Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis.

Cimetidine inhibits the tubular secretion of creatinine, without altering the glomerular filtration rate (GFR). During cimetidine administration the creatinine/inulin clearance ratio approaches unity in patients with renal failure. We determined the clearance of lithium (an index of fluid delivery to the distal nephron), inulin (a measure of the actual GFR) and creatinine during cimetidine administration to investigate the occurrence of tubular creatinine secretion in patients with compensated cirrhosis. A total of 12 patients with Child-Pugh A cirrhosis were studied initially. The subjects consumed a stable diet containing 100 mmol of sodium. On successive days, 9 h creatinine clearances were measured, first without and then with the oral administration of cimetidine (400 mg as a priming dose, followed by 200 mg every 3 h). During the first study day, 4 h renal lithium clearance was also calculated. A further group of five patients with fully compensated cirrhosis underwent the measurement (on successive days) of plasma inulin clearance, first without and then with the oral administration of cimetidine (same schedule of drug administration). Cimetidine administration unmasked a marked overestimation of GFR when calculated as creatinine clearance (baseline, 138+/-20 ml/min; +cimetidine, 89+/-13 ml/min; P<0.01). Consequently, during cimetidine administration the calculated lithium fractional excretion (a measure of the fraction of filtered sodium load that is delivered to the loop of Henle) rose from 21.4+/-13.2% to 32.3+/-18.9% (P<0.05), and the ratio between absolute distal tubular sodium reabsorption and filtered sodium load rose from 20.6+/-13.1% to 31.6+/-19.3% (P<0.01). Cimetidine caused no significant decrease in the actual GFR (i.e. inulin clearance) when administered to the second group of patients with compensated cirrhosis. Our data demonstrate significant tubular secretion of creatinine in patients with compensated cirrhosis and, consequently, a marked overestimation of GFR and filtered sodium load and an underestimation of the fractional distal tubular sodium reabsorption when these parameters are calculated by means of the traditional creatinine and lithium clearance computation. The true GFR (measured as inulin clearance) is unaffected by cimetidine administration.     

Diurnal variation of plasma atrial natriuretic peptide in normals and patients with enuresis nocturna.

The circadian variation of plasma atrial natriuretic peptide (ANP) in relation to urinary excretion of sodium (UNa) and potassium (UK) as well as clearance of creatinine (Ccrea) was assessed in 15 juvenile patients with enuresis nocturna and compared with 11 age-, sex-, and weight-matched normal subjects. Normal juveniles showed a highly significant diurnal variation (p less than 0.001) of plasma ANP with diurnal peak levels at midnight (0000 hours) and minimum levels at 0400 hours. Enuretic patients showed a similar diurnal rhythmicity with normal levels during day and night. In normals both UNa and UK showed significant diurnal rhythmicity with a marked reduction from daytime to night-time. Although the total diurnal excretions of UNa and UK were similar to normals, patients with enuresis showed abnormal diurnal variation in both UNa (p less than 0.05) and UK (p less than 0.01). The abnormal circadian rhythm of UNa and UK in enuretics seemed to be caused by abnormal tubular handling as similar abnormalities were found in the fractional excretions and as the circadian variation of Ccrea was normal. Especially during the first hours of sleep (2200 hours to 0000 hours), the patients showed polyuria (230 +/- 138 ml vs 116 +/- 58 ml, p less than 0.01), natriuresis (20.9 +/- 16.3 mmol l-1 vs 10.7 +/- 6.8 mmol l-1, p less than 0.01), and kaliuresis (7.3 +/- 6.3 mmol l-1 vs 3.7 +/- 2.3 mmol l-1, p less than 0.05), despite normal levels of plasma ANP. In conclusion, the study describes the diurnal variation of plasma ANP in relation to urinary excretion of sodium and potassium in a juvenile normal population. Patients with nocturnal enuresis show abnormal diurnal rhythmicity in the urinary excretion of sodium and potassium that is not correlated to the plasma levels of ANP.     

Pyrimethamine inhibits renal secretion of creatinine.

The mechanism of increased serum creatinine after administration of pyrimethamine and dapsone was evaluated for six healthy volunteers. Serum parameters, urine sediment, and clearances of creatinine, inulin, and para-aminohippurate were assessed prior to and 28 h after the ingestion of a single, combined dose of 100 mg of pyrimethamine and 200 mg of dapsone. In a second series, the same renal function tests were performed for nine human immunodeficiency virus-infected men before and after 1 month of prophylactic treatment with a weekly dose of 75 mg of pyrimethamine and 200 mg of dapsone to evaluate sustained effects on renal function. Serum creatinine increased within 28 h from 81 +/- 14 to 102 +/- 16 mumol/liter (P = 0.002) in the healthy volunteers. Blood urea nitrogen, beta 2-microglobulin, and urine remained normal. Creatinine clearance decreased from 125 +/- 27 to 91 +/- 26 ml/min (P < 0.02) without changes in inulin clearance. The effect was reversible within 21 days and attributable to pyrimethamine, as determined by administration of each drug alone. The sustained effect of four doses of pyrimethamine and dapsone in human immunodeficiency virus-infected patients consisted of an analogous rise in serum creatinine from 69 +/- 17 to 87 +/- 32 mumol/liter (P < 0.05). Both creatinine and inulin clearances, however, were unchanged, representing a new equilibrium between creatinine production and elimination at a higher level in serum. Pyrimethamine, thus, may reversibly inhibit renal tubular secretion of creatinine without affecting the glomerular filtration rate. This physiologic effect in pyrimethamine-treated patients must be differentiated from possible organ-related nephropathies.     

Vancomycin pharmacokinetics, renal handling, and nonrenal clearances in normal human subjects

The renal handling of vancomycin is unknown. Previously reported studies have not achieved steady-state conditions with constant vancomycin concentrations. We measured systemic vancomycin clearance simultaneously with the renal clearances of vancomycin, creatinine, inulin, and para-aminohippurate in nine healthy subjects at steady-state serum vancomycin concentrations of 7 and 14 mg/L. For all steady-state observations the renal clearance of vancomycin was 89 +/- 11 ml/min (mean +/- SE), the clearance of inulin 105 +/- 9 ml/min, the clearance of creatinine 117 +/- 9 ml/min, and the clearance of para-aminohippuric acid 496 +/- 41 ml/min. The systemic clearance of vancomycin was 131 +/- 7 ml/min. The clearances of creatinine, inulin, and para-aminohippuric acid and the renal clearance of vancomycin were not statistically different at both steady-state vancomycin concentrations. The ratio of the renal clearance of vancomycin to the clearance of inulin was 0.89 +/- 0.06 and to creatinine clearance 0.79 +/- 0.05. Both ratios were independent of vancomycin concentration, urine flow rate, and filtration fraction. The systemic clearance of vancomycin was 10% greater at serum vancomycin concentrations of 14 mg/L than at 7 mg/L (p less than 0.05) because of an increase in the nonrenal clearance. Therefore in healthy subjects, 30% of the systemic vancomycin clearance is by nonrenal mechanisms and this nonrenal clearance is concentration dependent. Assuming protein binding to be between 10% and 20%, renal vancomycin excretion is predominantly by glomerular filtration. Small amounts of tubular vancomycin transport cannot be excluded by these techniques.     

The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin.

Despite the increasing therapeutic use of recombinant human growth hormone (rhGH), its metabolic clearance has not been investigated in detail. To evaluate the kinetics of rhGH as a possible function of GH plasma concentration and glomerular filtration rate (GFR), we investigated the steady state metabolic clearance rate (MCR), disappearance half-life, and apparent volume of distribution of rhGH at low and high physiological as well as supraphysiological plasma GH levels during pharmacological suppression of endogenous GH secretion in human subjects with normal and reduced renal function. GH in plasma and urine was determined by an immunoradiometric assay, and GFR by inulin clearance. In all subjects MCR decreased and plasma half-life increased with increasing plasma GH concentrations (P < 0.001). MCR of rhGH was approximately half in patients with chronic renal failure at each GH level and plasma half-life was increased by 25-50%. Allowing for the linear dependence of MCR on GFR and assuming single-compartment distribution, the estimated renal fraction of total MCR was 25-53 and 4-15% in controls and patients, respectively. Saturation of extrarenal disposal of GH was suggested by an inverse hyperbolic relationship between extrarenal MCR and plasma GH concentrations in all subjects. Fractional GH excretion was up to 1,000-fold higher in patients than in controls. We conclude that MCR of hGH is a function of plasma GH concentrations and GFR. Extrarenal elimination is saturable in the upper physiological range of GH concentrations, whereas renal MCR is independent of plasma GH levels. The kidney handles GH like a microprotein involving glomerular filtration, tubular reabsorption, and urinary excretion.     

The effects of cimetidine on creatinine excretion, glomerular filtration rate and tubular function in renal transplant recipients

The renal clearance of endogenous creatinine (CCr), sodium (CNa) and lithium (CLi) was determined before and after a single intravenous bolus of cimetidine in nine renal transplant recipients. The glomerular filtration rate (GFR) was measured with 125I-iothalamate clearance (CTh). The initial CCr of 65 ml/min (median) was reduced to a nadir of 46 ml/min (p less than 0.01) during the first 2 h after infusion of cimetidine. GFR remained unchanged, and thus the fractional clearance of creatinine (CCr/CTh) was reduced from 1.43 (median) to 1.03 (p less than 0.01). CNa and the fractional excretion of sodium decreased throughout the study (p less than 0.05); CLi was unchanged. In conclusion cimetidine, when measured during 1-h clearance periods, interferes with tubular creatinine secretion in the denervated kidney of transplant recipients without affecting the glomerular filtration rate or proximal tubular flow. This suggests that on-going cimetidine treatment must be taken into account when graft function is evaluated by the CCr alone.     

Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep.

To define the roles of circadian rhythmicity (intrinsic effects of time of day independent of the sleep or wake condition) and sleep (intrinsic effects of the sleep condition, irrespective of the time of day) on the 24-h variation in glucose tolerance, eight normal men were studied during constant glucose infusion for a total of 53 h. The period of study included 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples for the measurement of glucose, insulin, C-peptide, cortisol, and growth hormone were collected at 20-min intervals throughout the entire study. Insulin secretion rates were derived from C-peptide levels by deconvolution. Sleep was polygraphically monitored. During nocturnal sleep, levels of glucose and insulin secretion increased by 31 +/- 5% and 60 +/- 11%, respectively, and returned to baseline in the morning. During sleep deprivation, glucose levels and insulin secretion rose again to reach a maximum at a time corresponding to the beginning of the habitual sleep period. The magnitude of the rise above morning levels averaged 17 +/- 5% for glucose and 49 +/- 8% for calculated insulin secretion. Serum insulin levels did not parallel the circadian variation in insulin secretion, indicating the existence of an approximate 40% increase in insulin clearance during the night. Daytime sleep was associated with a 16 +/- 3% rise in glucose levels, a 55 +/- 7% rise in insulin secretion, and a 39 +/- 5% rise in serum insulin. The diurnal variation in insulin secretion was inversely related to the cortisol rhythm, with a significant correlation of the magnitudes of their morning to evening excursions. Sleep-associated rises in glucose correlated with the amount of concomitant growth hormone secreted. These studies demonstrate previously underappreciated effects of circadian rhythmicity and sleep on glucose levels, insulin secretion, and insulin clearance, and suggest that these effects could be partially mediated by cortisol and growth hormone.     

Lack of effect of DX-619, a novel des-fluoro(6)-quinolone, on glomerular filtration rate measured by serum clearance of cold iohexol

DX-619 is a novel des-fluoro(6)-quinolone with activity against a broad range of bacterial strains, including methicillin-resistant Staphylococcus aureus. The effects of DX-619 on the glomerular filtration rate (GFR) were evaluated because drug-related increases in serum creatinine levels were observed in studies with healthy volunteers. Forty-one healthy subjects were randomized to receive intravenous DX-619 at 800 mg or placebo once daily for 4 days, and the GFR was directly measured by determination of the clearance of a bolus iohexol injection in 33 subjects who completed the study per protocol. DX-619 was noninferior to placebo for the GFR on the basis of a criterion for a clinically significant difference of -12 ml/min/1.73 m(2). The mean GFRs on day 4 were 101.1 +/- 14.2 ml/min/1.73 m(2) and 100.2 +/- 15.6 ml/min/1.73 m(2) for the volunteers receiving placebo and DX-619, respectively. On day 4 the mean serum creatinine concentration for volunteers receiving DX-619 increased by 30 to 40%, with a corresponding decrease in mean creatinine clearance. Both parameters normalized within 7 days after the cessation of DX-619 treatment. Nonclinical studies suggest that DX-619 increases the serum creatinine concentration by inhibiting excretory tubular transporters. In conclusion, DX-619 administered intravenously at 800 mg once a day for 4 days did not affect the GFR in healthy volunteers. Glomerular toxicity is not expected to present a risk to patients receiving DX-619 in clinical trials, but monitoring of the renal function, with an emphasis on the serum creatinine concentration, is still warranted.     

Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion

BACKGROUND: Glomerular hyperfiltration plays a role in the pathophysiology of diabetic nephropathy. An increase in the glomerular filtration rate (GFR) could result from primary actions at the glomerular/vascular level or could be the consequence of a primary increase in proximal tubular sodium reabsorption resulting in systemic volume expansion. Recently it was hypothesized that an increase in sodium reabsorption may lead to glomerular hyperfiltration through the tubulo-glomerular feedback mechanism (tubular-hypothesis) without volume expansion. DESIGN: We have studied 54 normoalbuminuric patients with type 1 diabetes. The GFR was measured by inulin clearance. Proximal and distal sodium reabsorption were calculated according to standard formulas using the free water clearance technique. Plasma volume, measured by the (125)I-albumin method, atrial natriuretic peptide (ANP) and the second messenger cyclic guanosine-3,5-monophosphate (c-GMP) were used as markers of extracellular volume expansion. RESULTS: Glomerular hyperfiltration (GFR >or= 130 mL min(-1) 1.73 m(-2)) was present in 14 out of 55 patients with diabetes (25%). There were no differences in plasma volume between normo-(NF) and hyper-filtrating (HF) patients (2933 +/- 423 in NF vs. 3026 +/- 562 mL in HF, NS). Also plasma ANP and c-GMP levels were not significantly different between the groups. The fractional proximal reabsorption of sodium was significantly increased in HF [fPRNa(+) (%) 90.1 +/- 2.0 vs. 91.5 +/- 1.6, P = 0.02]. There were no differences in distal sodium reabsorption or distal sodium load (approximately macula densa concentration of NaCl) in both groups. CONCLUSIONS: Our data suggest that the primary event in diabetic glomerular hyperfiltration is an increase in proximal tubular sodium reabsorption. They do not support the hypothesis that systemic volume expansion or ANP mediate glomerular hyperfiltration in patients with normoalbuminuric type 1 diabetes. As such, changes in tubular sodium handling most probably influence tubulo-glomerular feedback.     

Suppression of renal excretion of digoxin in hypokalemic patients

Inulin and digoxin clearances were simultaneously measured in 19 normokalemic and 4 hypokalemic patients. In normokalemia the renal digoxin clearance exceeded the inulin clearance, indicating both glomerular filtration and active tubular secretion of digoxin. The tubular secretion increased with increasing plasma digoxin concentration. In hypokalemia, however, the tubular secretion of digoxin was significantly reduced but increased after the plasma potassium level was raised to normal.     

Effects of insulin on renal haemodynamics and sodium handling in normal subjects

Diabetic patients treated with insulin injected subcutaneously are characterized by peripheral hyperinsulinaemia and an increased mass of total body exchangeable sodium. We hypothesized that this may cause, at least in part, the glomerular hyperfiltration seen in the diabetic state. Six normal subjects were studied on 2 days in random order. Day A: Basal state for 40 min, hyperinsulinaemic euglycaemic clamp for 1 h (insulin infusion rate 2 mU kg-1 min-1 and 50% glucose infusion) and hyperinsulinaemic euglycaemic clamp combined with volume expansion (2 1 isotonic sodium chloride) for 2 h. Day B: as day A, but without insulin and glucose infusion. During combined volume expansion and hyperinsulinaemia an increase in glomerular filtration rate (GFR) (128 +/- 6 vs 117 +/- 8 ml min-1 1.73 m-2, p less than 0.01) and lithium clearance (CLi) (50 +/- 4 vs 33 +/- 5 ml min-1 1.73 m-2, p less than 0.01) was observed compared with basal conditions. GFR and CLi were unchanged during day B. Insulin infusion reduced renal sodium excretion. Absolute proximal tubular reabsorption was unchanged on both days. Insulin infusion without volume expansion caused a decrease of 24% in the fractional distal sodium excretion. Superimposed volume expansion and the concomitant increase in GFR and CLi was accompanied by a subsequent enhanced fractional distal sodium excretion of 27%. The changes in plasma concentrations of aldosterone, renin, angiotensin II, atrial natriuretic peptide and catecholamines did not explain the differences in GFR. An increase in GFR of 10%, comparable with that observed in diabetic patients, was induced by combined hyperinsulinaemia and volume expansion in euglycaemic normal subjects. The enhanced GFR is probably a compensatory response to the sodium retention induced by the action of insulin on the distal tubules.     

Iopentol in patients with chronic renal failure: its effects on renal function and its use as glomerular filtration rate parameter.

Iopentol (mean dose 0.42 g I kg-1) was administered for abdominal aortography and pelvic angiography in 10 patients with advanced non-diabetic chronic renal failure (S-creatinine 672 +/- 259 mumol l-1, mean +/- SD). Renal glomerular function measured as creatinine clearance and plasma clearance of [99Tcm]-diethyl-enetriaminepentaacetic acid (DTPA) was unchanged by iopentol, as also was urinary excretion of the renal tubular enzymes N-acetyl-beta-glucosaminidase (NAG) and alkaline phosphatase (ALP). The elimination of iopentol from serum and urine was delayed, and detectable serum and urine concentrations were found 5 days after administration of the contrast medium. Creatine clearance was 47% higher than the corresponding renal iopentol clearance. Plasma iopentol clearance, measured as the total area under the plasma concentration curve, was 40% higher than renal iopentol clearance because of extrarenal elimination of iopentol. We conclude that abdominal aortography with iopentol can be performed without effects on renal glomerular or tubular function parameters in patients with advanced renal failure. If iopentol is used for measurement of glomerular filtration rate (GFR) in this group of patients, one should measure renal clearance, as plasma clearance overestimates GFR.     

Pathophysiology of protracted acute renal failure in man.

Postischemic acute renal failure (ARF) induced by cardiac surgery is commonly prolonged and may be irreversible. To examine whether persistence of postischemic, tubular cell injury accounts for delayed recovery from ARF, we studied 10 patients developing protracted (36 +/- 4 d) ARF after cardiac surgery. The differential clearance and excretion dynamics of probe solutes of graded size were determined. Inulin clearance was depressed (5.0 +/- 1.7 ml/min), while the fractional urinary clearance of dextrans (radii 17-30 A) were elevated above unity. Employing a model of conservation of mass, we calculated that 44% of filtered inulin was lost via transtubular backleak. The clearance and fractional backleak of technetium-labeled DTPA ([99mTc]DTPA, radius = 4 A) were identical to those of inulin (radius 15 A). The time at which inulin or DTPA excretion reached a maximum after an intravenous bolus injection was markedly delayed when compared with control subjects with ARF of brief duration, 102 vs. 11 min. Applying a three-compartment model of inulin/DTPA kinetics (which takes backleak into account) revealed the residence time of intravenously administered inulin/DTPA in the compartment occupied by tubular fluid and urine to be markedly prolonged, 20 vs. 6 min in controls, suggesting reduced velocity of tubular fluid flow. We conclude that protracted human ARF is characterized by transtubular backleak of glomerular ultrafiltrate, such that inulin clearance underestimates true glomerular filtration rate by approximately 50%, and by sluggish tubular fluid flow, which strongly suggests the existence of severe and generalized intraluminal tubular obstruction. Because all patients also exhibited extreme hyperreninemia (16 +/- 2 ng/ml per h) that was inversely related to inulin clearance (r value = -0.83) and urine flow (r value = -0.70), we propose that persistent, angiotensin II-mediated renal vasoconstriction may have delayed healing of the injured tubular epithelium.     

The acute effect of acetazolamide on glomerular filtration rate and proximal tubular reabsorption of sodium and water in normal man

The acute effects on kidney function of acetazolamide (250 mg) given intravenously were evaluated in seven healthy subjects. Glomerular filtration rate was measured as the renal clearance of 51Cr-EDTA, and fluid flow rate out of the proximal tubules was assessed by measurement of the renal lithium clearance. An 18% decline in glomerular filtration rate (ml/min) was observed after acetazolamide administration (109 +/- 16 vs 89 +/- 14, p less than 0.02), while lithium clearance (ml/min) increased by 35% (30 +/- 5 vs 38 +/- 8, p less than 0.02). Absolute proximal tubular reabsorption of water (ml/min) was reduced by about one third (79 +/- 12 vs 51 +/- 9, p less than 0.02), and fractional proximal reabsorption of water and sodium (%) declined (73 +/- 2 vs 58 +/- 6, p less than 0.02). Renal sodium clearance and absolute distal reabsorption of sodium increased, while fractional distal reabsorption of sodium declined. Acetazolamide reduces absolute and fractional proximal tubular reabsorption of sodium and water, and glomerular filtration rate. Primarily, this induces an increase in the output of fluid from the proximal tubules accounting for the diuretic effect of the drug. The acute fall in glomerular filtration rate is probably mediated by a temporary increase in proximal intratubular pressure and activation of the tubuloglomerular feedback mechanism.     

Renal handling of the monobactam azthreonam in healthy subjects

Azthreonam is a new completely synthetic, monocyclic beta-lactam antibiotic with potent activity in vitro against most gram-negative aerobic bacteria. Its renal handling was studied in six healthy men after an intravenous loading dose of 1200 mg over 2 min followed by a continuous infusion of 500 mg/hr for 4 hr with and without oral probenecid (1 gm b.i.d. for 2 days before azthreonam infusion and during the day of infusion). To assess glomerular filtration, each subject also received an intravenous loading dose and continuous infusion of inulin. Azthreonam was excreted in the urine by glomerular filtration and tubular secretion in essentially equal proportions. Probenecid reduced plasma clearance of azthreonam bY suppressing renal tubular secretion, without altering glomerular filtration rate or nonrenal elimination. Probenecid increased total and free azthreonam levels and the azthreonam plasma t1/2 while reducing plasma protein binding and the apparent steady-state volume of distribution.     

Hemodynamic roles of thromboxane A2 and prostaglandin E2 in glomerulonephritis

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. Our purpose was to determine the relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; para-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 +/- 0.2 vs. 2.6 +/- 0.2 ml/min. RPF is numerically increased, 10.0 +/- 1.0 vs. 7.0 +/- 0.6 ml/min. By 14 days GFR is normal, 2.2 +/- 0.2 ml/min, as a consequence of significantly increased RPF, 11.7 +/- 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold respectively at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38,485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. We conclude that PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.     

The effect of the plasma bicarbonate level on proximal tubule sodium reabsorption in NH4Cl-loaded dogs.

In an attempt to examine the effects of mild and severe chronic metabolic acidosis on proximal tubule sodium reabsorption, 6 dogs were given 10 mEq. per kilogram per day and 5 dogs were given 20mEq. per kilogram per day of ammonium chloride for 3 days and compared to 12 normal dogs during a steady-state water diuresis and following the administration of ethacrynic acid (EA) intravenously (2 mg. per kilogram) utilizing standard clearance methodology, In the severely acidotic group (pH decrease is greater tthan 0.2) plasma pH was 7.08 +/- 0.06 and plasma bicarbonate was 6.3 +/- 1.0 Eq. per liter compared to a pH of 7.33 +/-0.02 and bicarbonate of 13.4 +/- 0.7 in mild acidosis (pH decrease is less than 0.2). During a steady-state water diuresis urine flow was 14.2 +/- 0.9 in severely acidotic compared to 10.5 +/-0.7 ml. per minute per 100 ml. glomerular filtration rate (GFR) in normal dogs (p is less than 0.01). Following EA sodium clearance increased 38.4 +/- 3.5 in severely acidotic dogs and 27.6 +/- 2.0 ml. per minute per 100 ml. GFR in normal dogs (p is less than 0.02). In mild acidosis, steady-state fractional urine flow and the increase in fractional sodium clearance following EA were not significantly different than normal dogs. We conclude that chronic metabolic acidosis leads to an increase in distal solute load and enhanced natriuretic effect of EA secondary to a decrease in proximal tubule sodium reabsorption which may be dependent upon the degree of reduction in the plasma bicarbonate level.     

Prediction of glomerular filtration rate using aminoglycoside clearance in critically ill medical patients.

OBJECTIVE: The aim of this preliminary investigation was to evaluate the use of aminoglycoside serum concentrations as a surrogate measure of the glomerular filtration rate (GFR) in comparison with other measured and empiric methods against inulin, the criterion standard measure of GFR. DESIGN: A consecutive sample of all eligible patients. SETTING: An eight-bed medical intensive care unit in a university-affiliated tertiary-care teaching hospital. PATIENTS: Ten critically ill medical patients receiving gentamicin or tobramycin for presumed or documented gram-negative bacillary infection were enrolled in the study. The patients were mechanically ventilated and had underlying organ system dysfunction. All ten patients completed the study. INTERVENTION: Patients underwent renal functional assessment by measured inulin (Cl(in)) and 24-hour urinary creatinine clearance (Clcr). Aminoglycoside serum concentrations were used to estimate GFR and were compared with the two measured methods and a creatinine clearance calculated with the Cockcroft-Gault method (ClCG). All evaluations were performed the same day. RESULTS: Cl(in) averaged 51.6 +/- 35.0 mL/min and serum creatinine ranged from 0.3 to 5.4 mg/dL (26.5 to 477.3 mumol/L). Steady-state peak and trough aminoglycoside concentrations were 6.1 +/- 1.4 and 1.3 +/- 0.9 micrograms/mL, respectively. There were no statistically significant differences between the various methods, although the aminoglycoside-calculated GFR (Cl(amg)) 95 percent confidence intervals were smaller than Clcr and ClCG compared with Cl(in). Mean absolute errors were smaller with Cl(amg) than with Clcr and ClCG. Regression results indicated that only Cl(amg) and ClCG demonstrated agreement with Cl(in) (lines not different from y = x). However, the Cl(amg) showed closer agreement, with a mean square error almost half that of ClCG (9.6 vs. 18.1). CONCLUSIONS: Cl(amg) can be used routinely as an estimate of GFR in critically ill patients, with less error than empiric methods.     

Renal handling of iodothyronines in acromegaly

Measurement of the free serum concentration, the 24-h urinary excretion and the renal clearance of T4, T3, 3,3',5'-tri-iodothyronine (rT3), 3',5'-diiodothyronine (3',5'-T2) and 3,3'-di-iodothyronine (3,3'-T2) was performed in 13 patients with active acromegaly and in 18 healthy controls. The acromegalic patients had normal serum levels of the free iodothyronines, whereas the urinary excretion of T4 and T3 was increased approximately two-fold in the patients with acromegaly. The creatinine clearance, reflecting the glomerular filtration rate (GFR), was increased in the acromegalic patients, in median 133 ml/min versus 87 ml/min (p less than 0.01) in the controls. Compared to the creatinine clearance the clearance of T3 and 3,3'-T2 was higher (p less than 0.01) in acromegalics as well as in controls. The patients with acromegaly had higher renal clearance of T4 and T3 than controls, in median 81 ml/min versus 33 ml/min, and 269 ml/min versus 137 ml/min, respectively (p less than 0.01). These differences were not due to changes in creatinine clearance. The renal clearance of 3',5'-T2 tended to be enhanced in acromegalic patients (8.2 ml/min versus 3.9 ml/min, p less than 0.10), both before and after correction for creatinine clearance. The data suggest that in acromegaly, as in normal condition, iodothyronines are subject to both glomerular filtration and active tubular transport mechanisms. Further, active acromegaly results not only in increased GFR, but also in changes of the net tubular transport in favour of secretion of at least T4 and T3, and possibly also of 3',5'-T2.     

Renal handling of cathodic trypsin-like immunoreactivity in man

The renal handling of cathodic trypsin-like immunoreactivity (TLI) was examined in 60 healthy persons (group I), 59 patients with proteinuria (group II), 7 healthy men receiving intravenous lysine to partially inhibit renal tubular protein reabsorption (group III) and 20 patients who underwent diagnostic renal vein catheterization (group IV). The urinary TLI concentration and TLI ratio (TLI clearance divided with creatinine clearance) were higher in group II than group I (p less than 0.001, Mann-Whitney test). In group II negative correlations were present between serum TLI and creatinine clearance (Spearman's rho = -0.84, p less than 0.001) and between TLI ratio and creatinine clearance (rho = -0.76, p less than 0.001). In group III the renal TLI clearance was undetectable before lysine but increased to a maximal median value of 4.00 ml/min per 1.73 m2 (range: 2.44-9.25 ml/min per 1.73 m2) after lysine. In group IV, the renal arterio-venous extraction of TLI was correlated to inulin extraction (rho = 0.85, p less than 0.001). The glomerular filtrability (the ratio between TLI and inulin extractions) was median 0.53 (range: 0.13-0.94). In conclusion, TLI has a high glomerular filtration and an almost complete tubular reabsorption and catabolism (with normal kidney function).