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.

RENAL PATHOLOGY IN CAPTIVE ADULT ALAOTRAN GENTLE LEMURS (HAPALEMUR ALAOTRENSIS).

Full medical histories from captive Alaotran gentle lemurs or Bandro (Hapalemur alaotrensis) > 1 yr old that died between 1990 and 2016 were requested from holding institutions. Eighty-six individuals died during the period analyzed. Full postmortem reports were received from 40 (46.5%) animals from 16 different institutions across Europe (15) and North America (1). Eighteen animals (45%) showed azotemia within three months of death, with accompanying histological renal lesions. Another 17 (42.5%) showed histological renal lesions, but no renal function assessment was carried out antemortem, or results were within normal limits. Only five animals (12.5%) showed no renal lesions. Of the 35 (87.5%) animals with histological renal lesions, 18 were females, and 17 were males, 11 were wild caught, and 24 were captive born. Twenty-seven animals were euthanized, seven were found dead, and in one case, no details were provided. Sixty-four blood samples from 22 animals were available. Azotemia was observed on average 407 d antemortem, with a case observed as early as 2,318 d antemortem. Twenty-nine urinalyses from 12 animals were carried out antemortem. All animals showed hematuria or proteinuria in at least one antemortem sample. A pH decrease from 8.5 to 5.0 was observed in two animals antemortem. Gross renal lesions most frequently reported were irregular surface (n = 14), abnormal shape (n = 12), and/or presence of cysts (n = 9). The most common histological lesions were interstitial nephritis (n = 25), interstitial fibrosis (n = 26), tubule dilation (n = 16), and glomerulosclerosis (n = 12). Development of additional diagnostic tools, standardization of ante- and postmortem diagnostic protocols, and further investigation into potential etiologies, such as diets offered in captivity and genetic factors, should be considered as the next steps for the veterinary management of this species in captivity.

Permissive azotemia during acute kidney injury enables more rapid renal recovery and less renal fibrosis: a hypothesis and clinical development plan.

Preclinical models of acute kidney injury (AKI) consistently demonstrate that a uremic milieu enhances renal recovery and decreases kidney fibrosis. Similarly, significant decreases in monocyte/macrophage infiltration, complement levels, and other markers of inflammation in the injured kidney are observed across multiple studies and species. In essence, decreased renal clearance has the surprising and counterintuitive effect of being an effective treatment for AKI. In this Perspective, the author suggests a hypothesis describing why the uremic milieu is kidney protective and proposes a clinical trial of 'permissive azotemia' to improve renal recovery and long-term renal outcomes in critically ill patients with severe AKI.

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.

Immune response to influenza vaccination in ESRD patients undergoing hemodialysis vs. hemodiafiltration.

BACKGROUND: On-line hemodiafiltration (HDF) clears more azotemic toxins compared to high-flux hemodialysis (HD). The response to vaccination is impaired in dialysis patients. We wished to determine whether the immune responses to influenza vaccine in dialysis patients treated by HDF were stronger than those treated by HD. MATERIALS AND METHODS: We conducted a prospective cohort study in chronic dialysis patients during the 2016 and 2017 influenza seasons. All participants received a single standard dose of trivalent influenza vaccine, and we studied the elicited humoral immune response by hemagglutination inhibition test, and cell-mediated immune response by enumeration of lymphocyte cellular markers and proliferation assays. RESULTS: We immunized 60 end-stage renal disease (ESRD) patients: 42 (70%) treated with HD and 18 patients (30%) with HDF. The median (interquartile range) age was 65.0 (55.0-74.5) years. All patients developed seroprotection to at least one influenza vaccine strain at one month post-vaccination, and did not differ between groups. By logistic regression, age was the only factor independently associated with seroconversion to all vaccine strains (odds ratio 0.89, 95% confidence interval 0.80-0.98; p = 0.022). Seroprotection to all vaccine strains was sustained for longer in patients treated with HDF, and the results remained the same after age adjustment. For cellular immune response, patients who seroconverted to all vaccine strains had higher CD38+ T cell subpopulations pre-vaccination. Patients treated by HDF had higher lymphocyte proliferation to circulating influenza A strains. CONCLUSIONS: Seroconversion to all influenza vaccine strains was associated with age. Patients treated with HDF demonstrated seroprotection was sustained for longer compared to those treated by HD and greater lymphocyte proliferation to circulating influenza A strains. These encouraging results for HDF require confirmation in a larger dialysis population. TRIAL REGISTRATION: ClinicalTrial.gov, NCT04122222.

Induced pluripotent stem cell-derived endothelial progenitor cells attenuate ischemic acute kidney injury and cardiac dysfunction.

BACKGROUND: Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), which is associated with high morbidity and mortality. AKI is a serious and costly medical condition. Effective therapy for AKI is an unmet clinical need, and molecular mechanisms underlying the interactions between an injured kidney and distant organs remain unclear. Therefore, novel therapeutic strategies should be developed. METHODS: We directed the differentiation of human induced pluripotent stem (iPS) cells into endothelial progenitor cells (iEPCs), which were then applied for treating mouse AKI. The mouse model of AKI was induced by I/R injury. RESULTS: We discovered that intravenously infused iEPCs were recruited to the injured kidney, expressed the mature endothelial cell marker CD31, and replaced injured endothelial cells. Moreover, infused iEPCs produced abundant proangiogenic proteins, which entered into circulation. In AKI mice, blood urea nitrogen and plasma creatinine levels increased 2 days after I/R injury and reduced after the infusion of iEPCs. Tubular injury, cell apoptosis, and peritubular capillary rarefaction in injured kidneys were attenuated accordingly. In the AKI mice, iEPC therapy also ameliorated apoptosis of cardiomyocytes and cardiac dysfunction, as indicated by echocardiography. The therapy also ameliorated an increase in serum brain natriuretic peptide. Regarding the relevant mechanisms, indoxyl sulfate and interleukin-1ß synergistically induced apoptosis of cardiomyocytes. Systemic iEPC therapy downregulated the proapoptotic protein caspase-3 and upregulated the anti-apoptotic protein Bcl-2 in the hearts of the AKI mice, possibly through the reduction of indoxyl sulfate and interleukin-1ß. CONCLUSIONS: Therapy using human iPS cell-derived iEPCs provided a protective effect against ischemic AKI and remote cardiac dysfunction through the repair of endothelial cells and the attenuation of cardiomyocyte apoptosis.

Clinically Relevant Doses of Enalapril Mitigate Multiple Organ Radiation Injury.

Angiotensin-converting enzyme inhibitors (ACEi) are effective mitigators of radiation nephropathy. To date, their experimental use has been in fixed-dose regimens. In clinical use, doses of ACEi and other medication may be escalated to achieve greater benefit. We therefore used a rodent model to test the ACEi enalapril as a mitigator of radiation injury in an escalating-dose regimen. Single-fraction partial-body irradiation (PBI) with one hind limb out of the radiation field was used to model accidental or belligerent radiation exposures. PBI doses of 12.5, 12.75 and 13 Gy were used to establish multi-organ injury. One third of the rats underwent PBI alone, and two thirds of the rats had enalapril started five days after PBI at a dose of 30 mg/l in the drinking water. When there was established azotemic renal injury enalapril was escalated to a 60 mg/l dose in half of the animals and then later to a 120 mg/l dose. Irradiated rats on enalapril had significant mitigation of combined pulmonary and renal morbidity and had significantly less azotemia. Dose escalation of enalapril did not significantly improve outcomes compared to fixed-dose enalapril. The current data support use of the ACEi enalapril at a fixed and clinically usable dose to mitigate radiation injury after partial-body radiation exposure.

ACUTE CLINICAL LEPTOSPIROSIS (GRIPPOTYPHOSA SEROVAR) IN AN ADULT DROMEDARY CAMEL (CAMELUS DROMEDARIUS).

A 9-yr-old castrated male dromedary camel (Camelus dromedarius) presented with lethargy and partial anorexia. A diagnostic examination revealed fever, and further workup revealed a neutrophilia, hyperfibrinogenemia, renal azotemia, and a rapid onset of a high Leptospira antibody titer during the acute clinical period (Grippotyphosa serovar). The camel responded clinically to antimicrobial treatment with ceftiofur crystalline free acid injections, but renal azotemia persisted, presumably secondary to chronic renal damage. Subsequent Leptospira polymerase chain reaction testing on urine samples obtained over the following 4 mo revealed no evidence of urinary shedding, so a persistent infection was unlikely. Although often mentioned as a potential cause of reproductive loss, well-documented case reports of clinical leptospirosis in camelids are very rare. In this case, native wildlife contamination of a small watering hole is suspected to have been the source of infection. In response to this experience, the camel and two conspecifics were prescribed a vaccination regimen using an inactivated pentavalent Leptospira vaccine licensed for cattle.

Hyperammonaemia in four cats with renal azotaemia.

Hyperammonaemia is well reported in animals with advanced hepatic disease and portosystemic shunts, but is unreported in cats with renal disease. This case series describes four cats with severe renal azotaemia in which elevated ammonia levels were detected during the course of treatment. In two cases hyperammonaemia was detected at a time when neurological signs consistent with encephalopathy had developed. This raises the possibility that hyperammonaemia may play a role in the development of encephalopathy in cats with renal azotaemia.

Acute azotemia as a predictor of mortality in dogs and cats.

BACKGROUND: Acute kidney injury (AKI) has been shown to be a predictor of mortality in human medicine. Published studies in the veterinary literature evaluating relative changes in serum creatinine concentration as a prognostic factor are limited. OBJECTIVE: To evaluate an AKI grading system based on serum creatinine concentration to determine if it correlates with outcome prediction in dogs and cats. ANIMALS: Six hundred forty-five dogs and 209 cats that had at least 2 serum creatinine concentration measurements measured within 7 days. METHODS: Retrospective study. Dogs and cats with an initial serum creatinine concentrations of ≤ 1.6 mg/dL and that had more than 1 concentration measured within 2, 3, and 7 days were placed into levels (0-2) based on absolute changes. Mortality then was determined at 30 and 90 days. RESULTS: Based on odds ratios calculated with a 95% confidence interval, dogs placed in level 1 within 2 days were approximately 3 times more likely to die within 90 days. Dogs placed in level 2 within 2, 3, or 7 days were approximately 3 times more likely to die within 30 or 90 days. Cats placed in level 2 within 3 or 7 days were approximately 3 times more likely to die at 30 days and 4 times more likely to die if placed in this level within 7 days. If placed in level 2 within 2 or 3 days, cats were approximately 3 times more likely to die within 90 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Detecting increasing severity of azotemia helps predict mortality in dogs and cats.

Pulmonary abnormalities in dogs with renal azotemia.

BACKGROUND: Clinical signs associated with respiratory tract disease are regularly encountered in people with kidney failure, and have been anecdotally reported in dogs. OBJECTIVES: To compare clinical signs indicative of pulmonary disease, clinicopathologic findings, radiographic abnormalities, and histologic findings in dogs with acute kidney injury (AKI) or International Renal Interest Society Stage 3 or 4 chronic kidney disease (CKD) to nonazotemic dogs. To determine associations between abnormalities indicative of pulmonary disease and outcome in azotemic dogs. ANIMALS: One hundred sixty-seven pet dogs (54 AKI dogs, 50 CKD dogs, 63 nonazotemic control dogs diagnosed with intracranial disease). METHODS: Retrospective cohort study comparing signalment, clinical signs, clinicopathologic variables, prevalence, and severity of pulmonary radiographic patterns, histopathologic findings, and survival times in AKI, CKD, and control dogs. RESULTS: Clinical signs of pulmonary disease were significantly more common in AKI dogs. Prevalence of an alveolar lung pattern was greater in AKI and CKD dogs. Alveolar mineralization was the most common pulmonary histologic lesion in AKI dogs (6 of 8 dogs), with concurrent alveolar concretions or mineralization of pulmonary vessels or bronchioles noted in 1 dog each; mineralization of lung tissues was not noted in control dogs. Neither clinical signs nor presence of an alveolar pattern were associated with likelihood of survival to discharge or median number of days from discharge until death. CONCLUSIONS AND CLINICAL IMPORTANCE: Abnormalities indicative of pulmonary disease are more common in azotemic dogs than in control dogs; however, prognosis is not associated with presence of clinical or radiographic pulmonary dysfunction.

Retrospective evaluation of presenting temperature of urethral obstructed male cats and the association with severity of azotemia and length of hospitalization: 243 cats (2006-2009).

OBJECTIVES: To evaluate whether the presenting rectal temperature and level of azotemia predicts the length of hospitalization (LOH) in a population of obstructed male cats. To describe the relationships between physical examination parameters, blood electrolytes, and azotemia in a clinical population of obstructed male cats. DESIGN: Retrospective clinical study. SETTING: Emergency and referral specialty hospitals. ANIMALS: Two hundred and forty-three male cats that presented with urethral obstruction between 2006 and 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: No significant association between the hours of hospitalization and rectal temperature was detected (P = 0.39). Blood urea nitrogen (BUN) and creatinine (CREA) concentrations were positively correlated with LOH (P < 0.01). BUN and CREA were significantly higher (P < 0.01) for the hypothermic group compared to the normothermic group. Potassium was negatively correlated to heart rate and rectal temperature but positively correlated to BUN and CREA. CONCLUSION: No association with regard to rectal temperature and LOH could be demonstrated in this population of cats. However, the presence of azotemia in obstructed male cats appears to provide the clinician with additional information regarding the necessary LOH and eventual cost to the client.

Acute oxalate intoxication associated to ingestion of eshnan (Seidlitzia rosmarinus) in sheep.

An outbreak of acute oxalate intoxication in a sheep flock was associated to Seidlitzia rosmarinus (Chenopodiaceae) with a mortality rate of about 19%. Affected sheep showed marked azotemia and hypocalcemia. Post-mortem findings included congestion and hemorrhage in visceral organs, ruminitis frequently associated with precipitation of birefringent calcium oxalate crystals, and acute nephrosis with numerous birefringent calcium oxalate crystals in renal tubules. This is the first report of oxalate poisoning due to ingestion of S. rosmarinus in sheep.

Association between chronic azotemic kidney disease and the severity of periodontal disease in dogs.

Naturally occurring periodontal disease affects >75% of dogs and has been associated with cardiac lesions and presumptive endocarditis. However, the relationships between periodontal disease and chronic kidney disease (CKD) in dogs have not been studied. In a retrospective longitudinal study the incidence of azotemic CKD was compared between a cohort of 164,706 dogs with periodontal disease and a cohort of age-matched dogs with no periodontal disease from a national primary care practice. These dogs contributed 415,971 dog-years of follow-up from 2002 to 2008. Hazard ratios and 95% confidence intervals from Cox regression were used to compare the incidence of azotemic CKD in dogs with stage 1, 2, or 3/4 periodontal disease to dogs with no periodontal disease. The hazard ratio for azotemic CKD increased with increasing severity of periodontal disease (stage 1 hazard ratio=1.8, 95% confidence interval: 1.6, 2.1; stage 2 hazard ratio=2.0, 95% confidence interval: 1.7, 2.3; stage 3/4 hazard ratio=2.7, 95% confidence interval: 2.3, 3.0; P(trend)=<0.0001) after adjustment for age, gender, neuter status, breed, body weight, number of hospital visits, and dental procedures. Increasing severity of periodontal disease was also associated with serum creatinine >1.4 mg/dl and blood urea nitrogen >36 mg/dl, independent of a veterinarian's clinical diagnosis of CKD.

Evaluation of predictors of the development of azotemia in cats.

BACKGROUND: Chronic kidney disease (CKD) is a common condition in geriatric cats. Diagnosis is based on the development of persistent azotemia with inadequate urine concentrating ability. Biomarkers are sought for early identification. HYPOTHESIS: Clinical variables, urine concentrating ability, proteinuria, and N-acetyl-beta-D-glucosaminidase (NAG) index will be predictive of cats at risk of developing azotemia within 12 months. ANIMALS: Client-owned nonazotemic geriatric (>or=9 years) cats. METHODS: Prospective longitudinal cohort study monitoring a population of healthy nonazotemic geriatric cats every 6 months until development of azotemia, death, or the study end point (September 30, 2007). Multivariable logistic regression analysis was used to assess baseline clinical, biochemical, and urinalysis variables, urine protein to creatinine ratio (UP/C), urine albumin to creatinine (UA/C) ratio, and urinary NAG index as predictors of development of azotemia. RESULTS: One hundred and eighteen cats were recruited with a median age of 13 years. Ninety-five cats (80.5%) had been followed or reached the study end point by 12 months of which 30.5% (29/95) developed azotemia. Age, systolic blood pressure, plasma creatinine concentration, urine specific gravity, UP/C, UA/C, and NAG index were significantly associated with development of azotemia in the univariable analysis (P

Cardiac troponin I is elevated in dogs and cats with azotaemia renal failure and in dogs with non-cardiac systemic disease.

OBJECTIVE: To determine if dogs and cats with renal failure, or other severe non-cardiac disease, and no antemortem evidence of cardiac disease on basic clinical evaluation, have elevated levels of cardiac troponin I (cTnI). DESIGN: Cross-sectional study using 56 dogs and 14 cats with primary non-cardiac disease (39 dogs with azotaemic renal failure, 14 cats with azotaemic renal failure, 17 dogs with non-cardiac systemic disease); 7/25 dogs and 6/14 cats had murmurs detected on physical examination. Serum or heparinised plasma was collected and analysed for cTnI. RESULTS: Cardiac troponin I concentrations were elevated above reference intervals in 70% of dogs and 70% of cats with azotaemic renal failure and in 70% of dogs with a variety of systemic non-cardiac diseases. Cardiac troponin I concentrations did not correlate with the degree of azotaemia, presence of murmurs, hypertension or type of non-cardiac illness. CONCLUSIONS: Cardiac troponin I concentration is often elevated in dogs and cats with azotaemic renal failure and in dogs with other systemic non-cardiac illness, suggesting that these conditions often result in clinically inapparent myocardial injury or possibly altered elimination of cTnI.

Pre-renal azotemia: a flawed paradigm in critically ill septic patients?

The term pre-renal azotemia (or on occasion 'pre-renal renal failure') is frequently used in textbooks and in the literature to indicate an acute syndrome characterized by the presence of an increase in the blood concentration of nitrogen waste products (urea and creatinine). This syndrome is assumed to be due to loss of glomerular filtration rate but is not considered to be associated with histopathological renal injury. Thus, the term is used to differentiate 'functional' from 'structural' acute kidney injury (AKI) where structural renal injury is taken to indicate the presence of so-called acute tubular necrosis (ATN). This paradigm is well entrenched in nephrology and medicine. However, growing evidence from experimental animal models, systematic analysis of the human and experimental literature shows that this paradigm is not sustained by sufficient evidence when applied to the syndrome of septic AKI, especially in critically ill patients. In such patients, several assumptions associated with the 'pre-renal azotemia paradigm' are violated. In particular, there is no evidence that ATN is the histopathological substrate of septic AKI, there is no evidence that urine tests can discriminate 'functional' from 'structural' AKI, there is no evidence that any proposed differentiation leads or should lead to different treatments, and there is no evidence that relevant experimentation can resolve these uncertainties. Given that septic AKI of critical illness now accounts for close to 50% of cases of severe AKI in developed countries, these observations call into question the validity and usefulness of the 'pre-renal azotemia paradigm' in AKI in general.

Relationships between degree of azotaemia and blood pressure, urinary protein:creatinine ratio and fractional excretion of electrolytes in dogs with renal azotaemia.

Blood pressure (BP) was measured in 31 renal azotaemic dogs by oscillometric measurement at the posterior tibia artery, and urine and blood samples were collected. Haematology, blood chemistry and urinalysis were performed and urinary protein:creatinine ratio (UPC) and fractional excretions of electrolytes (FE(e)) were calculated. The results showed that only 19% of dogs with renal azotaemia were hypertensive, whereas almost all of them had high urinary protein and electrolyte excretions. There was no association between BP, UPC and FE(e). A positive correlation was found between all pairs of electrolyte fractional excretions. When the severity of renal impairment was observed using plasma creatinine concentration, neither BP nor UPC was correlated. Only the FE( e ) was associated with the degree of azotaemia. The results suggest that dogs with renal azotaemia do not necessarily have hypertension. The fractional urinary excretion of electrolytes may be a good indicator for severity of renal dysfunction in azotaemic dogs.