Changes In Urine Parameters Research Articles

Preclinical safety, toxicokinetics and metabolism of BIIB131, a novel prothrombolytic agent for acute stroke

BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings. The BIIB131 was poorly metabolized in microsomes with no inhibition of CYPs. BIIB131-glucuronide, formed by UGT1A1, accounted for 21.5% metabolism in human hepatocytes and 28–40% in rat bile. In rats, excretion was primarily via the bile. BIIB131 inhibited the hERG and Nav1.5 cardiac channels by 39% but showed no effect on cardiovascular parameters in monkeys. Toxicology findings were limited to reversable hematuria, changes in urinary parameters and local effects. A MTD of 30 mg/kg was established in monkeys, the most sensitive species, at total plasma Cmax and AUC of 6- and 14-fold, respectively, greater than the NOAEL. The Phase 1 study started with intravenous 0.05 mg/kg and ascended to 6.0 mg/kg which corresponded to safety margins of 147- to 0.9-fold (for Cmax) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development.

#3750 SERUM AMYLOID A AS PROGNOSTIC MARKER FOR CKD AND NON-CKD COVID-19 PATIENTS ADMITTED TO THE EMERGENCY ROOM

Abstract Background and Aims Patients with chronic kidney disease (CKD) and a SARS-CoV-2 infection are at higher risk of developing acute kidney injury (AKI) and of mortality after hospital admission. Herein, we assessed whether serum amyloid A (SAA) was associated with outcomes (AKI and/or death). Method The study group included 160 patients: 70 Covid-19-positive CKD patients (eGFR <60 mL/min), 50 Covid-19-positive patients with no history of kidney disease, 20 Covid-19-negative CKD patients, and 20 healthy controls. We collected data on patients’ gender, age, co-morbidities, and laboratory results from blood and urine samples taken at admission into the ER, and from healthy volunteers. All participants gave their informed consent for trial with protocol №12/31.05.2022 approved by the ethical committee KENIMUS of the Medical University of Sofia, Bulgaria. Laboratory values included calculated eGFR (by the CKD-EPI 2021 formula), highly sensitive inflammatory markers, D-dimer, blood-cell counts, and changes in urine parameters. Co-morbidities included hypertension, obesity, diabetes mellitus, vascular disease, and CKD. All patients had been treated by the official protocol of the Republic of Bulgaria for SARS-CoV-2. We determined the levels of SAA across the four groups to assess if this biomarker could predict AKI, risk of mortality, and if there was a significant difference between the CKD and non-CKD patients. Results Overall, median age of Covid-19 patients was 56.4 years; gender ratio was 50% M/F in all groups. Median duration of symptoms before hospitalization was 6 days. Of the 160 patients, 30% were febrile with temperatures >38oC. Overall, creatinine level on admission was elevated in 40% of cases; eGFR was <60 mL/min/1.73 m2 in 37.5% of patients. Mean value of eGFR on admission was 82.3 mL/min/1.73 m2 for the non-CKD Covid-19-positive group, 49.5 mL/min/1.73 m2 for the CKD Covid-19-positive group, 62.3 mL/min/1.73 m2 for the CKD patients without COVID-19, and 111.1 mL/min/1.73 m2 for the healthy control group. In total, three Covid-19 patients needed renal-replacement therapy: two patients from the CKD group and one from the non-CKD group. AKI occurred in 38 Covid-19 patients (23.7%). Of these, 31 had CKD (44.3% of the Covid-19 positive CKD patients). Overall, within our cohort of 160 patients, in-hospital mortality was 14.3% (23 patients): of these, 82.6% had AKI (19 patients). Overall, 100% of patients that did not survive Covid-19 also had CKD. We analyzed the levels of SAA across the groups. The reference limits considered for negative results were <7 pg/mL; the ELISA could measure values up to 300 pg/mL. Of the 23 patients that died, 19 had levels >300 pg/ml (82.6%), whilst the remainder had results >250 pg/mL. The other patients who survived the infection in our cohort had levels well below 200 pg/ml. When the patients with AKI and without AKI were compared on the basis of SAA, patients with AKI had significantly higher biomarker values (p- = 0.02). When compared across the four groups, no significant differences were found except when comparing the healthy control group with the other three groups, where there was significance of p<0.0001 in each comparison. Conclusion We confirm that SAA was a reliable biomarker for predicting AKI in Covid-19 patients. It also acted as a predictor for a fatal outcome in patients with severely Covid-19 infection. In conclusion, SAA is a reliable marker, highly informative in the emergency department setting, enabling us to have an early prognosis for the outcome of the Covid-19 infection for the patients in our cohort.

Risk Factors for Common Kidney Stones Are Correlated with Kidney Function Independent of Stone Composition

Introduction: Kidney stone type varies with age, sex, season, and medical conditions. Lower estimate glomerular filtration rate (eGFR) leads to changes in urine chemistry, and risk factors for kidney stones are thought to vary by stone type. We explore the association between eGFR, urine risk factors, and common stone compositions. Methods: This was a retrospective cohort study of 811 kidney stone patients seen at Yale Medicine between 1994 and 2021 with serum chemistries and 24-h urine chemistries matched within 1 year of baseline stone analysis. Patients’ eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. Demographics and medical history were compared by χ2 tests. 24-h urine chemistries and stone analyses were analyzed by one-way ANOVA. Linear regressions were performed to control for demographics, comorbidities, and stone composition. Results: With lower eGFR, the proportion of calcium stones declined while uric acid (UA) stones increased. On univariable analysis, lower eGFR was associated with lower urine pH, calcium, citrate, UA, magnesium, phosphorus, and ammonium. On multivariable analysis, controlling for age, sex, ethnicity, body mass index, comorbidities, and stone type, these factors remained significant. Stone formers with lower eGFR had elevated supersaturation for UA, but reduced supersaturations for calcium-containing stones. Though urine oxalate was significant on univariable analysis, it was not on multivariable analysis. Conclusion: Changes in urine parameters are strongly correlated with eGFR regardless of stone type. Renal function may play a key role in modulating kidney stone risk factors. Strategies to mitigate stone risk may need to vary with kidney function, especially when patient urine or stone composition data are unavailable.

Is the Urine Analysis, a Diagnostic Value in COVID-19 Patients?

Background: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), a novel coronavirus causing Coronavirus disease 19 (COVID-19) in December 2019, is now a pandemic infectious disease, primarily affecting the respiratory tract. To date, many investigations are available for the diagnosis of SARS-CoV-2. A viral nucleic acid test has been used for the diagnosis of COVID-19, and some hematological indicators have been used in the auxiliary diagnosis and identification of the severity of COVID-19. There are very few studies available in routine urine biochemical parameters and their relation with Covid-19 patients.
 Aim: This study is aimed to study the changes in urine parameter values in COVID-19 disease and to predict the severity of the disease with the changes in urine parameters.
 Materials and Methods: A total of 150 patients with COVID-19 were admitted at Saveetha Medical College and Hospital during the study period. All cases tested positive for SARS-CoV-2 by RT-PCR test done on nasopharyngeal swabs during the study period were included. Patients who tested negative by RT-PCR test were considered as controls. The relationship between the results of urine biochemical parameters and the severity of COVID-19 were analysed by Descriptive statistics, Chi-squared test.
 Results: The positive rates of proteinuria (PRO) and leucocytes were more significant in COVID-19 patients than in healthy controls. The urine specific gravity (SG) value was highly significant (p <0.001) while the blood, nitrites in urine, and potential of hydrogen (pH) value was insignificant.
 Conclusion: There were some considerable changes in few urine biochemical parameters between patients with the SARS-CoV-2 and healthy controls. So from this study we conclude, proteinuria is helpful for predicting COVID-19 severity and kidney function.

Is metformin use associated with changes in urinary parameters in stone formers?

Diabetes mellitus (DM) is associated with an increased risk of nephrolithiasis and is often treated with metformin. The relationship between metformin and nephrolithiasis formation remains unclear, as studies have demonstrated conflicting results. We conducted a cross-sectional analysis of stone-forming patients at our stone clinic prior to the initiation of stone-directed medical management. Patients were grouped based on diabetic status and diabetic medication regimen. Outcomes evaluated were 24-hour urinary parameters and specimen stone type using univariate Kruskal-Wallis and Chi-squared analyses. Multivariate analyses controlling for metabolic syndrome components and HbA1c were performed. Data were available for 505 patients, of whom 147 were diabetic and 358 were not. On multivariate analyses controlling for HbA1c and other comorbidities, diabetic patients on metformin still had worse urinary parameters, including urine pH, than non-diabetic patients (pH=-0.33, -0.37, p<0.05). Patients with DM on metformin did not exhibit significant differences in 24-hour urine findings compared to patients with DM not on metformin (p>0.05 for all urinary parameters). Stone-forming patients with DM on metformin were associated with urinary abnormalities similar to those not on metformin. Cohort studies comparing urinary parameters of patients prospectively started on metformin are necessary to further elucidate metformin's role, if any, in combatting nephrolithiasis.

PD12-02 THE EFFECTS OF EARLY METABOLIC SYNDROME ON 24-HOUR URINE PARAMETERS IN STONE FORMERS

INTRODUCTION AND OBJECTIVES:The association between metabolic syndrome and consequent changes in urinary parameters have been well established. We aimed to further investigate whether these changes...

Temporal change in urinary parameters and Ultrastructural pathology of kidney in cisplatin Induced nephrotoxicity in rats

Temporal change in urinary parameters and Ultrastructural pathology of kidney in cisplatin Induced nephrotoxicity in rats

Safety evaluation of a whey protein fraction containing a concentrated amount of naturally occurring TGF-β2

TM0601p is a whey protein isolate derived from cow milk, containing a concentrated amount of transforming growth factor β2 (TGF-β2), and is intended for nutritional use in infants and adults. In vivo and in vitro studies have been performed to evaluate the safety of this product. In a 13-week toxicity study, treatment of adult Sprague–Dawley rats by gavage at up to 2000mg/kg/day did not result in any significant findings other than minor non-adverse changes in urinary parameters in females. The no-observed-adverse-effect level (NOAEL) was established as 2000mg/kg/day. In a juvenile toxicity study, rat pups received 600mg/kg/day by gavage from postnatal day (PND) 7 to PND 49. Transient lower bodyweight gain in the pre-weaning period was attributed to gastrointestinal effects of the viscous test material; following weaning, bodyweight gain was comparable to the vehicle controls. Reduced eosinophil counts and changes in urinary parameters (females) were recorded in treated pups at PND 49, and higher thymus weights were recorded in males only at the end of the recovery period (Day 77). None of the findings were considered adverse. There were no other significant findings and the NOAEL was established as 600mg/kg/day. No evidence of genotoxicity was seen in the bacterial reverse mutation test or the in vitro micronucleus test. Overall the results obtained present a reassuring safety profile for TM0601p.

Dietary Management of Idiopathic Hyperoxaluria and the Influence of Patient Characteristics and Compliance

To assess the efficacy of dietary management for the treatment of idiopathic hyperoxaluria in a large tertiary care center and examine the influence of patient factors, compliance, and follow-up on oxalate reduction, which has not been previously investigated. Retrospectively, 149 patients with kidney stones with idiopathic hyperoxaluria who received dietary management at our stone clinic were evaluated. Changes in urinary parameters on 24-hour urine collections were calculated for all patients and those with abnormal values in the overall short-term (30-240 days) and long-term (>240 days) time periods. Changes in urinary oxalate were evaluated with respect to patient characteristics and compliance measures. Urine oxalate and supersaturation of calcium oxalate were significantly (P < .001) reduced by 8.9 ± 19.2 mg/d and 1.7 ± 4.3, respectively. A total of 48.3% of the patients reduced their urinary oxalate to normal. Urine oxalate reductions were similar in the short-term and long-term periods. Women lowered urine oxalate nearly twice as much as men (12.7 ± 2.0 mg/d vs 6.7 ± 2.2 mg/d, P = .022) and body mass index (BMI) negatively correlated with oxalate reduction (Pearson's r = -0.213). Reported noncompliance and keeping follow-up appointments did not affect oxalate, however, there was a significant correlation between increasing urine volume and reducing oxalate (Pearson's r = -0.21). This study confirms that meaningful reductions of urine oxalate and supersaturation of calcium oxalate can be achieved with dietary management of hyperoxaluria on a larger clinical scale. Furthermore, we identified that women and patients with low BMIs had greater urine oxalate reductions and urine volume may also be used by clinicians as a measure of dietary compliance.

Changes in Urine Parameters After Desert Exposure: Assessment of Stone Risk in United States Marines Transiently Exposed to a Desert Environment

Living in a desert environment has been associated with a higher incidence of kidney stone formation, likely because of concentrated urine output, higher production of vitamin D and genetic predisposition. We determined the changes in urinary parameters after a group of United States Marines temporarily transitioned from a temperate environment to a desert environment. A total of 50 Marines completed a questionnaire and performed 3, 24-hour urine collections before mobilization to the desert, after 30 days in the desert and 2 weeks after returning from the desert. Daily urine output decreased 68% to 0.52 L despite marked increased fluid intake (17 L per day). Total daily urinary excretion of calcium, uric acid, sodium, magnesium and potassium in the desert decreased by 70%, 41%, 53%, 22% and 36%, respectively. Urinary pH decreased from 6.1 to 5.6 while in the desert, and citrate and oxalate had minimal changes. After their return from the desert, apart from a decrease of 22% in oxalate, there were no statistically significant differences from baseline. While in the desert, relative supersaturation risks of uric acid and sodium urate were increased 153% and 56%, respectively. Brushite relative supersaturation decreased 24%. After their return there was no statistical difference from baseline. Our findings suggest that the kidneys preserved water and electrolytes while the Marines were subjected to the desert environment. Despite this conservation, relative saturations indicate increased risk of stones in healthy men exposed to a desert environment with rapid resolution upon return.

The relevance of the migration inhibitory factor (MIF) for peripheral tissue response in murine sublethal systemicAspergillus fumigatusinfection

We recently demonstrated that macrophage migration inhibitory factor deficient (MIF (- / -)) mice exhibited a higher susceptibility to lethal systemic Aspergillus fumigatus infections than genetically matched, wild-type (WT) C57BL/6 mice, and displayed altered cytokine profiles in the spleen when challenged by sublethal infections. In this report we focused on the potential involvement of MIF in the response of mice to sublethal systemic A. fumigatus infections in tissues other than spleen. Impaired fungal clearance from lungs, kidneys, liver and brain in MIF (- / -) mice was noted and was associated with histologically-evident differences in signs of inflammation in these organs. Higher values of some indicators of pathologic changes in urine parameters (increases in bilirubin, glucose and ketones), as well as a greater degree of brain tissue damage, pointed to multiple organs being affected in MIF (- / -) mice. Analysis of the lung response revealed differences in the composition of infiltrated cells between MIF-sufficient and MIF-deficient mice. MPO activity and reactive oxygen species production were impaired, as well as production of IL-17 and IFN-γ in MIF (- / -) mice as compared to WT counterparts. Lower systemic IL-1β and IL-6 levels in infected MIF (- / -) mice coincided with reduced blood neutrophil counts and organ infiltration. Collectively, this study identifies MIF as a resistance factor that orchestrates events in several non-lymphoid areas which provide a milieu that accomplishes anti-fungal A. fumigatus defense.

Differences in metabolic urinary abnormalities in stone forming and nonstone forming patients with primary hyperparathyroidism

Hyperparathyroidism is associated with hypercalciuria and nephrolithiasis. Urine calcium excretion decreases after parathyroidectomy, but whether there is a differential decrease between stone and nonstone formers remains controversial. We evaluated differences between stone formers and non-stone formers in serum and urinary parameters before and after parathyroidectomy. 90 patients, 40 with and 50 without a history of nephrolithiasis underwent parathyroidectomy for hyperparathyroidism; 24-hour urine samples were collected before and after parathyroidectomy. Overall, 92% of patients provided samples before parathyroidectomy and 63% after parathyroidectomy. Preoperative, postoperative and changes in urinary parameters were evaluated. Preoperative hypercalciuria was present in ∼65% in both groups (P = .68). Parathyroidectomy decreased serum levels of calcium, parathyroid hormone, and urinary calcium, but there were no differences between stone formers and nonstone formers. Stone formers were 12-fold (P = .001) more likely to resolve an increase in supersaturation of calcium oxalate (SSCaOx), and after adjustment for age, sex, and BMI were 46-fold (P = .002) more likely to resolve an increase in SSCaOx. After parathyroidectomy, the rate of stone recurrence was 23% and male sex (aOR 20, P = .032) and increasing BMI (aOR 1.23, P = .038) were the only independent predictors of stone recurrence after adjusting for age. No other factor evaluated preoperatively, postoperatively, or the change after parathyroidectomy differentiated stone and nonstone formers or predicted stone recurrence. Metabolic evaluation did not differentiate stone formers from nonstone formers reliably. Stone formers were more likely to resolve an increase in SSCaOx after parathyroidectomy. Male sex and increasing BMI were independently associated with stone recurrence after parathyroidectomy.

Cost-Effectiveness of Primary Prevention Strategies for Nephrolithiasis

Stone disease is a highly prevalent condition associated with substantial cost and morbidity. We evaluated the cost-effectiveness of a primary prevention strategy. A decision analysis model was constructed to compare the cost of ad hoc management of symptomatic stones vs the cost of primary prevention. A literature search was performed to determine the incidence of stone disease, the effectiveness of nonmedical prevention strategies and cost associated with stone management. One and 2-way sensitivity analyses were performed to determine conditions under which a strategy of primary prevention might be cost-effective. Assuming a 1% incidence of stones, a 50% risk reduction and a $100 cost per individual per year for primary prevention, the model was used to calculate the overall costs per individual per year without and with a primary prevention strategy of $46 and $123, respectively. One-way sensitivity analyses indicated that primary prevention was cost-effective if the incidence of stones exceeded 4.3% yearly or the cost of prevention was less than $23 per person yearly. Varying other factors (risk reduction, probability of requiring surgery, hours of lost work, emergency room cost) failed to reach cost equivalence under any circumstances or required unrealistic assumptions. Preventive strategies were more costly than no prevention unless the incidence of stone disease was at least 1%, the cost did not exceed $20 per person per year and the prevention strategy was at least 50% effective in preventing stones. Primary prevention strategies for stone disease have not been sufficiently evaluated but can theoretically be cost-effective if the population has a sufficiently high incidence of stone disease and the strategy is of low cost and moderately effective.

Pyridoxine and Dietary Counseling for the Management of Idiopathic Hyperoxaluria in Stone-forming Patients

To examine the effects of dietary manipulation and pyridoxine medical management for idiopathic hyperoxaluria in patients with nephrolithiasis. A retrospective longitudinal study of the patients treated in our stone clinics from July 2007 to February 2009 was performed. All patients were evaluated with pre- and postintervention 24-hour urine collection and met a registered dietician. Recommendations to keep urine volume above 2 L per day, sodium restriction, protein moderation, increased calcium intake with meals and low oxalate diet combined with oral pyridoxine were given. Initial dosage ranged from 50 to 100 mg per day depending on the baseline oxalate level, and was titrated to a maximum of 200 mg daily. Subjects with at least two 24-hour urine collections were included in the study. Of 314 patients with complete metabolic and urinary profile evaluation, 95 subjects were identified with idiopathic hyperoxaluria. Mean follow-up was 18.4 ± 14.8 months and mean age was 50.3 ± 12.8 years. In patients treated with the combination of dietary counseling and pyridoxine, there was a significant change in urinary parameters in 75% of patients with a significant decrease in urinary oxalate excretion (58.26 ± 27.05 to 40.61 ± 15.04, P < .0001). In all, 39% of the patients had a decrease from a high urine oxalate levels (>40 mg/d) to a normal range urine oxalate (55.30 ± 22.04 to 33.45 ± 3.93, P = .0004). No peripheral neuropathy was reported. Dietary management and medical treatment using pyridoxine may be an effective first-line therapy to decrease hyperoxaluria in patients who form stones.

Effect of n-3 Fatty Acid Supplementation on Urinary Risk Factors for Calcium Oxalate Stone Formation

Findings are inconsistent in a few studies of the effect of n-3 fatty acid supplementation on urinary calcium and oxalate excretion in stone formers. We evaluated the physiological effects of supplementation with eicosapentaenoic acid and docosahexaenoic acid on urinary risk factors for calcium oxalate stone formation under standardized conditions. We studied 15 healthy subjects initially while consuming a standardized diet for 5 days (control phase). During consecutive intervention phases 1-5-day standardized diet, 2-20-day free diet and 3-5-day standardized diet participants received 900 mg eicosapentaenoic acid and 600 mg docosahexaenoic acid daily. While ingesting the standardized diets, daily 24-hour urine samples were collected. After short-term supplementation with eicosapentaenoic acid and docosahexaenoic acid in phase 1 we noted no changes in urinary parameters compared to the control phase. After 30-day supplementation with eicosapentaenoic acid and docosahexaenoic acid in phase 3 relative supersaturation with calcium oxalate decreased significantly by 23% from a mean ± SD of 2.01 ± 1.26 to 1.55 ± 0.84 due to significantly decreased urinary oxalate excretion (p = 0.023). Other urinary variables were not affected by supplementation. Results show that 30-day n-3 fatty acid supplementation effectively decreases urinary oxalate excretion and the risk of calcium oxalate crystallization. The mechanism of the physiological effect may be decreased cellular oxalic acid exchange attributable to an altered fatty acid pattern of membrane phospholipids with concomitant changes in oxalate transporter activity. Calcium oxalate stone formers may benefit from long-term n-3 fatty acid supplementation.

Urothelial Carcinogenesis in the Urinary Bladder of Rats Treated with Naveglitazar, a γ-dominant PPAR α/γ Agonist: Lack of Evidence for Urolithiasis as an Inciting Event

Naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was tested for carcinogenicity in F344 rats in a 2-year study. Changes in urine composition and urothelial morphology were characterized in a companion 18-month investigative study. A significant increase in neoplasms of the bladder occurred only in females of the high-dose group (14/60) in the carcinogenicity study. Trends toward increased cell proliferation in the urothelium were noted in both sexes at all time points evaluated in the 18-month study. Group means for urothelial mitogenesis were increased statistically significantly only in high-dose females at 12 and 18 months. Urothelial hyperplasia occurred in high-dose females at 18 months. Morphologic changes in the urothelium at earlier time points were limited to hypertrophy and decreased immunolabeling of the superficial cells for cytokeratin 20 (a marker of terminal differentiation in urothelial cells) in both males and females. No treatment-related changes in urinary parameters, including urinary sediments, were associated with the occurrence of urothelial proliferation. Urinary pH was unaffected by treatment in both males and females, but expected diurnal changes were demonstrated. Collectively, these data indicate that naveglitazar was associated with hypertrophic and proliferative effects on the urothelium, but a link with changes in urinary parameters was not demonstrated.

Are changes in urinary parameters during pregnancy clinically significant?

Are changes in urinary parameters during pregnancy clinically significant?

Are changes in urinary parameters during pregnancy clinically significant?

We aimed to objectively determine changes in the various urinary parameters along with CaOx saturation level during pregnancy. The study included 15 pregnant women who had no known diseases and were taking no medication except prenatal supplements. Mean age of the patients was 26 years (range 20-30). In all of them, this study was carried out in each trimester and 3 months post partum. All participants were followed up, and blood and urine samples were obtained during the pregnancy and during 3 months post partum. All subjects collected 24-h urine samples. The pregnant women had hypercalciuria in all three trimesters. Except for the first trimester, urine calcium levels in all trimesters were significantly higher when compared with the post-partum period (P<0.01 for second trimester, P<0.05 for third trimester). Urine oxalate level in post-partum period was significantly higher than urine oxalate levels in each trimester (P<0.05). The urine citrate levels were similarly higher than normal levels in three trimesters. Urine citrate level of the post-partum period was in normal reference ranges. This difference was not statistically significant (P>0.05). We believe that hypercalciuria encountered at pregnancy is a reversible physiologic condition. Also, citrate and magnesium as urinary inhibitors increased in urine during gestation preventing stone formation. We think that long time periods are needed for hypercalciuria to be able to lead to the formation of urinary calculi in pregnant women (except women having a positive family history). Therefore, we think that the pregnancy alone does not predispose to a suitable condition for calculi.

Dose‐related proximal tubular dysfunction in male rats chronically exposed to lead

Male Wistar rats were given 0.5 and 2% lead acetate in drinking water for 2 months, 1% lead acetate for 3 months and sodium acetate equimolar to 2% lead acetate for 3 months. Glucose, total proteins, lactate dehydrogenase (LDH), lysozyme and beta 2-microglobulin (beta 2-m) were measured in 24-h urine every month. Kidney weight and histology were also examined. At the three doses, lead exposure produced a significant elevation of the kidney weight. No significant change in urinary parameters was observed in rats given 0.5% lead acetate. Exposure to 1% lead acetate increased the urinary excretion of beta 2-m only. At the 2% lead acetate dose the elevation of beta 2-m excretion was accompanied by an increased urinary output of glucose, total proteins, lysozyme and LDH. Observations of the kidneys by light microscopy were in agreement with these biochemical findings. The nephrotoxic effect of acetate was excluded by the lack of biochemical or histological effects of sodium acetate on the kidney. It is concluded that a proximal tubular dysfunction is induced in rats chronically exposed to high doses of lead.

Participation of urinary Na +, K +, pH, and L-ascorbic acid in the proliferative response of the bladder epithelium after the oral administration of various salts and/or ascorbic acid to rats

Changes in urinary parameters (particularly electrolyte levels and pH), and DNA synthesis and the morphology of the bladder epithelium were investigated in rats that were fed for 4 or 8 wk on diets containing various Na, K, Mg or Ca carbonate salts, with or without l-ascorbic acid (AsA). [The carbonate salts were fed at a level of 3% in the diet, and AsA or AsA-Na was administered at 5% in the diet. NH 4Cl was at 1% in the diet.] The effects of treatment with NH 4Cl (used as a urine acidifier), and of combined treatment with sodium ascorbate (AsA-Na) and NH 4Cl were also investigated. Urinary pH was significantly elevated in groups given NaHCO 3, K 2CO 3, AsA + NaHCO 3, AsA + K 2CO 3 and AsA-Na, whereas treatment with AsA or NH 4Cl alone caused a significant drop in urinary pH. An increase in urinary electrolytes or ascorbic acid was associated with the corresponding dosing regimen. DNA synthesis in the bladder epithelium was increased in groups given NaHCO 3, K 2CO 3, AsA + NaHCO 2, AsA + K 2CO 3 or AsA-Na. Furthermore, all treatments that induced an elevation of DNA synthesis also induced some morphological alterations in the bladder epithelium. The administration of AsA in conjunction with NaHCO 3 or K 2CO 3 induced levels of change greater than those with either salt alone. In contrast, the degree of response in the bladder epithelium of rats given AsA-Na was reduced by the simultaneous administration of NH 4Cl. These results suggest that the degree of DNA synthesis and/or morphological alteration in the rat-bladder epithelium after treatment with various bases may depend on changes in urinary concentrations of Na + or K + ions and/or pH, and the presence of ascorbic acid in the urine. The results are discussed in relation to the possible promotion by various treatment regimens (salts ± AsA) of urinary bladder carcinogenesis.