IL-6 mediates the hepatic acute phase response after prerenal azotemia in a clinically defined murine model.

Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6-/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response.NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.

Fish gall bladder consumption presenting as acute renal failure.

A forty two year old male was admitted with history of anuria and breathlessness following consumption of raw rohu fish gall bladder. He had azotemia and required hemodialysis. His renal failure improved over a period of about four weeks. Incidences have been reported from South East Asian countries associating consumption of raw rohu fish gall bladder with acute renal failure.

HYPERCALCEMIA AND METASTATIC MINERALIZATION INVOLVING FOOTPADS IN ROCK HYRAXES (PROCAVIA CAPENSIS).

Three rock hyraxes (Procavia capensis) maintained in a zoological collection had chronic hypercalcemia and azotemia. In addition, all animals displayed signs of lameness due to footpad lesions that were histologically characterized as marked metastatic mineralization with granulomatous inflammation, reminiscent of calcinosis circumscripta. Although the animals were managed with aggressive fluid therapy, calciuresis, and dietary modification, all were eventually humanely euthanized due to the severity of their footpad lesions and/or progression of renal disease. Metastatic mineralization was also noted in other soft tissues among the three cases, including the stomach, colon, lung, vascular wall, ovary, and kidney. Varying degrees of interstitial nephritis were confirmed on postmortem examination, and in the absence of other causes for hypercalcemia, metastatic mineralization was presumably the consequence renal dysfunction. The renal pathway is the primary mode of calcium excretion in the rock hyrax. In renal dysfunction, hypercalcemia may develop secondary to decreased calcium excretion. Footpad mineralization is an uncommon sequel to renal dysfunction in domestic animals but has not been reported in rock hyraxes. A retrospective review of mortality data in this collection revealed a notable prevalence of renal lesions, including two additional animals with metastatic mineralization and renal dysfunction. Expanding knowledge of renal diseases will further guide preventative and clinical measures, including screening for metastatic mineralization and therapeutic trials for management of hypercalcemia and calcium mineral deposition in the footpads and other soft tissues.

Acute kidney injury during pregnancy.

Acute kidney injury complicates the care of a relatively small number of pregnant and postpartum women. Several pregnancy-related disorders such as preeclampsia and thrombotic microangiopathies may produce acute kidney injury. Prerenal azotemia is another common cause of acute kidney injury in pregnancy. This manuscript will review pregnancy-associated acute kidney injury from a renal functional perspective. Pathophysiology of acute kidney injury will be reviewed. Specific conditions causing acute kidney injury and treatments will be compared.

Evaluation of the clinical outcome of hypercalcemia of malignancy and concurrent azotemia in dogs with lymphoma.

BACKGROUND: Hypercalcemia of malignancy (HM) secondary to lymphoma in dogs has the potential to cause renal injury. HYPOTHESIS/OBJECTIVES: Characterize outcomes related to acute kidney injury (AKI) secondary to HM. We hypothesized that dogs do suffer AKI regardless of HM severity at the time of lymphoma diagnosis or relapse. ANIMALS: Retrospective study. Twenty-nine dogs with lymphoma, HM, and azotemia (International Renal Interest Society [IRIS] grade II or higher AKI) that underwent chemotherapy were identified at 2 veterinary institutions. METHODS: Logistic regression and descriptive statistical analysis were performed to evaluate data for potential prognostic factors. RESULTS: After initiating treatment, resolution of hypercalcemia and azotemia occurred in 100% (29/29) and 79.3% (23/29) of dogs, respectively. Resolution of azotemia was influenced by serum creatinine concentration (odds ratio [OR], 0.148; Confidence interval [CI], 0.03-0.734; P = .02) and total hypercalcemia (OR, 0.36; CI, 0.14-0.93; P = .04) at diagnosis, whereas blood urea nitrogen concentration, IRIS grade, sex, and whether or not dogs were hospitalized were not significant factors. At data analysis, 13.8% (4/29) of dogs were alive or lost to follow-up. Of those dead, 4 dogs (15%) had renal disease at the time of death, 2/4 having concurrent lymphoma progression. CONCLUSIONS AND CLINICAL IMPORTANCE: Although AKI may be of clinical concern in dogs with HM secondary to lymphoma at diagnosis, death secondary to renal impairment appears to be infrequent.

Risk factors for cerebral edema in diabetic ketoacidosis in a developing country: role of fluid refractory shock.

OBJECTIVES: To study the clinical profile and risk factors of cerebral edema in children with diabetic ketoacidosis with specific reference to fluid refractory shock. DESIGN: Retrospective review of medical records. SETTING: Twelve-bed pediatric intensive care unit of a teaching hospital. PATIENTS: Seventy-seven patients admitted to pediatric intensive care unit with a diagnosis of diabetic ketoacidosis over 5 yrs. INTERVENTION: Medical records were reviewed, and data with respect to patients' age, clinical features, biochemical profile (blood glucose, osmolality, electrolytes, urea, creatinine, arterial pH, PaCO(2), and HCO(3) at admission, 6-12 hrs, 24 hrs, and beyond 24 hrs), cerebral edema, presence of sepsis and shock, treatment details, and primary outcome in terms of survival or death were retrieved. Patients with and without cerebral edema were compared. Variables that were significant on univariate analysis were entered in a multiple logistic regression analysis to determine the predictors for cerebral edema. Odds ratio and 95% confidence interval were calculated using SPSS version 15. MEASUREMENTS AND MAIN RESULTS: Mean age of the patients was 5.6 (standard deviation, 3.8) years. Fifty-five (71.4%) patients had new-onset diabetes mellitus. Cerebral edema was seen in 20 patients (26%). Blood glucose, serum osmolality, and CO(2) values at admission and rate of decline in glucose and osmolality during the first 12 hrs were similar in the cerebral edema and noncerebral edema groups. On multiple logistic regression analysis, fluid refractory shock (odds ratio, 7.3; 95% confidence interval, 1.3-41; p = .025) and presence of azotemia (odds ratio, 4.3; 95% confidence interval, 1.1-16; p = .034) at admission were predictors for development of cerebral edema. Mortality in cerebral edema group was 25% as compared to 3% in the noncerebral edema group. CONCLUSIONS: Patients with fluid refractory shock and azotemia at admission had higher odds for development of cerebral edema. Initial blood glucose, effective osmolality, or decline in glucose and osmolality had no association with cerebral edema.

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

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Treatment of portal vein thrombosis using vascular access port implantation in a Dalmatian dog: A case report.

Background: Portal vein thrombosis is a disease with potentially deleterious outcomes including portal vein hypertension and intestinal infarction. The factors contributing is various; however, dogs with with acute portal vein thrombosis or multiple thromboses are less likely to survive. Therefore, acute development of portal hypertension has a requires an immediate treatment. Case Description: A 10-year-old Dalmatian was referred for syncope and azotemia, hyperammonemia. After each examinations including computed tomography scan, we diagnosed with acute portal vein thrombosis with unknown cause. A portal vein port was inserted to prevent and control the portal vein thrombus. The port was placed in abdomen subcutaneously after the position of the catheter were stabilized. Low-molecular-weight heparin was injected from the port to manage thrombosis after the operation. This case responded well to this treatment. Syncope and azotemia, hyperammonemia resolved and no relapse of thrombosis was found 6 months after the operation. Conclusion: Implantable vascular access port is a drug delivery system with the advantage of dealing with treatment-resistant acute portal vein thrombosis.

Iodine contrast iso-attenuating with diagnostic gadolinium doses in CTA and angiography results in ultra-low iodine doses. A way to avoid both CIN and NSF in azotemic patients?

OBJECTIVES: To establish iodine (I) contrast medium (CM) doses iso-attenuating with gadolinium (Gd) CM doses regarded diagnostic in CTA and percutaneous catheter-angiography/vascular interventions (PCA/PVI) in azotemic patients. METHODS: CT Hounsfield units (HU) were measured in 20-mL syringes containing 0.01/0.02,/0.05/0.1 mmol/mL of iodine or gadolinium atoms and placed in phantoms. Relative contrast were measured in 20-mL syringes filled with iohexol at 35/50/70/90/110/140 mg I/mL and 0.5 M gadodiamide using radiofluoroscopy (RF), digital radiography (DX) and x-ray angiography (XA) systems. Clinical doses of Gd-CM at CTA/PCA/PVI were reviewed. RESULTS: At CT 91-116 and 104-125 mg I/mL in the chest and abdominal phantoms, respectively, were iso-attenuating with 0.5 M Gd at 80-140 kVp. At RF/DX/XA systems 35-90 mg I/mL were iso-attenuating with 0.5 M gadodiamide at 60-115 kVp. Clinically, 60 mL 91-125 mg I/mL (5.5-7.5 gram-iodine) at 80-140 kVp CTA and 60 mL of 35-90 mg I/mL (2.1-5.4 gram-iodine) at 60-115 kVp PCA/PVI would be iso-attenuating with 60 mL 0.5 M Gd-CM (=0.4 mmol Gd/kg in a 75-kg person). CONCLUSIONS: Meticulous examination technique and judicious use of ultra-low I-CM doses iso-attenuating with diagnostic Gd-CM doses in CTA and PCA/PVI may minimise the risk of nephrotoxicity in azotemic patients, while there is no risk of NSF.

Septic acute kidney injury: the culprit is inflammatory apoptosis rather than ischemic necrosis.

For a long time, acute kidney injury (AKI) was considered to be a primarily hemodynamic condition characterized by a reduction of renal blood flow, induced by either cardiogenic or distributive (septic) shock. Consequently, all efforts to treat AKI were essentially concentrated on increasing renal flow by enhancing cardiac flow output and perfusion pressure. At the beginning of this decade, Bellomo and co-workers produced new and intriguing data in an animal model of septic AKI that undermined existing concepts. They observed that medullar and cortical renal blood flow were both maintained and even increased in septic shock, underscoring that septic AKI was a totally different physiological phenomenon than nonseptic AKI. Also, apoptosis was found to play a more important role in sepsis and septic shock than pure necrosis. Despite these findings, the role of apoptosis as a main mechanism of organ dysfunction remains topic of debate.

The comparative benefits of the fractional excretion of urea and sodium in various azotemic oliguric states.

BACKGROUND: The fractional excretion of urea (FeUrea) may result in more reliable in the determination of renal function than sodium in the presence of oliguric azotemia; however, its usefulness remains controversial, perhaps due to an evolving understanding of urea transport within the kidney. METHODS: This was a prospective observational study of 100 consecutive patients referred to the nephrology service for azotemic oliguria. Multiple clinical variables were analyzed to determine variables responsible for the differences between the FeUrea and fractional excretion of sodium (FeNa) in the ability to distinguish pre-renal azotemia from intrinsic renal disease. RESULTS: Overall, the FeUrea was more accurate (95 vs. 54%, p < 0.0001), yet both tests accurately detected the presence of intrinsic renal disease (FeNa 75%, FeUrea 85%, p = NS). The FeUrea performed significantly better (98 to 49%, p < 0.0001) in detecting pre-renal azotemia, and that advantage came exclusively in patients taking diuretics (p < 0.0001); however, 4/5 cases incorrectly detected by the FeUrea were correctly detected by the FeNa. All 4 cases had infection. CONCLUSION: The FeUrea appears more accurate in patients receiving diuretics; however, the FeNa may have an advantage in patients with infection.

Refractory rickets in the tropics.

Rickets is an important problem in children. The majority of rickets in children is due to deficiency of calcium, phosphorus or vitamin D. However, rickets may also be a feature of renal diseases, e.g. renal tubular acidosis, hypophosphatemic rickets or rickets associated with renal insufficiency. The treatment varies with etiology and hence complete workup is essential before initiating therapy.

Retrospective Analysis of Mortality Cases in Advanced and Metastatic Solid Tumors With Concurrent Prerenal Azotemia.

BACKGROUND/AIM: A retrospective study of cases with metastatic or advanced solid tumors complicated with AKI (acute kidney injury) with prerenal azotemia. PATIENTS AND METHODS: Criteria included: (1) advanced or metastatic solid tumors that led to mortality; (2) prerenal azotemia identified upon renal function evaluation and (3) BUN to Cr ratio (BCR)≥15. We also compared the outcomes of patients with BCR>20 with those of patients with BCR=15-20. RESULTS: A total of 218 patients with solid tumors were enrolled. One hundred and forty (64%) and 78 (36%) patients had BCR>20 and 15-20, respectively. Before AKI occurrence, 136 (62%) had thromboembolic complications and 96 (44%) paraneoplastic syndromes. Median survival time was 1 week in all patients. Median survival time was statistically different between the groups with BCR15-20 and BCR>20 (p<0.005, log-rank test). CONCLUSION: Cancer patients with concurrent AKI and prerenal azotemia carry a very poor prognosis.

Pernicious azotaemia? A case series of subacute combined degeneration of the cord secondary to nitrous oxide abuse.

Nitrous oxide abuse is a rare cause of vitamin B12 deficiency and consequent subacute combined degeneration of the spinal cord. Worldwide and Australian statistics indicate that recreational use of nitrous oxide is increasing. We report four cases of females aged 18-24 years presenting with clinical symptoms of subacute combined degeneration of the spinal cord. MRI during admission demonstrated the classic findings of T2 hyperintensity, predominantly within the dorsal columns of the spinal cord, with variable involvement of the lateral corticospinal tracts. These cases highlight the ready availability of nitrous oxide and the fact that heavy prolonged recreational use is occurring in the community. It is important that clinicians in emergency and community settings are alerted to this unusual cause of subacute combined degeneration of the spinal cord because early aggressive vitamin B12 replacement together with behavioural change can reverse this disabling neurological syndrome.

Minimizing contrast medium doses to diagnose pulmonary embolism with 80-kVp multidetector computed tomography in azotemic patients.

BACKGROUND: In diagnosing acute pulmonary embolism (PE) in azotemic patients, scintigraphy and magnetic resonance imaging are frequently inconclusive or not available in many hospitals. Computed tomography is readily available, but relatively high doses (30-50 g I) of potentially nephrotoxic iodine contrast media (CM) are used. PURPOSE: To report on the diagnostic quality and possible contrast-induced nephropathy (CIN) after substantially reduced CM doses to diagnose PE in azotemic patients using 80-peak kilovoltage (kVp) 16-row multidetector computed tomography (MDCT) combined with CM doses tailored to body weight, fixed injection duration adapted to scan time, automatic bolus tracking, and saline chaser. MATERIAL AND METHODS: Patients with estimated glomerular filtration rate (eGFR) <50 ml/min were scheduled to undergo 80-kVp MDCT using 200 mg I/kg, and those with eGFR >or=50 ml/min, 120-kVp MDCT with 320 mg I/kg. Both protocols used an 80-kg maximum dose weight and a fixed 15-s injection time. Pulmonary artery density and contrast-to-noise ratio were measured assuming 70 Hounsfield units (HU) for a fresh clot. CIN was defined as a plasma creatinine rise >44.2 micromol/l from baseline. RESULTS: 89/148 patients (63/68 females) underwent 80-/120-kVp protocols, respectively, with 95% of the examinations being subjectively excellent or adequate. Mean values in the 80-/120-kVp cohorts regarding age were 82/65 years, body weight 66/78 kg, effective mAs 277/117, CM dose 13/23 g I, pulmonary artery density 359/345 HU, image noise (1 standard deviation) 24/21 HU, contrast-to-noise ratio 13/13, and dose-length product 173/258 mGy x cm. Only 1/65 and 2/119 patients in the 80- and 120-kVp cohorts, respectively, with negative CT and no anticoagulation suffered non-fatal thromboembolism during 3-month follow-up. No patient developed CIN. CONCLUSION: 80-kVp 16-row MDCT with optimization of injection parameters may be performed with preserved diagnostic quality, using markedly reduced CM doses compared with common routine practice, which should be to the benefit of patients at risk of CIN.

Survival, complications, and analysis of risk factors after renal transplantation in cats.

OBJECTIVE: To report survival, complications, and analyze risk factors for survival after renal transplantation (RTr) and cyclosporine-A based immunosuppression in cats. STUDY DESIGN: Historical cohort. ANIMALS: Cats (n=60). METHODS: Data were obtained from medical records of cats that had RTr. Influence of various perioperative factors on survival and complications was evaluated. Occurrence of postoperative hypertension (HT), seizures, infection, acute allograft rejection (AR), congestive heart failure (CHF), and delayed graft function (DGF) was evaluated. RESULTS: Survival to discharge after RTr was 77.5%. Estimated median overall survival time was 613 days; 6 month and 3 year overall survival proportions were 65% and 40%, respectively. Age, weight, and blood pressure influenced overall survival. Increased preoperative creatinine concentration, blood urea nitrogen, postoperative creatinine concentration, left ventricular wall thickness, and reduced creatinine reduction ratio influenced survival until discharge. HT was identified in 9/30 (30%) cats; however, no risk factors were identified, nor was HT related to seizures. AR was identified in 8/62 (13%) grafts. Infection, predominantly bacterial, developed in 22/60 (37%) cats. CHF occurred in 7/60 (12%) cats before discharge. Cats experiencing CHF were younger, had an increased incidence of heart murmurs, and poor initial graft function. DGF was identified in 5 cats and seizures in 2 cats. CONCLUSIONS: RTr affords cats with CRF long survival times. Older cats and cats with severe azotemia, HT, and cardiovascular disease may have increased mortality after RTr. Complications after RTr were common. CLINICAL RELEVANCE: Clinicians should be aware of these risk factors when recommending feline RTr.

Survival analysis to evaluate associations between periodontal disease and the risk of development of chronic azotemic kidney disease in cats evaluated at primary care veterinary hospitals.

OBJECTIVE To examine potential associations between periodontal disease (PD) and the risk of development of chronic azotemic kidney disease (CKD) among cats and determine whether the risk of CKD increases with severity of PD. DESIGN Retrospective cohort study. ANIMALS 169, 242 cats. PROCEDURES Cats were evaluated ≥ 3 times at any of 829 hospitals from January 1, 2002, through June 30, 2013. Cats with an initial diagnosis of PD of any stage (n = 56,414) were frequency matched with cats that had no history or evidence of PD (112,828) by age and year of study entry. Data on signalment, PD, and other conditions potentially related to CKD were extracted from electronic medical records. Cox proportional hazards modeling was used to estimate the association of PD with CKD after controlling for covariates. RESULTS PD was associated with increased risk of CKD; risk was highest for cats with stage 3 or 4 PD. Risk of CKD increased with age. Purebred cats had greater risk of CKD than mixed-breed cats. General anesthesia within the year before study exit and diagnosis of cystitis at any point prior to study exit (including prior to study entry) were each associated with increased CKD risk. Diagnosis of diabetes mellitus or hepatic lipidosis at any point prior to study exit was associated with decreased CKD risk. CONCLUSIONS AND CLINICAL RELEVANCE The findings supported the benefit of maintaining good oral health and can be useful to veterinarians for educating owners on the importance of preventing PD in cats.

Detection and seroprevalence of morbillivirus and other paramyxoviruses in geriatric cats with and without evidence of azotemic chronic kidney disease.

BACKGROUND: Feline morbillivirus (FeMV) is associated with the presence of tubulo-interstitial nephritis (TIN) in cats, however the seroprevalence of FeMV in the UK and the association between the presence of FeMV and renal azotemia is unknown HYPOTHESIS/OBJECTIVES: To identify whether paramyxoviruses are present in urine samples of geriatric cats and to develop an assay to assess FeMV seroprevalence. To investigate the relationship between both urinary paramyxovirus (including FeMV) excretion and FeMV seroprevalence and azotemic chronic kidney disease (CKD). ANIMALS: Seventy-nine cats (40 for FeMV detection; 72 for seroprevalence). METHODS: Retrospective cross-sectional, case control study. Viral RNA was extracted from urine for RT-PCR. PCR products were sequenced for virus identification and comparison. The FeMV N protein gene was cloned and partially purified for use as an antigen to screen cat sera for anti-FeMV antibodies by Western Blot. RESULTS: Feline morbillivirus RNA from five distinct morbilliviruses were identified. Detection was not significantly different between azotemic CKD (1/16) and nonazotemic groups (4/24; P = .36). Three distinct, non-FeMV paramyxoviruses were present in the nonazotemic group but their absence from the azotemic group was not statistically significant (P = .15). 6/14 (43%) azotemic cats and 40/55 (73%) nonazotemic cats were seropositive (P = .06). CONCLUSIONS AND CLINICAL IMPORTANCE: Feline morbillivirus was detected in cats in the UK for the First time. However, there was no association between virus prevalence or seropositivity and azotemic CKD. These data do not support the hypothesis that FeMV infection is associated with the development of azotemic CKD in cats in the UK.

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.