Increased reabsorptive capacity after ureteral obstruction reduces the ability of glucose to inhibit phosphate reabsorption in rat kidney.

BACKGROUND: Proximal tubular reabsorption of glucose (G), phosphate (Pi) and amino acids is energized by the transmembrane Na+ gradient, which explains why decreased concentration of one solute can enhance the transport of another. Accordingly, we postulated that the consistent increase in Pi reabsorption seen in the post-obstructed kidney (POK) could be caused, in part, by the low filtered load of glucose and reversed by glucose loading. METHODS: Renal function was examined before and after i.v. glucose loading in POKs (after release of 24 h of unilateral ureteral obstruction) and control kidneys (CK) of 10 adult rats. Brush-border membrane vesicle (BBMV) transports of Pi and glucose were assessed in POKs and CKs. RESULTS: In POKs GFR, urine flow and Na+ excretion were significantly reduced and tubular reabsorption of both Pi (T(P)/GFR) and glucose (TG/GFR) were significantly increased: T(P)/GFR, 2.0 +/- 0.2 vs 1.36 +/- 0.1; TmG/GFR, 23.4 +/- 1.7 vs 18.9 +/- 1.1 mmol/l. Glucose loading inhibited T(P)/GFR only in the CK. Initial Na+ gradient-dependent uptakes of D-glucose and Pi were similar in BBMVs from POK and CK. CONCLUSIONS: The increases in T(P)/GFR and TG/GFR seen in the POK do not result from decreased glucose delivery or from alterations in BBM Pi and glucose transporters. The reduced ability of glucose to inhibit Pi reabsorption in the POK results primarily from a generalized increase in proximal tubular reabsorption of Na+ and cotransported Pi and glucose. A specific rise in distal Pi transport capacity may be an additional adaptive response to the low filtered load of Pi in the POK. In addition, absent distal glucose reabsorption may further facilitate Pi reclamation at these sites.

Hyperadrenergic state following acute withdrawal from clonidine used at supratherapeutic doses.

Abrupt cessation of clonidine treatment precipitates a physiological withdrawal syndrome, thought to be due to a hyperactive state of central autonomic and cognitive adrenergic neuronal systems dependent on presynaptic alpha 2-adrenoceptors and/or imidazoline receptors. We hereby describe a 36-year-old male with history of end-stage renal disease, hypertension and medication non-compliance, who presented with severe hypertension and remarkable agitation. His daily clonidine intake was estimated to be 10 mg. The patient had abruptly discontinued his clonidine five days prior to admission. The following indices of adrenergic activity were measured in plasma (normal control values in parentheses): noradrenaline (NA) 8.59 nmol/l (1.32-4.56 nmol/l), adrenaline (Adr) 1.86 nmol/l (0.83-4.20) nmol/l), total 3-methoxy-4-hydroxyphenylglycol (MHPG) 152.8 nmol/l (45.1-111.5 nmol/l), and free MHPG 33.0 nmol/l (12.2-31.4 nmol/l). Plasma clonidine level was 3.53 ng/ml (15.9 nmol/l) with the usual therapeutic level being < 2.0 ng/ml (8.9 nmol/l). Initially, the patient received sedatives and was started on clonidine for the first 24 hours only, after which time period prazosin was started, with good response of his blood pressure and reversal of his mental status changes. At that point, the plasma values of indices of adrenergic activity had decreased compared with their corresponding initial values by the following percentages: NA 60.6%, Adr 22.6%, total MHPG 42.2% and free MHPG 11.5%. Plasma clonidine level had decreased now by 43.6% to an absolute value of 1.99 ng/ml (8.85 nmol/l). We emphasize that physicians should be aware of clonidine's abuse potential and caution should be taken, as well as the appropriate route chosen, when prescribing clonidine in patients who show features of poor compliance to medications and especially in patients with psychoses, suicide potential or personality disorders.

Atherogenic lipids and lipoproteins in hemodialysis patients.

Dyslipidemia may contribute to atherosclerosis in hemodialysis patients. While hypertriglyceridemia is relatively common in this population, hypercholesterolemia is not. Since abnormalities in various plasma cholesterol fractions and lipoproteins have been associated with an increased incidence of cardiovascular disease in the nonuremic population, we examined these abnormalities to determine whether they occur in patients with chronic renal failure. Twenty-four patients on maintenance hemodialysis were studied. We found that, despite relatively low plasma total cholesterol levels, a substantial number of patients had low high-density lipoprotein cholesterol, low apolipoprotein AI, and high apolipoprotein B levels. Furthermore, approximately 40% and 30%, respectively, of the patients had elevated plasma levels of lipoprotein(a) and remnants of chylomicron and very low-density lipoprotein. Lipoprotein(a) levels could not be predicted from any of the variables that were studied. The abnormal plasma levels of these potentially atherogenic lipids and lipoproteins suggest that they may contribute to the high incidence of cardiovascular diseases in the hemodialysis population.

Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy.

An interferon-gamma, tumor necrosis factor, and interleukin-1-inducible, high-output pathway synthesizing nitric oxide (NO) from L-arginine was recently identified in rodents. High-dose interleukin-2 (IL-2) therapy is known to induce the same cytokines in patients with advanced cancer. Therefore, we examined renal cell carcinoma (RCC; n = 5) and malignant melanoma (MM; n = 7) patients for evidence of cytokine-inducible NO synthesis. Activity of this pathway was evaluated by measuring serum and urine nitrate (the stable degradation product of NO) during IL-2 therapy. IL-2 administration caused a striking increase in NO generation as reflected by serum nitrate levels (10- and 8-fold increase [P less than 0.001, P less than 0.003] for RCC and MM patients, respectively) and 24-h urinary nitrate excretion (6.5- and 9-fold increase [both P less than 0.001] for RCC and MM patients, respectively). IL-2-induced renal dysfunction made only a minor contribution to increased serum nitrate levels. Metabolic tracer studies using L-[guanidino-15N2]arginine demonstrated that the increased nitrate production was derived from a terminal guanidino nitrogen atom of L-arginine. Our results showing increased endogenous nitrate synthesis in patients receiving IL-2 demonstrate for the first time that a cytokine-inducible, high-output L-arginine/NO pathway exists in humans.

Prescribing hemodialysis using a weekly urea mass balance model.

Prescribing hemodialysis by monitoring only predialysis BUN concentrations is not sufficient to guarantee adequate therapy. Results from the National Cooperative Dialysis Study have suggested that hemodialysis therapy is adequate if the protein catabolic rate is maintained greater than 1 g/day/kg body weight and simultaneously if sufficient hemodialysis is prescribed to maintain either a time-averaged BUN concentration (TACurea) less than 50 mg/dl or a value of Kt/V greater than unity. In the present study mathematical relationships were derived from a weekly urea mass balance model that permit an evaluation of TACurea and of protein catabolism via the urea generation rate (G) without the need for conventional urea kinetic modeling. The parameters TACurea and G were simply calculated from a midweek predialysis BUN concentration (BUNMW) by: TACurea = 0.7 BUNMW G = 0.7 BUNMW(Kr + Kd tau/T) where Kr, Kd, tau and T denote residual renal urea clearance, dialyzer urea clearance, number of minutes of hemodialysis per week, and number of minutes total in a week, respectively. Clinical results from 139 modeling sessions on 91 patients demonstrated that TACurea and G derived from urea kinetic modeling correlated highly with those calculated from the above equations (r = 0.96 and 0.94, respectively). It is concluded that individualized hemodialysis prescription and adequacy of therapy can be assessed by monitoring TACurea and G by calculation from a weekly urea mass balance model.

Effect of osmotic pressure on uptake of chemotherapeutic agents by carcinoma cells.

Intraperitoneal chemotherapy has been used to treat cancers which are confined to the abdominal cavity. Several variables which affect drug delivery into tumor cells have been identified, but the effect of osmotic pressure has not been studied. Tumor cell lines were used to evaluate the effect of fluid tonicity on drug uptake. HeLa cells and a murine teratoma cell line were suspended in solutions of tonicities 154, 308, and 616 mosM, each containing the same quantity of 5-fluorouracil, and uptake of the drug was measured at different intervals over 30 min. At all time points the amount of 5-fluorouracil taken up by cells in solutions of 154 mosM was greater than that in 310 mosM solutions, which was greater than the uptake in 616 mosM solutions, each by an average of 40-50%. Incorporation of drug into tumor cells was also assayed in vivo using a teratoma cell line propagated i.p. in mice. Tumor cell uptake of doxorubicin was increased to a similar extent when this drug was administered in hypotonic solutions of 154 mosM and was decreased by administration in hypertonic solutions of 465 mosM, as compared to solutions of 310 mosM. These results demonstrate that the uptake of chemotherapeutic agents into tumor cells is increased significantly when these drugs are infused in solutions of lower osmolalities, a finding which may be exploited in clinical situations.

Volume homeostasis in calves with artificial atria and ventricles.

We examined whether replacement of cardiac atria and ventricles with total artificial hearts (TAH), a procedure that removes cardiac nerves and all sources of atrial natriuretic factor (ANF), would cause alterations in volume homeostasis in awake calves. Preoperatively, extracted plasma immunoreactive (ir)ANF levels were 13.3 +/- 0.6 and remained postoperatively at 10.5 +/- 0.4 pg/ml (P less than 0.01). TAH implantation caused systemic and pulmonary hypertension (P less than 0.01), salt retention, edema, and significant elevations of plasma renin, aldosterone, and arginine vasopressin. In intact calves rapid infusion of 6 liters of normal saline raised irANF levels to 73.7 +/- 6.5 pg/ml (P less than 0.01) and elicited a large natriuresis and diuresis. No such response to 6 liters of normal saline was obtained after calves had recovered from TAH implantation. Reduction of cardiac output (CO) by 50% caused further salt retention and no change in irANF levels. Elevation of CO back to and 33% above base line produced only a diuresis, whereas salt retention persisted and irANF levels remained unchanged. The same maneuvers elicited in surgical control calves (artificial ventricles only, largely intact atria) a significant increase in irANF levels and a diuresis and natriuresis. In conclusion, alterations in volume homeostasis observed after TAH implantation seem to be the consequence of at least two pathophysiological mechanisms: 1) functional ANF "deficiency," characterized by apparently unregulated ANF secretion from noncardiac sites, and 2) cardiac denervation.

Atrial natriuretic factor and salt adaptation in the teleost fish Gila atraria.

It is unknown whether atrial natriuretic factor (ANF) is a mediator of environmental salt tolerance in euryhaline teleost fish. This was investigated in anesthetized Gila atraria, a euryhaline teleost native to springs of pleistocene Lake Bonneville. Plasma levels of immunoreactive (ir) ANF [using anti-human ANF-(99-126) antibodies] in fish obtained from a "fresh water" spring were significantly lower (146 +/- 27) than those in fish obtained from a "1% NaCl" spring (347 +/- 21 pg/ml, P less than 0.01). Electron micrographs of fish atrial and ventricular cardiocytes demonstrated many perinuclear granules, which closely resembled ANF-containing secretory granules seen in mammalian atriocytes. Fish heart extract contained ANF-like material of 3 kDa, which caused a marked diuresis and natriuresis in rats. In a second study, fish from a 1% NaCl spring were kept in tanks. One-third of the fish were maintained in 1% NaCl and one-third each were either adapted to fresh- or high-salt water. After 12 days, plasma irANF levels in 1% NaCl fish were 343 +/- 55, in fresh water fish 213 +/- 20 and in high-NaCl fish 691 +/- 79 pg/ml. These values differed significantly from each other (P less than 0.01). There was a close correlation between plasma irANF levels and both environmental and internal salt concentration. These data suggest that piscine ANF is an as yet unrecognized mediator of salt tolerance in this teleost and that ANF in these animals closely resembles mammalian ANF.

Rebound following hemodialysis of cimetidine and its metabolites.

The effect of hemodialysis on the pharmacokinetics of cimetidine and its metabolites was studied after the intravenous administration of a 300-mg dose of cimetidine. Serum concentrations were monitored before, during, and after hemodialysis. Cimetidine pharmacokinetics were similar to those in patients with end-stage renal failure, with a total body clearance of 3.3 +/- 1.0 mL/min/kg and a half-life of 4.1 hours. Dialysis caused an initial decrease in serum concentrations for cimetidine, hydroxymethyl cimetidine, and cimetidine sulfoxide, followed by a rebound in serum concentrations immediately after treatment. Dialysis clearances, as calculated from extraction ratios, were 83 +/- 15, 90 +/- 16, 93 +/- 24, and 126 +/- 23 mL/min for cimetidine, hydroxymethyl, sulfoxide, and creatinine, respectively. After four hours of dialysis, 10% +/- 3.2% of the cimetidine dose was recovered in the dialysate. The sulfoxide and hydroxymethyl metabolites demonstrated relatively constant serum concentrations for up to 24 hours postdosing, and therefore, estimates of their terminal half-lives were not possible. In one patient, accumulation of both metabolites occurred during multiple dosing. Hemodialysis is an ineffective means of decreasing the total body load of cimetidine and its metabolites. Presumably, sequestration of the drug in body tissues decreases the amount of drug present in the blood available for dialysis removal, with rebound occurring due to postdialysis re-equilibriation between blood and extravascular fluids.

Intraperitoneal insulin regimens and diabetic nephropathy.

Five patients with severe diabetic nephropathy (SN) and six patients with moderate diabetic nephropathy (MN) have been treated with intraperitoneal (i.p.) insulin administered by multiple injections. The five SN patients progressed to end-stage kidney disease. The six MN patients (five of whom are described) show stabilisation (and in two cases possibly some improvement) of renal function over time intervals ranging from eight to 23 months.

Pressure control of ultrafiltration rate with high-flux dialysis membranes.

Control of ultrafiltration with high-flux dialysis membranes is normally achieved using complex, expensive, volumetric control methods. By using high-flux dialyzers with distensible membranes (parallel-plate dialyzers) in the cocurrent rather than in the countercurrent mode, ultrafiltration can be controlled simply and inexpensively by controlling the outlet pressure differential. Since this is the traditional method of ultrafiltration control, only minor, inexpensive equipment modifications are needed. As expected from transport theory, small molecule clearances are lower with cocurrent than with countercurrent flow. They are, however, adequate and superior to those achieved with post-dilutional hemofiltration (urea clearance greater than 110 ml/min with cocurrent single-pass, high-flux dialysis). Ultrafiltration control with this method is so simple and predictable that clearances at zero net ultrafiltration rates can easily be measured rather than extrapolated. Since dialysate pressure is always positive, no deaeration systems would be needed in dialysis equipment designed for use with cocurrent single-pass, high-flux dialysis.

Controlled ultrafiltration during single-pass dialysis with the RP-6 dialyzer and evaluation of its time-dependent ultrafiltration index.

A simple and inexpensive method is described for controlling ultrafiltration when using the high flux RP-6 dialyzer. When th RP-6 is operated in the co-current mode and with single-pass dialysate delivery, (PBo-PDo) can be used to accurately and safely control ultrafiltration. Combined results from ten dialyses indicate there is a pressure-dependent concentration polarization which affects ultra-filtration as reported previously, and in addition, a time-dependent effect indicating a more complex dialyzer/blood interaction. The ultrafiltration index decreases linearly with time. The ultrafiltration can be adequately predicted by (Formula: see text).

Dialysis/hemofiltration in schizophrenia: a journey by night and cloud.

Hypotheses for the etiology of schizophrenia are discussed and related to possible treatments utilizing artificial kidney systems. For hemofiltration particularly, a theoretical framework is presented for treatment planning. Emphasis is placed on the necessity of using rigid diagnostic criteria for patient selection. Results are reported on two "strict" schizophrenic patients after a series of hemofiltration treatments. One patient showed no clinical improvement after seventeen treatments and died subsequently in a mountaineering accident. Though clinical improvement was noted in the second patient (22 treatments in four months), it is unjustifiable to attribute this solely to hemofiltration. Increased family and medical staff attention towards the patient is sufficient explanation for all changes noted in the patient's symptomatology. Chemical analyses so far have failed to detect any endorphins, normal or abnormal, in the hemofiltrates of either the two patients or two normal controls (sensitivity 30 pmol/L).

Combined technological-clinical approach to wearable dialysis.

To evaluate the constraints imposed upon the design of wearable dialysis systems, prototypes using currently available hardware were applied to three different dialysis formats: 1) the wearable artificial kidney (WAK) for hemodialysis (HD), 2) reciprocating peritoneal dialysis (RPD), and 3) alternating sorbent based dialysis/diafiltration(Ds/F) with a highflux membrane. 1) WAK dialysis has undergone extensive clinical trials with results comparable to standard HD. This system, including a self-contained power source, weighs 4.5 kg. The pulsatile blood flow can be disadvantageous, and cost of disposables is high. 2) RPD is shown to be an effective PD format, with the clearance of urea averaging 29.7 (23.9 to 41.5) ml/min in 14 patients, totalling 548 RPD dialyses. 3) After four conceptual trials, the Ds/F system was used for one treatment. Mass transfer results show removal of: urea nitrogen, 15.4 g; creatinine, 1.9 g; uric acid, 1.2 g; potassium, 89.2 mEq; and a positive bicarbonate balance of 94 mEq. The design constraints of these systems were elucidated, and prototype compact delivery systems have been constructed. It is concluded that a) non-mechanical PD wearability exists and b) true wearability of HD or Ds/F systems is not yet technologically feasible, but constraints are less rigid for Ds/F than for HD.