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1.  Reversal of Secondary Hyperparathyroidism by Cimetidine in Chronically Uremic Dogs 
Journal of Clinical Investigation  1981;67(6):1753-1760.
Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536±70 μleq/ml (mean±SE) (nl < 100 μleq/ml) before treatment to 291±25 μleq/ml at 12 wk (P < 0.001) and 157±32 μleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7±0.9 mg/dl to 3.4±0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4±4.3 pg/ml to 51.8±2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (−347±84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141±409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion.
These observations indicate that cimetidine suppressed circulating concentration of biologically active parathyroid hormone. A probable net decrease in the loss of phosphorus from bone to blood ensued, resulting in a fall in serum phosphorus. This may have stimulated synthesis of 1,25-dihydroxycholecalciferol and led to a positive calcium balance, thereby maintaining the serum ionized calcium concentration. The maintenance of phosphate balance, despite suppression of iPTH by cimetidine, indicates that factors other than hyperparathyroidism relate to phosphate homeostasis in chronically uremic dogs.
PMCID: PMC370753  PMID: 7240419
2.  Metabolic Consequences of Oral Administration of 24,25-Dihydroxycholecalciferol to Uremic Dogs 
Journal of Clinical Investigation  1980;65(3):571-576.
24,25-dihydroxycholecalciferol [24,25-(OH)2D3], once considered a relatively inert metabolite of vitamin D3, has been recently recognized as a metabolically active product in some species. In previous studies, we have shown that infusion of 24,25(OH)2D3 into the thyroid artery of normal dogs results in prompt and complete suppression of parathyroid hormone (PTH) secretion. In this study, we have examined the metabolic consequences of oral administration of this metabolite in dogs with experimentally induced renal hyperparathyroidism. Dogs with comparable degrees of renal insufficiency (glomerular filtration rate, 10-15 ml/min) were treated for 3 wk with daily doses of either 2 μg of 24,25(OH)2D3 or 50% ethanol, the vehicle in which the metabolite was suspended. After a 6-wk recovery period, treatments were reversed: dogs who had previously served as controls received the metabolite while dogs previously treated with metabolite received the vehicle. Administration of 24,25(OH)2D3 resulted in a 40-60% decrease of immunoreactive PTH. This was associated with a small (0.1-0.2 mg/dl) but unequivocal decrease of serum ionized calcium. Calcium balance, which was slightly negative under control conditions, became slightly but definitively positive on treatment with 24,25(OH)2D3. All other parameters measured, including total serum calcium, magnesium, phosphorus, creatinine, electrolytes, phosphorus excretion, and phosphorus balance, remained unchanged. The data support the hypothesis that 24,25(OH)2D3 not only decreases PTH secretion but also functions as an anabolic hormone in bone under the conditions of this experiment.
PMCID: PMC371397  PMID: 7354130
3.  Functional Profile of the Isolated Uremic Nephron 
Journal of Clinical Investigation  1978;61(6):1508-1518.
An in vitro approach to the study of single nephron function in uremia has been employed in evaluating the control of fluid reabsorption by the renal superficial proximal straight tubule (PST). Isolated segments of PSTs from the remnant kidneys of uremic rabbits (stage III) were perfused in vitro and their rate of fluid reabsorption compared with normal PSTs and with PSTs derived from the remnant kidneys of nonuremic rabbits (stage II). All segments were exposed to a peritubular bathing medium of both normal and uremic rabbit serum thereby permitting a differentiation to be made between adaptations in function which are intrinsic to the tubular epithelium and those which are dependent upon a uremic milieu.
Compared with normal and stage II PSTs, there was significant hypertrophy of the stage III tubules as evidenced by an increase in length and internal diameter, and a twofold increase in the dry weight per unit length. Fluid reabsorption per unit length of tubule was 70% greater in stage III than in normal and stage II PSTs, and was closely correlated with the increase in dry weight. Substitutions between normal and uremic rabbit serum in the peritubular bathing medium did not affect fluid reabsorption significantly in any of the three groups of PSTs. Perfusion of the tubules with an ultrafiltrate of normal vs. uremic serum likewise failed to influence the rate of net fluid reabsorption.
It has previously been observed that net fluid secretion may occur in nonperfused or stop-flow perfused normal rabbit PSTs exposed to human uremic serum. Additional studies were thus performed on normal and stage III PSTs to evaluate whether net secretion occurs in the presence of rabbit uremic serum. No evidence for net secretion was found.
These studies demonstrate that fluid reabsorption is greatly increased in the superficial PST of the uremic remnant kidney and that this functional adaptation is closely correlated with compensatory hypertrophy of the segment. Humoral factors in the peritubular environment do not appear to be important mediators of the enhanced fluid reabsorption.
PMCID: PMC372677  PMID: 659612
4.  On the Adaptation in Sodium Excretion in Chronic Uremia. THE EFFECTS OF “PROPORTIONAL REDUCTION” OF SODIUM INTAKE 
Journal of Clinical Investigation  1974;53(6):1736-1741.
Renal mass and glomerular filtration rate (GFR) were reduced from normal to approximately 15% of normal in two groups of dogs. One group received a constant salt intake (CSI) throughout the study. The second group was subjected to “proportional reduction” of sodium intake (PRS), a dietary regimen which involved the reduction of sodium intake in exact proportion to the decrement in GFR. In the CSI group, absolute sodium excretion rate (UNaV) remained essentially unchanged as GFR fell, while fractional sodium excretion (FENa) increased progressively from a mean control value of 0.3% to a final value of 4.4%. In the PRS group, UNaV decreased with each reduction in GFR and salt intake, and FENa remained constant throughout. In a second study, the fraction of serum that previously has been shown to possess natriuretic activity in studies of uremic patients was obtained from a group of uremic dogs on the CSI and from another group on the PRS regimen, and the effects of the fraction was measured on sodium excretion in rats. The serum fractions from the dogs on the CSI regimen produced a significant increase in both UNaV and FENa in the assay rats. The same serum fraction from the dogs on the PRS regimen failed to produce a significant increase in either UNaV or FENa.
The data are consistent with the view that (a) The increase in FENa in chronically uremic dogs is dictated by the requirements for external sodium balance and may be prevented by prospective manipulation of salt intake: (b) a natriuretic factor, previously shown to exist in the serum of patients with chronic uremia, is also demonstrable in the serum of uremic dogs; and (c) with the present bioassay system, the factor is not detectable in the serum fraction of uremic dogs in which the requirements for an increased natriuresis per nephron have been obviated.
PMCID: PMC302670  PMID: 4830234
5.  The Effects of the Natriuretic Factor from Uremic Urine on Sodium Transport, Water and Electrolyte Content, and Pyruvate Oxidation by the Isolated Toad Bladder 
Journal of Clinical Investigation  1974;53(6):1568-1577.
The urine of patients with chronic uremia contains a gel filtration fraction that is natriuretic in the rat. The effects of this fraction on the isolated urinary bladder of the toad were examined in the present studies. When added to the serosal surface of the bladder, a significant and substantial fall in short-circuit current and potential difference was observed. The changes began after a lag period of at least 10 min and continued over a period of 60 min. The decrease in short-circuit current at the end of 1 h averaged 44%. The same fraction from the urine of normal subjects produced no significant change in either short-circuit current or potential difference. When the isolated epithelial cells from the toad bladder were incubated in the presence of the inhibitor, intracellular sodium content increased significantly. There was no change in intracellular water content; hence the intracellular concentration of sodium increased by a mean of 7 meq/liter. The changes in intracellular potassium content and concentration were not satistically significant. When the isolated epithelia were incubated with the uremic factor, there was also a significant decrease in pyruvate utilization in relation to cells from paired hemibladders incubated in the absence of the fraction. The fraction from normal subjects produced no change in either intracellular sodium content or pyruvate oxidation.
The results suggest that the inhibitor acts from the serosal surface, inhibits sodium transport across the serosal barrier, and produces a decrease in substrate utilization in association with the change in transepithelial sodium transport.
PMCID: PMC302652  PMID: 4208469
6.  The Presence of a Natriuretic Factor in Urine of Patients with Chronic Uremia. THE ABSENCE OF THE FACTOR IN NEPHROTIC UREMIC PATIENTS 
Journal of Clinical Investigation  1974;53(6):1559-1567.
A gel filtration fraction of serum from chronically uremic patients has been shown previously to produce natriuresis in the rat. In the present studies, the same fraction from urine of uremic patients and normal subjects was studied for its natriuretic activity. Urine samples were obtained from 17 chronically uremic patients (mean glomerular filtration rate [GFR], 8.7 ml/min; mean fractional sodium excretion [FENa], 5.7%), and 14 normal subjects. The fraction from the uremic patients produced a significant increase in absolute sodium excretion (UNaV) and FENa; the fraction from normal subjects had no statistically significant effect on either UNaV or FENa; and the difference between the response to the uremic vs. normal fractions was highly significant for both parameters of sodium excretion. When a more concentrated urine fraction from uremic patients was administered, a striking natriuresis was observed with values for FENa rising to levels as high as 12%. Studies also were performed on eight patients with far advanced chronic renal insufficiency and the nephrotic syndrome. The serum fraction was studied in each of these patients and the urine fraction in three. For the group, UNaV in the assay rats decreased by 0.87 μeq/min and FENa decreased by 1.35% after infusion of the serum fraction. These results differ significantly from those of patients with chronic uremia without the nephrotic syndrome. The data are consistent with the view that the increased activity of the natriuretic factor in the serum of chronically uremic patients is not due to failure of excretion; rather it relates either to an increased rate of production and/or a decreased rate of degradation. The data also show that the inhibitor is detectable when FENa is increased, but not when uremia is associated with a sodium-retaining state.
PMCID: PMC302651  PMID: 4830222
7.  A natriuretic factor in the serum of patients with chronic uremia 
Journal of Clinical Investigation  1972;51(6):1514-1527.
Sera from chronically uremic and normal individuals were subjected to gel filtration with Sephadex G-25 and the same fraction of both was infused into rats with a decreased nephron population to determine the effects on sodium excretion. Sodium excretion rate and fractional sodium excretion increased slightly with the normal fractions; but the increase in both functional parameters produced by the uremic fractions was substantially and significantly greater. The natriuresis could not be explained by associated changes in glomerular filtration rate (GFR), para-aminohippurate (PAH) clearance, filtration fraction, hematocrit, or blood pressure. The possibility thus exists that the inhibitor affected some component part of the transepithelial sodium transport system. The elution characteristics of the fraction plus certain of its physicochemical properties suggest that the inhibitor of sodium reabsorption by the rat nephron may be identical with the inhibitor of PAH uptake by kidney slices and the inhibitor of transepithelial sodium transport by the frog skin and toad bladder previously found in the serum of chronically uremic patients.
PMCID: PMC292289  PMID: 5024044

Results 1-7 (7)