Prerenal Azotemia Research Articles

The Selective Proteasome Inhibitor Carfilzomib Is Well Tolerated in Experimental Animals with Dose Intensive Administration

Carfilzomib (CFZ) is a selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. Phase I trials have demonstrated that doses of carfilzomib from 11 – 20 mg/m2 were well tolerated, inhibited blood CT-L activity by ≥80%, and resulted in objective anti-tumor responses in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) (Blood 110:409 & 411). In order to further characterize the safety profile of CFZ, studies in mice, rats and monkeys were conducted to assess the toxicologic consequences of acute and chronic administration. In both rats and monkeys, a single dose of CFZ (equivalent to 24 mg/m2) resulted in > 80% inhibition of CT-L activity in blood and tissues with recovery occurring in most tissues with a t1/2 of 24 hr. At this dose, monkeys developed a pre-renal azotemia within 24 hr, which was characterized by increases in serum creatinine, blood urea nitrogen (BUN) levels and urine specific gravity. These changes resolved in 72 hr, were not associated with histologic changes in the kidney, and were not exacerbated by consecutive daily administrations, suggesting that CFZ may not have a direct nephrotoxic effect. A single dose in either rats or monkeys induced a transient drop in platelets within 48 hr that resolved within 7 days and neither the level of nor recovery from this thrombocytopenia were affected by consecutive daily administration. This phenomenon has also been noted with bortezomib (BTZ), and is observed clinically with both compounds, suggesting that thrombocytopenia is a hallmark of inhibition of proteasome CT-L activity. However, in contrast to BTZ, which has been reported to induce both lymphopenia and neutropenia in animals, CFZ treatment in both rats and monkeys resulted in acute increases in circulating neutrophils and monocytes which rose within 24 hr of a single dose and returned to baseline in 3 – 4 days. We were unable to detect a significant induction of cytokines or chemokines capable of mediating leukocyte fluxes. However, since the acute phase proteins fibrinogen and C-reactive protein were elevated during the same time period of leukocyte flux, cytokines may play a role in this response. In chronic studies, CFZ was administered on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle to rats and monkeys for 6 and 9 cycles, respectively. This dosing schedule results in anti-tumor activity in mouse models of MM, NHL and solid tumors and is currently being utilized in Phase 2 studies in MM and solid tumors. In these chronic studies, transient pre-renal azotemia and increases in circulating neutrophils were manifest in monkeys at 24 mg/m2 following the first dose of both the first and last cycles of treatment. However, no histologic signs of nephropathy were seen in the kidneys of rats receiving 6 cycles of treatment. In addition, chronic administration of CFZ at doses equivalent to those currently administered in the clinic did not impact on the neurobehavioral function of rats and monkeys. There was no severe degeneration in the dorsal root ganglion or in the sciatic, sural, and peroneal nerves of CFZ treated rats. The data with CFZ are in distinct contrast to the axonal swelling, demyelination and severe neural degeneration that is induced by BTZ in rodents and monkeys. In the clinic, peripheral neuropathy associated with CFZ treatment appears to be less severe and possibly less frequent than what is seen with BTZ. Overall, studies in rodents and monkeys have been largely predictive of the clinical experience to date with CFZ. Together with anti-tumor activity in human tumor xenograft models, the toxicologic data support that CFZ administered at therapeutic doses is well tolerated and prolonged treatment of patients with this agent will be feasible.

Acute kidney injury in cirrhosis

Acute renal failure (ARF), recently renamed acute kidney injury (AKI), is a relatively frequent problem, occurring in approximately 20% of hospitalized patients with cirrhosis. Although serum creatinine may underestimate the degree of renal dysfunction in cirrhosis, measures to diagnose and treat AKI should be made in patients in whom serum creatinine rises abruptly by 0.3 mg/dL or more (>/=26.4 micromol/L) or increases by 150% or more (1.5-fold) from baseline. The most common causes of ARF (the term is used interchangeably with AKI) in cirrhosis are prerenal azotemia (volume-responsive prerenal AKI), acute tubular necrosis, and hepatorenal syndrome (HRS), a functional type of prerenal AKI exclusive of cirrhosis that does not respond to volume repletion. Because of the progressive vasodilatory state of cirrhosis that leads to relative hypovolemia and decreased renal blood flow, patients with decompensated cirrhosis are very susceptible to developing AKI with events associated with a decrease in effective arterial blood volume. HRS can occur spontaneously but is more frequently precipitated by events that worsen vasodilatation, such as spontaneous bacterial peritonitis. Specific therapies of AKI depend on the most likely cause and mechanism. Vasoconstrictors are useful bridging therapies in HRS. Ultimately, liver transplantation is indicated in otherwise reasonable candidates in whom AKI does not resolve with specific therapy.

Sorbitol Induced Colonic Necrosis

Purpose: Sodium polystyrene sulfonate is a cation exchange resin, which primarily acts in the colon. It is often administered with an osmotic laxative (sorbitol), PO or rectally. Gastrointestinal adverse reactions include anorexia, nausea, vomiting, constipation, fecal impaction, and intestinal necrosis (rare). Here we present an uncommon case of ulceration of the ascending colon following multiple oral administrations of sodium polystyrene sulfonate-sorbitol. Methods: A 70 yo♀ was admitted with urinary tract infection and pre-renal azotemia. She received 5 oral doses of Sodium polystyrene sulfonate-sorbitol for hyperkalemia and later developed lower abdominal pain. Colonoscopy revealed a solitary 5 cm raised erythematous ulcer in the ascending colon (Fig. 1). Biopsy showed necrotic tissue and purple crystals in inflammatory exudates (Fig. 2). Patient's symptoms were improved spontaneously after discontinuation of therapy.Figure 2: Sodium polystyrene sulfonate (Purple) crystals within the Inflamatory exudates.Figure 1: Colonoscopic view of the ascending colon ulcer.Results: Colonoscopic and pathologic findings were consistent with Sorbitol induced colitis. First case of uremia and colonic necrosis after sodium polystyrene sulfonate-sorbitol enema was reported in 1987. A study in a rat model has shown that sorbitol is in fact the cause of the intestinal necrosis. The exact mechanism by which sorbitol induces intestinal necrosis is unknown. Conclusion: Sorbitol induced colitis is a rare condition which may have significant morbidity and mortality. Considering the adverse reactions, this therapy must be used with caution and should be limited to life-threatening hyperkalemia. Physicians must remain vigilant for any signs or symptoms of intestinal problems.

Survival in Cats with Naturally Occurring Chronic Kidney Disease (2000–2002)

Duration of survival of cats with naturally occurring chronic kidney disease (CKD) is poorly characterized. Stage of kidney disease based on serum creatinine concentration (SCr) at the time of diagnosis and after correction of prerenal azotemia is strongly associated with duration of survival in cats. Two hundred and eleven client-owned cats with naturally occurring CKD evaluated between April 2000 and January 2002. Retrospective case review of 733 cats with SCr > 2.3 mg/dL. Examination of the medical records identified 211 cats that met all other inclusion and exclusion criteria for this study. Clinical characteristics, clinicopathologic data, and survival times were extracted from the medical record. Owners and referring veterinarians were contacted by phone to obtain follow-up if it was not documented in the record. Kaplan-Meier survival curves were performed to determine survival times for International Renal Interest Society (IRIS) stage both at diagnosis and at baseline (ie, after correction of prerenal azotemia). Median survival for cats in IRIS stage IIb at the time of diagnosis was 1,151 days (range 2-3,107), and was longer than survival in stage III (median 778, range 22-2,100) or stage IV (median 103, range 1-1,920) (P-value< .0001). P-value for effect of stage at diagnosis was < .0001. IRIS stage of CKD based on serum creatinine at the time of diagnosis is strongly predictive of survival in cats with naturally occurring CKD.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective

Although emerging evidence indicates that the incidence of both acute kidney injury (AKI) and chronic kidney disease (CKD) in children is rising and the etiologies are dramatically changing, relatively little is currently known regarding the potential for transition from AKI to CKD. In both situations, early intervention can significantly improve the dismal prognosis. However, the lack of a uniform AKI definition and the paucity of early, predictive biomarkers have impaired our ability diagnose AKI early to institute potentially effective therapies in a timely manner. Fortunately, recent data has validated a multidimensional AKI classification system for children. In addition, the application of innovative technologies has identified candidates that are emerging as early biomarkers of both AKI and CKD. These include neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1. Studies to validate the sensitivity and specificity of these biomarkers in clinical samples from large cohorts and from multiple clinical situations are currently in progress, facilitated by the development of commercial tools for the reproducible measurement of these biomarkers across different laboratories.

Sensitivity and Specificity of a Single Emergency Department Measurement of Urinary Neutrophil Gelatinase–Associated Lipocalin for Diagnosing Acute Kidney Injury

A single serum creatinine measurement cannot distinguish acute kidney injury from chronic kidney disease or prerenal azotemia. To test the sensitivity and specificity of a single measurement of urinary neutrophil gelatinase-associated lipocalin (NGAL) and other urinary proteins to detect acute kidney injury in a spectrum of patients. Prospective cohort study. Emergency department of Columbia University Medical Center, New York, New York. 635 patients admitted to the hospital with acute kidney injury, prerenal azotemia, chronic kidney disease, or normal kidney function. Diagnosis of acute kidney injury was based on the RIFLE (risk, injury, failure, loss, and end-stage) criteria and assigned by researchers who were blinded to experimental measurements. Urinary NGAL was measured by immunoblot, N-acetyl-beta-d-glucosaminidase (NAG) by enzyme measurement, alpha1-microglobulin and alpha(1)-acid glycoprotein by immunonephelometry, and serum creatinine by Jaffe kinetic reaction. Experimental measurements were not available to treating physicians. Patients with acute kidney injury had a significantly elevated mean urinary NGAL level compared with the other kidney function groups (416 microg/g creatinine [SD, 387]; P = 0.001). At a cutoff value of 130 microg/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were 0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00), respectively, and positive and negative likelihood ratios were 181.5 (CI, 58.33 to 564.71) and 0.10 (CI, 0.03 to 0.29); these values were superior to those for NAG, alpha1-microglobulin, alpha1-acid glycoprotein, fractional excretion of sodium, and serum creatinine. In multiple logistic regression, urinary NGAL level was highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit (odds ratio, 24.71 [CI, 7.69 to 79.42]). All patients came from a single center. Few kidney biopsies were performed. A single measurement of urinary NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes.

Effects of hydrochlorothiazide and furosemide on creatinine clearance in some hypertensive Nigerians

Hydrochlorothiazide and furosemide have been reported to alter the glomerular filtration rate (GFR) and possibly the creatinine excretion by the kidneys. Also, therapy with these diuretics, especially in the elderly, can be complicated by volume depletion resulting in prerenal azotemia. Creatinine clearance (Clcr) is considered to be the most accurate test of renal function. Unfortunately, although these diuretics are widely used in the treatment of hypertension and heart failure in the young and elderly Nigerians, their effects on renal function have been poorly investigated. We, therefore, evaluated the effects of treatment with 21-day single daily oral doses of 25 mg hydrochlorothiazide or 40 mg furosemide on Clcr in this prospective randomized study of forty Nigerians with mild to moderate uncomplicated essential hypertension (20 males and 20 females) 32 to 80 years of age and 40 age and sex-matched healthy normotensive controls while on their usual diet. Blood and 24 h urine specimens were collected at baseline and on days 7, 14 and 21. Specimens were assayed for creatinine and the corresponding Clcr for each day was calculated. Analysis of variance did not show a statistically significant effect of the diuretic regimens on Clcr over the period. This study demonstrates that single daily doses of either of these diuretics do not have a significant effect on Clcr over a short-term monotherapy.

The L1 cell adhesion molecule is a potential biomarker of human distal nephron injury in acute tubular necrosis

The L1 cell adhesion molecule (CD171) is a multidomain membrane glycoprotein of the immunoglobulin superfamily. We evaluated its expression in human acute kidney injury and assessed its use as a tissue and urinary marker of acute tubular injury. Using immunohistochemical studies with antibodies to the extracellular or cytoplasmic domains, we compared L1 expression in normal kidneys in 24 biopsies taken from patients with acute tubular necrosis. L1 was found at the basolateral and the lateral membrane in all epithelial cells of the collecting duct in the normal kidney except for intercalated cells. In acute tubular necrosis, L1 lost its polarized distribution being found in both the basolateral and apical domains of the collecting duct. Further, it was induced in thick ascending limb and distal tubule cells. Apically expressed L1 found only when the cytoplasmic domain antibody was used in biopsy specimens of patients with acute tubular necrosis. The levels of urinary L1, normalized for creatinine, were significantly higher in all 24 patients with acute tubular necrosis compared to five patients with prerenal azotemia or to six patients with other causes of acute kidney injury. Our study shows that a soluble form of human L1 can be detected in the urine of patients with acute tubular necrosis and that this may be a marker of distal nephron injury.

A rare cause of melena: spontaneous esophageal hematoma

A 53-year-old woman with poorly controlled diabetes mellitus was hospitalized with sudden epigastric pain, melena, and dizziness. She was taking neither antiplatelet drugs nor anticoagulants. Physical examination was unremarkable, except for pale conjunctivae and epigastric tenderness. Laboratory evaluation revealed anemia (hemoglobin 6.3 g/dL [normal 11.0-16.0 g/dL]) and prerenal azotemia (blood urea nitrogen 111 mg/dL [5-22 mg/dL], creatinine 3.5 mg/dL [0.5-1.3 mg/dL]). An electrocardiogram and a chest film showed normal results.

A “Troponin” for the Kidney?

Elevated creatinine levels in patients who present to an emergency department can result from three distinct types of pathophysiology: acute renal injury (previously termed acute renal failure), preexisting renal disease, or prerenal azotemia. Distinguishing among these etiologies is difficult but important, because questions about whether to initiate treatment and which treatment is indicated are crucial. Neutrophil gelatinase–associated lipocalin (NGAL), one of several renal proteins excreted …

Hyperemesis gravidarum : une cause rare d'encéphalopathie de Wernicke

Wernicke encephalopathy - most often observed in alcoholic patients - is due to severe thiamine deficiency. We report here the case of a 30-year-old woman who presented with hyperemesis and vomiting during the first trimester of pregnancy (hyperemesis gravidarum). Hyperemesis can lead to severe, symptomatic thiamine deficiency and to severe dehydration with prerenal azotemia. Wernicke encephalopathy is a rare complication of hyperemesis gravidarum. It should be diagnosed as early as possible to prevent long-term complications.

Normotensive Ischemic Acute Renal Failure

Acute renal failure is defined as a rapid decrease in the glomerular filtration rate, occurring over a period of minutes to days. Because the rate of production of metabolic waste exceeds the rate of renal excretion in this circumstance, serum concentrations of markers of renal function, such as urea and creatinine, rise. The causes of acute renal failure are classically divided into three categories: prerenal, postrenal (or obstructive), and intrinsic. Prerenal azotemia is considered a functional response to renal hypoperfusion, in which renal structure and microstructure are preserved. Postrenal azotemia — obstruction of the urinary tract — is initially accompanied by few microscopical changes (early hydronephrosis, with enlargement of the pelvic cavity and minimal distention or blunting of the renal papilla) or none. In contrast, intrinsic renal azotemia is due to parenchymal injury of the blood vessels, glomeruli, tubules, or interstitium. In prerenal and postrenal azotemia, complete recovery may be seen 1 to 2 days after relief of the offending lesion, provided that normal perfusion or urinary outflow is reestablished before structural changes occur. A research focus group organized by the American Society of Nephrology recent­ ly recommended that the term “acute kidney injury” replace the term “acute renal failure.” 1 However, the group left the actual definition of acute kidney injury to be determined in the future. Thus, whether acute kidney injury refers only to acute tubular necrosis or includes prerenal and postrenal azotemia and parenchymal dis­ eases such as acute glomerulonephritis remains unclear. Most clinicians still use the term acute renal failure as defined above. The two forms of ischemic acute renal failure, prerenal azotemia and acute tubular necrosis, account for more than half the cases of renal failure seen in hospitalized patients and are familiar to most clinicians. 2-4 Yet in many patients with acute renal failure, the contribution of ischemia is initially unrecognized. Patients with ischemic acute renal failure typically have low systemic perfusion, sometimes caused by volume depletion, although their blood pressure may not fall dramatically but instead may remain within the normal range (in an adult, systolic blood pressure >90 to 100 mm Hg). In such cases, in the absence of frank hypo­ tension, the clinician may speculate that an unobserved drop in blood pressure must have caused the renal failure. Although this scenario cannot be ruled out, other causative mechanisms can usually be identified. This type of ischemic acute renal failure (termed normotensive, because the patient’s blood pressure is — at least temporarily — within the normal range) can occur as a result of several processes, most of which involve increased renal susceptibility to modest reductions in perfu­ sion pressure. Fortunately, the factors that lead to ischemic renal failure in patients with apparently normal blood pressure are discernible in most instances. Recogni­ tion of these factors allows the physician to make an early diagnosis and facilitates the interventions that can help to reestablish normal renal hemodynamics. The importance of addressing even mild renal failure is illustrated by a recent study showing that hospitalized patients with a modest increase in the serum

Azotemia in Cancer Patients During Inpatient Rehabilitation

This paper presents a study of the relationship between prerenal azotemia and rehabilitation outcomes of cancer patients. A retrospective chart review of 70 patients who underwent inpatient rehabilitation in a tertiary cancer center was undertaken. Eight patients with creatinine values >1.5 were excluded. The remaining 62 patients were divided into 2 groups according to the blood urea nitrogen/creatinine (BUN/Cr) ratio: 27 (44%) in the prerenal azotemia group (BUN/Cr > or = 20) and 35 (56%) in the non-azotemic group (BUN/Cr < 20). Age, gender, <10 g/dL of hemoglobin, co-morbidity (diabetes mellitus and/or hypertension), discharge destiny and median rehabilitation length of stay were not significantly different in these 2 groups. Prerenal azotemia was present in a significant number of cancer patients, but it did not impact the length of rehabilitation stay or discharge destiny.

Renal salt wasting without cerebral disease: Diagnostic value of urate determinations in hyponatremia

CASE PRESENTATION A 76-year-old woman, who sustained an accidental fracture of the femoral neck, developed hyponatremia after admission. The diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was made by the consulting internist and fluid restriction of 700 cc/day was instituted. Her serum sodium (Na) fluctuated between 122 and 129mmol/l and a renal consultation was requested on the eighth day after undergoing a hemiarthroplasty of the hip when she was ambulating and on no pain medication. Her blood pressure was 100/60 mm Hg, pulse 92 beats/min and there was poor tissue turgor, flat jugular veins, and dry mucous membranes. There was no edema, third spacing, postural hypotension or neurological abnormalities. Her medications included docusate sodium, milk of magnesia, simvastatin, and warfarin. She was not on drugs such as atorvastatin, fenofibrate, or losartan which reduce serum urate by increasing renal urate excretion. 1-3 A low baseline urine Na (UNa) concentration of 6 mmol/l suggested a hypovolemic condition with normal renal function 4 that should result in a prerenal state characterized by low UNa, azotemia, and hyperuricemia. The baseline serum urate of 3.4 mg/dl, however, was inconsistent with prerenal azotemia and its coexistence with hyponatremia was suggestive of SIADH or renal salt wasting. 4-6 The patient was, therefore, included in an IRB-approved protocol to differentiate SIADH from renal salt wasting. After obtaining an informed consent, a blood volume study was performed, using a radioisotope dilution technique.7 With a hematocrit of 31%, the red cell volume was decreased by 28% and the plasma volume increased by 4.7%, resulting in a net blood volume reduction of 7.1%. The pertinent baseline laboratory data are summarized in Table 1. The baseline plasma renin, aldosterone, antidiuretic hormone (ADH), and fractional urate excretion were elevated at 8.63ng/ml/h, 16.5ng/dl, 2.5pg/ml, and 29.6% (normal 5-10%), respectively. Plasma osmolality was decreased at 260 mosm/kgH 2 O, atrial natriuretic peptide was in the low normal range at 35 pg/ml, serum phosphorus and urate were decreased at 2.4 and 3.4 mg/dl, respectively. Renal, adrenal, and thyroid functions were normal. The chest X-ray and urinalysis were normal. Saline was then infused at 125 ml/h for 48 h. Urine osmolality of all spontaneously voided urine was immediately determined and when her urine osmolality decreased to 152 mosM/kgH 2 O at 13.3h, a repeat plasma ADH was undetectable when the serum osmolality was 268 mosm/kgH 2 O. At this time, she had received 1660 ml of saline overnight and excreted 955 ml of urine. The plasma renin and aldosterone decreased to 2.95 ng/ml/h and 7.6ng/dl, respectively, and plasma atrial natriuretic peptide increased to a high normal 65 pg/ml. The serum Na remained unchanged at 129mmol/l but the serum urate decreased from 3.4 to 1.7 mg/dl. It should be noted that the baseline urine osmolality of 321 mosm/kgH 2 O increased to 587 mosm/kgH 2 O and the UNa only increased from a baseline of 6 to 18 mmol/l in the first urine passed 4 h after initiation of saline infusion (Figure 1, Table 2). The serum Na gradually increased from 129 to 138 mmol/l at 45.8 h (Figure 2), as serum urate decreased to 1.0 mg/dl and fractional urate excretion remained elevated (Figure 2). Her UNa increased to a peak of 82 mmol/l at 8.1 h (Table 2).

Fractional excretion of urea in the follow-up of acute renal failure due to prerenal azotemia

Fractional excretion of urea (FEU) is a major issue to discriminate between prerenal azotemia and acute tubular necrosis in acute renal failure (ARF). Its role in the course of ARF remains unclear. The aim of this study was to evaluate FEU in the follow-up of ARF due to prerenal azotemia in order to predict the necessity of renal replacement therapy (RRT). The prospective study took place at the ICU of Stadtspital Waid, Zurich. All patients admitted starting from 19 February 2006 were evaluated for ARF according to the RIFLE classification. ARF due to prerenal azotemia was defined as ARF combined with FEU of less than or equal to 35%. FEU was calculated as [(urine urea/blood urea)/(urine creatinine/plasma creatinine)] × 100. Urine specimens were taken and FEU was calculated daily until complete or partial renal recovery was reached or the criteria for RRT were met. The goal of therapy was reconstitution of renal function by treatment of the underlying condition. RRT was initiated according to the usual criteria. Statistics were determined using Fisher's exact test. By 7 December 2006, 15 patients met the inclusion criteria for ARF due to prerenal azotemia (nine males, six females). The mean age was 71 ± 11 (SD) years for male patients and 58 ± 31 years for female patients. Twelve out of the 15 patients responded to conservative management and had complete or partial renal recovery. Three patients needed RRT. Two of them refused RRT and died during the course of the disease. During the first 48 hours after initiation of conservative therapy, FEU remains less than or equal to 35% in all three patients who needed RRT. By contrast, nine out of 12 patients in whom renal function recovered without RRT showed a FEU of more than 35% within the first 48 hours (P < 0.05) (Figure ​(Figure11). Figure 1 Fractional excretion of urea (FEU) in the follow-up of acute renal failure (ARF) due to prerenal azotemia. Data presented as mean ± SD. n = number of patients. In patients presenting with ARF due to prerenal azotemia, an increase of FEU above 35% within the first 48 hours after initiation of conservative therapy for ARF is a valuable parameter to predict renal recovery. After initiation of conservative therapy, measurement of FEU is of no value concerning discrimination of prerenal azotemia and acute tubular necrosis in ARF.

Acute renal failure in the elderly: particular characteristics

Elderly individuals comprise the faster growing patient population group and acute renal failure (ARF) is quite common among them, although exact numbers are not known. We reviewed the literature with regards to the characteristics of ARF in elderly patients and describe some useful guidelines. The ageing kidney is characterized by many structural and functional changes, which are mainly due to various chronic disorders, such as hypertension, diabetes and atherosclerosis, which are highly prevalent in these patients. A number of structural and functional changes characteristic of the ageing kidney make elderly people especially prone to renal damage. ARF in the elderly is frequently of multifactorial origin and often with an atypical presentation, like the "intermediate syndrome", which combines characteristics of pre-renal azotemia and acute tubular necrosis. Physical examination and laboratory blood and urine indices may sometimes be misleading occasionally leading to misdiagnosis. Prophylaxis remains the preferred approach to therapy: one should avoid nephrotoxic drugs and poly-pharmacy, adjust drug doses and achieve adequate hydration of the patient as cautiously as possible. Dialysis therapies can be used for treatment of ARF irrespective of age and carry a good prognosis.

Exosomal Fetuin-A identified by proteomics: A novel urinary biomarker for detecting acute kidney injury

Urinary exosomes containing apical membrane and intracellular fluid are normally secreted into the urine from all nephron segments, and may carry protein markers of renal dysfunction and structural injury. We aimed to discover biomarkers in urinary exosomes to detect acute kidney injury (AKI), which has a high mortality and morbidity. Animals were injected with cisplatin. Urinary exosomes were isolated by differential centrifugation. Protein changes were evaluated by two-dimensional difference in gel electrophoresis and changed proteins were identified by mass spectrometry. The identified candidate biomarkers were validated by Western blotting in individual urine samples from rats subjected to cisplatin injection; bilateral ischemia and reperfusion (I/R); volume depletion; and intensive care unit (ICU) patients with and without AKI. We identified 18 proteins that were increased and nine proteins that were decreased 8 h after cisplatin injection. Most of the candidates could not be validated by Western blotting. However, exosomal Fetuin-A increased 52.5-fold at day 2 (1 day before serum creatinine increase and tubule damage) and remained elevated 51.5-fold at day 5 (peak renal injury) after cisplatin injection. By immunoelectron microscopy and elution studies, Fetuin-A was located inside urinary exosomes. Urinary Fetuin-A was increased 31.6-fold in the early phase (2-8 h) of I/R, but not in prerenal azotemia. Urinary exosomal Fetuin-A also increased in three ICU patients with AKI compared to the patients without AKI. We conclude that (1) proteomic analysis of urinary exosomes can provide biomarker candidates for the diagnosis of AKI and (2) urinary Fetuin-A might be a predictive biomarker of structural renal injury.

Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen

The cardiorenal safety database from the Celecoxib Long-term Arthritis Safety Study (CLASS) was analyzed to examine whether supratherapeutic doses of celecoxib are associated with decreased renal function and blood pressure (BP) effects compared with standard doses of diclofenac and ibuprofen in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.In total, 8059 patients were enrolled; 7968 received at least one dose of study drug (RA: N = 2183; OA: N = 5785). Patients received celecoxib, 400 mg twice a day (b.i.d.). (N = 3987); ibuprofen, 800 mg three times a day. (N = 1985); or diclofenac, 75 mg b.i.d. (N = 1996). Effects measured included: investigator-reported hypertension, edema or congestive heart failure, clinically important BP elevations, incidence of patients starting new antihypertensive medication, and increases in serum creatinine or reductions in creatinine clearance. Celecoxib was associated with a similar incidence of hypertension or edema to diclofenac but significantly lower than ibuprofen. The celecoxib group had significantly fewer initiations of antihypertensives versus ibuprofen. Systolic BP increases of >20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P < 0.05) and ibuprofen (7.3%; P < 0.05). A supratherapeutic dose of celecoxib was associated with an improved cardiorenal safety profile compared with standard doses of either ibuprofen or diclofenac.

High urea and creatinine concentrations and urea transporter B in mammalian urinary tract tissues

Although the mammalian urinary tract is generally held to be solely a transit and storage vehicle for urine made by the kidney, in vivo data suggest reabsorption of urea and other urine constituents across urinary tract epithelia. To determine whether urinary tract tissue concentrations are increased as a result of such reabsorption, we measured urea nitrogen and creatinine concentrations and determined whether urea transporter B (UT-B) was present in bladder, ureter, and other tissues from dogs and rats. Mean urea nitrogen and creatinine concentrations in dogs and rats were three- to sevenfold higher in urinary tract tissues than in serum and were comparable to those in renal cortex. In water-restricted or water-loaded rats, urea nitrogen concentrations in bladder tissues fell inversely with the state of hydration, were proportional to urine urea nitrogen concentrations, and were greater than the corresponding serum urea nitrogen concentration in every animal. Immunoblots of rat and dog urinary tract tissues demonstrated the presence of UT-B in homogenates of bladder and ureter, and immunocytochemical analysis localized UT-B to epithelial cell membranes. These findings are consistent with the notion that urea and creatinine are continuously reabsorbed from the urine across the urothelium, urea in part via UT-B, and that urine is thus altered in its passage through the urinary tract. Urea reabsorption across urinary tract epithelia may be important during conditions requiring nitrogen conservation and may contribute to pathophysiological states characterized by high blood urea nitrogen, such as prerenal azotemia and obstructive uropathy.

Neurologic signs and hyperammonemia in a horse with colic

A 23-year-old Thoroughbred gelding was referred for the evaluation of acute onset of ataxia and depression, and a 2-day history of fever. On physical examination, the gelding was profoundly depressed and 10-12% dehydrated. The horse appeared very unstable, with a wide-based stance in the hind limbs, severe symmetric ataxia in all 4 limbs, and proprioceptive deficits in both hind limbs. Nasogastric intubation produced 4 L of brown, fetid reflux, and rectal examination revealed mild small intestinal and cecal distention. Hematologic abnormalities included neutropenia with toxic change, compatible with acute inflammation and endotoxemia, and prolonged coagulation times. Serum biochemical abnormalities included prerenal azotemia. metabolic acidosis, and electrolyte abnormalities consistent with enteritis. Blood ammonia concentration was markedly increased (406 micromol/L; reference interval 4-49 micromol/L), however, serum bile acids concentration and hepatic enzyme activities were within reference intervals. Histopathologic examination of a liver biopsy revealed no abnormalities and results of tests for several infectious agents were negative. Clinical signs resolved with correction of the dehydration and electrolyte abnormalities and with antibiotic therapy. The horse was diagnosed with hyperammonemic neuropathy associated with gastrointestinal disease. In such cases, hyperammonemia is caused by increased production of ammonia by organisms in the gastrointestinal tract in combination with increased gut permeability that facilitates ammonia absorption.