Goal setting & Network 9/10 efforts to improve care.

TRN, through its Medical Review Board, has developed, endorsed, and articulated goals for two aspects of dialysis treatment. These goals promote the use of continuous quality improvement by encouraging dialysis programs to perform internal examinations of their own data in the context of regional and national data. TRN believes that this combination of data feedback, CQI, and goal setting will impact positively on patient outcomes for all dialysis patients within The Renal Network.

Tyrosine phosphorylation of human platelet plasma membrane Ca(2+)-ATPase in hypertension.

Intracellular Ca(2+) is increased in the platelets of hypertensive individuals. Previously, we demonstrated that platelet plasma membrane Ca(2+)-ATPase (PMCA) activity inversely correlates with diastolic blood pressure and that inhibition of this Ca(2+) pump could explain the elevation of cytosolic Ca(2+) in hypertension. More recently, we discovered that PMCA is phosphorylated on tyrosine residues during thrombin-stimulated platelet aggregation and that this phosphorylation causes inhibition of PMCA activity. In the present work, we tested the hypothesis that tyrosine phosphorylation of PMCA in hypertensive patients could account for the observed inhibition of the Ca(2+) pump. Platelets were obtained from untreated hypertensive and normotensive volunteers. PMCA was immunoprecipitated from solubilized platelets, and tyrosine phosphorylation was quantified by chemiluminescence of immunoblots treated with anti-phosphotyrosine. PMCA content was measured on the same immunoblots by stripping and reprobing with anti-PMCA. Phosphorylation was reported as normalized phosphotyrosine chemiluminescence per nanogram PMCA (mean+/-SE). The average PMCA tyrosine phosphorylation for 15 normotensive subjects was 0.53+/-0. 09, whereas the average for 8 hypertensive individuals was 1.82+/-0. 25 (P<0.0005, Mann-Whitney U test). Age, gender, and systolic blood pressure did not correlate with PMCA phosphorylation. These results suggest that PMCA in platelets of hypertensive individuals is inhibited because of tyrosine phosphorylation, resulting in increased platelet intracellular Ca(2+), hyperactive platelets, and increased risk of heart attack and stroke.

Informatics and end-stage renal disease.

Medical informatics is an interdisciplinary field that deals with the intellectual activities; information management; and communication tasks of medical practice, basic science and clinical research, and medical education. By projecting the future of medical informatics as it specifically relates to applications in end-stage renal disease, this report focuses on some technical innovations, application of existing technology in novel ways, and program applications useful for practitioners caring for renal patients.

Pharmacokinetics of oral glyburide in subjects with non-insulin-dependent diabetes mellitus and renal failure.

To test the hypothesis that renal failure has no effect on the pharmacokinetics of glyburide, five subjects with non-insulin-dependent diabetes mellitus (NIDDM) and end-stage renal disease requiring hemodialysis, and four NIDDM subjects with normal renal function were studied. On days 0, 1, and 15, subjects consumed 33 carbohydrate grams, and glucose, insulin, and C-peptide were measured for 4 hours. On day 1, subjects received 3 mg glyburide and measured plasma concentrations for 48 hours. On day 3, multiple dosing on 3 mg glyburide daily began. On day 15, plasma concentrations were measured for 48 hours. The pharmacokinetics and pharmacodynamics of glyburide, glucose, insulin, and C-peptide were determined as well as daily fasting blood glucose. Glucose area under the curve (AUC) and daily fasting glucose levels did not change in either controls or hemodialysis subjects. The mean serum glyburide blood levels and pharmacokinetics did not differ after initial or chronic glyburide administration in NIDDM subjects with end-stage renal disease treated with hemodialysis compared with controls. Glyburide half-life averaged 3.3 hours in control subjects and 5.0 hours in hemodialysis subjects. Hemodialysis subjects had increased C-peptide and insulin AUC with chronic dosing. Renal failure does not affect the pharmacokinetics of 3.0 mg oral glyburide.

Hemodynamic, renal, and hormonal responses to lower body positive pressure in human subjects.

Studies in healthy human subjects subjected to lower body positive pressure (LBPP) have failed to elucidate many of the physiologic effects of this maneuver. In 7 healthy, well-hydrated men we studied the following responses to LBPP (35 mm Hg, 1 hour, supine position): systemic and renal hemodynamics; urine volume (UV), urine osmolality (Uosm), and urine sodium level (UNaV); free water (CH20) and osmolar (Cosm) clearances; plasma renin activity (PRA); levels of aldosterone (PA), cortisol (CORT), norepinephrine (NE), atrial natriuretic peptide (ANP), and vasopressin (AVP); osmolality (Posm); and serum sodium level. Subjects were restudied on a control day with zero trouser pressure. The recorded changes (p < 0.05) when comparing the LBPP day with the control day were as follows: fractional Na+ reabsorption increased (98.7% +/- 0.2% to 99.3% +/- 0.1%) and UNaV decreased (0.19 +/- 0.03 mEq/min to 0.10 +/- 0.01 mEq/min), with concomitant increases in PRA (1.7 +/- 0.2 ng/ml/90 min to 4.5 +/- 1.8 ng/ml/90 min), PA (7.7 +/- 0.7 ng/dl to 9.3 +/- 1.5 ng/dl), and CORT (13.0 +/- 2.6 mg/dl to 19.2 +/- 3 mg/dl); the increase in blood pressure with LBPP (96 +/- 3 mm Hg to 112 +/- 4 mm Hg) was greater than that during control conditions. Renal plasma flow tended to display an interactive pattern across days, with a slight decline during LBPP (5%) and a slight elevation under control conditions (9%). On the LBPP day only, filtered Na+ declined (15 +/- I mEq/min to 12 +/- 1 mEq/min) as a function of reduced glomerular filtration rate (112 +/- 5 ml/min to 91 +/- 7 ml/min), blood volume decreased (by 2.7% +/- 0.7%), CO decreased (5.5 +/- 0.3 L/min to 4.7 +/- 0.3 L/min), and stroke volume declined (101 +/- 6 ml to 84 +/- 3 ml). On both days, NE increased (control, 221 +/- 23 pg/ml to 340 +/- 33 pg/ml; LBPP, 236 +/- 17 pg/ml to 369 +/- 31 pg/ml) and ANP increased (control, 47 +/- 7 pg/ml to 97 +/- 21 pg/ml; LBPP, 49 +/- 10 pg/ml to 104 +/- 30 pg/ml). We concluded that LBPP reduces renal sodium excretion. The mechanism for this reduction is not known, although it did occur in association with an increase in plasma renin activity, which in turn results from mechanical reduction of renal perfusion, stress-related CORT stimulation, a reflex-based elevation in peripheral vascular resistance leading to a reflex increase in plasma renin activity, or a combination of these.

Application of artificial neural networks to clinical pharmacology.

Drug dosages and drug choices are determined by a knowledge of the drug's pharmacokinetics and pharmacodynamics. Often, insufficient information is available to determine the pharmacokinetics of a drug or which drug will have a desired effect for an individual patient. We propose that a form of nonlinear regression, an artificial neural network, can be used. We have demonstrated this use with 2 examples. In the first example we use a neural network to predict gentamicin peak and trough concentrations from routine therapeutic drug monitoring. In the second example we predict delayed renal allograft function as a guide for induction of immunosuppression therapy. Predictions were made using a multilayer feedforward perceptron and compared to nonlinear mixed effect modeling (NONMEM) and logistic regression. Neural network peak and trough gentamicin predictions were more precise and less biased than control predictions made using NONMEM. Prediction error for peak serum concentrations averaged 16.5% for the neural networks and 18.6% for NONMEM. Prediction error for trough concentrations were 48.3% for neural networks and 59.0% for NONMEM. When used for the prediction of delayed graft function, the neural network correctly predicted immediate graft function 73% of the time and delayed graft function 65% of the time. For those patients predicted to develop delayed graft function, alternate induction using anti-lymphocyte globulin may be indicated. These 2 examples demonstrate how an artificial neural network may be applied to predictions in clinical pharmacology.

Pharmacodynamics of atrial natriuretic peptide in isolated perfused Dahl rat kidneys.

Atrial natriuretic peptide (ANP) has been implicated in the development of hypertension in Dahl R and S rats. To test the responses of DR and DS kidneys in the absence of the influence of neural and humoral mechanisms, we investigated the pharmacokinetics and pharmacodynamics of ANP in isolated perfused DR and DS kidneys, obtained from rats given a high or low sodium diet, after a bolus injection of ANP (1 microgram) or after a bolus injection plus infusion of ANP to maintain the perfusate concentration at 1000 pg/ml. The elimination rate constant was not different between the groups (DR, 0.044 min-1 vs. DS, 0.050 min-1). Clearance of ANP was 4 times greater than the glomerular filtration rate, indicating that a receptor-mediated peritubular clearance is probably the primary route of elimination. DS kidneys excreted 50% less sodium than DR kidneys. However, ANP caused a 5-fold increase in fractional sodium excretion in both DR and DS. ANP also increased sodium excretion, creatinine clearance, and urine flow. No alteration in ANP kinetics occurred to account for the reportedly increased circulating concentrations of ANP seen in DS rats. We conclude that isolated DR and DS kidneys respond differently to ANP after bolus ANP administration to concentrations of 10,000 pg/ml. This difference in response is due to the sodium excretory defect inherent in the DS kidney and not to an alteration in the DS kidney's ANP responsiveness.

Population pharmacokinetics of the active metabolite of nabumetone in renal dysfunction.

We determined the pharmacokinetics of 6-methoxy-2-naphythylacetic acid (6-MNA), the active metabolite of nabumetone, in normal subjects and in subjects with impaired renal function, including subjects requiring hemodialysis. Subjects received a 1000 mg oral dose of nabumetone either as a single dose or daily for 15 days. We used a noncompartmental pharmacokinetic analysis and compared those results to a population pharmacokinetic analysis performed with nonlinear mixed-effects modeling (NONMEM). The results of the two different analyses were similar. The elimination half-life increased with decreased renal function and ranged from 22 to 44 hours. The area under the curve decreased significantly at steady state, regardless of renal function. The apparent clearance determined by NONMEM analysis increased from 0.68 L/hr after a single dose to 1.13 L/hr at steady state. The apparent volume of distribution was directly proportional to the nonalbumin protein concentration and ranged from 23 to 60 L. We conclude that the pharmacokinetics of 6-MNA in this population are complicated by possible protein binding changes. However, the increased half-life in patients with renal failure is offset by changes in the apparent volume of distribution that prevent the accumulation of 6-MNA in the serum of patients with impaired renal function. Therefore dosage adjustments may not be necessary in patients with decreased renal function.

Neural network predicted peak and trough gentamicin concentrations.

Predictions of steady state peak and trough serum gentamicin concentrations were compared between a traditional population kinetic method using the computer program NONMEM to an empirical approach using neural networks. Predictions were made in 111 patients with peak concentrations between 2.5 and 6.0 micrograms/ml using the patient factors age, height, weight, dose, dose interval, body surface area, serum creatinine, and creatinine clearance. Predictions were also made on 33 observations that were outside the 2.5 and 6.0 micrograms/ml range. Neural networks made peak serum concentration predictions within the 2.5-6.0 micrograms/ml range with statistically less bias and comparable precision with paired NONMEM predictions. Trough serum concentration predictions were similar using both neural networks and NONMEM. The prediction error for peak serum concentrations averaged 16.5% for the neural networks and 18.6% for NONMEM. Average prediction errors for serum trough concentrations were 48.3% for neural networks and 59.0% for NONMEM. NONMEM provided numerically more precise and less biased predictions when extrapolating outside the 2.5 and 6.0 micrograms/ml range. The observed peak serum concentration distribution was multimodal and the neural network reproduced this distribution with less difference between the actual distribution and the predicted distribution than NONMEM. It is concluded that neural networks can predict serum drug concentrations of gentamicin. Neural networks may be useful in predicting the clinical pharmacokinetics of drugs.

Platelet calcium transport in hypertension.

To determine platelet Ca2+ transport entities involved in increased cytosolic Ca2+ in the platelets of hypertensive individuals, we studied the relations between blood pressure and Ca2+ transporters in platelet membranes from 22 white male volunteers 32 to 68 years old. We used thapsigargin, a specific inhibitor of the internal membrane Ca(2+)-ATPase, to differentiate between plasma membrane and internal membrane Ca(2+)-ATPases. Inositol 1,4,5-trisphosphate-mediated and Ca2+ ionophore (A23187)-induced Ca2+ release was also assayed in membrane preparations using rhod-2, a fluorescent Ca2+ indicator. Levels of glycoprotein IIIa, a possible component of agonist-mediated Ca2+ influx, were measured by immunoblotting. The results show that plasma membrane Ca(2+)-ATPase is decreased as a function of diastolic blood pressure (P < .002), whereas the internal membrane Ca(2+)-ATPase is not (P < .148). Neither activity is correlated with age or systolic blood pressure. However, inositol trisphosphate-mediated Ca2+ release is negatively correlated with age (P < .024) but not blood pressure. Glycoprotein IIIa levels and A23187-induced Ca2+ release were not related to age or blood pressure, demonstrating that inhibition of the plasma membrane Ca(2+)-ATPase was not a result of differences in the proportion of plasma membrane in the preparation or differences in intravesicular Ca2+ concentration. Inhibition of the plasma membrane Ca(2+)-ATPase could directly cause elevation of cytoplasmic Ca2+ and enhancement of platelet sensitivity.

Initial intraperitoneal therapy for CAPD peritonitis: the Network 9 Peritonitis Study.

The choice of initial antibiotic therapy for continuous ambulatory peritoneal dialysis (CAPD) peritonitis is complex. To test the hypothesis that the initial choice of intraperitoneal antibiotics does not influence the outcome of therapy for CAPD peritonitis, we studied 1930 patients on peritoneal dialysis as of 1 January 1991, and recorded all episodes of peritonitis for one year. There were 1168 episodes of peritonitis for which 64% of the patients received intraperitoneal antibiotics as the first course of treatment. We determined peritonitis resolution, technique failure, hospitalization, and catheter removal rates as measures of successful treatment for peritonitis. Cephalothin, cefazolin, vancomycin, and ceftazidime were used alone or in combination with the aminoglycosides, tobramycin and gentamicin. The mean resolution rate was 65% following the first course of antibiotics and 76% by the third course of antibiotics, if necessary. The antibiotic regimens were not different with respect to resolution rate except when aminoglycosides were used alone. Technique failure was also greater in patients treated with aminoglycosides without other antibiotics. Hospitalizations were increased in patients treated with single drug therapy. If initial intraperitoneal therapy includes treatment for both gram-positive and gram-negative bacteria, the initial choice of intraperitoneal antibiotics does not influence the outcome of therapy for CAPD peritonitis.

Drugs and the kidney.

Renal insufficiency affects every organ system and every aspect of drug disposition by the body. Because the kidney is the organ responsible for the elimination of most drugs or their metabolites from the body, renal dysfunction results in substantial changes in drug therapy. Furthermore, the kidney is often a target organ for the expected physiological effects of the drugs that are given or for their toxicity. Finally, our therapeutic options for treating uremia complicate drug therapy by further changing drug disposition. This article reviews recent work aimed at understanding these processes.

Erythropoietin-induced antinatriuresis mediated by angiotensin II in perfused kidneys.

Erythropoietin (EPO)-induced hypertension is a common complication of EPO usage. The hypothesis that erythropoietin is antinatriuretic and that the sodium retention is mediated by intrarenal angiotensin II production was tested. Experiments were performed in Wistar rat kidneys perfused for 60 min in an isolated system. A dose-response curve was performed for EPO at 0, 10, 100, 1,000, and 10,000 mU/mL. EPO administration resulted in a dose-dependent decrease in sodium excretion to a maximum of 50% at the 1,000 mU/mL dose. In a second experiment, kidneys from five groups were perfused: controls, EPO (100 mU/mL), captopril (50 ng/mL), captopril (50 ng/mL) plus EPO (100 mU/mL), and the angiotensin receptor antagonist losartan (1 nM) plus EPO (100 mU/mL). The administration of EPO resulted in an immediate decrease in average sodium excretion (30%) with no change in GFR or other renal function parameters. Pretreatment with captopril or losartan blocked the effect of EPO. Captopril alone had no effect on renal function. A final experiment demonstrated the ability of losartan (10 nM) to block the pressor effects of angiotensin II (0.01, 0.1, and 1 nM). It was concluded that EPO acts within the kidney to cause the production of angiotensin II, which mediates the increased reabsorption of sodium.

Case report: acute focal bacterial pyelonephritis (lobar nephronia)--presentation as a palpable abdominal mass.

Acute lobar nephronia, or focal pyelonephritis, is an uncommon form of renal infection with a distinct computerized tomographic appearance. A patient is presented with lobar nephronia characterized by fever, flank pain, urosepsis, and painful abdominal mass. Differentiating this condition from abscess or other renal mass is important, because the treatment of lobar nephronia is nonsurgical. The infection responds to antibiotic therapy.

Therapeutic implications associated with renal studies of nabumetone.

Nonsteroidal antiinflammatory drugs (NSAID) decrease renal prostaglandins and may cause a decrease in renal blood flow, glomerular filtration, and sodium excretion. In some cases, these effects result in renal failure, edema, or hypertension. Patients with decreased effective circulating fluid volume are at greatest risk for development of these renal side effects. In addition, NSAID can cause interstitial nephritis. However, in double blind and open label controlled clinical trials, nabumetone had an effect on renal function in less than 1% of patients, regardless of sex or advanced age. Furthermore, in patients with normal or impaired renal function, single or multiple doses of nabumetone did not cause significant changes in creatinine clearance or serum creatinine values. However, with any NSAID including nabumetone, renal function should be measured before beginning therapy and periodically thereafter in patients at risk for the development of renal impairment.

Nonsteroidal anti-inflammatory drug induced renal syndromes.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause acute renal failure from unopposed vasoconstriction or acute interstitial nephritis. NSAID induced hemodynamic renal failure is characterized by sudden oliguria, often with decreased fractional excretion of sodium, occurring in patients with decreased effective circulating fluid volume or preexisting renal disease. Allergic interstitial nephritis from NSAIDs may occur at any time during therapy with the drugs and may present as renal failure with or without the nephrotic syndrome. Although chronic renal failure has been reported, both renal syndromes usually resolve when treatment with the NSAID is discontinued. Renal function should be measured soon after initiation of therapy in patients at risk for the hemodynamic effects of the drugs and periodically thereafter. Patients should be warned about the potential toxicity of the drugs.