Rate Of Tubular Secretion Research Articles

Tubular Secretion in CKD.

Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

Variation of Urate Transport in the Nephrons in Subtypes of Hyperuricemia

Background: Hyperuricemia cases (HU) can be classified into four subgroups by combining the two main causes of hyperuricemia, i.e. urate underexcretion and overproduction. These subgroups are as follows: underexcretion-type cases (UE); overproduction-type cases (OP); combined-type cases, and normal-type cases. Since urinary urate excretion (Uua) and urate clearance differ significantly between UE and OP, urate transport in the nephrons and the intratubular urate contents might also differ. Such differences might help clarify the pathophysiology of urate underexcretion in subgroups of hyperuricemia, and thus reveal its underlying mechanisms. Methods: Urate transport coefficients in each subtype of HU were determined employing the previously reported benzbromarone-loading urate clearance tests. The subtype cases of HU were plotted on a graph of urate transport coefficients versus Uua as coordinates. The characteristic features in the distribution of subtype cases on graphs were analyzed in relation to Uua. Results: The mean (±standard error) tubular secretion rate (TSR) in the UE (48.7 ± 1.7 ml/min) was significantly lower and the postsecretory urate reabsorption rate (R₂) in the UE (0.904 ± 0.004) was significantly higher than those in the normal controls (78.0 ± 2.1 ml/min and 0.877 ± 0.003) or the OP (61.1 ± 3.2 ml/min and 0.861 ± 0.009). Decrements of TSR and increments of R₂ in the UE were largest in the subtypes of the HU, in terms of case numbers and the deviation rate of the group. Conversely, decrements of TSR and increments of R₂ were smallest in the OP. A significant correlation was identified between TSR and Uua (r = 0.345, p < 0.0001), and a significant negative correlation was also found between R₂ and Uua (r = -0.393, p < 0.0001). Conclusion: In the UE, hyperuricemia is induced mainly by urate underexcretion, which results from the combination of two main causes in urate transporters of the nephron: significantly lower TSR and significantly higher R₂. Neither of these was observed in OP. Differences in urate transporters in subtypes of the HU might be important not only for understanding the pathophysiology and mechanisms of urate underexcretion and hyperuricemia, but also for providing a strategic therapy for hyperuricemia.

Quantitative Estimation of Urate Transport in Nephrons in Relation to Urinary Excretion Employing Benzbromarone-Loading Urate Clearance Tests in Cases of Hyperuricemia

Background: A four-component system for urate transport in nephrons has been proposed and widely investigated by various investigators studying the mechanisms underlying urinary urate excretion. However, quantitative determinations of urate transport have not been clearly elucidated yet. Methods: The equation C_ua = {C_cr(1 – R₁) + TSR}(1 – R₂) was designed to approximate mathematically urate transport in nephrons, where R₁ = urate reabsorption ratio; R₂ = urate postsecretory reabsorption ratio; TSR = tubular secretion rate; C_ua = urate clearance, and C_cr = creatinine clearance . To investigate relationships between the three unknown variables (R₁, R₂, and TSR), this equation was expressed as contour lines of one unknown on a graph of the other two unknowns. Points at regular intervals on each contour line for the equation were projected onto a coordinate axis and the high-density regions corresponding to high-density intervals of a coordinate were investigated for three graph types. For benzbromarone (BBR)-loading C_ua tests, C_ua was determined before and after oral administration of 100 mg of BBR and C_uaBBR(∞) was calculated from the ratio of C_uaBBR(100)/C_ua. Results: Before BBR administration, points satisfying the equation on the contour line for R₁ = 0.99 were highly dense in the region R₂ = 0.87–0.92 on all three graphs, corresponding to a TSR of 40–60 ml/min in hyperuricemia cases (HU). After BBR administration, the dense region was shifted in the direction of reductions in both R₁ and R₂, but TSR was unchanged. Under the condition that R₁ = 1 and R₂ = 0, urate tubular secretion (UTS) was considered equivalent to calculated urinary urate excretion (U_ex) in a model of intratubular urate flow with excess BBR; C_uaBBR(∞) = TSR was deduced from the equation at R₁ = 1 and R₂ = 0. In addition, TSR of the point under the condition that R₁ = 1 and R₂ = 0 on the graph agreed with TSR for the dense region at excess BBR. TSR was thus considered approximately equivalent to C_uaBBR(∞), which could be determined from a BBR-loading C_ua test. Approximate values for urate glomerular filtration, urate reabsorption, UTS, urate postsecretory reabsorption (UR₂), and U_ex were calculated as 9,610; 9,510; 4,490; 4,150, and 440 µg/min for HU and 6,890; 6,820; 4,060; 3,610, and 520 µg/min for normal controls (NC), respectively. The most marked change in HU was the decrease in TSR (32.0%) compared to that in NC, but UTS did not decrease. Calculated intratubular urate contents were reduced more by higher UR₂ in HU than in NC. This enhanced difference resulted in a 15.4% decrease in U_ex for HU. Conclusion: Increased UR₂ may represent the main cause of urate underexcretion in HU.

Characterization of tubular functional capacity in humans using para-aminohippurate and famotidine

Renal drug excretion by glomerular filtration and active tubular secretion may be altered by factors such as acute and chronic renal disease, nephrotoxins, and drug interactions. Thus, accurate and reproducible methods for quantitation of glomerular filtration rate (GFR) and tubular functional capacity are critical. We utilized a four-step sequential infusion method to characterize anionic [para-aminohippurate (PAH)] and cationic (famotidine) tubular functional capacity in healthy volunteers. Filtration and secretion rates were quantitated from renal clearance and iothalamate-derived GFR determinations. Concentration-dependent renal clearance of PAH was observed at plasma concentrations> 100 mg/L; renal clearances were 442 +/- 131 (mean +/- SD), 423 +/- 94, 233 +/- 45, and 152 +/- 18 mL/min/1.73 m2 at plasma concentrations of 18 +/- 2, 92 +/- 5, 291 +/- 47 and 789 +/- 28 mg/L, respectively. The apparent affinity (Km) and maximum secretory capacity (TmPAH) were 141 +/- 70 mg/L and 71 +/- 16 mg/min/1.73 m2, respectively. The unbound renal clearance and tubular secretory clearance of famotidine were 384 +/- 70 and 329 +/- 78 mL/min/1.73 m2, respectively, and were not significantly correlated with the unbound plasma concentrations, which ranged from 126 to 2659 ng/mL. The rate of tubular secretion was linear at unbound plasma concentrations up to 2659 ng/mL. These data indicate that a sequential infusion method using PAH may be used to characterize the anionic secretory component of proximal tubular function. The tubular clearance of famotidine may be a suitable index of the cationic secretory capacity of the proximal tubule in humans. Saturation of the cationic secretory pathway was not observed, and further investigation into parallel pathways of cationic secretion, such as p-glycoprotein, may be warranted.

Electrical transients in the cell-volume response to cyclic AMP of the tsetse fly Malpighian tubule

1. Using cyclic AMP to stimulate perfused tsetse fly Malpighian tubules bathed in SO42- Ringer frequently causes an immediate but transient peak in transtubular potential (Vt), before stabilisation of Vt at an increased value. 2. These transients were investigated by monitoring the associated changes in cable properties and current&shy;voltage (I/V) relationships. Tubules were perfused and bathed in either Cl- Ringer or SO42- Ringer (containing 8 mmol l-1 Cl-). 3. Tubules bathed in Cl- Ringer showed a transient swelling of the cells on exposure to cyclic AMP. Cable analysis confirmed the visually observed narrowing of the tubular lumen and revealed transient increases in core resistance (Rc) and transtubular resistance (Rt). As the cells returned to their initial volume, the lumen became distended, and Rc and Rt fell below their initial levels. These changes were accompanied by an increase, and a subsequent decrease, in the slope of the I/V plot. 4. None of the above changes was apparent in SO42- Ringer, other than a fall in Rt and in the slope of the I/V plot. 5. The results suggest that, in Cl- Ringer, cyclic AMP induces swelling of the tubular cells by promoting increased basolateral solute (and water) entry and that the subsequent rapid return to normal cell volume, with a concomitant progressive increase in the rate of tubular secretion, reflects the operation of a specific cell-volume regulatory mechanism of transepithelial transport. 6. The cyclic-AMP-induced peak that occurs in Vt in SO42- Ringer appears to be primarily due to a transient overshoot in the fall in series resistance (i.e. an increase in basolateral Na+ conductance), accompanied by a proportionately lesser increase in shunt resistance.

Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin.

To investigate the hypothesis that renal secretion of penicillins is enhanced in cystic fibrosis the maximal tubular secretion rate (Tmax) of ticarcillin and the serum concentration of ticarcillin at half-maximal secretion rate (TC50) were determined in patients with cystic fibrosis (n = 6) and control subjects (n = 6). Each subject received three consecutive constant-rate intravenous infusions of ticarcillin (4, 13, and 70 mg/kg/hr; 2 1/2 hours each) simultaneously with a constant-rate (30 mg/kg/hr) infusion of insulin. Urine samples were collected at 1/2-hour intervals and serum samples at the midpoint of the urine collections. Ticarcillin and inulin concentrations in serum and urine were determined by high-performance liquid chromatographic and a spectrophotometric method, respectively. Ticarcillin serum protein binding was determined by ultrafiltration. Steady-state ticarcillin serum concentrations were achieved at all three infusion rates. The TC50 was significantly lower (p < 0.05) in patients with cystic fibrosis (33.7 +/- 12.2 micrograms/ml) compared with that in control subjects (77.6 +/- 38.4 micrograms/ml). In contrast, the Tmax was similar (cystic fibrosis, 0.25 +/- 0.12 mg/min/kg; control, 0.22 +/- 0.14 mg/min/kg; p > 0.05). These data indicate that renal clearance of penicillins is enhanced in cystic fibrosis because of greater affinity of the renal secretory system for these drugs.

Pharmacokinetics of carteolol in patients with impaired renal function.

In order to determine the appropriate dosage of carteolol in renal dysfunction, the pharmacokinetics of carteolol has been examined in appropriate patients. The plasma concentrations and urinary excretion of carteolol were investigated in 15 patients with varying degrees of renal impairment during the administration of 5-20 mg carteolol hydrochloride (5 mg/tablet) for 2-45 months. Plasma carteolol levels were linearly correlated with the serum creatinine concentration (r = 0.87) and reciprocally with the creatinine clearance (r = 0.82). The urinary carteolol concentration was correlated with the urinary creatinine concentration (r = 0.69) and the urinary carteolol excretion was also correlated with the creatinine clearance (r = 0.79). These relationships become even closer when the plasma carteolol concentrations and urinary excretion rate of carteolol were factored by the administered tablets. The fractional renal excretion of carteolol was virtually constant at various degrees of renal function, and it always exceeded 100%, which indicates that carteolol was actively secreted, even in patients with renal failure. The estimated tubular secretion rate of carteolol was logarithmically correlated with the fractional renal excretion of carteolol (r = 0.93). The results indicate that the dose of carteolol should be determined according to the degree of renal impairment.

Discrepancy between circadian rhythms of inulin and creatinine clearance.

To elucidate the disparity between circadian rhythmicity of inulin and creatinine clearance, we simultaneously measured inulin and creatinine clearances every 3 hours during 1 day in 14 normal subjects and in 8 patients with nephrotic syndrome. All patients and normal subjects had a circadian rhythm for inulin clearance with a maximum during daytime and a relative amplitude of 21% +/- 2%. For creatinine clearance a rhythm was either absent or reduced in relative amplitude (p less than 0.01). In all subjects the rate of tubular creatinine secretion was higher at minimum of inulin clearance (night) than at maximum (day). The fractional clearance (relative to inulin) of creatinine was also higher during the night: normal subjects, 1.28 +/- 0.02 versus 1.10 +/- 0.02; patients, 1.78 +/- 0.08 versus 1.45 +/- 0.05 (p less than 0.005). This demonstrates the inaccuracy of creatinine clearance as a measure of glomerular filtration rate (GFR). By subsequent blocking of the tubular secretion of creatinine with cimetidine in four normal subjects, creatinine clearance became similar to inulin clearance during day and night. This confirms that high tubular secretion of creatinine during the night counteracts the normal rhythmicity of glomerular filtration of creatinine. As a result, plasma creatinine concentration is nearly constant during a 24-hour period. In conclusion, tubular creatinine secretion has a circadian rhythm with a phase opposite to the rhythm of GFR, thus blunting or causing absence of a circadian rhythm for creatinine clearance.

Effect of renal impairment on disposition of pentopril and its active metabolite.

Disposition of pentopril was studied in 15 male volunteers with varying renal functions. Mild to moderate compromise in renal function did not demonstrate any appreciable changes in plasma concentration of pentopril, the prodrug ester of the active angiotensin-converting enzyme (ACE) inhibitor CGS 13934. This is consistent with the known elimination pattern for pentopril, which is eliminated primarily by hydrolysis to the active inhibitor. In contrast, the plasma concentration of the active ACE inhibitor was sensitive to moderate changes in renal function. Because of the reciprocal relationship of AUC and clearance, AUC did not change to any appreciable extent until creatinine clearance (CLCR) dropped to about 50 ml/min. Below 50 ml/min of CLCR, AUC and half-life increased sharply with reduced kidney function. Because of the significant contribution of the renal secretion process to total renal elimination of both pentopril and the active metabolite, prediction of renal clearance from CLCR was poor at relatively normal kidney function (CLCR greater than 80 ml/min). However, renal secretory clearances for both pentopril and metabolite were well correlated to p-aminohippuric acid clearance. In patients with moderately compromised renal function (glomerular filtration rate less than 40 ml/min), tubular secretion rate of creatinine approaches its glomerular filtration rate and hence CLCR could be used as a predictor of renal clearance and other disposition parameters. Plasma ACE activity also demonstrated prolonged inhibition with decreased renal function. Based on the prolonged blockade of plasma ACE activity, some correction in dose or dosing interval is anticipated in patients with moderately compromised renal function (CLCR less than 50 ml/min).

Renal Excretion of Uric Acid and its Relation to Relapse and Remission in Acute Myeloid Leukaemia

The role of the kidney in uric acid homeostasis was investigated in 11 patients with acute myeloid leukaemia. Renal clearance studies were performed in all patients before and after the first course of anti-leukaemic therapy; in 5 patients at remission and in 2 of these during relapse. Urinary excretion of uric acid was much higher at lower serum urate levels in leukaemic patients than in normal subjects. The main renal regulatory mechanism of urate excretion appeared to be operated through variations in the rate of tubular secretion of urate (TSurate); with an increase in TSurate during anti-leukaemic therapy and during relapse. Proximal renal tubular dysfunction developed in all patients and large quantities of urate escaped reabsorption in the renal tubule during active disease. The size of the fraction of urate excretion attributable to incomplete tubular reabsorption was unpredictable, but often increased after chemotherapy and during relapse with a fall in the serum urate level and fell during remission with an increase in serum urate. This component of urinary excretion of urate interfered with the usual dependence of TSurate on serum urate, with the result that the urate profile of remission (normal serum urate and low TSurate) could be distinguished from that of relapse (low serum urate and high TSurate).

Renal effects of potassium niobate

The renal effects of a single intravenous dose of 30 mg/kg of niobium as potassium niobate were observed in female mongrel dogs and in female albino rats for various time intervals up to 30 days. In dogs, niobium produced marked decreases in glomerular filtration rate, the maximal rate of tubular secretion of p-aminohippurate, and the maximal rate of tubular reabsorption of glucose. Histologic studies of the kidneys revealed injuries in both the proximal and the distal tubules. Some tubular lumina were filled with granular pigment throughout all levels of cortex and medulla, while others contained casts. The epithelial cells were flattened in some areas and necrotic in others. Niobium-poisoned rats showed marked increases in water intake and urine volume, and decreases in urinary density and osmolality. Urinary sodium execretion increased for the first 2 days but decreased on day 7. Rats lost their urine-concentrating ability, failed to respond to injection of antidiuretic hormone, and peak urine excretion rate after a water load was delayed. Increases in kidney weight and kidney weight to body weight ratios were noted. The renal histologic changes, like those in dogs, involved both proximal and distal tubules, and consisted of tubular dilation and the presence of scattered hyaline casts and deposits of granular pigment. Tubules occasionally showed necrosis, regeneration, and early fibrosis.

Urinary and biliary excretion of dyes in acidosis and alkalosis in the dog.

Excretion of various phenol red derivatives [phenol red (PSP), bromphenol blue (BPB), and bromcresol green (BCG)] was studied in anesthetized dogs in metabolic acidosis and alkalosis. Similar studies were also made on a phthalein dye, Bromsulphalein (BSP), for comparison. In general, the rate of urinary excretion was greatest in PSP and decreased in BPB, BSP, and BCG in that order; the rate of biliary excretion was greatest in BSP and decreased in the following order; BPB, PSP, and BCG. Although alkalosis slightly augmented the urinary excretion of phenol red derivatives, it lowered the excretion of BSP. It is postulated that this differential rate of urinary excretion of various phenol red derivatives is primarily due to the difference in the rate of tubular secretion rather than that in subsequent reabsorption. The biliary excretion of the dye was practically identical in both acidosis and alkalosis, and this was attributed to the fact that the difference in hepatic bile pH between acidosis and alkalosis was very small. However, the biliary dye excretion was proportional to the rate of bile flow. The gall bladder acidified bile to a similar extent in both acidosis and alkalosis.