The clinician and estimation of glomerular filtration rate by creatinine-based formulas: current limitations and quo vadis.

The GFR has a paramount diagnostic and staging role in the Kidney Disease Outcome Quality Initiative Clinical Practice Guidelines for Chronic Kidney Disease (K/DOQI-CKD). The most widely used serum creatinine-based formulas in adults for estimated GFR (eGFR) are the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease Study (MDRD). Recently, a new Chronic Kidney Disease Epidemiology Collaboration equation has been developed. Review of the literature revealed that CG and MDRD formulas correctly assigned overall only 64% and 62%, respectively, of the subjects to their actual K/DOQI-CKD classification's GFR groups as determined by measured GFR (mGFR). This suggests that approximately 10 million (38%) subjects may have been misclassified on the basis of estimated CKD prevalence of 26.3 million adults in the United States. The purpose of this review is to help the clinician understand the limitations of using eGFR in daily practice. We also elaborate upon issues such as the differences among markers of mGFR, the validity of adjusting GFR for body surface area in certain populations, the limited data on boundaries for normal mGFR according to age, gender, and race, the need for calibration of a wide spectrum of serum creatinine measurements, the lack of actual eGFR value above 60 ml/min per 1.73 m(2) and reference for normal mGFR in the clinical laboratories' reports, and the performance evaluation of the eGFR formulas. Several pitfalls have to be overcome before we can reliably determine health and disease in daily nephrology practice to preserve the first rule of practicing medicine: primum non nocere.

Exercise and dehydration: A possible role of inner ear in balance control disorder.

To study the effect of exercise and dehydration on the postural sensory-motor strategies, 10 sportsmen performed a 45 min-exercise on a cycle ergometer at intensity just below the ventilatory threshold without fluid intake. They performed, before, immediately and 20 min after exercise, a sensory organization test to evaluate balance control in six different sensory situations, that combine three visual conditions (eyes open, eyes closed and sway-referenced visual surround motion) with two platform conditions (stable platform, sway-referenced platform motion). Blood samples were collected before and after exercise. Exercise induced a mild dehydration, characterized by body mass loss and increase in proteinemia. Postural performances decreased immediately after exercise, mainly in the standard situation (eyes open, stable visual surround and platform) and when only the vestibular cue was reliable (eyes closed and sway-referenced platform). Moreover, the decreased use of vestibular input was correlated with the dehydration level. Finally, postural performances normalized 20 min after exercise. Even though muscular fatigue could explain the decrease in postural performances, vestibular fluid modifications may also be involved by its influence on the intralabyrinthine homeostasis, lowering thus the contribution of vestibular information on balance control.

Estimating glomerular filtration rate: Cockcroft-Gault and Modification of Diet in Renal Disease formulas compared to renal inulin clearance.

BACKGROUND AND OBJECTIVES: Evaluation of renal function by estimation of the glomerular filtration rate (GFR) is very important for the diagnosis and treatment of patients with chronic kidney disease (CKD). The Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas are the most commonly used estimations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Estimated GFR values by each formula were compared with measured GFR (mGFR) by renal inulin clearance in 2208 European adults (46% women, 1.4% Caribbean blacks), with and without CKD, and mean mGFR 72.4 +/- 39.0 (range 2.2 to 177.2) ml/min/1.73 m(2). RESULTS: Overall, the CG and MDRD formulas showed bias (mean difference) -3.5 ml/min/1.73 m(2) (5.3%), P < 0.001, and -9.8 ml/min/1.73 m(2) (-6.4%), P < 0.001; precision (SD of bias) 21.5 ml/min/1.73 m(2) (43.1%) and 20.0 ml/min/1.73 m(2) (33.0%); limits of agreement (2 SD by Bland-Altman method) 39.5 to -46.5 (range 86.0) ml/min/1.73 m(2) and 30.2 to -49.8 (range 80.0) ml/min/1.73 m(2); and accuracy within +/-30% of mGFR 70.8 and 69.0%, respectively. Both formulas showed a trend for decreasing accuracy with lower mGFR levels. According to the Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD classification's five GFR groups, the CG and MDRD formulas properly assigned 61.6 and 57.1% of the entire population and had a range of positive predictive values 42.6 to 81.8% and 39.6 to 85.2% and of negative predictive values 81.7 to 96.6% and 76.4 to 97.5%, respectively. CONCLUSIONS: The CG and MDRD formulas had some limitations for proper GFR estimation and K/DOQI-CKD classification by GFR levels alone.

Reporting the eGFR and its implication for CKD diagnosis.

The process of diagnosing chronic kidney disease using the estimated GFR involves several pitfalls. The estimated GFR laboratory report should be requested only by practitioners who are familiar with how to interpret the result. Until a more reliable method is available to estimate the GFR, the current chronic kidney disease classification should be revised by reducing the central role of the GFR cutoff levels.

Myocardial lactate deprivation is associated with decreased cardiovascular performance, decreased myocardial energetics, and early death in endotoxic shock.

OBJECTIVE: We examined whether lactate availability is a limiting factor for heart function during endotoxic shock, and whether lactate deprivation thus induces heart energy depletion, thereby altering cardiovascular performance. The study goals were to determine whether muscle lactate production is linked to beta(2)-stimulation and to ascertain the effects of systemic lactate deprivation on hemodynamics, lactate metabolism, heart energetics, and outcome in a lethal model of rat's endotoxic shock. INTERVENTIONS: We modulated the adrenergic pathway in skeletal muscle using microdialysis with ICI-118551, a selective beta(2)-blocker. Muscle lactate formation in endotoxic shock was further inhibited by intravenous infusion of ICI-118551 or dichloroacetate (DCA), an activator of pyruvate dehydrogenase (DCA) and their combination. RESULTS: Muscle lactate formation was decreased by ICI-118551. During endotoxic shock both ICI-118151 and DCA decreased circulating and heart lactate concentrations in parallel with a decrease in tissue ATP content. The combination ICI-118551-DCA resulted in early cardiovascular collapse and death. The addition of molar lactate to ICI-1185111 plus DCA blunted the effects of ICI-118551+DCA on hemodynamics. Survival was markedly less with ICI-118551 than with endotoxin alone. CONCLUSION: Systemic lactate deprivation is detrimental to myocardial energetics, cardiovascular performance, and outcome.

Comparative effects of vasopressin, norepinephrine, and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock.

Norepinephrine (NE), a standard of care, AVP, an alternative candidate, and L-canavanine (LC), a selective inhibitor of inducible nitric oxide synthase, were compared for efficacy and innocuousness on global and regional hemodynamics, plasmatic and tissue lactate-to-pyruvate ratio (L/P), tissue high-energy phosphates, renal function, and tissue capillary permeability in a rat model of endotoxic normokinetic shock. Mean arterial pressure (MAP) decreased ( approximately 35%) but aortic blood flow increased during endotoxin infusion (P < 0.05 vs. control). Additionally, there was a decrease in mesenteric (MBF) and renal (RBF) blood flows along with regional-to-systemic ratio (P < 0.05 vs. control). All tested drugs restored MAP to basal levels but slightly decreased abdominal aortic flow; however, RBF and MBF remained unchanged. Endotoxin significantly decreased diuresis and inulin clearance ( approximately 3- to 4-fold), whereas AVP or LC attenuated this drop (P < 0.05 vs. control). In contrast, NE did not improve endotoxin-induced renal dysfunction. Endotoxin induced gut and lung hyperpermeability (P < 0.05 vs. control). Endotoxin-induced gut hyperpermeability was inhibited by AVP, LC, and NE. Endotoxin-induced lung hyperpermeability was further worsened by NE ( approximately 2-fold increase) but not AVP infusion (P < 0.05 vs. endotoxin). LC significantly improved endotoxin-induced pulmonary hyperpermeability. Endotoxin increased renal lactate and decreased renal ATP. NE did not change renal lactate or renal ATP. AVP and LC decreased renal lactate and normalized renal ATP. Finally, endotoxin was associated with increased lactate levels and L/P ( approximately 2- and 1.5-fold increases vs. control, respectively), whereas AVP and LC, but not NE, normalized both parameters after endotoxin challenge. These results suggest that, in a short-term endotoxic shock model, AVP improves systemic hemodynamics without side effects and has particular beneficial effects on renal function.

Predicting GFR in children and adults: a comparison of the Cockcroft-Gault, Schwartz, and modification of diet in renal disease formulas.

BACKGROUND: A rapid prediction of glomerular filtration rate (GFR) is often needed in clinics. Formulas based on plasma creatinine level are being increasingly used, Schwartz for children, supposed to give GFR; Cockcroft-Gault for adults, supposed to indicate the creatinine clearance; and a recent formula introduced by the Modification of Diet in Renal Disease (MDRD) group. Our objective was to test whether one single formula could suffice and which one gives the best estimation of GFR. METHODS: In 198 children (with two kidneys, single kidney, or renal transplant) and 116 adults (single kidney and transplanted), we measured inulin clearance and creatinine clearance and calculated Cockcroft-Gault, MDRD and, in children only, Schwartz. Data were compared with analysis of variance (ANOVA), regression statistics, and concordance studies. RESULTS: In patients over 12 years of age, Cockcroft-Gault was almost similar to GFR corrected for body surface and creatinine clearance exceeded GFR by more than 20%; Schwartz was above creatinine clearance excepted for transplanted children. In younger children, no prediction approached GFR. Predictions were well correlated with GFR, but concordance studies showed Schwartz with dispersed results and GFR overestimated (20 mL/min/1.73 m2); Cockcroft-Gault was close to GFR and results were dispersed; MDRD in children gave a large overestimation and badly dispersed results; in transplanted adults its prediction was good. CONCLUSION: Cockcroft-Gault prediction could be used for children over 12 years of age and adults; it should not be considered as creatinine clearance but as GFR corrected for body surface, it is merely a prediction, 95% of the results are between +/-40 mL/min/1.73 m(2) in children and +/-30 mL/min/1.72 m(2) in adults. In younger children no formula is satisfying.

Comparative effects of dexamethasone and L-canavanine in experimental septic shock.

Glucocorticoids can reverse hemodynamic disturbances and dependence on catecholamines in septic shock. The relevant beneficial mechanisms of steroids in septic shock are unknown, although inducible nitric oxide synthase could account for them. The aim of this study was to compare the effects of dexamethasone, a glucocorticoid and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in a rodent model of sepsis. Mean arterial pressure was restored by dexamethasone and L-canavanine administration at 24 h, no longer at 30 h. Dexamethasone but not L-canavanine improved aortic blood flow at 24 and 30 h. Although both dexamethasone and L-canavanine administration significantly reduced nitrite/nitrate production, and improved survival, steroids did better for survival. In conclusion, dexamethasone and L-canavanine displayed similar vasopressor effects. In addition, steroids improved blood flow suggesting that steroid-induced hemodynamic improvement in sepsis is not solely due to inhibition of inducible nitric oxide synthase.

Effects of epinephrine and norepinephrine on hemodynamics, oxidative metabolism, and organ energetics in endotoxemic rats.

OBJECTIVE: To determine whether epinephrine increases lactate concentration in sepsis through hypoxia or through a particular thermogenic or metabolic pathway. DESIGN: Prospective, controlled experimental study in rats. SETTING: Experimental laboratory in a university teaching hospital. INTERVENTIONS: Three groups of anesthetized, mechanically ventilated male Wistar rats received an intravenous infusion of 15 mg/kg Escherichia coli O127:B8 endotoxin. Rats were treated after 90 min by epinephrine ( n=14), norepinephrine ( n=14), or hydroxyethyl starch ( n=14). Three groups of six rats served as time-matched control groups and received saline, epinephrine, or norepinephrine from 90 to 180 degrees min. Mean arterial pressure, aortic, renal, mesenteric and femoral blood flow, arterial blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and 180 min after endotoxin challenge. At the end of experiments biopsy samples were taken from the liver, heart, muscle, kidney, and small intestine for tissue adenine nucleotide and lactate/pyruvate measurements. MEASUREMENTS AND RESULTS: Endotoxin induced a decrease in mean arterial pressure and in aortic, mesenteric, and renal blood flow. Plasmatic and tissue lactate increased with a high lactate/pyruvate (L/P) ratio. ATP decreased in liver, kidney, and heart. The ATP/ADP ratio did not change, and phosphocreatinine decreased in all organs. Epinephrine and norepinephrine increased mean arterial pressure to baseline values. Epinephrine increased aortic blood flow while renal blood low decreased with both drugs. Plasmatic lactate increased with a stable L/P ratio with epinephrine and did not change with norepinephrine compared to endotoxin values. Nevertheless epinephrine and norepinephrine when compared to endotoxin values did not change tissue L/P ratios or ATP concentration in muscle, heart, gut, or liver. In kidney both drugs decreased ATP concentration. CONCLUSIONS: Our data demonstrate in a rat model of endotoxemia that epinephrine-induced hyperlactatemia is not related to cellular hypoxia.

Hemodynamic effects of early versus late glucocorticosteroid administration in experimental septic shock.

Recent findings in human septic shock suggest that glucocorticosteroids can limit and even reverse hemodynamic disturbances and dependence on catecholamines. In a rodent model of hypotensive and hypokinetic septic shock, we investigated the effects of early or late dexamethasone administration on hemodynamics, response to catecholamines, and cardiac beta-adrenergic signalling. As compared with sham-operated rats, the untreated septic rats displayed significant arterial hypotension and reduced aortic blood flow. However, in vivo pressor response to epinephrine and phenylephrine was not different among sham and septic animals. Conversely, the chronotropic response to isoproterenol was significantly attenuated in septic animals. Steroid-treated septic animals displayed complete reversal of hypotension, improvement in aortic blood flow, and reduced plasma lactate and nitrite/nitrate concentrations as compared with untreated septic animals. The number of myocardial beta-adrenergic receptors and in vivo isoproterenol-stimulated myocardial cAMP content were similar in sham and septic animals. Glucocorticosteroids, although not changing these patterns, significantly decreased the receptors affinity when administered late, but not early. In this model of septic shock, hemodynamic abnormalities may not be related to adrenergic receptor desensitization. That steroids can improve them suggests that they could act mainly distal to adrenergic receptors, for instance, on myocardial and vascular smooth fiber contraction properties through mechanisms probably including inducible nitric oxide synthase inhibition.

Constitutive nitric oxide synthase inhibition combined with histamine and serotonin receptor blockade improves the initial ovalbumin-induced arterial hypotension but decreases the survival time in brown norway rats anaphylactic shock.

Anaphylactic shock accidents after allergen exposure are frequent. After immunization with ovalbumin (OVA), a common dietary constituent, we evaluated the efficacy of pretreatment with histamine-receptor or serotonin-receptor blockers administered alone or in combination with a nitric oxide synthase inhibitor (L-NAME) on OVA-induced anaphylactic shock in Brown Norway rats. Animals were allocated to the following groups (n = 6 each): control (0.9% saline); diphenydramine (15 mg kg(-1)); cimetidine (20 mg kg(-1)); diphenydramine + cimetidine; dihydroergotamine (50 microg kg(-1)); diphenydramine + cimetidine + dihydroergotamine; L-NAME (100 mg/kg) alone or associated with diphenydramine, cimetidine, diphenydramine + cimetidine, dihydroergotamine, or diphenydramine + cimetidine + dihydroergotamine. Mean arterial blood pressure (MABP), heart rate (HR), and survival time were monitored for 60 min following treatment. The shock was initiated with i.v. OVA. The MABP drop after i.v. OVA was worsened by diphenydramine and was modestly attenuated by cimetidine, dihydroergotamine, or both together. L-NAME potentiated slightly the effects of cimetidine and dihydroergotamine by lessening the initial MABP decrease, but this transient effect was not sufficient to prevent the final collapse or to improve survival time. Decreased vasodilatory (prostaglandins E2), increased vasoconstrictory (thromboxane B2) prostaglandins, and unchanged leukotriene C4 concentrations were contributory to the overall hemodynamic changes. Thus, the combined blockade of vasodilator mediators (histamine, serotonin, and nitric oxide) slowed the MABP drop in anaphylactic shock, but did not improve survival. More studies are needed to understand these discordant effects.

Effects of exercise-induced fatigue with and without hydration on static postural control in adult human subjects.

Postural instability can be the result of various factors, including fatigue. Although it is well known that exercise-induced fatigue may be responsible for a decrease in performance, its effects on postural control, as well as those of hydration, have been relatively little explored. This study evaluated the effects of fatigue, with and without rehydration, on postural control in 10 healthy subjects who regularly practice sports activities. All subjects were submitted to three types of ergocycle exercises: maximal oxygen uptake (Vo2max) and submaximal exercises in no-hydrated and hydrated conditions at a power corresponding to approximately 60% of the Vo2max of each subject. Static posturographic tests were performed immediately before (control) and after exercises. The postural control performance decreased from the best to the worst: control, hydration, dehydration, and Vo2max. Fast Fourier transformation of the center of foot pressure showed three patterns of amplitude spectral density, with an increase of spectral amplitude for dehydration, more important for Vo2max conditions. Spectral amplitudes for control and hydration conditions were relatively similar. This hierarchy suggests that fatigue mainly alters muscular effectors and sensory inputs, such as proprioception, resulting in poor postural regulation. Moreover, fluid ingestion could be responsible for the preservation of muscular functions and of sensory afferences accurately regulating postural control.