Usefulness of Extra Virgin Olive Oil Minor Polar Compounds in the Management of Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) is one of the most common chronic non-communicable degenerative diseases and it represents an important risk factor for cardiovascular morbidity and mortality. The Mediterranean diet, in which extra virgin olive oil (EVOO) is the main source of vegetal fats, represents a nutritional-diet regimen that is useful for the treatment of CKD and its comorbidities. We tested two different EVOOs, characterized by a high (Synergy) and medium (Luxolio) content of minor polar compounds (MPCs), detected by HPLC-DAD-MS analysis, in 40 nephropathic patients, at a dose of 40 mL/day for 9 weeks. We evaluated the effects of these two EVOOs on renal function, body composition, oxidative stress, and inflammatory state, after 9 weeks of EVOOs consumption (T1) and after 2 months of wash-out (T2). We observed an improvement of renal function biomarkers (estimated-glomerular filtration rate, albuminuria, azotemia, uric acid), lipid profile, oxidative stress, inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein) and in body composition at T1. These healthy effects were greater and persisted over time after the wash-out period in Synergy patients. The high MPC EVOO content seems to exert an antioxidant and anti-inflammatory effect in nephropathic patients and these protective actions are maintained over time.

Urine kidney safety biomarkers improve understanding of indirect intra-renal injury potential in dogs with a drug-induced prerenal azotemia.

Drug-induced kidney injury (DIKI) is a frequent occurrence in nonclinical drug development. It is well established that novel urine kidney safety biomarkers will outperform urea nitrogen (BUN) and serum creatinine (sCr) for monitoring direct drug injury to the kidney across numerous compounds spanning diverse mechanisms and efforts are underway for a formal regulatory clinical qualification. However, it remains unclear how these novel biomarkers will perform under prerenal azotemia when BUN and sCr are elevated but no intra-renal injury is suspected. This lack of knowledge is largely due to the dearth of such nonclinical animal models. We report here that treatment of dogs with a potent antihypertensive compound MK-5478 at a suprapharmacologic dose for up to 9 days results in the development of prerenal azotemia and, in some dogs, kidney toxicity through the dual sustained effects of MK-5478 as a nitric oxide donor and an angiotensin II receptor blocker (ARB). While conventional serum biomarkers BUN, and often sCr as well, were highly elevated in these dogs with or without kidney damage, urine kidney biomarkers clusterin (CLU) and neutrophil gelatinase-associated lipocalin (NGAL) showed increases only in dogs with kidney histopathologic changes following the sustained period of prerenal azotemia. Urine albumin (ALB) and total protein also tracked with kidney lesions but with less sensitivity. Thus, we present evidence for the first time that urine kidney safety biomarkers used together with BUN and sCr can distinguish intra-renal injury among dogs with prerenal azotemia while the conventional serum biomarkers alone are ambiguous, either being interpreted as false positives of kidney injury, or dismissed under circumstances as benign without appreciation for a threshold of impending injury.

Assessment and prediction of acute kidney injury in patients with decompensated cirrhosis with serum cystatin C and urine N-acetyl-ß-D-glucosaminidase.

BACKGROUND AND AIM: For appropriate management of acute kidney injury (AKI) in cirrhotic patients, accurate differentiation of the types of AKI, prerenal azotemia (PRA), hepatorenal syndrome (HRS), and acute tubular necrosis (ATN) is very important. Urine N-acetyl-ß-D-glucosaminidase (NAG) has been proposed as a good tubular injury marker in many studies, but its efficacy in cirrhosis is unclear. This study was performed to evaluate the usefulness of urine NAG in patients with decompensated cirrhosis. METHODS: In 114 hospitalized patients with decompensated cirrhosis, we assessed serum creatinine, cystatin C, and urine NAG levels as markers for AKI differentiation and development and patient mortality. RESULTS: Thirty patients diagnosed with AKI at baseline had significantly higher serum creatinine and cystatin C levels, urine NAG levels, and Child-Pugh scores than those without AKI. Only urine NAG levels were significantly higher in patients with ATN than those with PRA or HRS (116.1 ± 46.8 U/g vs 39.4 ± 20.2 or 54.0 ± 19.2 U/g urinary creatinine, all P < 0.05). During a median follow up of 6.1 months, AKI developed in 17 of 84 patients: PRA in nine, HRS in six, and ATN in three. Higher serum cystatin C and urine NAG levels were independent predictors of AKI development in patients with decompensated cirrhosis. Survival was significantly associated with low serum cystatin C and urine NAG levels. CONCLUSION: Serum cystatin C and urine NAG levels are useful to differentiate types of AKI and are strong predictors for AKI development and mortality in patients with decompensated cirrhosis.

[Potential biochemical factors for the development of urolithiasis in patients with spinal cord injuries].

A comparative analysis of biochemical parameters of blood serum and daily urine in patients with urolithiasis developed after spinal cord injury (study group--35 patients) and patients without development of the disease (comparison group--20 patients) was performed. It was found that patients after spinal cord injury have developed productive azotemia, which led to the disruption of renal excretory function (accumulation of urea and creatinine in blood, and lowering their clearance). Against this background, there is violation of excretion of uric acid, magnesium, decreased sensitivity of the renal tubules to aldosterone (in patients with nephrolithiasis K/Na ratio in urine was lower). As a result, patients have decreased reabsorption of sodium and water retention, increased urine osmolality; against the background of electrolyte imbalance in urine, this leads to the formation of stones. In patients with spinal cord injuries, main trigger mechanism of formation of urinary stones was excessive posttraumatic azotemia. The high concentration of the products of protein-nitrogen catabolism in the serum of patients in the acute and early periods of spinal cord injury may be unfavorable criterion determining the significant risk of developing of kidney stones.

Urinary MCP1 and Microalbumin increase prior to onset of Azotemia in mice with polycystic kidney disease.

Urinary biomarkers may offer a more sensitive and less invasive means to monitor kidney disease than traditional blood chemistry biomarkers such as creatinine. CD1(pcy/pcy) (pcy) mice have a slowly progressive disease phenotype that resembles human autosomal dominant polycystic kidney disease with renal cyst formation and inflammation. Previous reports suggest that dietary protein restriction may slow disease progression in mice and humans with polycystic kidney disease. Accordingly, we fed pcy mice either a standard chow (22.5% protein) or a protein-restricted (11.5% soy-based protein) diet from weaning until 34 wk of age. Every 6 wk we measured markers of kidney disease, including serum creatinine, BUN, and serum albumin as well as urinary monocyte chemoattractant protein 1 (MCP1), microalbumin, and specific gravity. Progression of kidney disease was equivalent for both diet groups despite dietary protein restriction. Urinary biomarkers proved useful for early detection of disease, in that urinary microalbumin was elevated as early as 22 wk of age and urinary MCP1 was increased by 28 wk of age, whereas increases in serum creatinine and BUN were detected later (at 34 wk of age) in both diet groups. Thus, urinary microalbumin and MCP1 analyses provided earlier, noninvasive indicators for detection of kidney disease and disease progression in pcy mice than did serum creatinine and BUN.

Plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) in dogs with acute kidney injury or chronic kidney disease.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a protein that is used in human medicine as a real-time indicator of acute kidney injury (AKI). HYPOTHESIS: Dogs with AKI have significantly higher plasma NGAL concentration and urine NGAL-to-creatinine ratio (UNCR) compared with healthy dogs and dogs with chronic kidney disease (CKD). ANIMALS: 18 healthy control dogs, 17 dogs with CKD, and 48 dogs with AKI. METHODS: Over a period of 1 year, all dogs with renal azotemia were prospectively included. Urine and plasma samples were collected during the first 24 hours after presentation or after development of renal azotemia. Plasma and urine NGAL concentrations were measured with a commercially available canine NGAL Elisa Kit (Bioporto® Diagnostic) and UNCR was calculated. A single-injection plasma inulin clearance was performed in the healthy dogs. RESULTS: Median (range) NGAL plasma concentration in healthy dogs, dogs with CKD, and AKI were 10.7 ng/mL (2.5-21.2), 22.0 ng/mL (7.7-62.3), and 48.3 ng/mL (5.7-469.0), respectively. UNCR was 2 × 10(-8) (0-46), 1,424 × 10(-8) (385-18,347), and 2,366 × 10(-8) (36-994,669), respectively. Dogs with renal azotemia had significantly higher NGAL concentrations and UNCR than did healthy dogs (P < .0001 for both). Plasma NGAL concentration was significantly higher in dogs with AKI compared with dogs with CKD (P = .027). CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma NGAL could be helpful to differentiate AKI from CKD in dogs with renal azotemia.

Evaluation of mass spectrometry of urinary proteins and peptides as biomarkers for cats at risk of developing azotemia.

OBJECTIVE: To evaluate proteomic delineation of feline urine by mass spectrometry as a method for identifying biomarkers in cats at risk of developing azotemia. SAMPLES: Urine samples from geriatric cats (> 9 years old) with chronic kidney disease and nonazotemic cats that either remained nonazotemic (n = 10) or developed azotemia (10) within 1 year. PROCEDURES: Optimization studies with pooled urine were performed to facilitate the use of surface enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF-MS) for analysis of the urinary proteome of cats. Urine samples from nonazotemic cats at entry to the study were analyzed via SELDI-TOF-MS with weak cation exchange and strong anion exchange arrays. Spectral data were compared to identify biomarkers for development of azotemia. RESULTS: Low protein concentration in feline urine precluded direct application to array surfaces, and a buffer exchange and concentration step was required prior to SELDI-TOF-MS analysis. Three preparation conditions by use of weak cation and strong anion exchange arrays were selected on the basis of optimization studies for detection of biomarkers. Eight potential biomarkers with an m/z of 2,822, 9,886, 10,033, 10,151, 10,234, 11,653, 4,421, and 9,505 were delineated. CONCLUSIONS AND CLINICAL RELEVANCE: SELDI-TOF-MS can be used to detect urinary low-molecular weight peptides and proteins that may represent biomarkers for early detection of renal damage. Further study is required to purify and identify potential biomarkers before their use in a clinical setting.

Fractional excretion of uric acid as a predictor for saline responsiveness in long-term kidney transplant patients.

BACKGROUND/AIMS: Subclinical hypovolemia may contribute to allograft dysfunction in long-term kidney transplant (KT) patients. In order to predict responsiveness to saline hydration, indices for tubular transport were investigated. METHODS: Fifty-four clinically euvolemic long-term KT patients with recently aggravated azotemia were given intravenous hydration as follows: 0.9% saline 5 ml/kg over 1 h, followed by 0.9% saline 1 ml/kg/h over 12 h and 1 liter of 0.45% saline over the next 24 h. Serum and urine data were collected and analyzed to assess responses. RESULTS: In all patients, saline hydration relieved azotemia, as shown by blood urea nitrogen (46.9 ± 17.2 vs. 39.3 ± 15.4 mg/dl; p < 0.01) and serum creatinine levels (2.9 ± 1.1 vs. 2.5 ± 1.1 mg/dl; p < 0.01) on day 0 versus day 2. In 38 patients, serum creatinine did not increase in the following month (70% responders). Compared with the nonresponders, the responders had a higher urine-to-plasma creatinine ratio and lower fractional excretion of sodium, uric acid and urea at admission. Multivariate logistic regression analysis revealed that responsiveness to saline hydration was independently associated with lower fractional excretion of uric acid. CONCLUSION: Subclinical hypovolemia should be considered in long-term KT patients with azotemia of unexplainable causes. Fractional excretion of uric acid may predict responsiveness to saline hydration.

Diagnostic value of urinary sodium, chloride, urea, and flow.

Up to 30% of hospitalized critically ill patients may have a rise in serum creatinine concentration. In addition to history and physical examination, there is diagnostic value in assessing urinary electrolytes, solute excretion, and urine flow in these patients. The correct interpretation of these urinary parameters can avoid unnecessary volume overload and mechanical ventilation, risk factors for increased mortality in patients with rising serum creatinine. The present article also discusses the role of arterial underfilling in causing prerenal azotemia in the presence of an increase in total body sodium and extracellular fluid expansion. As with extracellular fluid volume depletion, arterial underfilling secondary to impaired cardiac function or primary arterial vasodilation can delay or prevent recovery from ischemic or toxic acute tubular necrosis. The present brief review discusses the various aspects of the correct interpretation of urinary electrolytes, solute excretion, and urine flow in the setting of a rising serum creatinine concentration.

Toward the optimal clinical use of the fraction excretion of solutes in oliguric azotemia.

While the fractional excretion of solutes have long been considered excellent research tools to investigate tubular physiology, their clinical use has become common over the last 40 years in the diagnoses of many disorders; however, none have reached the clinical utility of the fractional excretion of sodium in the ability to distinguish pre-renal azotemia from acute tubular necrosis. Nevertheless, there are many drugs and medical conditions that interfere with that utility and recently other solutes, including urea, uric acid and lithium, have been recently investigated to improve the diagnostic ability in clinical situations where the fractional excretion of sodium is known to be unreliable. We review the tubular physiology of these solutes and show how the differences in tubular physiology might be exploited to develop a strategy for their optimal clinical use.

Measurement of urinary cauxin in geriatric cats with variable plasma creatinine concentrations and proteinuria and evaluation of urine cauxin-to-creatinine concentration ratio as a predictor of developing azotemia.

OBJECTIVE: To evaluate urine cauxin immunoreactivity in geriatric cats with variable plasma creatinine concentrations and proteinuria and to assess urinary cauxin-to-creatinine concentration ratio (UC/C) as a predictor of developing azotemia. ANIMALS: 188 client-owned geriatric (>or= 9 years of age) cats. PROCEDURES: A direct immunoassay was developed and validated for the quantification of urinary cauxin relative to a standard curve generated from a urine sample with high cauxin immunoreactivity. Relationships among UC/C, plasma creatinine concentration, and proteinuria were assessed. Nonazotemic cats were recruited and followed for 12 months. Urinary cauxin-to-creatinine concentration ratio was evaluated as a predictor of development of azotemia in these cats. RESULTS: No relationship was evident between UC/C and plasma creatinine concentration. A weak positive correlation was identified between UC/C and urine protein-to-creatinine concentration ratio (r = 0.212). At entry to the longitudinal study, those cats that later developed azotemia had a UC/C that was significantly higher than in those remaining nonazotemic after 12 months. CONCLUSIONS AND CLINICAL RELEVANCE: The UC/C did not vary with severity of azotemia but appeared contributory to the feline urinary proteome. High UC/C values were predictive of the geriatric cats in our study developing azotemia. However, it seems unlikely that UC/C will provide additional information about the measurement of urine protein-to-creatinine concentration ratio as a biomarker for the development of azotemia in cats.

Cystatin C as a marker of acute kidney injury in the emergency department.

BACKGROUND AND OBJECTIVES: The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, which is a poor marker of early renal dysfunction. The discriminative and predictive abilities of serum and urinary cystatin C were examined for the prediction of AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this prospective cohort study, serum and urinary cystatin C were serially measured in a heterogeneous group of patients (n = 616) presenting to a tertiary care emergency department. The primary outcome was AKI, classified according to RIFLE and AKIN criteria. The secondary outcome was an adjudication based on clinical criteria to AKI, prerenal azotemia, chronic kidney disease (CKD), and normal kidney function. RESULTS: Patients were adjudicated to have AKI in 21.1%, prerenal azotemia in 25.8%, CKD in 2.4%, and normal kidney function in 50.7%. For the diagnosis of AKI, the discriminatory ability of urinary creatinine and cystatin C was marginal. Both serum cystatin C and serum creatinine (at presentation and 6 hours later) showed high discriminatory ability for the diagnosis of AKI. However, only serum cystatin C attained a significant early predictive power (Hosmer-Lemeshow P value > 0.05). Serum cystatin C could differentiate between AKI and prerenal azotemia, but not between AKI and CKD. CONCLUSIONS: Serum cystatin C is an early, predictive biomarker of AKI, which outperforms serum creatinine in the heterogeneous emergency department setting. However, neither biomarker discriminated between AKI and CKD. Additional biomarkers continue to be needed for improved specificity in the diagnosis of community-acquired AKI.

Identification of diagnostic urinary biomarkers for acute kidney injury.

Acute kidney injury (AKI) is an important cause of death among hospitalized patients. The 2 most common causes of AKI are acute tubular necrosis (ATN) and prerenal azotemia (PRA). Appropriate diagnosis of the disease is important but often difficult. We analyzed urine proteins by 2-dimensional gel electrophoresis from 38 patients with AKI. Patients were randomly assigned to a training set, an internal test set, or an external validation set. Spot abundances were analyzed by artificial neural networks to identify biomarkers that differentiate between ATN and PRA. When the trained neural network algorithm was tested against the training data, it identified the diagnosis for 16 of 18 patients in the training set and all 10 patients in the internal test set. The accuracy was validated in the novel external set of patients where conditions of 9 of 10 patients were correctly diagnosed including 5 of 5 with ATN and 4 of 5 with PRA. Plasma retinol-binding protein was identified in 1 spot and a fragment of albumin and plasma retinol-binding protein in the other. These proteins are candidate markers for diagnostic assays of AKI.

Assessment of urinary N-acetyl-beta-D-glucosaminidase activity in geriatric cats with variable plasma creatinine concentrations with and without azotemia.

OBJECTIVE: To validate a non-automated technique for the measurement of urinary N-acetyl-beta-D-glucosaminidase (NAG) activity in cats and assess the correlation between NAG index, plasma creatinine concentration, and proteinuria. ANIMALS: 197 client-owned cats (> or = 9 years old; 119 neutered males and 78 neutered females) of which 103 had previously been determined to have chronic kidney disease (CKD). PROCEDURES: Preliminary assay validation was performed for a non-automated colorimetric technique for quantification of NAG activity. The effect of storage of samples was examined. A cross-sectional study was performed to assess urinary NAG index in cats with variable plasma creatinine concentrations and with proteinuria, as quantified by use of the urine protein-to-creatinine ratio (UP:C). RESULTS: Interassay coefficients of variance (CVs) in cats with low (mean, 0.64 U/L), medium (mean, 4.38.U/L), and high (mean, 8.48 U/L) urine NAG activity were 25.9%, 14.4%, and 25.1%, respectively, but intra-assay CVs were < 20%. Urine NAG activity was stable for 4 freeze-thaw cycles and for storage at -20 degrees C. There was no significant difference in log NAG index when cats (n = 197) were grouped according to plasma creatinine concentration, but a moderate positive correlation was found between log NAG index and log UP:C (r2 = 0.259). CONCLUSIONS AND CLINICAL RELEVANCE: N-acetyl-beta-D-glucosaminidase activity can be quantified in feline urine by use of a non-automated colorimetric technique. However, data should be interpreted cautiously because of high interassay CVs. The NAG index in cats with CKD may be indicative of ongoing lysosomal activity rather than active proximal tubular cell damage.

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.

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

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.

[Effect of mineral water on metabolic processes].

The paper comparatively analyzes the effect of the mineral water "Penta" on the biochemical parameters of blood and urine, which characterize the functional activity of renal metabolic processes. A group comprising 10 examinees without renal disease took water by the routine mineral water scheme for 4 days. Comparison of the biochemical parameters before and after water taking revealed a significant reduction in azotemia and uric acid levels with its simultaneously enhanced excretion, as well as an increasing tendency for the excretion of oxalates, i.e. the most important parameters determining the formation of urate and oxalate calculi. These findings allow use "Penta", to a certain degree, in the treatment of renal disease, urolithiasis in particular, and in the prevention of stone formation.