, and 741 mg/kg-day groups exhibited moribundity, kidney toxicity, uremia, and a stress response. BMDL 10 s of 17.2 and 33.7 mg/kg-day were derived for females and males, respectively. Comparison with the NOAEL for perchlorate-induced thyroid toxicity in rats (0.009 mg/kg-day) suggests sodium periodate is less toxic than perchlorate on a subacute basis., (Copyright © 2016. Published by Elsevier Inc.)

P-cresol is a well-known uremic toxin and environmental toxicant that may affect platelet functions. In this study, p-cresol (1-5 μM) inhibited the arachidonic acid (AA)-induced platelet aggregation, with 47% and 82% of inhibition at concentrations of 2 and 5 μM, respectively. Under similar experimental condition, p-cresol showed little effect on the U46619-induced platelet aggregation. p-cresol (<500 μM) revealed no discernable cytotoxicity to platelets as analyzed by quantification of lactate dehydrogenase release. Antiplatelet effect of p-cresol was related to inhibition of thromboxane A(2) (TXA(2)) and prostaglandin D(2) (PGD(2)) formation. P-cresol (2-100 μM) partly inhibited the AA-induced reactive oxygen species (ROS) production as well as the extracellular signal-regulated kinase (ERK1/2) and p38 phosphorylation in platelets. P-cresol further inhibited the AA-induced aggregation of rabbit platelet-rich plasma (PRP) with an IC50 of 2 μM and aggregation of human PRP (IC50 = 13.6 μM). Intravenous administration of p-cresol (250-1000 nmole) into mice effectively suppressed the ex vivo platelet aggregation, whereas showed little effect on the value of RBC, hemoglobin (HGB), hematocrit, MCV, MCH, MCHC, platelets and lymphocyte counts. These results indicate that in acute p-cresol-poisoning and long-term exposure to cresol as in severe uremic patients, p-cresol may potentially inhibit blood clot formation and lead to hemorrhagic disorders via inhibition of platelet aggregation, ROS production, ERK/p38 activation and TXA(2) production., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Severe edema developed around the kidneys of rats after several days of uremia induced by large intravenous doses of mercuric chloride. Edema was prevented when the kidney was removed or had its hilum ligated, or when rats were deprived of fluid intake. The edema fluid had a very low protein content. These facts suggested that the edema was derived from the kidneys, probably from the glomerular filtrate, and that the edema depended on some degree of remaining renal function. Increased permeability of the necrotic proximal tubules and obstruction by casts in the collecting tubules may have been involved. Histologic study suggested that the fluid diffused through the intact renal capsule. These experiments provide a model for perinephric (perirenal) fluid accumulation in certain human diseases and in certain intoxications of grazing animals.

Unlabelled: 22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis., Background: 22-Oxacalcitriol (OCT) is a unique vitamin D analogue with less calcemic activity than calcitriol, and it effectively suppresses parathyroid hormone (PTH) secretion in uremic rats. This study was performed to examine the long-term effect of intravenously administered OCT on high-turnover bone disease in model rats of slowly progressive renal failure., Methods: Slowly progressive renal failure rats were made by a single injection of glycopeptide isolated from rat renal cortical tissues. At 250 days, glycopeptide-induced nephritis (GN) rats were divided into three groups with the same levels of serum creatinine and PTH, and they received either OCT (0.03 or 0.15 microg/kg body wt) or vehicle given intravenously three times per week for 15 weeks., Results: Renal function of GN rats deteriorated very slowly but progressively, as assessed by the increase of serum creatinine concentration. At sacrifice, serum PTH levels, bone formation markers, bone resorption markers, and fibrosis volume were significantly elevated in vehicle-treated GN rats compared with those of sham-operated rats, suggesting the development of high-turnover bone disease with osteitis fibrosa. In contrast, in the GN-OCT 0.15 microg/kg group, these high PTH levels and high-turnover bone and fibrosis were significantly decreased. Such amelioration of bone abnormalities by OCT was not accompanied by either hypercalcemia or further deterioration of renal function., Conclusions: These data indicate that OCT may be a useful and safe agent not only for the suppression of PTH, but also for the amelioration of osteitis fibrosa and high-turnover bone without causing hypercalcemia in chronic dialysis patients.

When administered to a 45-year-old woman who was ill with severe hypertension, combined enalapril and hydrochlorothiazide therapy resulted in acute renal failure, leading to a successful search for renal artery stenosis. Acute renal failure as an adverse reaction to enalapril therapy occurs in approximately 20% of patients with secondary hypertension from renovascular disease. On the other hand, in a group of essential hypertensives this occurs at a rate of approximately 0.2%. Thus, a likelihood ratio of 100 is produced, and given the prevalence of renovascular hypertension of approximately 2% in all hypertensives, a posterior probability of 0.67 can be calculated. The occurrence of this adverse effect should indicate that a diagnostic work-up to rule out renovascular hypertension in such patients should be pursued. The sensitivity and specificity of this "test" are 0.20 and 0.998, respectively. This illustrates that the mathematic aids in decision theory need not be applied solely to those more traditional aspects of diagnostic testing, but may be useful in other situations as well.

A variety of side effects have been reported with the use of interleukin-2 alone or in combination with lymphokine-activated killer cells in patients with disseminated neoplasms. The present study was undertaken to determine the effects of high-dose interleukin-2 administration in normal rats. Sprague-Dawley rats were treated with intravenous recombinant interleukin-2 (900,000 IU/kg/day) for 9 consecutive days. Animals were placed in individual metabolic cages, and arterial blood pressure, food intake, body weight, and urine output were monitored. On day 10, animals were killed by exsanguination, various tissues were harvested, and a variety of hematologic and chemical assays were performed. The results were compared with those of placebo-injected normal control and pair-fed groups. The interleukin-2-treated group exhibited anorexia, weight loss, hypotension, anemia, leukocytosis, lymphocytosis, eosinophilia, hypercalcemia, azotemia, and a marked urinary concentration defect. Histologic examination of various tissues revealed widespread infiltration with mono-nuclear cells and eosinophils in most organs, especially in the lungs and liver of interleukin-2-treated animals. Other abnormalities included severe panlobular hepatitis, hepatocellular necrosis, and thymic involution. Renal involvement was mild and consisted of focal interstitial infiltration by mononuclear cells. According to these observations, administration of high-dose interleukin-2 in normal rats results in a score of significant functional, biochemical, and histologic abnormalities.

In a multicentre trial of adjuvant chemotherapy in gastric adenocarcinoma, a number of patients developed chronic haemolysis and renal failure following long-term treatment with 5-fluorouracil and mitomycin-C. This was exacerbated by blood transfusion, leading to an acute intravascular haemolytic state accompanied by rapid decline in renal function. One patient investigated extensively was treated with antiplatelet drugs, steroids, and fresh frozen plasma without success. At necropsy this patient and another had renal changes typical of the haemolytic-uraemic syndrome and no evidence of tumour recurrence. Long-term treatment with this drug combination is potentially dangerous, and routine monitoring of renal function is recommended.

After treatment with mitomycin C, a patient developed pulmonary hypertension with interstitial infiltrates, microangiopathic hemolytic anemia, systemic hypertension, and renal failure with the nephrotic syndrome. Open lung biopsy documented intracapillary fibrin thrombi in the pulmonary vasculature. Renal biopsy documented glomerular and arteriolar changes that were most consistent with a thrombotic-thrombocytopenic-like process. Treatment with corticosteroids, fresh-frozen plasma, and total plasma exchange was ineffective. The patient died six months after the onset. When mitomycin-C therapy is given, the clinician should be aware of the pulmonary, renal, and microangiopathic changes that can be associated with such therapy.

One hundred and thirty-nine febrile episodes in 120 patients were treated with sisomicin after a combination of carbenicillin and a cephalosporin antibiotic had failed. These patients were randomized to receive sisomicin either by continuous or by intermittent infusion. The response rate for patients treated with sisomicin was 61 percent by continuous infusion and 46 percent by intermittent infusion, which was not statistically significant. Pneumonia, septicemia, and soft tissue infections were the most frequent infections. Most (96 percent) of the identified pathogens were gram-negative bacilli with the most frequent being Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. The response rate was higher in those patients whose neutrophil count increased or remained the same while on therapy. The worst response was obtained if there was a decrease in the neutrophil count during therapy. The major toxicity of sisomicin was found to be azotemia and occurred in 17 percent of episodes treated by continuous infusion and in 21 percent treated by intermittent infusion. Hearing loss in the high frequency range occurred in five patients. Sisomicin is effective in the treatment of gram negative infections in neutropenic cancer patients.

Amikacin, a new aminoglycoside antibiotic, was utilized in the treatment of 49 cases of infection which occurred in 39 neutropenic cancer patients. Thirty-four patients (69 per cent) responded to this antibiotic. Pneumonia and septicemia were the most common types of infection treated and the response rates were 65 per cent and 75 per cent, respectively. Gram-negative bacili were responsible for 93 per cent of the identified infections and 74 per cent responded. E. coli, Ps. aeruginosa, and organisms of the Klebsiella-Enterobacter-Serratia group were the most common gram-negative bacilli causing infection. Responses were more frequent among patients who maintained higher serum concentrations of antibiotic, but the differences were not statistically significant. Patients with severe neutropenia (less than 100 neutrophils/mm3) had a response rate of 68 per cent. Toxicity was manifested as azotemia and hearing loss which occurred in 13 per cent and 6 per cent, respectively. However, toxicity was directly related to serum concentration and to the number of treatments with amikacin. This antibiotic is of potential importance because of its efficacy against gram-negative bacilli infections. Best results were obtained when sufficient drug was given as a continuous intravenous infusion to maintain serum concentrations of about 15 mu g/ml.

Metabolic balance and morphologic studies were performed on rats receiving gentamicin 100 mg/kg/day for a period of 8--10 days and during the recovery period. Daily urine flow rate increased with the administration of gentamiccin and remained elevated up to 20 days following the discontinuation of gentamicin, although BUN and plasma creatinine were virtually normal 10 days after the discontinuation of gentamicin. During the development of renal failure means daily electrolyte excretion remained normal. During the recovery period, however, sodium and potassium excretion exceeded control values while chloride and net acid excretion remained normal. Proteinuria developed during the administration of gentamicin and returned to normal 6--10 days after the discontinuation of gentamicin. Ten days of netilmicin administration (150 mg/kg/day) resulted in only mild tubular degeneration and no azotemia.

Studies were performed to evaluate the contribution of the urea appearance rate to the elevated plasma urea concentration found during diuretic-induced sodium depletion. Negative sodium balance of -1162 + 29 microEq/100 g body wt was induced over a four day period by the administration of furosemide, 20 to 30 mg/kg/d i.p., to rats ingesting a sodium free diet. When compared with sodium replete controls, sodium depletion significantly increased the plasma urea concentration (65.0 +/- 3.1 vs. 26.4 +/- 1.1 mg/dl) through both an increase in the urea appearance rate (160 +/- 5.2 vs. 125 +/- 3.5 mg/day/100 g body wt), and a decrease in the urea clearance rate (1.99 +/- 0.14 vs. 3.16 +/- 0.12 ml/min/kg). The urea appearance rate increased on the first day of diuretic administration, remained elevated three days after stopping diuretics, rapidly returned to control levels after sodium repletion, and was significantly correlated with the magnitude of sodium deficit. Similar results were obtained when diuretic-induced sodium depletion was produced in adrenalectomized animals. After four days of sodium depletion the plasma concentration was increased for some amino acids but not for the plasma total amino acid, nitrogen concentration. The results indicate that sodium depletion increases the urea appearance rate through a mechanism that is independent of adrenal function. Thirty to sixty percent of the elevation in plasma urea concentration that occurs in the rat during diuretic-induced sodium depletion can be accounted for by an enhanced urea appearance rate.

The cure rate of infections in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum creatinine greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients.