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Biomedical subjects

A Besarab

Publications and source records attributed to A Besarab.

At least 55 records · Page 3Linked to original sources
PubMed1987

Dynamics of erythropoiesis following renal transplantation.

We examined the temporal dynamics of the correction of anemia following renal transplantation in 65 recipients using a sensitive radioimmunoassay for erythropoietin to determine the effects of modern immunosuppressive agents, delayed graft function, and early acute rejection. Pretransplant mean erythropoietin (25.6 +/- 3.3 mU/ml) was only 25% of the expected value at the mean hematocrit of 27.2 +/- 0.7, and erythropoietin correlated positively with hematocrit (r = 0.37, P less than 0.05). Following onset of graft function, erythropoietin increased to 109 +/- 13 mU/ml and then decreased in a negative feedback fashion over the next several months. Delayed graft function was associated with delay in the assumption of this orderly process irrespective of the immunosuppressive regimen used. Cyclosporine A produced a biphasic response despite delayed graft function in recipients with underlying adult polycystic kidney disease. Correction of anemia required resumption of graft function. Onset of acute graft rejection within the first month posttransplantation (14 episodes in 11 patients) abrogated the hematopoietic response until the rejection was successfully reversed. We conclude that a major cause for the anemia of renal failure is subnormal production of erythropoietin. Following transplantation, anemia corrects in an orderly manner with restoration of the normal biofeedback process between erythropoietin and red cell mass. This process is delayed by failure of graft to function initially and interrupted by acute early rejection, re-commencing following successful reversal.

Adolescent↗
PubMed1987

Use of the isolated perfused kidney model to assess the acute pharmacologic effects of cyclosporine and its vehicle, cremophor EL.

"Nephrotoxicity" secondary to cyclosporine and its clinically used vehicle, Cremophor EL, was examined in the isolated perfused rat kidney model. This model allows the serial determination of renal hemodynamic and tubular functional studies over a 3-hr duration using a normothermic, low hematocrit (13-15%) perfusion system. Initial studies indicated that the addition of small quantities of Cremophor EL resulted in marked renal vasoconstriction with decreased renal blood flow and deterioration in renal tubular function. These effects were highly significant and were of the same magnitude whether or not cyclosporine was present in the system. Cyclosporine was therefore examined after being dissolved in another vehicle, methanol. A 10% (v/v) amount of plasma was necessary in the perfusate to prevent significant adsorption of cyclosporine to the perfusion apparatus. Cyclosporine at concentrations below 100 ng/ml resulted in minor changes in renal hemodynamics. Beginning at 100 ng/ml glomerular filtration rate dropped significantly and renal vascular resistance increased three-fold. Fractional excretion of sodium significantly increased and the urine:plasma inulin ratio significantly decreased. We conclude that the clinically used drug vehicle, Cremophor EL, has significantly adverse effects on renal hemodynamics and tubular function. In addition, CsA causes similar renal toxicity in a dose-dependent fashion. Simultaneous administration of these two nephrotoxic agents could contribute to the high incidence of acute renal failure seen after transplantation. These observations suggest that an alternate vehicle with less renal toxicity might significantly decrease the incidence of this clinical problem.

Animals↗
PubMed1987

False-positive digoxin measurements due to conjugated metabolite accumulation in combined renal and hepatic dysfunction.

A 41-year-old man with combined renal and hepatic dysfunction was noted to have marked elevations in serum digoxin concentration subsequent to the discontinuation of digoxin therapy. These elevations (peak value 8.6 ng/ml), as measured by both radioimmunoassay and fluorescence polarization immunoassay, were not associated with electrocardiographic evidence of digitalis toxicity. Using a combined high-performance liquid chromatography/radioimmunoassay, accumulation and immunoassay cross-reactivity of conjugates of digoxigenin monodigitoxoside (cardioinactive metabolites of digoxin) were found to be the basis of the observed false elevation in digoxin concentration.

Acute Kidney Injury↗
PubMed1986

Intracranial calcification in adults with chronic lead exposure.

Computed tomographic (CT) findings of cerebral and cerebellar calcification are described in three American adults with raised serum lead levels and known exposure to lead for 30 or more years. Calcification patterns were punctiform, curvilinear, speck-like, and diffuse and were found in the subcortical area, basal ganglia, vermis, and cerebellum. Admission serum lead levels ranged from 54 to 72 micrograms/dl (normal, 0-30 micrograms/dl). Nonspecific neurologic manifestations consisted of dementia, diminished visual acuity, peripheral neuropathy, syncope, dizziness, nystagmus, easy fatigue, and back pain. Two patients developed chronic renal disease and hypertension; in both cases, serum parathormone was elevated. Blood, calcium, and phosphorus were normal in all three. No other structural abnormalities were observed with CT. Although the pathophysiologic mechanism of these findings remains poorly understood, it is suggested that chronic lead exposure should be included in the differential diagnosis of unexplained intracranial calcifications in adults.

Brain Diseases↗
PubMed1985

Dialysis-induced hypoxemia: membrane dependent and membrane independent causes.

Hypoxemia during hemodialysis may result from several differing processes. We initially studied patients undergoing standard acetate hemodialysis. At 15 minutes of dialysis, leukopenia (primarily neutropenia), a decline of platelet count, and hypoxemia occurred, but without a significant change in mean minute ventilation. Complement activation (V/A ratios of C5a greater than 1.0) persisted throughout dialysis. Leukocyte count returned to baseline by one hour. To separate the effects of solute and/or gas fluxes from those of blood-membrane interaction we studied changes in Po2, WBC, C5a, TxB2, and PGI2 during a period of blood membrane interaction without dialysis, and during subsequent acetate dialysis. Patients were studied with both polyacrylonitrile (PAN) and cuprophan membranes containing different priming solutions during membrane contact alone. Despite leukopenia and complement activation, hypoxemia failed to occur during membrane contact alone. At 15 minutes of subsequent acetate dialysis, significant hypoxemia occurred with both membranes. However, the degree of hypoxemia was twice as great with a cuprophan membrane primed with acetate (18.6 +/- 3.3 mm Hg) compared with air or bicarbonate (9.1 +/- 1.4 and 7.0 +/- 2.0 mm Hg, respectively), or compared with PAN (8 +/- 2.8 mm Hg). Changes in thromboxane B2, PGI2, and C5a did not correlate with changes in Po2. We conclude that there are two major components to dialysis related hypoxemia. One is membrane independent, and may relate to the metabolic effects of acetate or to dialyzer CO2 loss. The remaining portion is membrane dependent, occurring with cuprophan, but not with PAN, and is conditioned by an acetate dependent interaction between blood and membrane.

Adolescent↗
PubMed1985

Effect of cyclosporine and delayed graft function on posttransplantation erythropoiesis.

The effect of delayed graft function and immunosuppressive drugs on posttransplant erythropoiesis was studied prospectively in 18 living-related (LR) and 84 cadaver-donor (CD) recipients. Eight of 18 LR and 20 of 84 CD recipients received antilymphoblast globulin (ALG) in addition to azathioprine and prednisone. Sixty-four CD recipients received cyclosporine (CsA) with prednisone. In the absence of rejection reticulocytosis began 6.7 +/- 0.2 days following graft implantation in azathioprine-only-treated LR recipients. This was lengthened by ALG to 9.4 +/- 0.3 and 9.9 +/- 0.7 days in LR and CD recipients, respectively, whose grafts functioned immediately. Delayed graft function prolonged onset of reticulocytosis to 15.9 +/- 0.9 days in ALG-treated but not in CsA-treated recipients (5.8 +/- 0.4 days). The shortest latency was noted in CsA-treated recipients (4.9 +/- 0.5 days) with immediately functioning grafts. The earlier onset of reticulocytosis of CsA-treated recipients was followed by statistically significant blunting of peak reticulocytosis, which correlated with a slower rate of correction of anemia (delta Hct = 0.19/day) compared with non-CsA-treated recipients (delta Hct = 0.34/day). Early rejection was associated with abrogation of reticulocytosis and correction of anemia without regard to immunosuppressive regimen) until rejection was reversed. Erythropoietin (EPO) was measured sequentially in 5 patients with immediate function. In 4 of 5 cases changes in EPO preceded those in reticulocytosis. EPO rose from a mean of 13 mU/ml pretransplant to a peak of 50 within 3 weeks and decreased to 18 mU/ml within 6 weeks of graft implantation. At six months posttransplant, normalized reticulocyte counts were only 55% higher (1.75 vs. 1.13%) but hematocrit had increased from 26 +/- 1% to 42 +/- 1%. Hematocrit varied inversely with serum creatinine, which was highest in CsA-treated patients with initial delayed graft function. We conclude that correction of anemia posttransplantation is driven by EPO but other factors may also be important, that neither ATN nor ALG-therapy have clinically important effects on erythropoiesis, and that CsA reduced "effective" erythropoiesis and influences correction of anemia--particularly if delayed graft function complicates the initial course posttransplantation.

Antilymphocyte Serum↗
PubMed1985

Why the kidney?

Severe erythrocytosis is associated with increased whole blood viscosity and impaired blood flow. Since a reduced blood flow will cause tissue hypoxia and since tissue hypoxia is associated with increased synthesis of erythropoietin, erythrocytosis per se should cause an increase in the rate of red cell production. This, however, does not occur and severe erythrocytosis in patients with polycythemia vera does not lead to increased synthesis of erythropoietin. We propose here that the reason for this discrepancy is that decreased blood flow to the kidneys, the site of erythropoietin synthesis, does not cause renal tissue hypoxia. The oxygen tension in the kidneys is to a great extent determined by the consumption of oxygen used for sodium reabsorption and since sodium reabsorption is roughly proportional to glomerular filtration, a decreased flow of blood should be matched by a decreased oxygen consumption leaving the tissue tension of oxygen unchanged. Consequently, the location of an oxygen sensor in the kidneys controlling erythropoietin production appears to be most fortuitous since it prevents the development of a vicious circle, with erythrocytosis causing more erythrocytosis.

Blood Viscosity↗
PubMed1984

Effect of plasma proteins and buffer in flushing solutions on rat kidney preservation by cold storage.

The isolated rat kidney perfused at 37 C was used to evaluate the effect of adding plasma proteins to, and varying osmolality of, cold-storage flushing solutions with or without buffering. Addition of albumin improved immediate poststorage kidney function (glomerular filtration rate [GFR], fractional sodium reabsorption, and fractional protein clearance) of all flushing solutions tested after 6 hr and 24 hr of storage. At 6 hr, these improvements also correlated with less weight gain. Flushing solutions containing citrate and sulfate produced significantly better return of function after 24 hr of cold storage than Krebs' or Collins'-derived solutions. Osmolality was unimportant with solutions containing citrate. Collins' solution with reduced MgSO4 yielded better poststorage function than conventional solution. An all-citrate isotonic solution buffered with 15 mmol THAM preserved poststorage function at 48 hr better than a similarly buffered solution containing both citrate and sulfate. Loss of dry weight during storage and subsequent perfusion appeared to correlate, in these experiments, with loss of poststorage function. The isolated rat kidney provides discrimination among various flushing solutions. The technique might be useful in the assay of additional variables that might affect the quality of kidney preservation.

Animals↗
PubMed1984

Tachyphylaxis to PTH in the isolated perfused rat kidney: resistance of anticalciuria.

Downregulation of renal responses to amino-terminal 1-34 parathyroid hormone (PTH) was studied in the isolated perfused rat kidney. PTH induced a sigmoid dose-response relationship in phosphate and urinary cAMP excretion over the concentration range 0.2-36 nM. Renal responses to a second maximally phosphaturic PTH concentration following variable initial PTH concentrations showed tachyphylaxis of both phosphate and urinary cAMP excretion but not of decreased calcium excretion. The sigmoid relationship between integrated phosphate and cAMP excretion was shifted to the right during tachyphylaxis. Administration of a maximal phosphaturic PTH dose prevented any effect on phosphate or cAMP excretion of an equivalent or smaller PTH dose administered 1 h later. Anticalciuria, however, was prolonged by the second dose. These studies indicate that downregulation in the kidneys is restricted to the phosphaturic and urinary cAMP responses but not to the anticalciuric response. They also suggest that the nephron site mediating anticalciuria behaves differently with respect to hormone-receptor interactions from those sites mediating phosphaturia.

Animals↗
PubMed1983

Some effects of preservation and acute renal failure on function and proteinuria of renal transplants.

We assessed the effects of preservation on subsequent graft function by measuring and comparing creatinine and fractional protein clearances in 18 live-related (LR) and 38 cadaver-donor (CD) grafts, the latter selected on the basis of short warm ischemia times (less than 5 mins) and stable donor hemodynamic status prior to organ recovery. CD recipients with immediate graft function had lower initial creatinine clearances and greater fractional protein clearances than LR recipients. The role of preservation in producing greater fractional protein clearance was suggested by the observation of time-dependent increasing proteinuria during continuous hypothermic perfusion of four human CD kidneys and the significant correlation between the initial degree of proteinuria at onset of diuresis and the duration of cold preservation of those CD kidneys with immediate function. One-half of CD grafts, however, manifested acute renal failure (ARF) after implantation and in these grafts no correlation between cold preservation duration and fractional protein clearance at onset of diuresis was noted. Development of ARF in CD grafts was associated with still lower creatinine clearances, but higher fractional protein clearances during the first week of diuresis. These effects of preservation and those of preceding ARF on fractional protein clearances were no longer noted 2 wk after onset of diuresis in nonrejecting CD grafts. These observations suggest the presence of preservation-induced injury to grafts even when "immediate function" occurs.

Acute Kidney Injury↗
PubMed1983

Effect of delayed graft function and ALG on the circaseptan (about 7-day) rhythm of human renal allograft rejection.

Postimplantation records of 157 kidney transplant recipients with first rejection episodes within 50 days of surgery were studied. Of these 36 had living-related and 121 cadaver donors. Recipients of cadaver donor kidneys were divided into four subgroups: with and without postoperative acute renal failure (ARF), and with and without approximately two weeks of immunosuppression by antilymphoblast globulin (ALG) added to conventional therapy. All recipients with immediate function without ALG showed evidence of periodicity in probability of occurrence of rejection that was highly significant for a 7-day period beginning at the time of surgery. The remaining groups showed less significant periodicity or no significant periodicity beginning at the time of surgery, but they did show a highly significant circaseptan rhythm of rejection episodes beginning with cessation of ALG treatment or with onset of diuresis following ARF in the absence of ALG. It is suggested that clinical manifestation of the immunologic attack of recipient upon graft has an intrinsic development period of about 7 days beginning with implantation. However, initiation of the first period may be blocked by ALG or by low renal blood flow during ARF.

Acute Kidney Injury↗
PubMed1982

Effect of exogenous adenosine 3':5'-cyclic monophosphate, parathyroid hormone and acetazolamide on electrolyte hormone and acetazolamide on electrolyte excretion by the isolated perfused rat kidney.

The effects of exogenous adenosine 3':5'-cyclic monophosphate (cyclic AMP), parathyroid hormone (PTH) and acetazolamide (Az) on renal calcium and phosphate excretion of the isolated perfused rat kidney were compared. Both PTH and Az evoked an early increase in urinary cyclic AMP excretion followed by a later more prolonged increase in phosphate excretion. All of the increased urinary cyclic AMP was derived from renal cells. Calcium excretion decreased with PTH but was unchanged with Az. Sodium and potassium excretion increased with Az but not PTH. Transitory urinary cyclic AMP excretion rates following bolus additions of exogenous cyclic AMP to perfusate were up to twentyfold greater than those evoked by PTH or Az but unassociated with changes in calcium, phosphate, sodium or potassium excretion. Sustained perfusate levels (above 0.5 microM) and excretion rates of cyclic AMP induced phosphaturia proportional to the perfusate cyclic AMP concentrations achieved up to 2.0 microM. Clearances of exogenous cyclic AMP exceeded inulin clearance at perfusate concentrations greater than 1.0 microM. Aminophylline evoked a small phosphaturia which increased further on addition of cyclic AMP to 5 microM. Glomerular filtration was not affected by any of the agents except Az. Since increased phosphate excretion could be evoked only at perfusate concentrations exceeding either plasma or intracellular concentrations observed in vivo, it is concluded that circulating cyclic AMP at levels in vivo is unlikely to mediate a significant fraction of the renal effects of PTH.

Acetazolamide↗
PubMed1982

Differences in effects of amino-terminal and intact parathyroid hormone on calcium, phosphate, and cAMP excretion by the isolated perfused rat kidney.

Urinary cAMP (UcAMP) reflects activation of renal adenylate cyclase by parathyroid hormone (PTH). UcAMP excretion and the phosphaturic, anticalciuretic responses to bovine PTH by a stable isolated perfused rat kidney were compared. Dose-response curves were obtained for two synthetic amino-terminal [1-34] PTH preparations and three highly purified intact [1-84] PTH preparations. With all preparations, anticalciuria occurred at lower concentrations (less than 10(-10) M) than those needed to produce a significant increase in UcAMP excretion or phosphate excretion. Maximal decreases in calcium clearance with [1-34] PTH were independent of concentrations between 10(-10) and 10(-7) M whereas cAMP and phosphate increased sigmoidally at PTH concentrations above 10(-10) M. The two synthetic [1-34] PTH preparations had identical anticalciuretic and phosphaturic dose-response curves despite their significantly different effects on cAMP excretion. Intact [1-84] PTH concentration-response curves were identical to those of [1-34] PTH at concentrations less than 3 x 10(-9) M. At higher concentrations, phosphaturia was greater and anticalciuria blunted compared to [1-34] PTH. These latter changes were associated with natriuresis and kaliuresis, effects not seen with [1-34] PTH. The isolated kidney may be a useful model for further studies of PTH action and also constitutes a bioassay system to evaluate hormone potency.

Animals↗