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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).

Adolescent↗

Normalisation of glomerular filtration rate measurements.

The result of a glomerular filtration rate (GFR) measurement on a particular patient is of limited use to the referring physician since normal GFR values vary widely with the patient's age and build, etc. To overcome this problem, it is usual to normalise the measured GFR by dividing it by the patient's surface area and multiplying the result by the surface area of a 'standard' man. This transforms the measurement onto a scale which applies to all patients, young and old, large and small, where normal values fall within a well-defined range and where the degree of renal impairment can be quantified. We have examined the generally accepted surface area (SA) and the less well-known extracellular volume (ECV) normalisation methods of GFR measurements in a series of 110 patients. The results show that both methods produce essentially the same result; however, ECV normalisation is theoretically more correct, can be found directly without the patient's ECV being measured and does not require the use of empirical formulae. Mathematical justification for ECV normalisation is presented, and a proposed distribution pattern for the normalised measurement is introduced. A simple mathematical model shows that accurate GFR measurements can be made in the presence of an enlarged ECV, but normalisation of these will produce misleading low values.

Body Surface Area↗

Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate.

Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance. Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/Cll) ranged from 1.14 to 2.27. With cimetidine, ClC/Cll approached unity in 8 patients (mean 1.02 [SD 0.03]), but considerably exceeded unity in 8 others (1.33 [0.14]). Plasma cimetidine/creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p = 0.01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibited previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures GFR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.

Adolescent↗

Common charge-shift mutation Glu65Lys in K+ channel β₁-Subunit KCNMB1: pleiotropic consequences for glomerular filtration rate and progressive renal disease.

BACKGROUND: Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca(2+) influx, which is controlled by the regulatory β₁-subunit (KCNMB1) of large-conductance heteromeric K+ ('BK') channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. METHODS: We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). RESULTS: The 65Lys variant was relatively common, occurring on ∼5-10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). CONCLUSIONS: Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.

Black or African American↗

A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate.

BACKGROUND: In clinical practice, the glomerular filtration rate (GFR) is often estimated from plasma creatinine. Several studies have shown cystatin C (cys C) to be a better parameter for the diagnosis of impaired renal function. No data are available, however, on the performance of cys C in follow-up of patients, compared with creatinine. Also, comparisons of cys C with the Cockcroft and Gault (C&G) formula for estimation of GFR are few. METHODS: Plasma samples were obtained from 93 consecutive patients seen for GFR determination and from 30 patients with diabetes mellitus type 2, of whom 23 were investigated a second time after 2 years. GFR was determined with [125I]iothalamate. Plasma creatinine was determined enzymatically and the creatinine clearance calculated according to C&G. Cys C was measured with a particle-enhanced immunonephelometric method. RESULTS: GFR correlated with 1/cys C (r = 0.873) as well as with C&G (r = 0.876). The area under the curve (AUC) of the receiver operating curves (ROCs), a measure of diagnostic accuracy, for cys C (0.931) and C&G (0.938) were equal (P = 0.815) and both better than the creatinine AUC (0.848; P = 0.006). Bland and Altman analysis showed that the simple formula GFR = -4.32 + 80.35 x 1/cys C, derived from our data, gave more accurate (P < 0.0001) and more precise (P = 0.024) GFR estimates than obtained with the C&G formula. The day-to-day variation (biological +analytical) for cys C was small (3.1%, SD 2.51%) in diabetic patients. In the follow-up study in diabetic patients, cys C was the parameter which had the best correlation (r = 0.66) with changes in GFR. CONCLUSIONS: Cys C shows a high correlation with GFR. With a very simple formula, cys C gives a good estimate of GFR, more accurate and precise than C&G. Because biological variation is low, cys C gives also a good assessment of GFR changes during follow-up. Cys C is the preferred endogenous parameter for GFR.

Adolescent↗

Lack of dependence of urine PCO2 upon reduction of glomerular filtration rate in alkalotic dogs.

1. The PCO2 gradient between alkaline urine and arterial blood (U-B PCO2) is thought to depend primarily on distal hydrogen ion secretion. However, other variables affecting the U-B PCO2 include the urine flow rate, the urinary bicarbonate and phosphate excretion rates and the glomerular filtration rate. 2. In order to evaluate the effects of acute changes in these factors on the U-B PCO2, bicarbonate-loaded dogs with maximal U-B PCO2 values were subjected to either acute unilateral elevations of ureteral pressure or hypotension caused by nitroprusside infusion. The results demonstrate that acute reduction in the glomerular filtration rate does not cause a decrease in the U-B PCO2 as long as the urinary concentrations of phosphate and bicarbonate do not decline. 3. Urinary concentrations of phosphate and bicarbonate appeared more important than their excretion rates in the maintenance of elevated U-B PCO2 values.

Alkalosis↗

Comparison between terminal slope rate constant and "slope/intercept" as measures of glomerular filtration rate using the single-compartment simplification.

Several whole-body variables are available for indexing glomerular filtration rate (GFR), including extracellular fluid volume (ECF volume, ECV), which has the advantage that GFR based only on the terminal exponential, alpha 2, of the chromium-51 ethylene diamine tetraacetic acid (51Cr-EDTA) plasma clearance curve is a measure already indexed for ECV. This slope-only method, however, is open to the theoretical criticism of a lack of robustness not present in the more conventional slope/intercept method, which generates GFR in absolute units before indexation to body surface area (BSA). To further evaluate the slope-only method, a large database of routine three-sample GFR measurements, based on 51Cr-EDTA, was analysed with the aim of comparing GFR/BSA with GFR/ECV, identifying the main sources of error in their respective measurements and explaining why they might be discrepant. The database was subdivided into 304 patients (group A) in whom the correlation coefficient of the fit to the three data points was greater than 0.99 and 31 patients in whom it was less than 0.99 (noisy data; group B). There was modest agreement between GFR/BSA and GFR/ECV in group A (r = 0.77; mean ratio 1.01 +/- 0.21). The difference between them correlated significantly with BSA (r = 0.52; P < 0.001), as would be expected given that small individuals have a relatively high BSA. Subdividing group A into four subgroups stratified according to BSA led to a slight improvement in the correlation between GFR/BSA and GFR/ECV. Because an error in alpha 2 is balanced by an opposing error in the intercept (which leads to a change in distribution volume in the opposite direction), and therefore impacts on both GFR/BSA and GFR/ECV, whereas an error in administered dose affects only GFR/BSA, it is possible to evaluate such errors by examining the respective relationships of GFR/BSA and GFR/ECV with indexed ECV. In group A, GFR/BSA correlated positively with ECV/1.73 m2, not surprisingly as ECV/BSA is effectively the ratio GFR/BSA to GFR/ECV, while GFR/ECV correlated negatively with ECV/1.73 m2. This implies that errors other than alpha 2, probably principally in administered dose, were as important as errors in alpha 2. This conclusion was supported by disappearance of the positive correlation between GFR/BSA and ECV/BSA in group B, brought about by the greater errors in alpha 2 in this group. This study suggests that, because of the effects of errors in the slope/intercept method that do not affect alpha 2, GFR based on slope only is at least as robust as that based on slope/intercept.

Adolescent↗

Renal reserve: a functional view of glomerular filtration rate.

The hyperfiltration theory challenged the view that glomerular filtration rate is a fixed function as well as that there is a good correlation between GFR and renal parenchymal damage. Glomerular filtration rate is a dynamic parameter that is diet-dependent and can be altered by hemodynamic maneuvers. Therefore, it is not a good indicator of renal lesion. The renal reserve is an indicator of the workload per nephron and may be a useful parameter to assess the progression of renal disease in the presence of dietary or pharmacological intervention.

Dietary Proteins↗

Increased kidney size and glomerular filtration rate in untreated juvenile diabetes: normalization by insulin-treatment.

Glomerular filtration rate (GFR), renal plasma flow (RPF) and roentigenographic kiendy size were measured in six newly diagnosed male diabetics with a mean age of 25 years. Glomerular filtration rate was elevated before treatment to the same extent as found previously. A significant fall in both kidney size and glomerular filtration rate was found after treatment with insulin for 3 months. These results support further the concept that there is a basal connection between enlarged kidneys and the elevated GFR of early diabetes.

Diabetes Mellitus, Type 1↗

Increased glomerular filtration rate as a predictor of diabetic nephropathy--an 8-year prospective study.

The objective was to study the natural history and the predictive value of glomerular filtration rate, albumin excretion rate, blood pressure, and hemoglobin A1c for diabetic nephropathy. A cohort of 75 type-1 diabetic adolescents with a diabetes duration of 8 years was studied. Thirty-one females, 33 males, mean age 16.9 +/- 0.3 (SEM) participated in the follow-up study. Glomerular filtration rate, albumin excretion rate, blood pressure, and hemoglobin A1c were measured every second year during 8 years to determine the predictive value of glomerular filtration rate for future nephropathy. Initial differences and patterns of changes in glomerular filtration rate, albumin excretion rate, and hemoglobin A1c were examined in patients who did (group 1) and did not (group 2) develop incipient or overt nephropathy. Five of 64 patients developed overt nephropathy. They had an initial glomerular filtration rate of greater than 125 ml/min/1.73 m2. Fifteen of 53 initially normoalbuminuric patients developed incipient and three of 53 overt nephropathy. Age, age at onset, diabetes duration, initial albumin excretion rate, initial blood pressure, and hemoglobin A1c were similar in groups 1 and 2. Glomerular filtration rate was initially higher in group 1 than in group 2 (P = 0.01). The positive predictive value for combined incipient and overt nephropathy of an initial glomerular filtration rate greater than 125 ml/min was 53%. The negative predictive value of glomerular filtration rate less than 125 ml/min was 95%. In initially normoalbuminuric patients multiple regression revealed initial glomerular filtration rate as the only significant independent predictor for nephropathy when also corrected for hemoglobin A1c (P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗

The relationship between glomerular filtration rate and sodium reabsorption by the proximal tubule of the rat nephron.

We have tested two of the hypotheses proposed to explain the adjustment in sodium reabsorption in the proximal tubule that follows a change in the rate of glomerular filtration (glomerulotubular balance). Using the recollection micropuncture technique, we were able to measure the immediate and late changes in reabsorptive rate after an acute alteration in filtration rate produced by aortic constriction and release of constriction. It was found that fractional reabsorption, as measured by the inulin tubule fluid to plasma (TF/P) ratio, increased after aortic constriction and decreased after release, but that in most instances, absolute reabsorptive rate changed in parallel to glomerular filtration rate. The change was similar whether the collections were made less than 1 or more than 5 min after the change in blood pressure. The rapid time course of this adjustment in reabsorptive rate is viewed as evidence against an intrarenal humoral feedback mechanism. In the same experiments we measured the (TF/P)(In), transit time, and flow rate of fluid in single nephrons before and during aortic constriction or release of aortic constriction. The change in reabsorptive rate and the simultaneous change in calculated cross-sectional area of the tubule lumen were rarely proportional, i.e., C/pir(2) was not constant. In other experiments, these same measurements were made before and during periods of increased ureteral pressure. Despite large increments in calculated cross-sectional area, the absolute rate of reabsorption either remained relatively unchanged or fell in proportion to the change in filtration rate. It is concluded that under these conditions, reabsorptive rate is governed by some factor other than tubule geometry.

Animals↗

Prevalence and predictors of cardiovascular calcium in chronic kidney disease (from the Prospective Longitudinal RRI-CKD Study).

Although the determinants of cardiovascular calcium have been well described in dialysis patients, the prevalence and predictors in predialysis chronic kidney disease (CKD) are less known. One hundred six patients with CKD from the Renal Research Institute-CKD Study underwent multidetector computed tomography for the assessment of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve. Cardiovascular risk factors and renal function-related parameters (glomerular filtration rate, glomerular filtration rate slope, serum creatinine, serum urea nitrogen, hemoglobin, albumin, calcium, phosphate, and parathyroid hormone) were included in multivariate regression models to predict cardiovascular calcium. Prevalences of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve were 69%, 46%, 39%, and 16%, respectively. On multivariate analysis, coronary artery calcium score was predicted by age (p < 0.0001), gender (p = 0.0001), diabetes (p = 0.024), and history of coronary artery disease (p = 0.016), but not by renal function related parameters. Similarly, renal function related parameters were not predictive of aortic or valvular calcium. In conclusion, predialysis CKD is associated with a high prevalence of cardiovascular calcium. The extent of cardiovascular calcium in patients with predialysis CKD is related to some of the traditional risk factors for atherosclerosis but not to indexes of abnormal renal function or progression in renal dysfunction.

Adult↗

Octreotide long-term treatment in patients with portal hypertension: persistent inhibition of postprandial glucagon response without major changes in renal function.

BACKGROUND/AIMS: Octreotide acutely decreases splanchnic blood flow and postprandial portal pressure in patients with portal hypertension. Inhibition of glucagon release parallels the hemodynamic changes. We studied the hormonal and renal effects of long-term treatment with octreotide (100 microg s.c., t.i.d., immediately before meals, for 2 weeks) in 12 patients with cirrhosis and portal hypertension. METHODS: Postprandial blood levels of glucagon, insulin and glucose, and renal function tests were monitored in a study where patients acted as their own controls. Eleven patients completed the study, octreotide being discontinued in one patient who developed jaundice after 6 days of therapy. RESULTS: Long-term treatment did not cause any change in fasting hormonal levels measured 12 h after the last injection of octreotide. However, pre-prandial injection of octreotide induced a marked fall in blood glucagon (163+/-49 pg/ml, after 20 min, vs. 254+/-71 pg/ml, basal; p<0.01), thus preventing the postprandial response occurring without treatment (322+/-102 pg/ml, 30 min-peak, vs. 249+/-77 pg/ml, basal; p<0.03). Inhibition of postprandial glucagon was maintained after 2 weeks of therapy (159+/-33 pg/ml, after 20 min, vs. 237+/-54 pg/ml, basal; p<0.01). Octreotide abolished the insulin postprandial response with no major change in glycemic control. Treatment had no long-term effect on renal plasma flow (effective renal plasma flow: 596+/-79 ml/min, baseline, vs. 609+/-71 ml/min, at 2 weeks; p>0.5), glomerular filtration rate (glomerular filtration rate: 99+/-11 vs. 99+/-12 ml/min; p>0.5), blood urea and creatinine, whereas it induced a mild decrease in plasma electrolyte levels (p<0.02). CONCLUSIONS: Long-term octreotide treatment persistently suppresses the postprandial glucagon response of patients with portal hypertension without causing deterioration in their renal function.

Adult↗

Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure.

The effects of prenatal protein restriction on adult renal and cardiovascular function have been studied in considerable detail. However, little is known about the effects of life-long protein restriction, a common condition in the developing world. Therefore, we determined in rats the effects of combined pre- and postnatal protein restriction on adult arterial pressure and renal function and responses to increased dietary sodium. Nephron number was also determined. Male Sprague-Dawley rats were born to mothers fed a low [8% (wt/wt), LP] or normal [20% (wt/wt), NP] isocaloric protein diet throughout pregnancy and maintained on these diets after birth. At postnatal day 135, nephron number, mean arterial pressure (MAP), and renal function were determined. A high-NaCl [8.0% (wt/wt), high-salt] diet was fed to a subset of rats from weaning. MAP was less in LP than in NP rats (120 +/- 2 vs. 128 +/- 2 mmHg, P < 0.05) and was not significantly altered by increased salt intake. Nephron number was 31% less in LP than in NP rats (P < 0.001). The volume of individual glomeruli was also less in LP than in NP rats, as were calculated effective renal plasma flow and glomerular filtration rate. Glomerular filtration rate, but not effective renal plasma flow, appeared to be increased by high salt intake, particularly in LP rats. In conclusion, protein restriction induced a severe nephron deficit, but MAP was lower, rather than higher, in protein-restricted than in control rats in adulthood. These findings indicate that the postnatal environment plays a key role in determining the outcomes of developmental programming.

Algorithms↗

Sex differences in renal hemodynamics in rats.

These studies were designed to investigate sex differences in renal hemodynamics under control conditions and in response to two different cyclooxygenase inhibitors. Studies were performed under anesthesia in males, females, and ovariectomized (OVX) rats and in separate groups of conscious, chronically catheterized male and female rats of a different strain. In the control periods, before cyclooxygenase inhibition, the male kidney was vasodilated relative to the female. Because male and female rats have the same number of glomeruli per kidney, the total vascular resistance per glomerulus is substantially greater in females than males. Cyclooxygenase inhibition in the anesthetized intact female rat produced significant increases in single-nephron glomerular filtration rate, glomerular plasma flow rate, glomerular filtration rate, and renal plasma flow, whereas afferent and efferent arteriolar resistances and renal vascular resistance fell. In contrast, anesthetized male and OVX female rats showed no renal hemodynamic response to cyclooxygenase inhibition. In the absence of anesthesia and recent surgery, intact awake female rats responded similarly to conscious male rats in that neither showed any response to cyclooxygenase inhibition. These data suggest a functional sex difference in both baseline renal hemodynamics and the renal response to cyclooxygenase inhibition, the latter unveiled by surgical stress.

Animals↗

Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate.

This study was designed to investigate the effect of protein intake on glomerular filtration rate, and to demonstrate and evaluate the functional reserve of the kidney. Normal subjects ingesting a protein diet had a significantly higher creatinine clearance than a comparable group of normal subjects ingesting a vegetarian diet. A progressive increment in protein intake in normal volunteers resulted in a significant increase in creatinine clearance. Diurnal variations in creatinine clearance were found. These daily variations correlated well with the periods of food intake. The capacity of the kidney to increase its level of function with protein intake suggests a renal function reserve. In short-term studies, the effect of a protein load on glomerular filtration rate was evaluated. Normal subjects showed an increase in glomerular filtration rate two and a half hours after protein load to a maximal glomerular filtration rate of 171.0 +/- 7.7 ml per minute. In patients with a reduced number of nephrons, renal functional reserve may be diminished or absent.

Adult↗

Validity of rapid estimation of glomerular filtration rate in type 2 diabetic patients with normal renal function.

BACKGROUND: Rapid estimation of the renal function is widely used in clinical practice. METHODS: The validity of rapid estimation of renal function as well as long-term changes in renal function from the Cockcroft-Gault formula for estimation of creatinine clearance or from serum creatinine measurements was evaluated against the 51Cr-EDTA plasma clearance technique in 36 type 2 diabetic patients with normal renal function followed for 5.2 (2.7-7.5) (mean (range) years. RESULTS: Compared with 51Cr-EDTA plasma clearance the Cockcroft-Gault formula significantly underestimated glomerular filtration rate by 21%. The degree of underestimation was observed over the whole range of glomerular filtration rate studied and increased with increasing levels of isotopically measured glomerular filtration rates. Serum creatinine was not significantly associated with glomerular filtration rate. The average long-term change in renal function was significantly overestimated by the Cockcroft-Gault formula (-2.8+/-2.3 ml/min/year) compared with the measured rate (-1.5+/-2.5 ml/min/year) (P=0.002). The difference in change rate between the two methods was highest when the measured fall rates were small and tended to disappear in patients with faster fall rates. Changes in serum creatinine correlated significantly, but imprecisely, with the rate of decline of measured glomerular filtration rate (r=-0.48, P=0.003). The variability of the estimated fall rate of renal function was unacceptably high for all approaches. CONCLUSION: Valid estimates of glomerular filtration rate as well as the rate of change in glomerular filtration rate cannot be obtained by estimation of creatinine clearance from the Cockcroft-Gault formula or from serum creatinine concentration measurements in type 2 diabetic patients with normal renal function.

Aged↗

Glomerular filtration rate in Nigerian children with homozygous sickle cell disease.

The study proposed to assess glomerular filtration rate as determined by endogenous creatinine clearance in steady state Nigeria children with homozygous sickle cell disease and normal controls. Twenty-four hours urinary creatinine clearance was estimated over a 6-month period in 54 steady-state homozygous sickle cell disease and 57 normal control children aged 5 to 13 years. Each child was admitted and a 24-hour urine sample (8.00 am to 8.00 am) was collected both for volume measurement and creatinine concentration determination. Blood was also collected from each child 30 minutes to end of urine collection for plasma creatinine concentration determination, haematocrit and reticulocyte counts. The results were compared between the two groups of children using student's t-test and the chi (X2) square test where necessary. The mean glomerular filtration rates +/- SD (ml/min/1.73 M2) for homozygous sickle cell disease children and normal controls were not significantly different (p > 0.05). Glomerular filtration rate did not differ significantly between the age groups in both patients and normal controls; haematocrits correlated weakly with glomerular filtration rates in the patients (r = +0.213; p < 0.001). Nigerian children with homozygous sickle cell disease who are in steady states have normal glomerular filtration rate that is hardly influenced by increasing age and low haematocrit level.

Adolescent↗