Absolute Glomerular Filtration Rate Research Articles

Role of the donor in post-transplant renal function.

The donor, i.e. adult or paediatric, might influence the outcome of the graft function. The glomerular filtration rate (GFR) of 120 transplanted children (47 girls) aged 10.4+/-4.6 years (0.7-17.2) was prospectively assessed over a 5-year period. The patients were divided into two groups according to the age of donor: adult (donor age > 18 years; n=33) and paediatric (donor age < 18 years; n=87). GFR was assessed by inulin clearance at 3, 6 and 12 months and yearly thereafter. The average GFR was stable in the range of 70 ml/min/1.73 m2 for the whole follow-up period. The adjusted GFR in adult graft recipients was significantly higher at 3 months post-transplantation: 80.6+/-36.9 vs 65.1+/-22.0, P=0.02. However, from the second year post-transplantation, the adjusted GFR in paediatric graft recipients became significantly higher than that of adult graft recipients. Such results could be due to an improvement in the absolute GFR (ml/min) of paediatric graft recipients with time (P=0.0001) whereas that of the adult graft recipients remained stable despite the children's growth. The adjusted GFR of adult graft recipients was significantly higher than that of paediatric graft recipients in the early post-transplant period. In the long-term, a progressive decrease in adjusted GFR was noted in adult graft recipients. On the one hand, this may be due to a functional adaptation and/or inadequate compensatory growth of the graft. On the other hand, the absolute GFR of paediatric graft recipients increased, suggesting an ongoing capacity for growth and/or compensatory hypertrophy after child-to-child renal transplantation.

Évolution de la fonction du greffon après transplantation rénale chez l'enfant

Since renal transplantation is known to be the best choice for the growing child with end-stage renal failure, we prospectively evaluated early and late graft function in transplanted children. The study included 78 children (32 girls, 46 boys) 10.4 +/- 0.6 years at the time of transplantation. Renal investigations were performed at 3, 6 and 12 months post-transplantation and yearly thereafter. Inulin clearance was used to evaluate the glomerular filtration rate (GFR), and the reabsorption rates of Na, P and Ca were measured concomitantly. The overall adjusted GFR was approximately 70 mL/min/1.73 m2 and remained unchanged during the first 5 years post-transplantation. In the mean time the absolute GFR increased significantly, suggesting a remaining capacity for compensatory hypertrophy of the transplanted kidney. Renal function was significantly influenced by the number of rejection episodes during the first 2 years post-transplantation but no correlation was found between GFR and the number of HLA mismatches or the use of preemptive transplantation.

Influence of donor and recipient ages and sex on graft function after pediatric renal transplantation.

Adult donor grafts adapt to the smaller size of the child recipient by reducing their absolute glomerular filtration rate (GFR) (ml/min). The question arises whether these grafts can increase the absolute GFR when the child recipient grows or whether a child donor graft can better increase its function. The aim of this study was to evaluate the influence of donor and recipient ages and sex on renal function. Eighty-five children and adolescents, aged 0.4-20.5 years at transplantation, were monitored annually, by GFR and effective renal plasma flow (ERPF), determined by clearances of inulin and para-aminohippuric acid. The patients received 90 grafts from donors aged 3-67 years. Follow-up time was around 5 years. Absolute GFR and ERPF (ml/min) of grafts from donors <20 years of age (all cadaveric donor grafts) increased during follow-up, resulting in a constant relative GFR and ERPF (ml/min/1.73 m2), whereas absolute GFR and ERPF of grafts from donors >20 years of age remained constant during follow-up, resulting in a significant decrease in relative values. Relative GFR and ERPF fell during follow-up in young recipients (<12 years of age), but remained constant in older recipients (>12 years). Donor and recipient sex did not influence renal function. Child donor grafts seem better able to increase their function with the growth of the child recipient than adult grafts. However, the limited access to pediatric grafts and the fact that pediatric cadaveric grafts might involve technical problems in connection with grafting restrict their use.

Age-dependent enzymuria, proteinuria and changes in renal blood flow and glomerular filtration rate in rats

The time course of urinary excretion of two enzymatic indicators of renal damage, N-acetyl-β-D-glucosaminidase (NAG) and alanine aminopeptidase (AAP) was measured in female Wistar rats at different ages. NAG and AAP are localized at different sites of the nephron and are released into the urine when kidney damage occurs. Total protein flow, urinary volume and creatinine flow were also determined. In a parallel experiment, the effect of aging on renal blood flow (RBF) and glomerular filtration rate (GFR) was examined in young (1.5-month) adult (3-month) and elderly (20-month) female rats. Clearance following a single injection of [ 131I] o-iodohippurate (hippuran, OIH) was used for the measurement of effective RBF and as an index of tubular cell function. [ 125I]Iothalamate (IOT) clearance was used to measure GFR. With advancing age, an increase in NAG and AAP urinary flow appeared. The increases in protein excretion were greater than and previous to those of enzyme excretion. It is shown that absolute RBF and GFR (ml/min) in old rats are greater than in young or adult animals. When absolute RBF or GFR was divided by kidney weight (ml/min/g) no clearance changes appeared in any age group studied; only when clearance was expressed in relation to body weight (ml/min/100 g), a decrease in RBF and GFR was evidenced. This indicates that the rate of increase of both RBF and GFR with age is similar to that of kidney weight and lower than that of body weight. The present findings indicate that urinary markers of renal injury increase with age, whereas GFR and RBF only decrease when expressed as clearance related to body weight.

STABILITY OF RENAL ALLOGRAFT GLOMERULAR FILTRATION RATE ASSOCIATED WITH LONG-TERM USE OF CYCLOSPORINE A

Renal allograft glomerular filtration rate (GFR) was measured at 4-month intervals for up to 1 year in 43 CsA-treated patients using x-ray fluorescence determination of plasma iohexol clearance. Study patients were divided into cohorts based on time (years) after transplantation at study entry (0-1; 1-2; 2-3; and > 3 years) and entry GFR levels (20-29; 30-39; 40-49; and > or = 50 ml/min/1.73 m2). GFR at study entry was 42 +/- 2 and was comparable in CAD (n = 31) versus LRD (n = 12) allografts (42 +/- 2 and 44 +/- 4 ml/min/1.73 m2, respectively). Range of entry GFR levels was similar in each of the "time at entry" cohorts defined above. Serum creatinine concentrations of 1.5-2.5 mg% were associated with GFR levels of 20-60 ml/min/1.73 m2. Serial GFR levels obtained at 4-month intervals for 1 year (n = 34 patients) were not consistent with a pattern of progressively declining GFR occurring as a function of either time after transplantation or absolute GFR level at study entry (intraindividual coefficient of variation 10.3 +/- 1.0%). Patients in the lower quartile of "entry GFR" levels (< 34 ml/min/1.73 m2) were more likely than their counterparts to have had a history of acute rejection. Results are consistent with retrospective population studies of aggregate serum creatinine levels, indicating that long-term CsA use is not uniformly associated with accelerated loss of renal allograft function consequent to a progressive, toxic nephropathy. The data also suggest that neither absolute GFR level nor time after transplantation represent indications for routine dose reduction or conversion to AZA.

Serial measurements of GFR in infants using the continuous iothalamate infusion technique

We undertook a preliminary study to determine if a clinical trial was feasible that would compare the effect of a low protein vs a control formula on GFR and growth in infants with congenital renal insufficiency (CIo < 55 ml/min/1.73 m2). In this report from the Infant Diet Protein Study, we describe validation of a method using the plasma clearance of iothalamate (CIo) as an estimate of glomerular filtration rate (GFR) and results of the preliminary study relating to renal function. The plasma CIo method was validated as an accurate estimate of GFR by showing it to be the same as the plasma clearance of inulin (CIn). In the preliminary study infants who qualified for the study were randomly assigned to a low protein or control formula and were followed from 8 to 18 months of age. CIo was measured at 8, 14 and 18 months of age in 21 of the infants and at 8 and 18 months of age in all twenty four infants that entered the study. Average absolute GFR in the 24 infants increased in the 10 month period from 5.3 +/- 2.7 to 7.6 +/- 4.5 ml/min. The percent increase in GFR was no different in infants whose GFR at 8 months of age was severely reduced from those whose GFR was only moderately reduced. When adjusted for age and body size, GFR did not change. Change in mean CIo or serum creatinine (SCr) from 8 to 18 months of age between the infants in each diet groups was not different. We conclude that a clinical trial enrolling more infants and extending the study period is necessary to evaluate dietary protein effect.

Renal function following kidney transplantation in children treated with cyclosporine.

The study was performed to evaluate the long-term renal function of children treated with cyclosporine after kidney transplantation. Renal function was determined with clearances of inulin and aminohippurate sodium for evaluating glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Thirty-six children aged 0.4-16.2 (median 6.9) years at transplantation were examined within 5 months of transplantation and then yearly over 0.3-7.1 years. Twenty-five children and young adults, 1.5-20 (median 7.7) years of age, with solitary kidneys because of renal agenesis or nephrectomy, served as controls. The GFR and ERPF within 1 year of transplantation were significantly lower than those of controls (65 +/- 19 and 345 +/- 88 vs 96 +/- 12 and 474 +/- 91 ml/min per 1.73 m2, respectively). GFR remained constant 4 years after transplantation, but ERPF decreased significantly. Significant inverse correlations were found between GFR within 5 months of transplantation and the mean cyclosporine concentration and the number of rejection episodes. The frequency of hypertension decreased from 82% within 5 months of transplantation to 0% after 4 years. The absolute GFR increased during follow-up. In conclusion, kidney transplantation results in a reduced renal function compared with that of solitary native kidneys. The reduction in renal function correlated with the number of rejection episodes and the cyclosporine load. The increase in absolute GFR during follow-up suggests a remaining capacity for growth and/or compensatory hypertrophy.

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.

Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma

The pharmacokinetics of carboplatin and etoposide were studied in four testicular teratoma patients receiving four courses each of combination chemotherapy consisting of etoposide (120 mg/m2 daily x 3); bleomycin (30 mg weekly) and carboplatin. The carboplatin dose was calculated so as to achieve a constant area under the plasma concentration vs time curve (AUC) of 4.5 mg carboplatin/ml x min by using the formula: dose = 4.5 x (GFR + 25), where GFR is the absolute glomerular filtration rate measured by 51Cr-EDTA clearance. Carboplatin was given on either day 1 or day 2 of each course and pharmacokinetic studies were carried out in each patient on two courses. Etoposide pharmacokinetics were also studied on two separate courses in each patient on the day on which carboplatin was given and on a day when etoposide was given alone. The pharmacokinetics of carboplatin were the same on both the first and second courses, on which studies were carried out with overall mean +/- SD values (n = 8) of 4.8 +/- 0.6 mg/ml x min, 94 +/- 21 min, 129 +/- 21 min, 20.1 +/- 5.41, 155 +/- 33 ml/min and 102 +/- 24 ml/min for the AUC, beta-phase half-life (t 1/2 beta), mean residence time (MRT), volume of distribution (Vd) and total body (TCLR) and renal clearances (RCLR), respectively. The renal clearance of carboplatin was not significantly different from the GFR (132 +/- 32 ml/min). Etoposide pharmacokinetics were also the same on the two courses studied, with overall mean values +/- SD (n = 8) of: AUC = 5.1 +/- 0.9 mg/ml x min, t 1/2 alpha = 40 +/- 9 min, t 1/2 beta = 257 +/- 21 min, MRT = 292 +/- 25 min, Vd = 13.3 +/- 1.31, TCLR = 46 +/- 9 ml/min and RCLR = 17.6 +/- 6.3 ml/min when the drug was given alone and AUC = 5.3 +/- 0.6 mg/ml x min, t 1/2 alpha = 34 +/- 6 min, t 1/2 beta = 242 +/- 25 min, MRT = 292 +/- 25 min, Vd = 12.5 +/- 1.81, TCLR = 43 +/- 6 ml/min and RCLR = 13.4 +/- 3.5 ml/min when it was given in combination with carboplatin. Thus, the equation used to determine the carboplatin accurately predicted the AUC observed and the pharmacokinetics of etoposide were not altered by concurrent carboplatin administration. The therapeutic efficacy and toxicity of the carboplatin-etoposide-bleomycin combination will be compared to those of cisplatin, etoposide and bleomycin in a randomised trial.

The control of glomerular filtration rate and renal blood flow in chronically volume-expanded rats.

1. Chronic volume expansion by dietary salt loading practically abolishes tubuloglomerular feed-back (TGF) by means of a humoral inhibitor in tubular fluid. Elimination of the vasoconstrictor influence of feed-back does not, however, increase glomerular filtration rate (GFR) and renal blood flow (RBF), implying that chronic salt loading induces additional preglomerular vasoconstriction. This being so, the feed-back response which, although absent in free-flowing nephrons, can still be elicited by loop of Henle perfusion with Ringer solution, should be essentially normal, except that nephron GFR at any loop perfusion rate should be lower than in controls. Persistence of RBF, GFR and nephron GFR autoregulation would imply that autoregulation is achieved by a preglomerular resistance control system independent of feed-back. 2. These hypotheses were tested by clearance and micropuncture experiments in rats chronically fed a diet containing 40 g NaCl (kg food)-1. 3. RBF and GFR autoregulation indeed persisted, the former down to 90 mmHg compared with 105 mmHg in controls. In controls, nephron GFR measured distally was autoregulated down to 90 mmHg whereas that measured proximally was autoregulated only above 105 mmHg. In high-salt rats nephron GFR from both sites was autoregulated to 90 mmHg. 4. Loop of Henle perfusion with homologous tubular fluid in high-salt rats confirmed attenuation of feed-back. Loop perfusion with Ringer solution yielded a response comparable to that in controls (maximal reduction of nephron GFR to 57%, compared with 56% in controls). Absolute nephron GFR at any loop perfusion rate was lower in high-salt rats than in controls. 5. These observations confirm the initial hypotheses. Considering feed-back and autoregulation as independent, preglomerular resistance control mechanisms, together with elementary haemodynamic considerations, allows formulation of a renal haemodynamics model whose quantitative predictions regarding characteristics of RBF, GFR and feed-back control are remarkably consistent with the literature.

Postnatal development of renal function during the first year of life.

Several aspects of renal function vary considerably during the 1st year of life and differ markedly from the equivalent values in the adult. Glomerular filtration rate (GFR) increases little, prior to the time an infant reaches a conceptional age of 34 weeks, the point in renal development from which the absolute GFR (ml/min) increases gradually to mature values when linear growth is completed during adolescence. GFR corrected for body size is not comparable with adult normal values until after 12 months of age; therefore, whether GFR is estimated from Scr or measured by timed urine collection, there is no easily recalled range of normal values for infants. One must know the changes in the renal function of normal infants that take place following birth during the 1st year of life. Despite several attempts to do so, renal function during the 1st year of life cannot be assessed from urine flow rate. A urine flow rate of less than 1 ml/kg per hour may be normal and appropriate and may not be harmful either to preterm or full-term infants with normal GFR. Impaired concentrating ability of the neonatal kidney is probably of no clinical significance in all but the most extreme circumstances and is not a major factor in an infant becoming dehydrated, developing hypernatremia or being at greater risk of acute renal injury. Acid-base status in infants must be interpreted appropriately to know when alkali therapy should be introduced to avoid growth failure secondary to true metabolic acidosis. When plasma renin activity is measured in the infant with renal failure of hypertension, one must compare the result with the normal range of values related to postnatal age of normal infants.

A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: Noninvasive assessment of body composition and growth

The management of the preterm infant often requires rapid assessment of glomerular filtration rate (GFR). We sought to develop a screening test using GFR = kL/Pcr, where GFR is expressed as ml/min/1.73 m2, L is body length in centimeters, Pcr is plasma creatinine concentration, and k is a constant that depends on muscle mass. The value for k in 118 appropriate for gestational age preterm infants (0.34 +/- 0.01 SE) was significantly less than that of full-term infants (0.43 +/- 0.02, P less than 0.001). There was no difference between 12- to 24-hour single-injection inulin clearance and either 0.33 L/Pcr or creatinine clearance in preterm infants. We compared the body habitus of preterm and full-term infants using the assessment of muscle mass from urinary creatinine excretion (UcrV) and from upper arm muscle area (AMA) and volume (AMV), and that of fatness from the sum of five skinfold thickness measurements. During the first year of life, premature infants were found to have a lower percentage of muscle mass than term infants did. On the other hand, they took on a relatively greater amount of subcutaneous fat. There was a very good correlation between AMA or AMV and urinary creatinine excretion (r = 0.91 and 0.94, respectively) in 68 infants with heterogeneous body composition during the first year, indicating the validity of the urinary creatinine measurement. Absolute GFR (ml/min) was also well estimated from AMA or AMV factored by Pcr. We conclude that GFR can be well estimated from 0.33 L/Pcr in preterm infants. The lower value for k reflects the smaller percentage of muscle mass in preterm versus term infants. As a screening test, 1.5 X k or 0.05 L/Pcr predicted low values of GFR with an efficiency of 73%, specificity of 67%, and sensitivity of 88%.

Maturation of glomerular filtration in preterm and mature babies.

Glomerular filtration rate (GFR) was measured in 39 healthy infants (gestation 27-40 weeks, birthweight 0.68-3.71 kg) by prolonged inulin infusion between 2 and 63 days of age. Absolute GFR showed a logarithmic rise with conceptional age (gestational plus postnatal age) which was independent of postnatal age. GFR per kilogram showed a slow rise with gestational age, and a rapid rise with increasing postnatal age which was shown to be due to a temporary cessation of growth rather than a true acceleration in renal maturation. GFR per unit surface area showed similar, but steeper rises. Formulae were constructed to predict GFR in the first month of life from postnatal age (PA), weight and birthweight (BW); (GFR = (0.24 BW + 0.18 PA + 0.45) X weight), or from conceptional age (CA); (GFR = 100.0618 CA-1.859). 95% of the predictions fell within 66 and 151%, and 58 and 172% of the measured values, respectively. Data from 14 studies were expressed in the same format where possible. The agreement between the reported data and this study was close. Apparent contradictions between these studies had been largely due to their different forms of presentation.

Glomerular filtration rate in children: determination from the Tc-99m-DTPA renogram.

Analysis of the Tc-99m-DTPA renogram is usually limited to calculating the relative function of each kidney. To develop a method to determine the absolute glomerular filtration rate (GFR), various methods of analyzing the renogram were examined to determine which gave the best correlation with GFR. That regression could then be used to predict GFR without the need for blood samples. Fifty children were studied using Tc-99m-DTPA renograms and GFR measured simultaneously by plasma disappearance. The renogram variables were adjusted for detector sensitivity and for dose divided by weight, which was used as an index of plasma concentration. GFR correlated better with the slope of the second phase than with the area under the renogram curve. For the best correlation with GFR (using background subtraction and depth correction) r = .971 and the mean residual = 4.8 ml/min. For GFR normalized for body surface area (using background subtraction and no depth correction) r = .954 and the mean residual = 9.1 ml/min/1.73 m2. This method can accurately estimate GFR from the renogram in children.

The glomerular filtration rate of isogeneically transplanted rat kidneys

The glomerular filtration rate (GFR) was determined in rats with an isogeneic kidney transplant and compared with that of unilaterally nephrectomized rats. Experiments were carried out in adult rats, 3 months of age, weighing approximately 300 g, as well as in juvenile rats, 6 to 8 weeks of age, weighing approximately 170 g. All donor kidneys were taken from adult rats. The GFR was measured regularly, using a chromium 51-EDTA clearance technique which permitted repeated measurements to be taken in the same animals, during a 15-week followup period. After unilateral nephrectomy the GFR per 100 g body weight (BW) increased compared with that of a single normal kidney. Adult transplant recipients had a GFR per 100 g BW of about 80% of that of unilaterally nephrectomized rats. There was no statistical difference in the GFR when comparing adult recipients of either a normal or a hyperfunctional kidney. When isografts were transplanted to juvenile recipients, there was an initial decrease in the absolute GFR compared with the donor value in the case of a normal adult donor kidney. This decrease was even more pronounced when a hyperfunctioning kidney was transplanted to a juvenile recipient. However, when related to BW the GFR was, as in the adult recipients, about 80% of that of unilaterally nephrectomized juvenile rats. During the followup period the systolic blood pressure was measured regularly by tail plethysmography, in order to detect any blood pressure elevations, which are a frequent complication in adult and pediatric human renal transplantation. However, no hypertension was observed after isogeneic kidney transplantation in the various groups. These results show that the GFR of isogeneically transplanted rat kidneys amounts to about 80% of the maximally attainable level. Isogeneic transplantation of an adult kidney to a juvenile recipient results in a rapid adaptation of the GFR to the smaller size of the body and does not cause an increase in blood pressure.

Renal studies in the hypothyroid rat

Whole kidney clearance studies were performed on 27 hypothyroid rats (H) and 25 euthyroid littermate rats (C). Absolute glomerular filtration rate (GFR) was less in hypothyroid rats (1.02 versus 1.39 ml/min), but when factored by body surface area (BSA) the two groups were comparable ( GFR BSA = 2.26 versus 2.24 μl /min/sq/cm ). Absolute and fractional (per GFR) sodium clearance was greater in the hypothyroid animals ( C Na GFR:H = 0.36, C = 0.11, p < 0.001 ), but total electrolyte (Na + + K +) excretion and clearance were comparable. End proximal tubular fluid (TF) micropuncture collections in 20 animals revealed no change in fractional reabsorption ( TF P inulin) in hypothyroid rats ( TF P insulin, 2.5 versus 2.7), but showed a decrease in single nephron GFR (Vo, 17 versus 36 nl/min) and absolute reabsorption (11 versus 20 nl/min). Hypothyroidism is associated with a decrease of sodium reabsorption at nephron sites distal to the convoluted proximal tubule. With ad libitum electrolyte and water intake most rats can maintain themselves in volume-sodium balance, but an occasional animal may display this distal leak syndrome in the extreme. One such rat had a urinary sodium concentration U Na of 147 mEq/liter and a urinary flow rate of 56.0 μl/min (H = 3.33, C = 1.39). In addition, its hydropenic normal end proximal TF P inulin mean of 2.7 confirmed the inability of the proximal nephron to compensate for this late leak. This rat's plasma sodium was 128 mEq/liter (H = 147, C = 148), dilutional hyponatremia. These renal problems are similar to those reported in man and suggest that the rat is an appropriate model for the study of human hypothyroidism.