Assessment and interpretation of the tubular threshold for phosphate in infants and children

Studies in the last decade demonstrated that in children tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) is identical to TP/GFR; TP indicating tubular phosphate reabsorption under basal conditions, without phosphate load. TP/GFR is calculated from the formula TP/GFR=S_P–U_P×S_CrU_Cr, based on simultaneous urine and blood creatinine and phosphate concentrations, and is applicable in both the fasting and non-fasting child. These studies also demonstrated that the use of Walton and Bijvoet nomogram in children may result in overestimation of TmP/GFR compared with TP/GFR calculated from the above formula. When using the formula, one should bear in mind that creatinine is used to express GFR and as a result a significant deviation from true GFR may occur in patients with renal failure. Therefore when employing TP/GFR for the investigation of the renal handling of phosphate in children, three factors should be taken into consideration: (1) the formula in reality expresses TP/C _Cr; (2) only data obtained by exactly the same methodology can be used as reference values; data obtained from studies in which the nomogram was utilized or in which methods other thanC _Cr were used to measure GFR should not be used for reference; (3) in patients with renal failure, TP/C _Cr will significantly overestimate TP/C _inulin.     

Beneficial effect of thyroxin in the treatment of ischemic acute renal failure

To evaluate the effect of thyroxin (T₄) on recovery from ischemic acute renal failure, rats were treated with T₄ (10 or 20 g/100 g body wt.) or normal saline (NS) either immediately prior to, immediately after or 24 h after 45 min of renal ischemia. Animals given T₄ prior to ischemia had no significant increase in Inulin clearance (C_in) (377±40 l/min per 100 g body wt.) as compared with saline-treated ischemic controls (306±54). In contrast, animals treated immediately after ischemia with either dose of T₄ demonstrated significantly better kidney function (C_in 515±59 l/min per 100 g body wt., U_osm 842±88 mosmol/kg, FE_Na 0.52%±0.12% and C_in 543±71, U_osm 939±103, FE_Na 0.48±0.12, for 10 and 20 g/100 g body wt., respectively). Moreover, the improvement in renal function was sustained and C_in was significantly better at day 3 (748±70) and day 7 (990±75) compared with saline controls (560±30 and 732±45, respectively). Animals which received T₄ 24 h after ischemia showed significantly higher C_in when compared with ischemic controls. To assess the impact of T₄ on recovery of renal ATP,³¹P-NMR was used. T₄-treated rats demonstrated 90%±5% recovery of renal ATP by 120 min of reflow, whereas NS animals had only 64%±1%. In addition, cellular morphology was better preserved in T₄ animals. These data indicate that animals treated postischemically with T₄ showed accelerated and sustained recovery from acute renal failure. This beneficial effect appears to be related to cellular mechanisms which are essential for the restoration of sublethally injured cells.     

Developmental changes in the renal capacity for sulfate reabsorption in the guinea pig

During growth, immature guinea pigs maintain a positive inorganic sulfate balance. In the present study, renal clearance techniques were used to determine the maximum renal capacity for sulfate reabsorption [T_mR_si/glomerular filtration rate (GFR)] in three groups of guinea pigs at different stages of development (10–34 days, 35–80 days and >120 days of age). These ages are comparable to infant, adolescent, and adult guinea pigs. The guinea pigs were weaned at 10 days and then maintained on normal guinea pig chow (0.13% sulfate). The T_mR_si/GFR was determined by infusions of increasing concentrations of sulfate (0–16.8 mol/min). T_mR_si/GFR was significantly greater in young (infant and adolescent) than in older (adult) guinea pigs (2.20±0.26mol/ml and 1.80±0.27 mol/ml vs 0.942±0.08 mol/ml,P<0.05). These results demonstrate that the tubular capacity for inorganic sulfate reabsorption per milliliter of glomerular filtrate is enhanced in immature guinea pigs and decreases with age.     

Renal functional reserve in children with reduced renal mass: study by two dietary periods

It has been suggested that the renal functional reserve (RFR) defined by the rise in glomerular filtration rate (GFR) after a protein load could disappear in patients with severe nephron loss but with a normal GFR. This study compared, in 17 children, inulin clearance (C _in) measured by the plasma inulin plateau at the end of two 14-day randomized periods differing in protein intake: 100% (low protein, LP), or 200% (high protein, HP) of recommended dictary allowances (RDA). Diets were aimed at maintaining food habits and energy intake. Compliance was assessed by records of the last 3–4 days, an interview with the dietician and by urinary nitrogen measurements. Mean actual protein intake was 109% (56%–139%) RDA for the LP period and 220% (163%–319%) RDA for the HP period.C _in did not change in 14 children with GFR below (n=7) or within (n=7) the normal range.C _in was higher in the HP period than in the LP period (+32, 50, 63%) in 3 children who had a 50% (single kidneys) or a 25% (sclerosed glomeruli) nephron loss. Non-responding children had a GFR below 105 ml/min per 1.73 m². Nephron loss (70% sclerosed glomeruli) was estimated in only 1 child with no RFR. The results suggest that GFR measurement after prolonged dietary stimulation could help in evaluating the severity of nephron loss in children with normal or borderline GFR. The prognostic value of this test has to be confirmed by long-term follow-up.     

Direct measurement of TP/GFR: a simple and reliable parameter of renal phosphate handling

As the Walton-Bijvoet nomogram for estimating renal phosphate (P) threshold (TmP/GFR) is not applicable to children of all ages, we sought an alternative method for measuring renal handling of P. Recognizing that the nomogram represents an indirect correlation between TmP/GFR and TP/GFR under fasting conditions, we examined this directly in 26 children. An excellent correlation was found, expressed as TmP/GFR = (fasting TP/GFR X 1.1) -0.3 (r = 0.95). The regression line in adults, expressed as TmP/GFR = (fasting TP/GFR X 1.4) -0.9 (calculated from published studies) is markedly different at the higher values typical for children. Since no advantage could be seen in the use of a mathematically derived TmP, we investigated the direct use of measured TP/GFR (tubular P reabsorption per 100 ml glomerular filtrate) as a measure of renal P handling in clinical practice. No differences were found between morning fasting and nonfasting values. Measurements in 151 healthy subjects aged 3 days to 53 years established normal values in relation to age. The use of this parameter in patients is shown to accurately reflect defects and changes in renal P handling. We believe it to be the preferred parameter because it represents a directly measured physiologic function applicable to all age-groups.     

Renal adaptation to phosphate deprivation: lessons from the X-linkedHyp mouse

The X-linkedHyp mutation, a murine homologue of X-linked hypophosphatemia in humans, is characterized by renal defects in phosphate reabsorption and vitamin D metabolism. In addition, the renal adaptive response to phosphate deprivation in mutantHyp mice differs from that of normal littermates. WhileHyp mice fed a low phosphate diet retain the capacity to exhibit a significant increase in renal brush-border membrane sodiumphosphate cotransport in vitro, the mutants fail to show an adaptive increase in maximal tubular reabsorption of phosphate per volume of glomerular filtrate (TmP/GFR) in vivo. Moreover, unlike their normal counterparts,Hyp mice respond to phosphate restriction with a fall in the serum concentration of 1,25-dihydroxyvitamin D [1,25(OH)₂D] that can be ascribed to increased renal 1,25(OH)₂D catabolism. The dissociation between the adaptive brush-border membrane phosphate transport response and the TmP/GFR and vitamin D responses observed inHyp mice is also apparent in X-linkedGy mice and hypophysectomized rats. Based on these findings and the notion that transport across the brush-border membrane reflects proximal tubular function, we suggest that the adaptive TmP/GFR response requires the participation of 1,25(OH)₂D or a related metabolite and that a more distal segment of the nephron is the likely target for the 1,25(OH)₂D-dependent increase in overall tubular phosphate conservation.     

Clinical Evaluation of Segmental Tubular Reabsorption of Sodium and Fluid in Man: Lithium vs Free Water Clearances

Segmental sodium reabsorption in the proximal and distal tubulewas evaluated by different methods in seven healthy subjects,seven patients with recurrent calcium nephrolithiasis, fivepatients with isolated renal glucosuria and three patients withFanconi syndrome. In all the subjects, the delivery of fluidfrom the proximal tubule, evaluated as ‘chloride’factor during maximal water diuresis (DD_Cl, 12.4±5.5ml/dl GFR), was lower (P<0.001) than ‘volume’or ‘chloride’ factors during maximal water diuresisplus frusemide administration (40 mg i.v.) (V_f, 22.5±7.5and DD_Clf, 27.1±8.9 ml/dl GFR, respectively), and oflithium clearance (FE_Li, 28.1±12.6%). V_f was lower thanDD_Clf (P<0.001) and FE_Li (P<0.005), while DD_Clf and FE_Lidid not differ; these unequal results are likely to representdifferent degrees of free water back-diffusion along distaltubule segments in the free water clearance studies. Accordingly, estimation of sodium reabsorption in the distaltubule showed corresponding differences within the four methodsas those observed for the distal delivery: it was 25.5±12.2%when evaluated as [FE_Li–FE_Cl]; 24.8±8.3 ml/dl GFRwhen evaluated as [C_H2Of/GFR+FE_Cl] (i.e. free water clearanceduring frusemide plus the frusemide-induced absolute increasein FE_Cl); 19.5±6.7 ml/dl GFR (P<0.001 vs [FE_Li–FE_Cl]and [C_H2Of/GFR+FE_Cl] when evaluated as [(C_H2O+C_H2OBD)/GFR] (i.e.C_H2O before frusemide plus the frusemide-induced absolute increasein urine flow rate); and 10.0±4.8 ml/dl GFR when evaluatedas C_H2O (P<0.001 vs all the other evaluations). FE_Li showed a mean 40% increase after frusemide administration;the percentage increase correlated significantly with the percentageincrease of chloride excretion (r=0.83; P<0.001), but notof phosphate excretion. These results would suggest that eitherfrusemide substantially increases distal delivery (so that freewater clearance studies should not be taken as a good indexof proximal tubule sodium reabsorption), or that lithium itselfmight undergo reabsorption in post-proximal sites (so that evenlithium might not be a specific proximal tubule marker in humans).     

Creatinine for estimation of glomerular filtration rate

The aim of this study was to evaluate the plasma creatinine concentration (P_Cr) and creatinine clearance (C _Cr) for estimation of glomerular filtration rate (GFR). Inulin clearance (C _in) was used as the reference standard for GFR. Thirty-nine concurrentC _in andC _Cr studies provided data for comparingC _in with the measuredC _Cr and with the calculatedC _Cr (calc-C _Cr). (Calc-C _Cr=k·L/P_Cr, where L=height in centimeters and k is the proportionality constant.) Thirty-one children 5.3–20.8 years of age, withC _in ranging from 2.8 to 138.8 ml/min per 1.73 m², participated in these studies at The Children's Mercy Hosptial. The measuredC _Cr was 16.7±10.3 ml/min per 1.73 m² (P<0.001) greater than theC _in, and the calc-C _Cr overestimatedC _in by a mean of 31.6±20.8 ml/min per 1.73 m² (P<0.001). Although there is good correlation betweenC _in andC _Cr (r=0.96), andC _in and calc-C _Cr (r=0.90), the 95% confidence intervals are quite broad. Hence, theC _Cr and the calc-C _Cr, derived using Schwartz values for k, consistently overestimate GFR. However, if the k value in the equation GFR=k·L/P_Cr is derived from k=C _in/L, rather than from k=C _Cr·P_Cr/L, a more accurate estimate of GFR may be obtained.     

Evaluation of bone resorption and renal tubular reabsorption of calcium and phosphate in malignant and nonmalignant hypercalcemia

Tubular reabsorption of calcium (Ca) is becoming recognized as a determinant of malignant hypercalcemia. However, its importance as compared to increased bone resorption has not yet been widely investigated. We determined Ca fluxes of bone resorption and tubular reabsorption in 141 rehydrated patients with hypercalcemia of malignant or benign origin, before any specific treatment. Bone resorption (BRI) was evaluated by fasting urinary Ca excretion and Ca tubular reabsorption using an index (TRCaI) calculated from a nomogram relating fasting urinary Ca excretion and calcemia. The relationship between alterations in TRCaI and in the tubular capacity to reabsorb inorganic phosphate (Pi), as judged by TmPi/GFR, was also examined for each cause of hypercalcemia. Among 101 cases with malignancy, 67% had overt bone metastases, but all displayed increased BRI. Calcemia was highest in breast cancer and lowest in prostate carcinoma. BRI was markedly increased in breast cancer, lymphoma, and multiple myeloma, whereas it was slightly elevated in lung squamous cell, renal, and liver carcinomas. TRCaI was increased in 49% of malignant hypercalcemia, particularly in epidermoid (above the upper normal limit in 71% of the cases), renal, and liver carcinomas. It was elevated in 54% of breast cancer and normal in multiple myeloma and prostate cancer. In nonmalignant hypercalcemia, BRI was markedly increased in vitamin D intoxication, sarcoidosis, and immobilization. In primary hyperparathyroidism (PHP), BRI was moderately increased. TRCaI was abnormally elevated in PHP, but normal in vitamin D intoxication, sarcoidosis, and immobilization. In malignant hypercalcemia, TmPi/GFR was low in 77% of patients and in all types of tumors, except in prostate carcinoma. The index ratio [TRCaI/(TmPi/GFR)] gave a better discrimination of PHP from other causes of nonmalignant hypercalcemia than the use of either TRCaI or TmPi/GFR taken alone. Thus, in malignant hypercalcemia, increased bone resorption is associated with an elevation in tubular Ca reabsorption in half the patients surveyed, whereas low tubular Pi reabsorption is observed in more than 75%. Increased TRCaI is restricted to some types of tumor, whereas decreased TmPi/GFR is observed in all types except prostate carcinoma. In nonmalignant hypercalcemia, a significant increase in mean TRCaI was only observed in PHP, of which individual cases can be fully discriminated from other conditions by using a new index taking into account alteration in the renal transport capacity of both Ca and Pi.     

Glomerular filtration rate assessment in individuals after orthotopic liver transplantation based on serum cystatin C levels

Individuals after orthotopic liver transplantation (OLT) often show renal dysfunction, which may substantially affect the post-OLT course. Renal function after OLT is commonly assessed by means of serum creatinine (S_cr) concentration or renal creatinine clearance (C_cr). A glomerular filtration rate (GFR) estimate based on S_cr level is not accurate enough because even a more marked decrease in GFR need not be associated with an increase in S_cr level, especially in jaundiced patients. The study intends to try to estimate GFR in individuals after OLT by means of determining serum cystatin C (S_cyst) concentrations. In 58 individuals (mean age, 49 ± 7 years; 31 men, 27 women) at various intervals from OLT (mean, 14 ± 10 months), GFR was estimated by using simultaneous determinations of S_cyst, S_cr, C_cr, and renal inulin clearance (C_in). In most subjects (91.3%), C_in was decreased to less than the lower limit of normal (80 mL/min/1.73 m²). A significant correlation (r = 0.70; P < .001) was found between 1/S_cyst and C_in. Receiver operating characteristic analysis was performed on S_cyst and S_cr using a C_in cutoff value of 80 mL/min/1.73 m². The area under the curve for S_cyst was 0.912 ± 0.044, and that for S_cr, 0.899 ± 0.049. There was no statistically significant difference between these values. The sensitivity for a S_cyst level of 1.20 mg/L (upper limit of normal value) to detect a decrease in GFR (measured as C_in) below the lower limit of normal (80 mL/min/1.73 m²) was 96.1%. The sensitivity of S_cyst level was significantly greater (P < .01) than the sensitivity of S_cr level for men and at borderline significance for women (P = .05). Findings support the assumption that a S_cyst level less than 1.2 mg/L indicates with a high degree of probability (P < .001) that GFR is not decreased to less than the normal limit. S_cyst assessment in individuals after OLT could be proposed as a confirmatory test of a decrease in GFR in individuals with normal S_cr levels. (Liver Transpl 2002;8:594-599.)     

The effect of 1α-hydroxyvitamin D3 on renal function in normal subjects

The effects of short-term administration of 1 μg daily of 1α-hydroxyvitamin D₃ (1αOHD₃) on plasma biochemistry and renal function have been studied in six normal subjects using the ⁵¹Cr-labelled edetic acid (⁵¹Cr-EDTA) infusion method to measure glomerular filtration rate. 1αOHD₃ was administered for two weeks, subjects being studied before treatment, at the end of the first and second weeks of treatment and one week after stopping treatment.Mean plasma creatinine concentration rose throughout the four weeks of the study, but this change was not statistically significant. Plasma creatinine levels in fact decreased in two subjects after 1αOHD₃ administration. There was no significant change in glomerular filtration rate as measured by the ⁵¹Cr-EDTA infusion method or in endogenous creatinine clearance. Plasma phosphate levels increased in all subjects during 1α0HD₃ administration and the maximum tubular reabsorption capacity for phosphate relative to the glomerular filtration rate (Tm_po4/GFR) increased in five. There were no significant changes in plasma calcium or immunoreactive parathyroid hormone levels.It is concluded that short-term administration of 1αOHD₃, 1 μg daily, has no direct adverse effect on glomerular filtration rate in subjects with normal renal function.     

Acute obstructive jaundice and chronic cirrhosis protect against the adverse renal effects of pneumoperitoneum: role of nitric oxide

Background

Obstructive jaundice and cirrhosis are associated with impaired renal function. Previously we demonstrated that increased intra-abdominal pressure (IAP, pneumoperitoneum) in normal rats induced renal dysfunction. This study investigated the renal effects of pneumoperitoneum in rats with acute jaundice and cirrhotic rats.

Methods

Following a baseline period, rats with obstructive jaundice or cirrhosis induced by acute or chronic bile duct ligation (BDL), respectively, and their sham-controls were subjected to consecutive IAPs of 10 and 14 mmHg for 45 min each. Urine flow (V), Na⁺ excretion (U_NaV), glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary NO metabolites ( $ {\text{U}}_{{{\text{NO}}_{ 2} + {\text{NO}}_{ 3} }} $ ) and cGMP (U_cGMP) were determined.

Results:

Elevating IAP from 0 to 10 and 14 mmHg in normal rats caused IAP-dependent reductions in V, U_NaV, GFR, RPF, $ {\text{U}}_{{{\text{NO}}_{ 2} + {\text{NO}}_{ 3} }} , $ and U_cGMP. Basal renal function and hemodynamics were lower in rats with obstructive jaundice. In contrast to normal rats, application of elevated IAP of 10 and 14 mmHg significantly improved V, U_NaV, GFR, RPF, and MAP along with increased $ {\text{U}}_{{{\text{NO}}_{ 2} + {\text{NO}}_{ 3} }} $ and preserved U_cGMP. Similarly, when identical IAP conditions were applied to cirrhotic rats, no deleterious changes in V, U_NaV, GFR or RPF were observed.

Conclusions

Application of pneumoperitoneum to rats with acute BDL improves kidney function and renal hemodynamics. Likewise, increased IAP does not exert adverse renal effects in cirrhotic rats. These effects are distinct from the deleterious renal consequences of increased IAP in normal rats. Perturbations in the generation of NO/cGMP during IAP in normal rats but not in rats with BDL or cirrhosis may contribute to these differences.     

Renal function and kidney size in glycogen storage disease type I

Renal failure has been reported recently as a late complication of glycogen storage disease type I (GSD I). We studied the renal function of 23 patients, mean age 10.9 years (range 2.2–21.6 years). The mean glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were 188±50 and 927±292 ml/min per 1.73 m², respectively (normal values for adult controls 90–145 and 327–697, respectively). Hyperfiltration (GFR >145 ml/min per 1.73 m²) was found in 19 of 23 patients. There was no difference in GFR and ERPF between age groups 2–10 and 11–22 years. After a mean follow-up of 2.5 years (range 1–7.5 years) GFR and ERPF did not significantly change. At follow-up 3 patients (all older than 15 years) developed persistent glomerular proteinuria (0.1, 0.5 and 0.9 g/day). Besides a slight increase in fractional excretion of ₂-microglobulin (FE-₂m) in 6 patients, proximal tubular function tests (FE-₂m, tubular reabsorption of phosphate and glucosuria) were normal. In patients with increased kidney length related to body height, GFR and ERPF were significantly higher than in patients with normal kidney length. We conclude that GSD I is characterised by hyperfiltration and hyperperfusion. The relative increment in kidney length is related to the degree of hyperfiltration.     

Validation of the CKiD formulae to estimate GFR in children post renal transplant

Background

The Chronic Kidney Disease in Children (CKiD) study reported new formulae to estimate glomerular filtration rate (eGFR). The study reported here aimed to assess the accuracy of these formulae in estimating levels and changes in GFR in pediatric renal transplant recipients and generate a new formula in our cohort.

Methods

Two hundred and fifty-two studies of plasma disappearance of ¹²⁵I-iothalamate (C_IO) were used to measure GFR in 155 renal transplant recipients. The CKiD bedside formula (CKiD-BS) was compared with C_IO. A mixed logistic regression model was fit to evaluate the performance of estimating change in posttransplant C_IO using CKiD-BS. We used mixed-effects linear regression to fit a multiplicative model of C_IO. The CKiD cystatin-C-based formula (CKiD-Cys) was also used for comparison in 32 additional transplant recipients. Comparisons were made using Bland–Altman plots.

Results

CKiD-BS underestimates C_IO by 20 % for GFR >25 ml/min per 1.73 m². Percentage change in CKiD-BS performed reasonably well in estimating 15 % change of C_IO beginning 6 months posttransplant [area under the curve (AUC)?=?0.791)] The multiplicative constant in the CKiD-BS was recalibrated [R-Bedside?=?0.461?×?ht(cm)/S_Cr).]A GFR model [GFR-M)?=?10.73?×?[(ht(cm)]0.51/(S_Cr)0.90?×?(BUN)0.23] has higher specificity but similar sensitivity for C_IO compared with R-Bedside. CKiD-Cys overestimates C_IO by 10 ml/min per 1.73 m² across a broad range of GFR.

Conclusions

In our cohort, the CKiD-BS underestimates C_IO; however, changes in CKiD-BS can be used to estimate changes in C_IO. CKiD-Cys overestimates C_IO and is not accurate in estimating C_IO.     

Nitric oxide metabolism following unilateral renal ischemia/reperfusion injury in rats

Renal ischemia/reperfusion (I/R) injury results in decreased glomerular filtration and renal blood flow (RBF) and increased urine output, characterized by natriuresis and impaired concentrating ability. We studied unilateral I/R in rats to assess renal handling of nitric oxide (NO). Prior to I/R, we measured urine flow rate (V), inulin clearance (C _IN), para-aminohippuric acid clearance (C _PAH), NO clearance (C _NOx determined from metabolites NO₂ and NO₃), tubular transport of NO_x (T_NOx, filtered load ± urinary excretion), urine sodium and potassium excretion (U_NaV, U_KV), fractional excretion of sodium (FENa), and fractional excretion of NO_x (FENO_x) in each kidney. The left renal artery was then ligated for 30 min, followed by 30 min of reperfusion, and all measurements were repeated. C _IN and C _PAH were decreased in I/R kidneys compared with the contralateral kidney or pre-ischemia controls. V, FENa, and U_KV were all significantly increased in I/R kidneys. Plasma NO_x concentration was lower after injury in all animals (23.3±2.8 post injury vs. 30.4±7.7 μM pre injury, P <0.05). C _NOx was significantly higher in I/R kidneys (0.14±0.05 ml/min per g kidney weight) than in pre-injury kidneys (0.03±0.02 right, 0.04±0.30 left) or the contralateral controls (0.04±0.02) (P <0.05 for all three controls). T_NOx showed net tubular reabsorption of NO_x in all kidneys (11±6 in post-ischemic left kidneys vs. 25±20 in left pre-ischemia, 33±13 in right pre-ischemia, and 21±4 right post-ischemia, nM/min per g kidney weight, P = NS). FENO_x was higher in injured kidneys (28%±18) than in pre-injury (3%±0.6, 5%±3) or contralateral controls (6%±3) (P <0.05 for all three controls). Renal NO_x excretion and clearance are increased despite decreased plasma levels of NO metabolites after I/R injury. This increased excretion is not dependent on RBF or glomerular filtration, but may be related to impaired tubular reabsorption of NO_x combined with increased intra-renal NO production. Received December 30, 1996; received in revised form July 17, 1997; accepted July 22, 1997     

Comparison of two formulae for estimation of glomerular filtration rate in children

Glomerular filtration rate (GFR) was measured in 216 studies in 151 children using the cimetidine protocol. This was compared with the GFR calculated using Légers pharmacokinetic equation and with that calculated using k*L/[Cr]_s (constant × length in centimeters divided by serum creatinine concentration). The GFR calculated using the equation GFR=k*L/[Cr]_s yielded a closer approximation to the measured GFR than that using Légers pharmacokinetic equation. Currently there is focus on screening children for decreased GFR to identify those with asymptomatic chronic kidney disease at a time when intervention may delay progression to chronic renal failure. This study showed close approximation of the calculated GFR with the measured GFR using the equation GFR=k*L/[Cr]_s, when the values for k were determined in the laboratory in which creatinine was measured.     

Renal functional reserve in children with a previous episode of haemolytic-uraemic syndrome

Renal function [creatinine clearance (C _Cr)] and renal functional reserve (RFR) was measured in 16 children who had had haemolytic-uraemic syndrome (HUS) an average of 6.6±0.72 years previously. All patients had normal plasma creatinine and blood pressure and only 3 had proteinuria, which was mild in every instance. Patients were studied whilst ingesting three diets which provided an average of 1.5, 2.1 and 3.1 g protein/kg body weight per day, respectively. Diets were administered over three consecutive periods of 7 days each andC _Cr was measured on the 7th day of each diet. Values tended to correlate with protein intake. They were in the normal range when patients were taking 1.5 and 2.1 g protein diets and increased markedly in 13 of the 16 patients (P<0.001) when they ingested the high-protein diet (3.1 g). The effect on glomerular filtration rate (GFR)-measured byC _Cr and inulin clearance (C _in)-of an acute oral protein load was studied in 12 of the HUS patients and four control subjects. In the control periods, prior to the protein load, values forC _Cr were similar in the HUS and control subjects (104.0±11.0 vs 121.6±10.1 ml/min per 1.73 m², NS). HoweverC _in values were significantly reduced in HUS patients (59.5±9.2 vs 102.7±12.4 ml/min per 1.73 m², (P<0.025). TheC _Cr/C _in ratio in the patients averaged 2.10 compared with 1.13 in controls. Acute protein loading was accompanied by an increase inC _in in all controls but in only 8 of the 12 patients. Baseline values forC _in did not correlate with the presence or absence of protein-stimulated enhancement ofC _in. TheC _Cr/C _in ratios after protein loading remained twice as high in HUS patients as in controls. The data indicate thatC _Cr is not an accurate indicator of GFR in children who have had acute renal injury. Tubular secretion of creatinine represents a greater proportion of excreted creatinine in these children, may maintain serum creatinine in the normal range and mask the decrease in GFR. The study also emphasizes the problems of measuring RFR in these children.     

Longitudinal Changes in Estimated and Measured GFR in Type 1 Diabetes

Estimation of GFR from serum concentrations of creatinine and cystatin C has been refined using cross-sectional data from large numbers of people. However, the ability of the improved estimating equations to identify changes in GFR within individuals over time has not been rigorously evaluated, particularly within the normal range of GFR. In cross-sectional and longitudinal analyses of 1441 participants in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study with type 1 diabetes, we compared GFR estimated from creatinine (eGFR_Cr), cystatin C (eGFR_Cys), or both (eGFR_Cr+Cys) with iothalamate GFR (iGFR), including changes in each over time. Mean (SD) iGFR was 122.7 (21.0) ml/min per 1.73 m². In cross-sectional analyses, eGFR_Cr+Cys estimated iGFR with the highest correlation (r=0.48 versus 0.39–0.42), precision, and accuracy. In longitudinal analyses, change in eGFR_Cr+Cys best estimated change in iGFR; however, differences between estimates were small, and no estimate accurately classified change in iGFR. Over a median 23 years of follow-up, mean rate of change in eGFR was similar across estimates of eGFR_Cr, eGFR_Cys, and eGFR_Cr+Cys (−1.37, −1.11, and −1.29 ml/min per 1.73 m² per year, respectively). Associations of BP and hemoglobin A1c with change in eGFR were strongest for eGFR_Cys and eGFR_Cr+Cys. Together, these results suggest that the addition of cystatin C to creatinine to estimate GFR may improve identification of the causes and consequences of GFR loss in type 1 diabetes, but may not meaningfully improve the tracking of GFR in clinical care.Reduced GFR leads to ESRD and metabolic complications of CKD. Estimation of GFR from serum concentrations of creatinine and cystatin C has been refined using cross-sectional data from large numbers of people.¹ As a result, individuals with reduced GFR and increased risk of adverse clinical outcomes can be more accurately identified within populations.^1,2 However, the ability of the improved estimating equations to identify changes in GFR within individuals over time has not been rigorously evaluated, particularly within the normal range of GFR (≥60 ml/min per 1.73 m²). Detecting changes in GFR within individual patients is important to develop, evaluate, and implement strategies to prevent CKD.Identifying changes in GFR within individuals may be particularly useful in type 1 diabetes. Patients with type 1 diabetes often have GFR higher than normal early in the course of disease (hyperfiltration).³ Over many years of follow-up, some of these patients develop overtly reduced GFR (<60 ml/min per 1.73 m²).^4,5 Tracking GFR during this interval is challenging, because large changes in GFR may cause only small changes in serum creatinine and cystatin C concentrations. In addition, it is now clear that macroalbuminuria (urine albumin excretion≥300 mg/d) is not a sensitive marker of early GFR loss. Rather, some patients lose substantial GFR with microalbuminuria (30–299 mg/d) or even normoalbuminuria (<30 mg/d).^5–7In this study, we evaluated longitudinal changes in estimated and measured GFR among participants in the Diabetes Control and Complications Trial (DCCT) and its observational extension, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. The DCCT/EDIC study included participants with type 1 diabetes who had normal or high GFR at baseline.^8,9 In this population, we used two complementary approaches to compare GFR estimated from serum concentrations of creatinine and cystatin C combined with GFR estimated from either creatinine or cystatin C alone. First, we compared each GFR estimate with GFR measured as the urinary clearance of ¹²⁵Iiothalamate. We hypothesized that change in GFR estimated from serum creatinine and cystatin C together would most accurately and precisely correlate with, and most accurately classify, change in measured GFR. Second, we tested associations of known risk factors for GFR loss with change in each GFR estimate over long-term follow-up (median of 23 years). We hypothesized that higher BP and hemoglobin A1c would be most strongly associated with change in GFR estimated from creatinine and cystatin C combined. Substantial improvements in accuracy, precision, classification, and association would suggest that the addition of cystatin C to creatinine to estimated GFR may improve the tracking of GFR within its normal range in type 1 diabetes.     

Biochemical changes before and during oral calcium tolerance test in calcium stone formers

Summary 116 normocalcemic and 8 primary hyperparathyroid (PHPT) patients with calcium (Ca) nephrolithiasis and 10 normal controls underwent 1 g of oral Ca tolerance test following 4 days of Ca restricted diet (400 mg/day). On the basis of urinary Ca/creatinine (Cr) ratio obtained by the test, the 116 patients with normocalcemic nephrolithiasis were divided into 3 groups (normocalciuric nephrolithiasis; NN, absorptive hypercalciuria; AH, renal hypercalciuria; RH) according to our criteria which were slightly modified from Pak et al. Changes in urinary Ca/Cr ratio, and those in serum Ca and phosphorus (P), tubular maximum reabsorption of phosphate/glomerular filtration rate (TmPO₄/GFR), nephrogenous adenosine 3,5-monophosphate (NcAMP) and plasma immunoreactive parathyroid hormone (iPTH) were determined. As a result, the 116 patients were divided into 82NN, 13AH and 21RH. In general, a rise in serum Ca and fall in NcAMP were seen first, followed by rises in urinary Ca/Cr ratio, serum P and TmPO₄/GFR although the changes were small. The group PHPT showed abnormality in the changes of TmPO₄/GFR, NcAMP and plasma iPTH. The former one decreased constantly during the test and the latter two did not fall to within the normal range, suggesting parathyroid autonomy or abnormal suppressibility. Regarding the normal controls, all the changes were smallest among the 5 groups and clear parathyroid suppression was not observed while it was seen in the groups NN, AH and RH. In conclusion, oral Ca tolerance test is useful not only to separate NN, AH and RH, but also for the diagnosis of PHPT by demonstrating parathyroid autonomy or abnormal suppressibility assessed by NcAMP and/or TmPO₄/GFR.     

The diagnosis of hypercalciuria in children

Calcium loading tests were performed in 21 children with hypercalciuria, haematuria and/or nephrolithiasis and 10 control subjects. Comparisons of 24-h calcium excretion before and after loading were evaluated rather than fasting urinary calcium to urinary creatinine ratio. The differences in calcium excretion before and after loading clearly distinguished absorptive from renal hypercalciuria. A difference higher than 0.035 mmol/kg indicated absorptive hypercalciuria in 6 of 21 patients, whereas in the remaining 15 much lower differences indicated renal hypercalciuria. Resorptive hypercalciuria caused by low serum values of 25-hydroxyvitamin D was considered in 6 of the 15 patients with renal hypercalciuria. These patients had low values of phosphate reabsorption (TmP/GFR) and could be clearly separated by high values of calcium reabsorption (TmCa/GFR), in contrast to patients with renal hypercalciuria who had normal values of TmP/GFR and low values of TmCa/GFR. The correct treatment and prevention of nephrolithiasis caused by hypercalciuria in children should be based on accurate diagnosis; this can be achieved by using the calcium loading test described in this report.