Mordecai M. Popovtzer

RECOVERY FROM “HEPATORENAL SYNDROME” AFTER ORTHOTOPIC LIVER TRANSPLANTATION

Abstract Three patients with progressive renal failure and advanced hepatic insufficiency due to cirrhosis of the liver underwent orthotopic liver transplantation. All three patients had immediate improvement in hepatic function and within two weeks after liver replacement regained nearly normal kidney function. However, the renal recovery was delayed in each case, and its course was not uniform. Plasma renin activity was high, and renin substrate was low before transplantation in one case in which these measurements were obtained; both returned to normal soon after liver replacement. (N Engl J Med 289:1155–1159, 1973)

Renal Tubular Acidosis Associated with Toluene Sniffing

Abstract Sniffing of toluene-containing substances, such as paint, paint thinners and glue, has been thought to be associated primarily with neurologic complications. In our study causality is documented between toluene sniffing and a severe renal tubular acidification defect. Toluene was an ingredient (60.4 per cent) of the paint sniffed by one patient, and pure toluene was sniffed by the other. Both had toluene in the blood. The tubular defect was documented by the presence of metabolic acidosis (pH, 7.2 to 7.3) with a normal anion gap, hyperchloremia (level of 118 to 120 mEq per liter) and an inappropriately high urinary pH (>6.0). There was no evidence of azotemia, or of excessive excretion of bicarbonate, phosphate, amino acids or glucose in the urine. Complete recovery, followed by recurrence of the tubular defect, was demonstrated on several occasions during avoidance and use of toluene sniffing. A life-threatening complication of toluene sniffing may be the induction of a renal tubular acidi...

The Acute Effect of 25-Hydroxycholecalciferol on Renal Handling of Phosphorus: EVIDENCE FOR A PARATHYROID HORMONE-DEPENDENT MECHANISM

The acute effect of i.v. and direct intrarenal arterial infusion of 25-hydroxycholecalciferol (25HCC) and 1,25-dihydroxycholecalciferol (1,25-DHCC) on renal handling of phosphorus was evaluated in the following groups of rats: (a) intact animals, (b) parathyroidectomized (PTX) hypocalcemic rats, (c) PTX rats in which normocalcemia was maintained with calcium supplements and (d) PTX animals in which urinary phosphorus was augmented by (i) i.v. sodium phosphate, (ii) expansion of the extracellular fluid volume with normal saline, and (iii) i.v. parathyroid hormone (PTH). Clearances of inulin (C(In)), phosphorus (C(P)), and fractional clearances of phosphorus (C(P)/C(In)) of the experimental groups were compared with those of the corresponding control groups, and the clearances of the infused kidneys with those of the contralateral kidneys. In intact animals, i.v. 25HCC decreased C(P)/C(In) from 0.29+/-0.04 (mean +/-SE) to 0.19+/-0.04, and i.v. 1,25-DHCC decreased C(P)/C(In) from 0.25+/-0.04 to 0.15+/-0.02. The intrarenal infusion of both 25HCC and 1,25DHCC into intact animals failed to produce a unilateral change; however, it decreased C(P)/C(In) bilaterally. i.v. and intrarenal infusions of 25HCC or 1,25DHCC in PTX hypocalcemic and normocalcemic rats, and i.v. infusions of 25HCC in PTX rats receiving either sodium phosphate or normal saline, all failed to produce significant changes in C(P)/C(In). In contrast, 24HCC given i.v. to PTX animals receiving exogenous PTH was associated with a significant fall in C(P)/C(In), from 0.34+/-0.08 to 0.13+/-0.02. These results indicate that 25HCC enhances tubular reabsorption of phosphorus in rats, only in the presence of either endogenous or exogenous circulating PTH, but not in its absence and thus imply a PTH-dependent mechanism of 25HCC action on the kidney. This effect does not appear to be related to the conversion of 25HCC into 1,25DHCC, since the latter fails to affect tubular reabsorption of phosphorus in PTX rats.

Variations in Arterial Blood Pressure after Kidney Transplantation Relation to Renal Function, Plasma Renin Activity, and the Dose of Prednisone

The course of hypertension within the first 2 months after kidney transplantation was correlated with renal function, plasma renin activity (PRA), and the daily maintenance dose of prednisone in 18 homograft recipients. During acute rejection blood pressure (BP) closely correlated with PRA. Patients with normal homograft function showed an increase in BP early after transplantation which in most returned to normal 3-8 weeks later. In the latter group no correlation could be found between the level of BP and PRA, however the BP correlated closely with the dose of prednisone. These observations suggest that during acute rejection the increase in BP may at least partly be mediated by a renal pressor mechanism, whereas with normal renal function the high dose of glucocorticoids may play an important role in the development of hypertension.

The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.

The acute effects of chlorothiazide (CTZ) on total (TSCA) and ionized (SCA-plus 2) serum calcium concentrations were studied in three groups of people: (a) eight subjects with normal parathyroid function; (b) six patients with hypoparathyroidism; and (c) two patients with hyperparathyroidism. Most subjects were studied on four occasions; at least 3 days intervened between studies on an individual subject. During each experiment the subject received an i.v. influsion of 5% dextrose in water at 1 ml/min from 8 a.m. to 4 p.m. Additions to the infusions were (a) none; (b) CTZ to deliver 3.33 mg/kg/h; (c) parathyroid extract to deliver 1 U/kg/h; or (d) both CTZ and parathyroid extract at the rates previously indicated. CTZ, when used, was added to the infusion at 10 a.m., parathyroid extract at 8 a.m. When CTZ was infused, the diuretic-induced losses of Na and water were replaced by i.v. infusion. In normal subjects 2 h after the start of CTZ infusion, there was a transient increase in SCA-plus 2 which coincided in time of day with a transient decrease in SCA-plus 2 in control experiments. At that time of day SCA-plus 2 was 4.18 plus or minus 0.12 mg/100 ml in control experiments and 4.56 plus or minus 0.08 in experiments with CTZ, P smaller than 0.025. The corresponding values for (TSCA) were 9.32 plus or minus 0.15 and 9.80 plus or minus 0.30, P smaller than 0.01. Such differences were not observed in the group with hypoparathyroidism. In the two patients with hyperparathyroidism, CTZ produced sustained increases in TSCA and SCA-plus 2. In normal subjects and those with hypoparathyroidism, CTZ plus parathyroid extract infusion resulted in sustained increases in both SCA-plus 2 and TSCA throughout the periods of observation when compared to experiments in which only parathyroid extract was infused, P smaller than 0.01 in all instances. The results suggest that the acute hypercalcemic action of CTZ requires the presence of circulating parathyroid hormone.

Serious Pulmonary Hemorrhage, Glomerulonephritis, and Massive Steroid Therapy

A patient suffered from acute glomerulonephritis with modest renal impairment and life-threatening pulmonary hemorrhage. The pulmonary hemorrhage caused severe hypoxia that necessitated artificial ventilation. As a last resort, 1 g/day of methylprednisolone was administered intravenously. Rapid cessation of pulmonary hemorrhage ensued with clearing of the lungs fields. We suggest that large doses of glucocorticosteroids should be administered to patients with life-threatening pulmonary hemorrhage before considering bilateral nephrectomy, especially if the renal function is still adequate. Bilateral nephrectomy is an irreversible approach and, as with massive doses of steroids, has yet to be proved to be a consistently effective mode of therapy.

Furosemide-Induced Reduction in Ionized Calcium in Hypoparathyroid Patients

Six hypoparathyroid patients were treated with oral furosemide for 4 days. All six had a significant decrease in serum ionized calcium level from the control period (4.05 +/- 0.31 mg/dl) to the furosemide period (3.46 +/- 0.26 mg/dl, P less than 0.005). In five patients, the decrease in serum ionized calcium concentration occurred in association with an increase in urinary calcium excretion. Although serum immunoreactive parathyroid hormone level increased in five patients, it was insufficient to return serum ionized calcium to control levels. Changes in serum phosphorus, magnesium, or pH could not account for the observed decrease in serum ionized calcium concentration. It is necessary to monitor serum ionized calcium level in hypoparathyroid patients during furosemide therapy.

Unsuccessful attempts to control hyperacute rejection of human renal homografts with F(ab') 2 and citrate organ pretreatment.

The presence of preformed cytotoxic antidonor antibodies in the serum of potential allograft recipients leads to the rapid destruction of the graft by the now well known events of hyperacute rejection (10, 21, 24-27). Experimental work in the past several years at our center and in other laboratories has been oriented to the solution of this difficult immunological problem, not only in the presensitized homotransplantation model but also in strongly incompatible xenograft combinations. Antibody and complement depletion (3-5, 7, 8, 13, 16, 19, 21, 23), or treatment by the chelating agents, sodium citrate (12, 14) and ethylenediaminetetraacetate (EDTA) (1), has been shown to delay hyperacute kidney rejection in both experimental models, whereas anticoagulation with heparin (15) or cobra venom (6) has yielded equivocal results. Even the most effective of these therapeutic procedures only delayed the destruction of the graft. n nMore recently, encouraging results were obtained by several workers (11, 20, 22) with pretreatment of the organ with antidonor IgG fragments (F(ab′)2). It was suggested that F(ab′)2 fragments were protective by occupying the donor antigen receptor sites. n nUnsuccessful attempts to control hyperacute rejection in one of our patients who had preformed circulating cytotoxic antibodies are reported here, using homografts pretreated with sodium citrate or digested IgG.

Renal handling of phosphorus in oliguric and nonoliguric mercury-induced acute renal failure in rats

The renal handling of phosphorus was evaluated in rats with acute renal failure (ARF) induced by injection of mercuric chloride (HgCl(2)). Clearances of endogenous creatinine (Ccr) and of phosphorus (Cp) were measured in the following groups: 1. Intact animals (control); 2. Parathyroidectomized rats (PTX) with normal kidney function (PTX control); 3. Animals with mercury-induced acute renal failure (Hg-ARF); 4. PTX rats with Hg-ARF; 5. Rats with Hg-ARF maintained normophosphatemic with dietary phosphate restriction; 6. Animals with oliguric ARF following renal artery constriction; 7. Rats with unilateral Hg-ARF. In addition, radioinulin clearances were measured in 6 normal and in 14 azotemic animals and correlated with simultaneously recorded endogenous Ccr. Radioinulin clearance was also used as an estimate of GFR (glomerular filtration rate) in the animals of group 7. The Cp/GFR in the intact animals (group 1) was 0.25 +/-0.06 (mean +/-SD). PTX (group 2) caused a subsequent decrease in Cp/GFR to 0.11 +/-0.04 P < 0.0005. The ARF animals in group 3 were classified either as oliguric (U(vol) [urine volume] <2 ml/24 hr, Ccr 0.008 +/-0.005 ml/min) or nonoliguric (V(vol) >2 ml/24 hr, Ccr 0.136 +/-0.12). The Cp/GFR in the oliguric animals (0.16 +/-0.09) was lower than that in group 1, P < 0.0005, and failed to increase following administration of exogenous parathyroid hormone. The Cp/GFR in the oliguric animals in groups 5 and 7 was also lower than the clearance ratio in group 1, 0.030 +/-0.08 and 0.077 +/-0.006, respectively. In the nonoliguric ARF animals of group 3 the Cp/GFR (0.94 +/-0.29) was higher than that in group 1, P < 0.0005. In the nonoliguric ARF animals of group 4 the Cp/GFR 0.27 +/-0.08 did not differ from the clearance ratio in group 1, however it was higher than that in the PTX animals (group 2) P < 0.0005. Cp/GFR in the nonoliguric animals of group 5 was not different from that in the nonoliguric rats of group 3. In the animals with nonoliguric unilateral Hg-ARF Cp/GFR on the affected side 0.51 +/-0.16 was higher than that on the control (contralateral) side, 0.23 +/-0.07, P < 0.0005. These results indicate that the low Cp/GFR observed in the oliguric ARF animals was not related to the level of circulating parathyroid hormone nor to the presence or absence of azotemia but probably was due to a reduced renal cortical perfusion. The high Cp/GFR in the nonoliguric ARF animals could be explained by secondary hyperparathyroidism and impaired phosphorus reabsorption due to tubular injury.

Effects of alternating phosphorus and calcium infusions on osteoporosis

The osteoblastic effect of inorganic phosphorus and the inhibitory action of calcium on parathyroid hormone secretion formed the basis for a therapeutic trial in which both elements were given intravenously in an alternating sequence for one year to five patients with severe osteoporosis. During treatment, calcium and phosphorus balances were positive, and serum phosphorus concentrations decreased. Iliac crest bone biopsy specimens obtained one year after beginning treatment demonstrated an increase in the thickness of cortical bone. All patients experienced lasting relief of bone pain, and the rate of spontaneous fractures decreased from at least one fracture per year to none following the beginning of treatment. These findings suggest that long-term treatment with alternating phosphorus and calcium infusions may result in lasting relief of symptomatic osteoporosis. It is proposed that the observed improvement reflects an increase in bone mass resulting from enhanced bone formation.