Exposure to Nickel-Cadmium Contamination of Drinking Water Culminates in Liver Cirrhosis, Renal Azotemia, and Metabolic Stress in Rats.

Drinking water polluted by heavy metals has the potential to expose delicate biological systems to a range of health issues. This study embraced the health risks that may arise from subchronic exposure of thirty-four male Wistar rats to nickel (Ni)-cadmium (Cd)-contaminated water. It was done by using the Box-Behnken design (BBD) with three treatment factors (Ni and Cd doses at 50-150 mg/L and exposure at 14-21-28 days) at a single alpha level, resulting in seventeen experimental combinations. Responses such as serum creatinine (CREA) level, blood urea nitrogen (BUN) level, BUN/CREA ratio (BCR), aspartate and alanine aminotransferases (AST and ALT) activities, and the De Ritis ratio (DRR), as well as malondialdehyde (MDA) level, catalase (CAT), and superoxide dismutase (SOD) activities, were evaluated. The results revealed that these pollutants jointly caused hepatocellular damage by raising AST and ALT activities and renal dysfunction by increasing CREA and BUN levels in Wistar rats' sera (p < 0.05). These outcomes were further supported by BCR and DRR values beyond 1. In rats' hepatocytes and renal tissues, synergistic interactions of these metals resulted in higher MDA levels and significant impairments of CAT and SOD activities (p < 0.05). In order to accurately forecast the effects on the responses, the study generated seven acceptable regression models (p < 0.05) with r-squared values of > 80% at no discernible lack of fit (p > 0.05). The findings hereby demonstrated that Wistar rats exposed to these pollutants at varied doses had increased risks of developing liver cirrhosis and azotemia marked by metabolic stress.

An unusual cause of fever and jaundice.

A 52 year old previously healthy woman from Mumbai presented with fever and jaundice of 10 days duration. At admission, she was jaundiced with tachycardia, tachypnea, hypoxia, hypotension, conjunctival congestion and mild erythematous flush over the skin. She had very high WBC counts and CRP's with direct hyperbilirubinemia and azotemia. Investigations for infectious causes of fever were negative. RT-PCR for SARS-CoV-2 in the nasopharynx was negative. However her SARS-CoV-2 antibodies were reactive. She also had echocardiographic and biochemical evidence of cardiac dysfunction. The diagnosis of Multisystem inflammatory syndrome-Adult (MIS-A) was thus established. She rapidly improved with intravenous immunoglobulin (2 gm/kg) and high dose steroids.

Pathophysiology and Pathology of Acute Kidney Injury in Patients With COVID-19.

Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease or end-stage kidney disease. An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19.

Very low protein diet enhances inflammation, malnutrition, and vascular calcification in uremic rats.

AIMS: Clinical studies have shown that very low protein diet (VLPD) has negative effects on long-term survival. It remains unclear why VLPD induces premature death. The present study determined the underlying mechanism whereby VLPD exerts its harmful effects on uremic rats. MAIN METHODS: Rats were divided into four groups and fed a normal diet or diets containing 0.3% adenine and low/normal protein with high/low phosphate. After 6 weeks, body weight, urinary biochemistry (creatinine and phosphate), serum biochemical parameters (urea, creatinine, fibroblast growth factor 23, albumin, and fetuin-A), systemic inflammatory markers (serum tumor necrosis factor-alpha and urinary 8-hydroxy-2'-deoxyguanosine), calcium content in the aorta, and serum calcium-phosphate precipitates were evaluated. Hepatic mRNA levels were also determined. KEY FINDINGS: Rats fed the diet containing 0.3% adenine developed severe azotemia. Rats fed VLPD developed malnutrition (decreases in body weight, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-α and urinary 8-hydroxy-2'-deoxyguanosine) independent of phosphate status. VLPD decreased the serum fetuin-A level and hepatic fetuin-A synthesis and increased serum calcium-phosphate precipitates, a marker of calciprotein particle. A high-phosphate diet induced arterial medial calcification, which was enhanced by VLPD. Serum calcium-phosphate precipitate levels were correlated with the degree of inflammation, malnutrition, and aortic calcium content. Dietary phosphate restriction prevented VLPD-enhanced vascular calcification, but could not halt inflammation and malnutrition induced by VLPD. SIGNIFICANCE: VLPD enhances inflammation, malnutrition, and vascular calcification in uremic rats, among which only vascular calcification is prevented by dietary phosphate restriction.

Rapid renal alpha-1 antitrypsin gene induction in experimental and clinical acute kidney injury.

Alpha-1-antitrypsin (AAT) is a hepatic stress protein with protease inhibitor activity. Recent evidence indicates that ischemic or toxic injury can evoke selective changes within kidney that resemble a hepatic phenotype. Hence, we tested the following: i) Does acute kidney injury (AKI) up-regulate the normally renal silent AAT gene? ii) Does rapid urinary AAT excretion result? And iii) Can AAT's anti-protease/anti-neutrophil elastase (NE) activity protect injured proximal tubule cells? CD-1 mice were subjected to ischemic or nephrotoxic (glycerol, maleate, cisplatin) AKI. Renal functional and biochemical assessments were made 4-72 hrs later. Rapidly following injury, 5-10 fold renal cortical and isolated proximal tubule AAT mRNA and protein increases occurred. These were paralleled by rapid (>100 fold) increases in urinary AAT excretion. AKI also induced marked increases in renal cortical/isolated proximal tubule NE mRNA. However, sharp NE protein levels declines resulted, which strikingly correlated (r, -0.94) with rising AAT protein levels (reflecting NE complexing by AAT/destruction). NE addition to HK-2 cells evoked ∼95% cell death. AAT completely blocked this NE toxicity, as well as Fe induced oxidant HK-2 cell attack. Translational relevance of experimental AAT gene induction was indicated by ∼100-1000 fold urinary AAT increases in 22 AKI patients (matching urine NGAL increases). We conclude: i) AKI rapidly up-regulates the renal cortical/proximal tubule AAT gene; ii) NE gene induction also results; iii) AAT can confer cytoprotection, potentially by blocking/reducing cytotoxic NE accumulation; and iv) marked increases in urinary AAT excretion in AKI patients implies clinical relevance of the AKI- AAT induction pathway.

The effect of feeding a renal diet on plasma fibroblast growth factor 23 concentrations in cats with stable azotemic chronic kidney disease.

BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a phosphatonin, which is increased in cats with azotemic CKD. Dietary phosphate restriction decreases FGF-23 concentrations in humans and rodents, but this relationship has not previously been examined in the cat. OBJECTIVES: To investigate the effect of feeding renal diet on plasma FGF-23 concentrations in cats with stable azotemic CKD. ANIMALS: Azotemic, client-owned cats (≥ 9 years); 33 cats ate renal diet (RD group) and 11 cats did not eat renal diet (comparator group) over 28-56 days. METHODS: Retrospective longitudinal study: Plasma FGF-23, PTH, and phosphate concentrations were measured at baseline and after 28-56 days. Cats in the RD group were classified as hyperphosphatemic (HP) or normophosphatemic (NP) based on the International Renal Interest Society targets for plasma phosphate concentration. Nonparametric tests were performed. RESULTS: In the HP group (n = 15), feeding renal diet was associated with a significant decrease in plasma phosphate (P = .001), PTH (P = .007), and FGF-23 (P = .008), but not creatinine concentrations (P = .91). In the NP group (n = 18), feeding renal diet was associated with a significant decrease in plasma FGF-23 (P = .006), but not phosphate (P = .48), PTH (P = .35), or creatinine concentrations (P = .10). No significant changes were seen in any parameters in the comparator group during the study period. CONCLUSIONS AND CLINICAL IMPORTANCE: Feeding renal diet is associated with reductions in plasma FGF-23 concentrations in hyper- and normophosphatemic cats with stable azotemic CKD, suggesting that dietary phosphate restriction may enable cats with CKD to maintain normal plasma phosphate concentrations in association with lower plasma FGF-23 concentrations.

Agreement of the serum Spec fPL™ and 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester lipase assay for the determination of serum lipase in cats with suspicion of pancreatitis.

BACKGROUND: Serum lipase activities measured by catalytic assays are claimed to be of limited utility for diagnosing pancreatitis in cats. The Spec fPL assay currently is believed the most sensitive test; however, studies comparing different lipase assays are lacking. 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester (DGGR) assay for the determination of lipase activity has been evaluated in dogs, but no information is available in cats. OBJECTIVES: To investigate the agreement of DGGR-lipase activity and Spec fPL concentration in cats with clinical signs consistent with pancreatitis. ANIMALS: Two hundred fifty-one client-owned cats. METHODS: DGGR-lipase activity and Spec fPL concentration measured from the same blood sample in cats undergoing investigation for pancreatitis. The agreement between DGGR-lipase and Spec fPL at different cutoffs was assessed using Cohen's kappa coefficient (κ). Sensitivity and specificity were calculated for 31 cases where pancreatic histopathology was available. RESULTS: DGGR-lipase (cutoff, 26 U/L) and Spec fPL (cutoff, >5.3 µg/L) had a κ of 0.68 (standard error [SE] 0.046). DGGR-lipase (cutoff, 26 U/L) and Spec fPL (cutoff, >3.5 µg/L) had a κ of 0.60 (SE, 0.05). The maximum κ at a Spec fPL cutoff >5.3 µg/L was found when the DGGR-lipase cutoff was set >34 U/L and calculated as 0.755 (SE, 0.042). Sensitivity and specificity were 48% and 63% for DGGR-lipase (cut-off, 26 U/L) and 57% and 63% for Spec fPL (>5.3 µg/L), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Both lipase assays agreed substantially. DGGR assay seems a useful and cost-efficient method compared to the Spec fPL test.

Evaluation of glomerular filtration rate in cats with reduced renal mass and administered meloxicam and acetylsalicylic acid.

OBJECTIVE: To determine whether administration of meloxicam or acetylsalicylic acid alters glomerular filtration rate (GFR) in cats with renal azotemia. ANIMALS: 6 young adult cats. PROCEDURES: 3 sexually intact male cats and 3 sexually intact female cats had surgically reduced renal mass and azotemia comparable to International Renal Interest Society chronic kidney disease stages 2 and 3. Renal function was evaluated by measurement of serum creatinine concentration, urinary clearance of exogenously administered creatinine, and the urine protein-to-creatinine concentration ratio (UP:C). Measurements taken in cats receiving placebo at the beginning and end of the study were compared with results obtained at the end of 7 days of treatment with either meloxicam (0.2 mg/kg, SC, on day 1; 0.1 mg/kg, SC, on days 2 to 7) or acetylsalicylic acid (20 mg/kg, PO, on days 1, 4, and 7). RESULTS: No significant treatment effects on urinary clearance of exogenously administered creatinine, serum creatinine concentration, or UP:C were detected. Mean ± SEM serum creatinine concentration and urinary clearance of exogenously administered creatinine measurements following 7 days of treatment with meloxicam (serum creatinine concentration, 2.67 ± 0.17 mg/dL; urinary clearance of exogenously administered creatinine, 1.34 ± 0.08 mL/min/kg) and acetylsalicylic acid (serum creatinine concentration, 2.62 ± 0.12 mg/dL; urinary clearance of exogenously administered creatinine, 1.35 ± 0.07 mL/min/kg) were not significantly different from the mean baseline values for these variables (serum creatinine concentration, 2.77 ± 0.14 mg/dL; urinary clearance of exogenously administered creatinine, 1.36 ± 0.07 mL/min/kg). CONCLUSIONS AND CLINICAL RELEVANCE: Neither meloxicam nor acetylsalicylic acid had a measurable effect on urinary clearance of exogenously administered creatinine, serum creatinine concentration, or UP:C. These results are consistent with the hypothesis that GFR of euvolemic cats with normal or reduced renal function is not dependent on cyclooxygenase function.

[Nutrition of patients with stomach acid-dependent pathology and inflammatory diseases of the urogenital system].

In work some, often meeting nosological forms urogenithal surgical diseases which last years frequently proceed against gastritises, stomach ulcer of a stomach and 12-perstnoj guts owing to increase of occurrence of the last are presented. For treatment various medicamentous schemes, which do-polnjajutsja rational diet-correction for the purpose of increase efficaci and qualities of treatment are used. The work purpose--to present features ratsional pathogenetic correctic a food at persons from an aggravation acid-deprndent to a pathology against constant reception prepara apropos urogenithal diseases.

Early research on renal function and drug action.

Since the 1960s, systematic studies of drug action in renal failure have found many differences between patients with renal failure and those without. Impaired excretion of drugs was known much earlier and was related to glomerular filtration rate. Kunin first tabulated the pharmacokinetics of antimicrobials and dosage recommendations for azotemic patients in 1967. Other effects of renal failure on drug action include increases in some pathways of drug metabolism with decreases in others and no change in the rest. Some changes in specific drug distribution, drug-protein binding, and drug sensitivity have been demonstrated. This knowledge makes the response of an azotemic patient to a specific dose of a specific drug more predictable than before. This predictability makes drug therapy both safer and more effective for azotemic patients.

The cardiac biomarker sodium-calcium exchanger (NCX-1) can differentiate between heart failure and renal failure: a comparative study of NCX-1 expression in dogs with chronic mitral valvular insufficiency and azotemia.

BACKGROUND: The sodium-calcium exchanger (NCX-1), an established cardiac biomarker, was postulated previously as differentiating between heart failure (HF) and renal failure (RF) in dogs. The effect of azotemia on NCX-1 expression has not been studied. HYPOTHESIS: In contrast to other cardiac biomarkers (eg, N-terminal-proBNP), we hypothesized that the expression level of NCX-1 is not influenced by either azotemia or decreased renal clearance. ANIMALS: Fifteen client-owned healthy control dogs, 14 dogs with chronic mitral valvular insufficiency (CMVI), classified based on severity of the disease by the established International Small Animal Cardiac Health Council classification system, and 15 dogs with RF, grouped according to the International Renal Interest Society stage classification. METHODS: A comparative study of the expression levels of NCX-1, evaluated in peripheral blood samples from dogs with HF, RF, and healthy controls by quantitative PCR. RESULTS: NCX-1 expression was significantly increased in moderate (2.99±0.61 [fold changes relative to normal group]) to severe (4.35±1.44) CMVI dogs (P<.01). In contrast, NCX-1 expression was not increased in the azotemic dogs. Furthermore, there was also no correlation between increased concentrations of creatinine and urea nitrogen in serum and NCX-1 expression in the RF group. CONCLUSIONS AND CLINICAL IMPORTANCE: Azotemia likely does not affect NCX-1 expression.

Uremia induces proximal tubular cytoresistance and heme oxygenase-1 expression in the absence of acute kidney injury.

Acute kidney injury (AKI) induces adaptive responses within proximal tubular (PT) cells that serve to protect them from further ischemic or toxic damage. However, it is not known whether uremia, a potential consequence of AKI, independently alters susceptibility to tubular injury. To address this issue, we subjected CD-1 mice to bilateral ureteral transection (BUTx), which produces uremia (blood urea nitrogen approximately 150 mg/dl) in the absence of direct renal damage. PT segments were then isolated from BUTx and control mice and subjected to in vitro hypoxic injury. Additionally, "in vitro uremia" was modeled in isolated tubules or in cultured PT (HK-2) cells by addition of 1) peritoneal dialysate (obtained from mice with bilateral ureteral obstruction), 2) peritoneal fluid (from BUTx mice), or 3) normal human urine (pH 7.4, with and without boiling). Effects on injury severity (lactate dehydrogenase release) were assessed. Finally, because uremia is a prooxidant state, it was hypothesized that BUTx would increase renal lipid peroxidation (malondialdehyde) and induce heme oxygenase-1 (HO-1), a redox-sensitive cytoprotective protein. BUTx conferred striking protection against hypoxic damage. This could be partially modeled in tubules and HK-2 cells by induction of in vitro uremia. Urine's protective action was heat labile (largely destroyed by boiling). BUTx caused a tripling of renal malondialdehyde and HO-1 protein levels. Increased HO-1 transcription was likely involved, as indicated by a tripling of HO-1 mRNA and RNA polymerase II binding along the HO-1 gene (chromatin immunoprecipitation assay). "Gene-activating" histone modifications [H3K4 trimethylation (H3K4m3) and histone 2 variant (H2A.Z)] at HO-1 gene loci were also observed. Uremia, per se, can contribute to the AKI-induced cytoresistance. Low-molecular-weight, heat-labile, cytoprotective factor(s) and uremia-induced renal stress responses (e.g., HO-1 gene activation) are likely involved. Finally, renal HO-1 induction following AKI may reflect direct cell injury effects and adaptations to uremia.

Relationships between oxidative stress markers and red blood cell characteristics in renal azotemic dogs.

Oxidative stress parameters and erythrocyte characteristics were studied in 15 normal healthy dogs and 33 renal azotaemic dogs from Small Animal Hospital, Faculty of Veterinary Science, Chulalongkorn University. Dogs with renal azotaemia had reduced mean corpuscular volume (MCV) (P<0.01), packed cell volume (PCV) (P<0.001) and increased mean corpuscular hemoglobin concentration (MCHC) (P<0.001). The relationship was found between degree of azotaemia and MCV, PCV and MCHC. Dogs with severe renal azotaemia had higher intraerythrocytic sodium contents (RBC-Na) (P<0.05). The red blood cell catalase activity and glutathione and plasma malondialdehyde were unaltered while urinary malondialdehyde-creatinine ratio (U-MDA/Cr) increased significantly (P<0.001). The U-MDA/Cr was correlated significantly with plasma creatinine concentration (P<0.05), urinary protein-creatinine ratio (P<0.05) and fractional excretion of sodium (P<0.001). The results suggest some changes in RBC characteristics and urine oxidative stress marker in renal azotaemic dogs. Moreover, the U-MDA/Cr is a sensitive biochemical parameter which increased along with degree of renal dysfunction.

A scoring system to predict renal outcome in IgA nephropathy: from a nationwide prospective study.

BACKGROUND: Immunoglobulin A (IgA) nephropathy is the most common form of glomerulonephritis in the world, and a substantial number of patients develop end-stage renal disease (ESRD). Although there are several prognostic indicators, it remains difficult to predict the renal outcome in individual patients. METHODS: A prospective cohort study was conducted in 97 clinical units in Japan from 1995 to 2002. We analysed the data from 2269 patients using proportional hazards models in order to determine the predictors of ESRD in IgA nephropathy and to develop a scoring system to estimate ESRD risk. RESULTS: During the follow-up (median, 77 months), 207 patients developed ESRD. Systolic hypertension, proteinuria, hypoproteinaemia, azotaemia and a high histological grade at initial renal biopsy were independently associated with the risk of ESRD. Mild haematuria predisposed patients to ESRD more than severe haematuria. A scoring system was developed to estimate the 7-year ESRD risk from eight clinical and pathological variables. Actually, this prognostic score accurately classified patients by risk: patients with estimates of 0.0-0.9, 1.0-4.9, 5.0-19.9, 20.0-49.9, and 50.0-100.0% had a 0.2, 2.4, 12.2, 40.2 and 80.8% of ESRD incidence over 7 years, respectively. The corresponding area under the receiver operating characteristic curve was 0.939 [95% confidence interval (CI), 0.921-0.958]. This score was verified in repetitions of the derivation-validation technique. CONCLUSIONS: Although the quality of some data collected by the mail survey is limited and the influence of therapy could not be considered, this scoring system will serve as a useful prognostic tool for IgA nephropathy in clinical practice.

Eighty-peak kilovoltage 16-channel multidetector computed tomography and reduced contrast-medium doses tailored to body weight to diagnose pulmonary embolism in azotaemic patients.

The aim of this study was to assess the feasibility of minimising contrast-medium (CM) doses using 80-peak kilovoltage (kVp) 16-channel multidetector computed tomography (MDCT) with CM dose tailored to body weight, when diagnosing pulmonary embolism (PE) in azotaemic patients. Twenty-nine patients (68-93 years; 38-79 kg) with an estimated glomerular filtration rate of 12-49 ml/min underwent 80 kVp MDCT at a median dose of 200 mg iodine (I)/kg and 15 s injection time. Pulmonary artery (PA) enhancement where compared with our own reference material using 320 mg I/kg at 120 kVp and with reported figures in the literature at 120-140 kVp and a 42 g iodine CM dose. Median (1st and 3rd quartiles) values regarding CM dose were 12.2 (9.9-12.8) g iodine; density of left main and lower lobe segmental PA 339 (275-395) Hounsfield units (HU) and 354 (321-442) HU, respectively. Those enhancement values were similar to those obtained from the reference population at 120 kVp and those reported in the literature at 120-140 kVp. One patient had a transient increase in plasma creatinine. Three months' follow-up revealed deep venous thrombosis among 1/18 patients with negative results from computed tomography (CT). We conclude that 80 kVp 16-channel MDCT to diagnose PE in azotaemic patients may be performed with markedly reduced CM doses, implying a lesser risk for CM-induced nephropathy.

Clinical research on navel application of Shehuang Paste combined with Chinese herbal colon dialysis in treatment of refractory cirrhotic ascites complicated with azotemia.

AIM: To explore the efficacy and mechanism of a novel therapeutic method of traditional Chinese medicine in patients with refractory cirrhotic ascites complicated with azotemia. METHODS: Seventy-five cases of refractory cirrhotic ascites complicated with azotemia were randomly divided into 3 groups: comprehensive treatment (n = 29), simple treatment (n = 24), and control (n = 22). The basic treatment methods were the same in all groups, including liver protecting medicines, diuretics and supportive drugs. The control group underwent only the basic treatment. Shehuang Paste (SHP) was applied to the navels of the two treatment groups once a day for 30 d. Colon dialysis with Chinese herbs was administered to the comprehensive treatment group once every two days. Before and after treatment, we measured abdominal circumference, BUN, Cr, serum Na+, urine Na+/K+, liver function, endotoxin content, NO, and ET-1. Color Doppler ultrasonography was conducted to measure the portal vein blood flow. RESULTS: The total effective rate for ascites was 72.4% in the comprehensive treatment group, 45.8% in the simple treatment, contrasting with 18.2% in the controls. Between the two treatment groups and the controls, there were significant differences in the effective rates (P < 0.01, and P < 0.05). There was also a significant difference (P < 0.05) between the two treatment groups. Measurements of Cr and BUN showed higher values for the treatment groups, with the comprehensive better than the simple group (P < 0.05). Sera Na, urine Na/K were different, P < 0.01 between pre- and post-treatment in the comprehensive group, and P < 0.05 in the simple group. The treatment groups' endotoxin content was also significantly reduced (P < 0.01, and P < 0.05), with the comprehensive group better than the simple group (P < 0.05). Portal vein blood flow and NO content significantly reduced (P < 0.05), as did ET-1 content (P < 0.01). There were no significant changes in the control group (P > 0.05). The comprehensive treatment group's pre- and post-treatment portal vein and splenic vein blood flows showed a positive correlation to NO, ET-1 and endotoxin contents. CONCLUSION: When treating refractory cirrhotic ascites complicated with azotemia, Shehuang Paste combined with Chinese herbal dialysis is better than Shehuang Paste alone for ascites resolution, azotemia, and endotoxin elimination. However, both methods on their own were also effective for reducing portal and splenic vein blood flow, and lowering the contents of NO, ET-1 in the two treatment groups.