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Long-term renal function preservation after renal artery stenting in patients with progressive ischemic nephropathy.

We assessed the long-term effect of successful renal artery stent revascularization on renal function, blood pressure control, and survival in patients with progressive renal dysfunction due to ischemic nephropathy. Ischemic nephropathy presents a potentially serious risk of complete loss of renal function. Surgical renal revascularization is associated with significant risk of mortality/morbidity in this patient population. The potential role and long-term effect of renal artery stent revascularization in this patient population is not well defined. A cohort of 51 patients (mean age, 72 years; 52.9% men) with progressive azotemia, defined as a preprocedure serum creatinine (Scr) value of >or= 1.5 mg/dl and a negative slope of the reciprocal 1/Scr curve during the 12 months preceding revascularization, underwent successful primary stent deployment in 93 atherosclerotic renal artery lesions (42 bilateral, 9 solitary kidneys). Estimated glomerular filtration rate (EGFR) and serum creatinine values, blood pressure, antihypertensive medication requirements, and survival rates were monitored over a mean of 30-month follow-up. Renal artery duplex Doppler or renal angiography were performed at a mean of 13 months (range, 7-15 months) to assess stent patency. Stent implantation was successful in 92/93 (98.9%) stenotic renal arteries (mean preprocedure serum creatinine 2.3 +/- 0.9 mg/dl; range, 1.5-8.2 mg/dl). Forty-seven patients were eligible for 30-month follow-up of the procedural effect on renal function, blood pressure control, number of antihypertensive medications, and survival. At 1-year follow-up, the slope of the 1/Scr curve increased and the EGFR values significantly improved compared to preprocedure values (19.9 +/- 6.2 to 26.8 +/- 10.1 ml/min; P < 0.0001), serum creatinine decreased from the mean preprocedure value to 1.75 +/- 0.69 mg/dl (P < 0.001), with renal function improvement or stabilization observed in 94% of patients; three patients (7.3%) required permanent hemodialysis during the 30-month follow-up period. Systolic and diastolic blood pressure significantly decreased (from 177 +/- 28 to 148 +/- 25 mm Hg and from 92 +/- 15 to 78 +/- 14 mm Hg, respectively; P < 0.001) with fewer antihypertensive medications required to control blood pressure (3.5 +/- 0.9 vs. 1.9 +/- 1.3; P < 0.001). The patient survival rate after 30-month follow-up was 87%, with three deaths related to end-stage renal failure. Renal artery stent revascularization reversed progressive renal dysfunction within the first 12 months and maintained the improved level of renal function at 30-month follow-up while improving blood pressure control and reducing the number of antihypertensive medication requirements. Renal stent revascularization should be considered a valid therapeutic option for the long-term treatment of ischemic nephropathy.

Aged↗

Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma.

BACKGROUND: Interleukin-2 (IL-2) has activity in metastatic melanoma when given in high doses by the intravenous (IV) route, but its side effects and effectiveness when given in intermediate to high doses by the subcutaneous (SC) route have not been studied adequately. This study sought to determine the maximum tolerated dose (MTD) of IL-2 administered once daily by the SC route. METHODS: Outpatients with progressive metastatic melanoma after chemotherapy were enrolled in a Phase I trial of IL-2 administered SC daily for 5 days per week for 4 consecutive weeks, repeated at 6-week intervals. Patients were instructed to drink at least 2 L of fluid daily. IL-2 pharmacokinetic studies were performed at the two highest dose levels. Toxicity was recorded weekly using the National Cancer Institute Common Toxicity Criteria. Response was assessed at 6-week intervals. RESULTS: Three patients, 6 patients, 6 patients, and 4 patients received a median of 2 courses of SC IL-2 at dose levels of 6 MIU/m(2), 9 MIU/m(2), 12 MIU/m(2), and 15 MIU/m(2), respectively. Failure to maintain adequate fluid intake was responsible for 2 episodes of syncope at the 9 MIU/m(2) dose level and for 2 incidents of reversible prerenal azotemia at the 15 MIU/m(2) dose level. IL-2 treatment was resumed in these patients without incident. At the 15 MIU/m(2) dose level, 2 patients had severe headaches, depression, and visual hallucinations requiring discontinuation of treatment. Cough and fluid retention at the end of the third and fourth weeks at the 15 MIU/m(2) dose level approximated the symptoms reported by inpatients treated by continuous IV infusion at 9 MIU/m(2) on the same schedule. There was a partial response and a complete response in subcutaneous disease at the 12 MIU/m(2) and 15 MIU/m(2) dose levels, respectively, each lasting < 2 months. Plasma IL-2 levels after SC injection of 1000-5000 pg/mL reached maximum by 3 hours and were detectable for up to 48 hours after administration. The half-lives for SC IL-2 absorbance and clearance were 1.6 hours and 5.2 hours, respectively, and the calculated area under the curve was 30,584 pg/mL x hour. CONCLUSIONS: SC IL-2 was well tolerated and had high sustained bioavailability at the higher doses studied. The MTD for a daily SC regimen was 12 MIU/m(2) and is recommended for future studies.

Adult↗

Determinants of the renal clearance of digoxin.

The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean plus or minus SD values were: blood urea nitrogen (BUN), 26.1 plus or minus 12.8 mg per 100 ml; creatine, 1.1 + 0.41 mg per 100 ml; creatinine clearance, 78 plus or minus 42 ml/min/1.73 m2; digoxin clearance, 66.6 plus or minus 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 plus or minus 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and BUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patinets digoxin clearance was significantly related to urine flow rate. These findings are compatible with the hypothesis that digoxin undergoes some degree of tubular reabsorption as well as filtration and secretion.

Adult↗

Pharmacokinetics and hemodialyzability of cefazolin in uremic patients.

Cefazolin may be used in azotemic patients at reduced dosage as suggested by others. Although hemodialysis removes some of the drug, therapeutic levels are maintained throughout dialysis after a single intravenous dose of 500 mg. Imperfect transport from blood to dialysate is related to protein binding but varies with the degree of azotemia. Small amounts of cefazolin may be administered to patients during dialysis by addition to dialysate.

Adult↗

Salmon calcitonin in hypercalcemia.

We have undertaken a study of 24 hypercalcemic patients with the use of salmon calcitonin as a therapeutic agent. Seventy-five percent of the patients exhibited a clinically significant decrease in serum calcium and approximately half became normocalcemic within 2 hr. Throughout salmon calcitonin administration, the mean serum calcium of the patients was lower than the pretreatment values. Although the drug did not always lower the calcium level to normal, it often brought the hypercalcemia to more tolerable levels. During the course of calcitonin therapy, the number of patients with normal or near-normal serum calcium ranged from 31.3% (at 96 hr) to 82.4% (at 30 hr). Many of the patients improved symptomatically. The only significant side effects were nausea and vomiting in 12.5% of the patients, which necessitated cessation of therapy in only one. The drug was well tolerated in patients with azotemia. Calcitonin-induced hypocalcemia was not encountered. Salmon calcitonin can be used safely alone or in conjunction with other hypocalcemic therapies.

Aged↗

Acute liver damage in anorexia nervosa.

We report a case of a 26-year-old White woman with a history of anorexia nervosa who developed severe liver damage and multiorgan dysfunction. At admission to our medical unit, her body mass index (BMI) was 10.8. Biochemical evaluation showed a marked increase in serum levels of aspartate aminotransferases (AST = 9,980 IU/L), alanine aminotransferase (ALT = 3,930 IU/L), amylase (1,002 IU/L), lipase (1,437 IU/L), creatine phosphokinase (CPK; 783 IU/L), and lactate dehydrogenase (LDH = 6,830 IU/L). Glomerular filtration rate was reduced (35 ml/min), reflecting dehydration and prerenal azotemia. No other cause of acute liver damage except malnutrition was evidenced. Hydration and nutritional support were the unique medical treatment. A rapid recovery occurred in few days and all laboratory data were normal at discharge after a 37-day hospitalization.

Acute Disease↗

Gentamicin nephrotoxicity in extrahepatic cholestasis: modulation by dietary calcium.

The present study was designed to test the hypothesis that the presence of a specific hepatobiliary disease, namely common bile duct obstruction, in the absence of other risk factors will exacerbate gentamicin nephrotoxicity. Furthermore, since bile duct ligation decreases urinary calcium excretion, we studied the role of calcium supplementation in the prevention of gentamicin nephrotoxicity in this model. Male Sprague-Dawley rats were allocated to sham groups and common bile duct ligation groups. Gentamicin at 40 and 100 mg per kg per day for 5 days induced a more severe azotemia in common bile duct ligation animals than in sham controls. Furthermore, higher levels of renal gentamicin were found in common bile duct ligation rats than in sham rats early in the course of therapy, at its termination and during the recovery period. Pretreatment of common bile duct ligation animals with dietary calcium supplementation significantly attenuated gentamicin nephrotoxicity and the increased renal gentamicin accumulation, whereas initiation of calcium supplementation concurrent with gentamicin administration had no salutary effect. We conclude that experimental extrahepatic cholestasis in the rat, in the absence of any other factor, potentiates gentamicin nephrotoxicity. The effect is prevented by pretreatment with dietary calcium supplementation but is not modified by concurrent administration of a high-calcium diet.

Animals↗

A comparative study of captopril and enalapril in patients with severe hypertension.

Twenty patients with moderate to severe essential hypertension were randomized in a paralleled, double-blind, 22-week study of captopril (ten) and enalapril (ten) following four weeks of hydrochlorothiazide (50 mg/d) baseline treatment. The captopril group was administered 25 mg tid and increased to 100 mg tid, while the enalapril group began with 5 mg bid and increased to 20 mg bid, depending on the patient's blood pressure (BP) response. Methyldopa, 250 mg to 500 mg bid and 1,000 mg bid, was administered to patients in both groups if BP was not adequately controlled. Patients were seen every two weeks for BP monitoring and metabolic evaluation. Each group showed a significant and equal decrease in BP, with the effect being the greatest on the diastolic pressure, supine and upright. Of the 20 patients, ten (four whites and six blacks) required methyldopa for adequate BP control. Four patients, two from each group, developed reversible prerenal azotemia (BUN [blood urea nitrogen] congruent to 50 mg/dL). No other clinical or metabolic side effects were noted. We concluded that captopril and enalapril were equally effective in lowering BP in the dosages given; no racial differences in BP response were noted, although more black patients required the addition of methyldopa for adequate BP control; and both drugs were safe and well tolerated.

Antihypertensive Agents↗

Pharmacology, therapeutic efficacy, and adverse effects of bumetanide, a new "loop" diuretic.

Bumetanide is a recently developed natriuretic and diuretic agent, belonging to the "loop" class of diuretics. Since it is rapidly and almost completely absorbed after oral administration, oral and parenteral formulations have a similar pharmacokinetic profile. Peak plasma levels are achieved approximately 30 min after oral administration. The apparent half-life is 1.2-1.5 hr, and the volume of distribution is about 25 liters. Plasma clearance is 228-255 ml/min. Bumetanide is promptly and almost completely eliminated by metabolism of the butyl side chain and urinary excretion of the parent drug and its metabolites. The principle renal site of action is the ascending limb of the loop of Henle, with a minor effect on the proximal tubule. The drug causes decreases in both free water clearance (during water diuresis) and solute free water reabsorption (during hydropenia), increased fractional delivery of sodium chloride to the distal tubule and a natriuresis approaching 20% of the filtered load of sodium, calciuria, phosphaturia, and minimal bicarbonaturia. Extensive clinical studies have been conducted with both oral and parenteral bumetanide in patients with a variety of edematous conditions. The agent has been clearly demonstrated to be an effective diuretic in the treatment of edema due to cardiac disease (congestive heart failure) and edema, with or without ascites, due to hepatic disease. Bumetanide has also been shown effective in treating edema due to renal disease, even when modest to severe renal insufficiency is present, and it may be useful in the treatment of edema refractory to other loop diuretics. As would be predicted for any potent diuretic, bumetanide administration has been associated with hypokalemia, hypochloremia, metabolic aklalosis, hyperuricemia, and prerenal azotemia. Alterations in glucose metabolism are an inconsistent finding. Transient thrombocytopenia and granulocytopenia have been noted, but no consistent or important alterations in biochemical parameters have been observed. In some patients, especially those with renal failure receiving high doses, myalgias and muscle tenderness have been described. To date only a very limited potential for ototoxicity has been observed. Bumetanide has been administered without difficulty to patients having side effects from other loop diuretics.

Animals↗

Asymptomatic primary hyperparathyroidism.

Of 118 consecutive white patients referred for asymptomatic primary hyperparathyroidism, the diagnosis was clinically confirmed in 100, of whom 85 adults had a serum calcium less than 3.0 mM (12 mg/dl) and no skeletal, rheumatic, or significant neuropsychiatric symptoms, azotemia, or other significant illnesses. Among these 85, 68 had both asymptomatic and medically uncomplicated hyperparathyroidism, whereas 17 had historical, radiographic, or ultrasonic evidence of renal stone disease. The 20% with past or present renal calculi concentrated their urine significantly better than the 68 others (p = 0.05), but these two groups were otherwise not distinguished by the tests we performed, so all 85 patients were analyzed together. Systolic and diastolic blood pressures were normal, but premature osteopenia and/or impaired renal function were present in 29-36% of the patients. Micrometer measurements of metacarpal radiographs and 125I photon absorptiometry at the shaft of the radius revealed cortical osteopenia. Osteopenia was equally significant in the distal radius (cortical plus trabecular bone). These quantitative measurements were superior to routine bone radiography, and ROC analysis showed that 125I absorptiometry at either site was superior (p less than 0.01) to metacarpal cortex measurements for detecting premature osteopenia, which was present in more than a third of these patients. Creatinine clearances (24 h) and maximum urine concentrating capacity (overnight dehydration plus the synthetic vasopressin analog DDAVP) were each significantly reduced, despite all patients' normal BUN and serum creatinine levels. Sequential performance of a 24 h creatinine clearance and a urine concentration test revealed abnormalities in the renal function of 27 of 74 patients (36%), with a specificity of 95% and a higher sensitivity than either test alone (27-29%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Sonographic evaluation of the nonfunctioning kidney.

The results of B-mode ultrasound examinations in 113 consecutive patients with unilateral renal nonfunction or severe azotemia were reviewed. The causes of nonfunction included the following: hydronephrosis; renal parenchymal disease; renal agenesis; atrophy or dysplasia; multicystic, medullary cystic, and polycystic kidneys; renal arterial or venous occlusive disease; extensively infiltrating neoplasm. The sonographic findings were consistent with the final diagnosis in 92 percent of the cases. A coronal view of the kidney for diagnosing hydronephrosis is described. This view demonstrates the dilated calyces in continuity with the renal pelvis and, when combined with transverse views, improves the reliability of the sonographic diagnosis of hydronephrosis. In cases where the renal landmarks appear totally normal, obstruction can be excluded as a cause of nonfunction, and retrograde pyelography may be avoided. The sonographic manifestations of other parenchymal abnormalities associated with nonfunction, such as cystic renal disease, glomerulonephritis, and renal transplant rejection, are also discussed.

Abscess↗

The pathophysiology of the jejunal conduit syndrome and its exacerbation by parenteral hyperalimentation.

Supravesical urinary diversion using a jejunal conduit may be associated with hyponatremia, hypochloremic-acidosis, hyperkalemia, azotemia, and a clinical picture of nausea, vomiting, dehydration, muscular weakness, elevated temperature, and lethargy. This syndrome is secondary to the loss of sodium chloride into the urine passing through the conduit and absorption of potassium and urea from it. Treatment and prevention of this syndrome consist of adequate supplements of sodium chloride and hydration. Intravenous hyperalimentation as the precipitating factor of a severe form of this syndrome and its successful management are described. The pathophysiology of the jejunal conduit syndrome is also discussed. Great selectivity and extreme caution are recommended with respect to the use of intravenous hyperalimentation in patients with jejunal conduits.

Adenocarcinoma↗

The use of low-dose prednisone and melphalan in the treatment of poor-risk patients with multiple myeloma.

A study was designed to evaluate the effectiveness of prednisone therapy in poor-risk patients with multiple myeloma. Patients were treated with melphalan alone or in combination with prednisone at doses of either 0.6 mg/kg or 0.3 mg/kg. The group of patients receiving melphalan and prednisone 0.6 mg/kg had significantly improved responses in hemoglobin, lowering of the M-protein concentration, and reduction of azotemia. Significant benefits attributable to prednisone were not demonstrated in the group receiving 0.3 mg/kg. Good responses have been shown to produce improved survival. The combination of melphalan and prednisone is effective in producing good responses, but the dose of steroids is important. A dose of prednisone of 0.6 mg/kg in gradually decreasing doses has been found to be effective in production of good responses, especially in the uremic patient.

Dose-Response Relationship, Drug↗

Hypocalcemia complicating acute leukemia.

Eighteen of 54 adults with acute leukemia developed severe hypocalcemia during a 20 month period. Hypocalcemia (mean lowest serum calcium 6.3 mg/100 ml with a range of 4.1 to 7.0 mg/100 ml) lasted 2-29 days and was symptomatic in all but one patient. Six patients were hypocalcemic at the time of death, 5 died within 1 week of hypocalcemia, and 2 had antibiotic-induced respiratory arrest. All patients had severe infections; 17 of 18 were with gram-negative organisms. No patient had severe azotemia, diarrhea, alkalosis, or hypoalbuminemia. Hypophosphatemia was seen in 14 patients, suggesting no hypoparathyroidism. The serum calcium of patients with acute leukemia should be measured frequently, especially when they have infection. Hypocalcemia is a sign of poor prognosis and should signal the need for careful observation of ventilation, caution in the use of aminoglycoside antibiotics, and vigorous attempts at calcium administration.

Adolescent↗

Sequential chemotherapy of advanced colorectal cancer with standard or high-dose methotrexate followed by 5-fluorouracil.

Thirty patients with advanced measurable colorectal cancer were randomized to receive either methotrexate (MTX) 200 mg/m2 or 40 mg/m2, followed in four hours by 5-fluorouracil (5-FU) 600 mg/m2. Patients receiving the higher dose MTX were given leucovorin rescue 24 hours later. Eight of 13 patients treated with 200 mg/m2 MTX + 5-FU developed severe hematologic toxicity, leading to two toxic deaths. In addition, 9/13 developed mild azotemia, and three patients had severe gastrointestinal toxicity. No patients with prior chemotherapy responded to either regimen. Among those without prior chemotherapy, there were two of six and three of eight partial responses, respectively, in the 200 mg/m2 and 40 mg/m2 MTX regimens. Sequential 200 mg/m2 MTX followed by 5-FU after four hours has unacceptable toxicity. Sequential treatment with standard dose MTX + 5-FU is tolerable and merits further study.

Aged↗

Severe hyperphosphatemia following acute tumor lysis syndrome.

We report on a 14-year-old boy with acute lymphoblastic leukemia (lymphoma-leukemia) who had two episodes of acute tumor lysis syndrome during induction of remission with oral prednisolone alone and oral prednisolone, intravenous vincristine, and doxorubicin, respectively. Subsequently he had severe hyperphosphatemia (29.3 and 14.1 mg/dl; 9.46 and 4.55 mmol/L), hypocalcemia, hyperuricemia, hyperkalemia, and azotemia. Multiple stones and tumor cells infiltration were demonstrated in both kidney. He responded favorably to hemodialysis.

Antineoplastic Combined Chemotherapy Protocols↗

Localisation and pathology of Mortierella wolfii toxin in mice.

Using 125I labelled M. wolfii toxin the site of action in mice was shown to be the kidney. Autoradiographic studies revealed the label to be localised in the proximal convoluted tubules of the kidney, where there was a marked necrosis and degeneration of the epithelium causing the tubules to become considerably distended. Although the distal and collecting tubules maintained their integrity, many contained amorphous casts. An injected dose of 1 toxic unit (10 mug protein) was sufficient to produce damage to the kidney with subsequent anaemia, azotemia and albuminuria. Other organs appeared to be essentially normal and renal failure was the probable cause of death of mice.

Animals↗

Somatomedin inhibitors from human serum produce abnormalities in mouse embryos in culture.

Two human serum fractions, one from normal individuals (Mr 1,150-1,310 daltons) and the other (Mr 800-1,100 daltons) from patients suffering with uremia (renal failure, azotemia), were added to the medium used to grow embryos in whole-embryo culture (WEC) beginning at the 3-5 (day 9) or 18-21 (day 10) somite stage. Both of these fractions possessed somatomedin (insulin-like growth factor) inhibitory activity. Day 9 embryos exposed to either of the serum fractions for 24 hr exhibited incomplete rotation and neural tube closure defects and were smaller than control embryos (decreased total protein content). Developmental abnormalities induced in day 10 embryos following 24 hr in culture included a marked decrease in expansion of the brain regions, hypoplasia of the first two branchial arches, and decreased amounts of total protein compared to controls. The visceral yolk sacs (VYSs) of somatomedin inhibitor (SI)-exposed conceptuses were opaque, and those from day 10 conceptuses contained significantly more protein than controls. Morphologically, the VYS endoderm cells from SI-exposed embryos contained a much higher density of "vacuoles" than controls. These results mimic those produced by exposure of conceptuses to an SI of Mr800-1,100 obtained from the serum of diabetic rats and suggest that similar substances and mechanisms are involved.

Animals↗