The search continues--an ideal marker of GFR.
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Biomarkers↗
Biomedical subjects
S K Swan
Publications and source records attributed to S K Swan.
Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis.
BACKGROUND: Heavy proteinuria and progressive renal injury recur after transplantation in up to 40 percent of patients with renal failure caused by idiopathic focal segmental glomerulosclerosis. A circulating factor may be responsible for this recurrence. METHODS: To determine whether patients with focal segmental glomerulosclerosis have a circulating factor capable of causing glomerular injury, we tested serum samples from 100 patients with the disorder in an in vitro assay of glomerular permeability to albumin. Of the 56 patients who had undergone renal transplantation, 33 had recurrences. Sixty-four patients, many of whom had undergone transplantation, were being treated with dialysis. Thirty-one patients with other renal diseases and nine normal subjects were also studied. RESULTS: The 33 patients with recurrent focal segmental glomerulosclerosis after transplantation had a higher mean (+/-SE) value for permeability to albumin (0.47+/-0.06) than the normal subjects (0.06+/-0.07) or the patients who did not have recurrences (0.14+/-0.06). After plasmapheresis in six patients with recurrences, the permeability was reduced (from 0.79+/-0.06 to 0.10+/-0.05, P = 0.008), and proteinuria was significantly decreased. Patients with corticosteroid-sensitive nephrotic syndrome or with membranous nephropathy after transplantation had low levels of serum activity. The circulating factor bound to protein A and hydrophobic-interaction columns and had an apparent molecular mass of about 50 kd. CONCLUSIONS: A circulating factor found in some patients with focal segmental glomerulosclerosis is associated with recurrent disease after renal transplantation and may be responsible for initiating the renal injury.
Adult↗
Determination of residual renal function with iohexol clearance in hemodialysis patients.
Residual renal function (RRF) may contribute significantly to the total dialysis prescription. Conventional quantitation of RRF in hemodialysis (HD) patients is measured by urea clearance and requires a 24-hour urine collection which is often difficult to perform and inaccurate. The renal clearance of iohexol was evaluated as an alternative method for RRF assessment (iohexol-derived RRF) in hemodialysis patients. An intravenous bolus of iohexol (12 ml; 300 mg iodine/ml) was administered to 42 hemodialysis patients following routine HD. A single blood sample was obtained approximately 44 hours later (pre-HD) to determine the plasma clearance of iohexol using x-ray fluorescence methods. Total body clearance of iohexol (CTBio) and non-renal clearance of iohexol (CNRio) 2.87 +/- 0.3 ml/min (mean +/SEM) were used to calculate iohexol-derived RRF (CTBio-CNRio). Iohexol-derived RRF determinations were then compared to urea clearance-derived RRF measurements. The RRF contribution to the dialysis prescription was also calculated utilizing iohexol-derived RRF compared to urea-derived RRF. Iohexol-derived RRF did not differ from urea-derived RRF (2.48 +/- 0.3 vs. 2.64 +/- 0.4 ml/min, P = 0.21). The RRF contribution to the weekly dialysis prescription (Kt/V) did not differ when iohexol-derived RRF was compared to urea-derived RRF (0.94 +/- 0.1 vs. 0.93 +/- 0.1, P = 0.9). Additionally, the effect of iohexol on RRF was assessed in 17 HD patients. Urea-derived RRF determinations one week after iohexol exposure did not differ from those measured one week prior to iohexol exposure (3.17 +/- 0.6 vs. 2.91 +/- 0.5 ml/min, respectively). Thus, renal clearance of iohexol can be an accurate and safe measure of RRF in HD patients and potentially simplify delivery of the dialysis prescription.
Adult↗
Dopamine does not enhance furosemide-induced natriuresis in patients with congestive heart failure.
The objective of this study was to determine whether the addition of low-dose (renal-dose) dopamine to furosemide therapy enhances natriuresis in patients with compensated congestive heart failure, New York Heart Association Class II or III. We performed a randomized, controlled, open-label, crossover study wherein urinary sodium, creatinine, and furosemide excretion rates and GFR determined by inulin clearance rates were measured during each of three treatment interventions: furosemide infusion alone, dopamine infusion alone, and furosemide and dopamine infusions administered concurrently. Six of eight recruited subjects (4 male, 2 female) were able to complete the study. The baseline sodium excretion rate after equilibration on a metabolic diet was 6.7 +/- 0.7 mEq (mean +/- SE) over 3 h. Infusion of dopamine alone caused a slight nonsignificant increase in natriuresis to 36.7 +/- 8.5 mEq/3 h. Furosemide alone markedly increased sodium excretion to 276.6 +/- 47.2 mEq/3 h. No significant additional increment in natriuresis occurred when dopamine and furosemide were administered concurrently (253.8 +/- 73.6 mEq/3 h). Neither dopamine, furosemide, or their coadministration affected GFR. In conclusion, infusion of low-dose dopamine does not enhance furosemide-induced urinary sodium excretion rates in patients with compensated congestive heart failure, New York Heart Association Class II or III.
Aged↗
Immunosuppressive effects of leflunomide in experimental chronic vascular rejection.
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Animals↗
Pharmacologic profile of diaspirin cross-linked hemoglobin in hemodialysis patients.
Various hemoglobin compounds have been evaluated as potential oxygen-carrying, blood volume expanders, but toxicity has prevented clinical application. Diaspirin cross-linked hemoglobin (DCLHb) represents a modified hemoglobin compound that is derived from human red blood cells and maintained in a tetrameric configuration by cross-linkages between the two alpha chains of the hemoglobin molecule. In a randomized, placebo-controlled, single-blind, cross-over trial, DCLHb's safety and pharmacologic parameters were evaluated in 18 subjects receiving chronic hemodialytic therapy. A 30-minute infusion of 25, 50, or 100 mg/kg DCLHb or placebo was given at the start of routine hemodialysis. One week later, the alternate treatment (placebo or DCLHb) was administered. Maximum plasma hemoglobin concentrations and terminal half-life values were calculated for each dosage group. Dialysate was collected and assayed for hemoglobin. Changes in systolic and diastolic blood pressure from baseline and the volume of hypertonic saline administered for treatment of hypotension during hemodialysis were measured. The maximum plasma hemoglobin concentrations increased with DCLHb dose and occurred at the end of DCLHb infusion. The mean (+/- SD) terminal half-life ranged from 2.1 +/- 1.0 hours in the 25 mg/kg DCLHb group to 4.3 +/- 1.4 hours in the 100 mg/kg group, but did not differ significantly between groups. Mean baseline plasma hemoglobin corrected areas under the plasma concentration-time curves increased from 89 to 1,136 mg/hr/dL across the fourfold dose range. Diaspirin cross-linked hemoglobin was not dialyzable as none was detected in dialysate. The maximum increase in systolic blood pressure from baseline increased significantly with DCLHb dose compared with placebo (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effect of lovastatin on the development of polycystic kidney disease in the Han:SPRD rat.
Proliferation of tubular epithelial cells is a major element leading to cyst formation in Han:SPRD rats with autosomal dominant polycystic kidney disease (PKD). ras proteins are important in the control of renal cell proliferation, and ras gene expression is increased in PKD. Farnesyl pyrophosphate, an intermediate in the conversion of acetyl-CoA to cholesterol, is required for the activation of ras guanosine triphosphate (GTP)-binding proteins that are important in the execution of several cellular functions, including cell proliferation. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, such as lovastatin, reduce farnesyl production in responsive cells and thereby have potential for ameliorating the accelerated epithelial cell proliferation of PKD. We administered lovastatin to heterozygous (Cy/+) Han:SPRD rats (4 mg/kg/d subcutaneously) from age 4 to 10 weeks, a period of rapid cystic disease progression in these animals. Untreated male Cy/+ rats developed larger cystic kidneys and had more severe renal functional impairment than females, as reported previously. In males, lovastatin significantly decreased cystic kidney size (referenced to body weight), the volume density of cysts, and the serum urea nitrogen level 14.5%, 24.4%, and 25.6/%, respectively. The corresponding changes in females were insignificant, and lovastatin had no effect on kidney weight or serum urea nitrogen in homozygous (+/+) normal male animals. On the basis of these results we conclude that lovastatin diminishes the severity of PKD in heterozygous male Han:SPRD rats.
Analysis of Variance↗
Long-term effects of reduced renal mass in humans.
The long-term risks of kidney donation have not been well defined. We carried out meta-analysis of investigations that examined the long-term effects of reduced renal mass in humans. We used multiple linear regression to combine studies and adjust for differences in the duration of follow-up, the reason for reduced renal mass, the type of controls, age and gender. We analyzed 48 studies with 3124 patients and 1703 controls. Unilateral nephrectomy caused a decrement in glomerular filtration rate (-17.1 ml/min; 95% confidence interval -20.2 to -14.0 ml/min) that tended to improve with each 10 years of follow-up (1.4 ml/min/decade; 0.3 to 2.4 ml/min/decade). Patients with single kidneys had small, progressive increases in proteinuria (76 mg/day/decade; 52 to 101 mg/day/decade), but proteinuria was negligible after nephrectomy for trauma or kidney donation. Nephrectomy did not affect the prevalence of hypertension, but there was a small increase in systolic blood pressure (2.4 mm Hg; -0.3 to 5.1 mm Hg, P > 0.05) which rose further with duration of follow-up (1.1 mm Hg/decade; 0.0 to 2.2 mm Hg/decade). Diastolic blood pressure was higher after nephrectomy (3.1 mm Hg; 1.8 to 4.4 mm Hg), but this increment did not change with duration of follow-up. Thus, in normal individuals, unilateral nephrectomy does not cause progressive renal dysfunction, but may be associated with a small increase in blood pressure.
Blood Pressure↗
The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats.
Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.
Angiotensin Receptor Antagonists↗
Isoprenoids and Ras: potential role in chronic rejection.
Protein prenylation, the post-translational attachment of isoprenoids to certain cellular proteins, increases protein hydrophobicity and promotes protein-membrane interactions. Of the many cellular proteins that undergo protein prenylation, particular attention has been paid to the protooncogene product Ras. Prenylated Ras protein localizes to the inner cell membrane and appears to function as a "molecular switch" through which peptide growth factors such as PDGF, IGF-1, and FGF, and cytokines such as IL-2, IL-6, and GM-CSF stimulate intracellular events. Binding of these substances to their respective receptors on target cells can activate Ras, triggering intracellular signaling cascades which culminate in processes such as cell proliferation, differentiation, and T-cell activation. Protein prenylation inhibitors block Ras prenylation, prevent membrane localization of Ras, and inhibit growth and proliferation of a variety of cell types. Recent studies in our laboratory have begun to examine the possible role of Ras in chronic allograft rejection. Abdominal aorta segments from donor Lewis rats were transplanted into Buffalo recipient rats. Recipients treated with the HMG-CoA reductase inhibitor lovastatin, which inhibits isoprenoid production, showed significantly decreased allograft intimal area after 12 weeks, when compared with untreated recipients. In a separate study, recipients treated with the agent leflunomide, which inhibits growth factor receptor tyrosine kinases that can activate Ras, had significantly decreased allograft intimal area after 12 weeks. These results suggest that Ras may be important in chronic allograft rejection, and that agents that interfere with Ras protein prenylation or activation by growth factor receptors may ameliorate chronic rejection.
Animals↗
Diuretic strategies in patients with renal failure.
A thorough understanding of the clinical pharmacology of diuretic agents, particularly loop diuretics, is crucial in patients with abnormal (and those with normal) renal function. Renal insufficiency represents a pathophysiological state characterised by diuretic resistance. Diuretic resistance is defined as a diminished pharmacological response, or diminished natriuresis, to a given dose of a diuretic. The phenomenon of diuretic resistance is demonstrated by a shift in the dose-response curve relating urinary diuretic excretion rates (dose) with sodium excretion (response). Pharmacokinetic factors underlie the diuretic resistance observed in patients with renal failure. Diminished renal blood flow and sodium filtration, accumulation of organic acids that inhibit tubular secretion of the diuretic, and inadequate cumulative sodium excretion to meet patients' needs contribute to the diuretic-resistant state. In contrast, the pharmacological response of remnant (i.e. remaining) nephrons to diuretic agents remains intact. The time course of delivery of diuretics to their intraluminal site of action is an independent determinant of natriuretic response. An administration regimen that continuously maintains effective rates of excretion of diuretics into the urine would be expected to cause a greater overall natriuretic effect than the same amount of diuretic administered in intermittent doses. Thus, diuretic administration strategies that take account of the altered pharmacological responses in patients with renal failure are necessary to provide effective and safe treatment. Additionally, such strategies warrant revision by the prescribing physician as renal function changes over time.
Diuretics↗
Pharmacologic limits of the protective effect of polyaspartic acid on experimental gentamicin nephrotoxicity.
Polyaspartic acid (PAA) ameliorates experimental gentamicin nephrotoxicity despite marked accumulation of gentamicin in the renal cortex. The experiments described here probe the extent of PAA's nephroprotective action when increasing doses of gentamicin, in excess of an established nephrotoxic dose (40 mg/kg of body weight per day), are administered. After 10 days, virtually complete nephroprotection was conferred by PAA coadministered to animals receiving three times the nephrotoxic dose (120 mg/kg/day) of gentamicin.
Animals↗
On the probability that kidneys are different in autosomal dominant polycystic disease.
We hypothesized that highly variable cyst fluid sodium concentrations are a characteristic of every kidney in autosomal dominant polycystic kidney disease (ADPKD). We added our data on sodium concentrations in 124 fluids from ten ADPKD kidneys to data published by others of concentrations in 32 fluids from five kidneys. The values ranged from 3 to 207 mEq/liter; none fell between 59 and 74 mEq/liter. Fluids were designated as low (< 60 mEq/liter; 50 fluids) or high (> 60 mEq/liter; 106 fluids) sodium fluids. Transmission electron microscopy identified differences in the depths of apical tight junctions between cells from cyst walls of 12 of the low and 10 of the high sodium fluids from two kidneys (mean +/- SE depths of 2039 +/- 74 A vs. 386 +/- 18 A respectively; P < 0.0001). When fluids were grouped by kidney of origin, six of the 15 kidneys had only high sodium fluids. The probability that chance had led to the sampling of only high sodium fluids in these organs, given that 32% of all fluids were low sodium fluids, was calculated at < 0.00015. The possibility must be considered that all kidneys are not alike in ADPKD.
Adult↗
Duration of the protective effect of polyaspartic acid on experimental gentamicin nephrotoxicity.
It is known that daily polyaspartic acid (PAA) protects the kidney from gentamicin nephrotoxicity in a standardized rat model despite marked cortical accumulation of the aminoglycoside. The present experiments address the duration of PAA protection. When administered every other day, PAA provided functional and histologic protection against gentamicin-induced toxicity. A stepwise reduction in nephroprotection occurred as the dosage interval was prolonged.
Animals↗
Zidovudine pharmacokinetics in five HIV seronegative patients undergoing continuous ambulatory peritoneal dialysis.
A few reports in the literature describe zidovudine (AZT) pharmacokinetics in patients undergoing hemodialysis; however, the effect of continuous ambulatory peritoneal dialysis (CAPD) on the drug's disposition has not been studied. The pharmacokinetics of AZT were evaluated in five patients, age 37-62 years, who were seronegative for the human immunodeficiency virus and were undergoing CAPD. Serial plasma, urine, and dialysate samples were collected after oral administration of AZT 200 mg. Samples were assayed using radioimmunoassay (RIA). Model-independent analysis was used to determine total plasma clearance, apparent volume of distribution, mean residence time, and half-life. Net peritoneal dialysis clearance was calculated to measure the effect of CAPD on AZT disposition. We found wide interpatient variability in AZT pharmacokinetics. Peak serum concentrations ranged from 0.3-47.8 microns and area under the curve from 0.5-26.1 mg x hour/L. These differences resulted in corresponding differences in clearance (range 66-3176 ml/min/1.73 m2) and volume of distribution (range 16-825 L). Interpatient variability in glucuronidation may partially account for this variability. Net peritoneal dialysis clearance of AZT was 5 ml/minute. Although the effect of peritoneal dialysis on AZT disposition was negligible, clinicians should be aware of the large differences in the way in which individual patients with renal dysfunction handle this drug.
Administration, Oral↗
Drug dosing guidelines in patients with renal failure.
The metabolism and excretion of many drugs and their pharmacologically active metabolites depend on normal renal function. Accumulation and toxicity can develop rapidly if dosages are not adjusted in patients with impaired renal function. In addition, many drugs that are not dependent on the kidneys for elimination may exert untoward effects in the uremic milieu of advanced renal disease. A familiarity with basic pharmacologic principles and a systematic approach are necessary when adjusting drug dosages in patients with abnormal kidney function. The distinct steps involve calculating the patient's glomerular filtration rate, choosing and administering a loading dose, determining a maintenance dose, and a decision regarding monitoring of drug concentrations. If done properly, therapy in renal patients should achieve the desired pharmacologic effects while avoiding drug toxicity. Physicians must not oversimplify the pharmacologic complexities presented by patients with renal failure by relying excessively on nomograms and "cookbook" equations. In addition to a reduced glomerular filtration rate, patients with renal disease often have alterations in pharmacokinetics such as bioavailability, protein binding, hepatic biotransformation, and volume of distribution. An awareness of biologically active or toxic metabolites of parent compounds that accumulate when the glomerular filtration rate is reduced is also necessary to avoid toxicity. The effects of dialysis on drug elimination and the need for supplemental dosing are additional considerations in patients undergoing renal replacement therapy.
Drug Monitoring↗
Pharmacokinetics of ganciclovir in a patient undergoing hemodialysis.
The pharmacokinetics and effect of hemodialysis on the clearance of ganciclovir were evaluated in a patient with cytomegalovirus (CMV) retinitis and pneumonitis requiring dialytic support. A dose of 300 mg ganciclovir (5 mg/kg) was administered by intravenous infusion over a 60-minute period. Blood samples were obtained over the next 10 hours and used to assess plasma ganciclovir concentrations. The patient underwent hemodialysis the following day during which paired arterial and venous blood samples were obtained to determine dialyzer clearance of this antiviral agent. High-performance liquid chromatography was used to quantify ganciclovir plasma concentrations. Ganciclovir levels declined in a monoexponential manner following infusion and prior to dialysis. The patient's peak ganciclovir concentration was markedly elevated (20 micrograms/mL) compared with previously reported peak concentrations in patients with normal renal function. Similarly, the elimination half-life (t1/2) was increased (6.3 hours) in this patient compared with values reported in patients with normal renal function. The volume of distribution (0.21 L/kg) and total body clearance prior to hemodialysis (35.5 mL/min) were diminished in this patient. Hemodialysis reduced ganciclovir levels by approximately 62% with an extraction coefficient of 0.29 resulting in a dialyzer clearance of 48.3 mL/min. This supports supplementation of ganciclovir in patients receiving this antiviral agent when they are undergoing hemodialysis. Additionally, close monitoring of ganciclovir concentrations in patients with abnormal renal function is necessary in order to make appropriate dosage adjustments.
Adult↗
Long-term protection of polyaspartic acid in experimental gentamicin nephrotoxicity.
Polyaspartic Acid (PAA) protects the kidney from experimental gentamicin nephrotoxicity despite large increases in renal cortical gentamicin content. In these experiments, prominent cytoplasmic vacuoles were noted in all animals that received PAA with or without gentamicin. The present study showed that there were no renal structural or functional consequences of PAA given alone or with gentamicin for up to 14 days, followed by a 16-week washout period. Creatinine clearance was similar to that of controls in animals that received gentamicin and in those that received PAA alone. Thus, complete functional protection was conferred by PAA and gentamicin, confirming previous reports from our laboratory. There was no protection by PAA from the nephrotoxic effects of mercuric chloride and cis-platinum.
Animals↗