Defining hypercalciuria in nephrolithiasis

The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid.     

Reduced glomerular filtration rate can maintain a rise in plasma bicarbonate concentration in humans

In humans, deficiency of chloride and potassium were found to perpetuate the hyperbicarbonatemia that attends metabolic alkalosis induced by gastric aspiration partly by increasing renal bicarbonate reabsorption, commensurate with the attendant increase in filtered bicarbonate load, and partly by decreasing glomerular filtration rate (GFR), which minimizes the degree of which the filtered bicarbonate load increases and thereby minimizes the requisite increase in bicarbonate reabsorption. The relative contribution of stimulated renal bicarbonate reabsorption might increase, however, if the supply of extrarenal bicarbonate is increased, in which case a greater degree of hyperbicarbonatemia would be sustained. To investigate that possibility, we reexamined the mechanism of perpetuation of gastric alkalosis in normal subjects eating a low NaCl diet supplemented with bicarbonate salts. Prior to gastric aspiration, plasma bicarbonate concentration ([HCO3]p) and pH were higher than in similarly studied subjects not receiving bicarbonate: 29.9 +/- 0.6 vs. 25.3 +/- 0.1 and 7.43 +/- 0.008 vs. 7.41 +/- 0.002 mEq/l, respectively. With continued bicarbonate supplementation, gastric aspiration induced a further significant increase (p less than 0.05) in [HCO3]p of 10.8%, to values not significantly different from those in nonbicarbonate-loaded subjects with gastric alkalosis: 33.2 +/- 1.2 mEq/l. GFR decreased significantly by 8.4% (from 98 +/- 4 to 90 +/- 3 ml/min, p less than 0.025), offsetting nearly commensurately the increase in [HCO3]p so that total bicarbonate reabsorption was not significantly increased (2.90 +/- 0.12 vs. 2.97 +/- 0.19 mEq/min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Expressing glomerular filtration rate in children

We have reviewed the studies that provide the current standards of reference for glomerular filtration rate (GFR) in normal children from 14 days to 12 years of postnatal age. These standards currently are presented as ml/min per 1.73 m², i.e., adjusted to average adult body surface area. Children from birth to 1 year of age have adjusted values below the adult range, making comparisons of observed to reference values difficult. Currently, there is no accepted way of obtaining reference values that vary smoothly with age. An analysis of the absolute GFR values in normal children taken from published studies led to an equation that estimates average GFR in relation to weight and term-adjusted age from-2 months (7 months gestational age) to 12 years in children at least 14 days post delivery. When these data are transformed to percentage of normal (% nl) for age and weight (i.e., percentage of the estimated average), it is possible to describe approximate apparent lower limits of normal GFR as is now done for adults and older children. For children with loss of renal mass, GFR expressed as % nl for age and weight provides a convenient standardization which has several useful applications. First, results expressed as % nl for children of different ages, particularly under 1 year of age, can be combined with those of older children for summary purposes. Second, the course of GFR measured serially in children is more appropriately described using this method for expressing GFR. Reporting GFR in absolute values is also useful, particularly in patients whose body mass is significantly distorted or whose absolute GFR is low.     

Estimating absolute glomerular filtration rate in children

Normal values of glomerular filtration rate (GFR) in children are often expressed in a value adjusted to adult ideal body surface area. These values work well for many clinical situations, but in infants and children, especially those with atypical body mass, they may not accurately reflect renal function. Most body composition values in children are expressed in developmentally appropriate ranges. Absolute GFR (ml/min) also changes during childhood increasing rapidly in infancy and then gradually with age and body size. Previously, we developed a bedside equation for estimating GFR (ml/min) in children that accounted for changes with age and body size, and which correlated well with steady-state cold iothalamate GFR (ml/min) measurements: GFR (ml/min) = k_*sqrt[(age(months) + 6)*wt (kg)/serum Cr (mg/dl)], where k=0.95 for females and 1.05 for males. In the present study GFR (ml/min) measured by iothalamate infusion was compared by correlation analysis with estimates calculated from the above equation in 566 children. This equation provides clinicians with a simple bedside method to estimate absolute GFR (ml/min).     

Estimating and measuring glomerular filtration rate in children

PURPOSE OF REVIEW: Glomerular filtration rate is the best determinant of kidney function in children. A decline in glomerular filtration rate may be the only sign of renal disease. A knowledge of glomerular filtration rate allows the clinician to appropriately dose medications, administer fluids, and intervene early to prevent end-stage renal failure. The aim of this review is to discuss the current options for determining glomerular filtration rate in children and the latest advances in research on this topic. RECENT FINDINGS: Owing to the limited availability of inulin, the gold standard for measuring glomerular filtration rate, and the concern for using radioactivity, the plasma disappearance of iohexol has been utilized to measure glomerular filtration rate in children, and this represents a practical option for glomerular filtration rate determination in both clinical and research studies. By contrast, creatinine-based estimates of glomerular filtration rate (e.g. Schwartz formula) are more practical for bedside use. To improve their precision, recent formulas have incorporated the use of additional endogenous markers, such as cystatin C, albumin, and blood urea nitrogen. SUMMARY: Iohexol plasma clearances should be used to accurately measure glomerular filtration rate in children. New estimating equations with multiple endogenous markers are being developed for everyday clinical use. However, at present, there is no substitute for an accurate glomerular filtration rate determination, particularly in children with conditions affecting muscle mass or body habitus.     

Estimation of glomerular filtration rate in children

The aim of this study was to develop a method to predict the glomerular filtration rate (GFR) in children by using the population pharmacokinetic approach. This powerful approach is widely used for drug development in order to study relationships between patients' characteristics (demographic, morphological, biological covariates) and pharmacokinetic parameters. For the first time, (51)Cr-EDTA plasma concentrations from 64 children (development data set) were analyzed using the Non-linear Mixed Effects Model (NONMEM) program to determine the most appropriate equation to relate (51)Cr-EDTA clearance (as a measurement of GFR) and patient characteristics. The most predictive equation was based on body weight, square height, and plasma creatinine (PCr, determined by the Jaffé method). This equation was then validated using the data from a further 33 patients. This equation produced estimates of GFR that were less biased and more precise than those obtained using the widely used Schwartz formula. The coefficient of correlation between estimated and actual GFR was 0.83, and the 10th to 90th percentiles for percentage errors were -20% to +30%. Finally, analysis of the whole data set (97 patients) led to an equation (i.e., GFR (ml/min)=[56.7 x Body weight (kg)+0.142 x Length(2)(cm)]/PCr ( microM)) very similar to that obtained from the development data set. This equation would be useful for estimating GFR in children when isotopic determination of the (51)Cr-EDTA clearance cannot be performed.     

Estimated glomerular filtration rate and renal function

Glomerular filtration rate (GFR) is an important clinical indicator of kidney function. It can be used as an independent predictor of long-term survival after cardiac surgery. Definition, methods of measurement, and corrected value by body surface area are briefly introduced in this paper. Details of the calculation of estimated GFR (eGFR) by Levey's formula with serum creatinine, age, gender, and race are offered. The relationship between estimated GFR and the four factors is shown graphically and discussed. An eGFR/creatinine conversion table for individual patients derived from the eGFR equation with clinically significant cutpoints is given, which can be used by physicians as a pragmatic reference.     

Glucocorticoids and control of glomerular filtration rate

Glucocorticoids given acutely or chronically at physiological/pharmacological doses increase GFR in both experimental animals and humans. Glomerular micropuncture studies have shown that in the normal rat kidney, glucocorticoids vasodilate both the preglomerular and efferent resistances and result in an increase in glomerular plasma flow, which is the sole factor responsible for the increase in GFR. However, the mechanism(s) initiating these alterations in the glomerular microcirculation remain obscure. The glucocorticoid-induced increase in GFR does not appear to be due to volume expansion or alteration in tubulo-glomerular feedback activity. Chronic glucocorticoid administration has been shown to increase renal prostaglandin synthesis in some but not all species; however, a link between increased prostaglandin production and glucocorticoid-induced increase in GFR has not been established. A number of studies have examined glucocorticoid-induced alterations in renal vascular reactivity to vasoconstrictor agonists and the data have been conflicting. The suggestion that glucocorticoid-stimulated ANP production evokes the increase in GFR is unlikely to be correct based on substantial differences in the glomerular hemodynamic changes seen with ANP or glucocorticoids. An interesting proposal that appears well worth exploring is that glucocorticoids may increase GFR through their effects on catabolism of proteins to increase production of amino acids. Amino acid infusion markedly elevates GFR and has a similar glomerular hemodynamic profile as that of glucocorticoids. By virtue of their action to increase GFR, glucocorticoids increase the rate of electrolyte and water delivery into the nephron. Therefore, glucocorticoid-induced alterations in electrolyte and water excretion may be secondary to an elevation in GFR, in addition to direct actions of glucocorticoids on the tubule. Also, by determining the hemodynamic state of the kidney, and hence, rate of fluid delivery through the nephron, glucocorticoids may influence the sensitivity of the nephron to regulatory influences. Glucocorticoids have their most profound effect (especially clinically) by modifying the immunological or cellular mechanisms responsible for glomerular injury. Less important is their ability to increase GFR. In view of some evidence that suggests increasing glomerular pressure accelerates the progression of established renal disease, some might speculate that glucocorticoids actually increase glomerular damage under certain conditions.     

Slope‐only glomerular filtration rate and single‐sample glomerular filtration rate as measurements of the ratio of glomerular filtration rate to extracellular fluid volume

Aims: The Jacobsson single‐sample equation for measuring glomerular filtration rate (GFR) after bolus injection is based on two factors of questionable theoretical validity for correcting the single‐compartment assumption. The aims were to redevelop a more transparent equation, show its fundamental similarity with ‘slope‐only’ GFR and compare it with the original equation and with slope‐only GFR. Methodology: The modified Jacobsson equation is k = (1/t).ln[V(t)/V(0)], where k is the rate constant of the terminal exponential and V(0) and V(t) are distribution volumes at times 0 and t. V(0) exceeds extracellular fluid volume (ECV): that is k′ = (1/t).ln[V(t)/ECV], where k′ > k. Moreover, [GFR/ECV] >k (= k + [15.4.k²]). The ratio k/k′ was determined in 476 patients to calculate single‐sample k (3 or 4 h post‐injection). Slope‐only and single‐sample GFR/ECV were measured using Cr‐51‐EDTA in 105 further studies, multiplied by ECV (estimated from weight), scaled to 1.73 m² and compared with GFR/1.73 m² from the original Jacobsson equation against reference multi‐sample GFR/1.73 m² simultaneously and independently measured with iohexol. Results: The relation between k and k′ was linear. k/k′ was 0.827 at 3 h and 0.864 at 4 h. There was no difference in bias or precision between the original Jacobsson and modified equations. In both, precision was better than slope‐only GFR/BSA. When GFR remained scaled to ECV, slope‐only GFR showed marginally better precision against reference GFR/ECV. Conclusions: Single‐sample and slope‐only techniques give GFR as k. Although the theory of the modified Jacobsson equation is more transparent than the original equation, it gives the same result. It is, however, easier to use.     

Cystatin C and acute changes in glomerular filtration rate

The identification of an effective marker of acutely changing kidney function is a priority in clinical nephrology. While serum creatinine is the most widely used surrogate for glomerular filtration rate (GFR), its vulnerability to non-glomerular clearance results in biased estimates of GFR and may delay the identification of acute changes. Alternatively, cystatin C (CysC) has been recognized as a promising marker of GFR. Controlled physiological studies in diabetes, protein-induced glomerular hyperfiltration and extreme exercise demonstrated that acute changes in CysC provide a better approximation of GFR than serum creatinine. Clinical studies examining contrast induced nephropathy, acute kidney injury, and kidney transplantation have also demonstrated several possible advantages of CysC with respect to accurately measuring GFR and early diagnosis of renal dysfunction. CysC measurements also provide ancillary benefits such as improved prediction of patient outcomes and prognosis. Our aim was to review the literature on short-term changes in CysC over days, weeks and months to explore the clinical utility of CysC in the acute setting. Based on existing evidence, CysC may improve clinicians' ability to detect acute changes in kidney function.