Gemcitabine nephrotoxicity and hemolytic uremic syndrome: report of 29 cases from a single institution.

BACKGROUND: Gemcitabine is used in a variety of advanced malignancies. Hemolytic uremic syndrome has been reported as a side effect. METHODS: we reviewed medical records of 29 patients with gemcitabine nephrotoxicity. RESULTS: The median cumulative dose of gemcitabine was 22 g/m2 (4 - 81) given over 7.5 months (2 - 34). Prior chemotherapy with mitomycin had been given to 9 patients, and in 4 the hemolytic uremic syndrome was particularly severe and appeared shortly after gemcitabine initiation. All patients had renal insufficiency. Microhematuria and proteinuria were present in 27 patients and red blood cell casts were seen in 8. Renal biopsies in 4 patients showed thrombotic microangiopathy. Worsening or new-onset hypertension was seen in 26 patients. Edema, shortness of breath and congestive heart failure were present in 21, 15 and 7 patients, respectively. All had anemia, thrombocytopenia and elevated serum lactate dehydrogenase. Haptoglobin was low in 23 of the 26 patients who had it measured. Schistocytes were present in 21 of the 24 patients who had blood smear reviewed. Gemcitabine was discontinued once hemolytic uremic syndrome was recognized. Full or partial recovery of renal function occurred in 19 patients. 7 patients progressed to end-stage renal disease and 3 patients developed chronic renal failure. CONCLUSIONS: Gemcitabine nephrotoxicity presents as new-onset renal disease with associated hypertension, thrombocytopenia and microangiopathic hemolytic anemia. Prior chemotherapy with mitomycin, especially when given in close proximity, may be synergistic. A high index of suspicion is essential to make an early diagnosis. Stopping gemcitabine improves the outcome.

Effects of acetazolamide on proximal tubule C1, Na, and HCO3 transport in normal and acidotic dogs during distal blockade.

It has been suggested that the establishment of a tubular fluid to plasma chloride gradient in the late proximal tubule by the reabsorption of bicarbonate (and other anions) in the early proximal tubule is responsible for a significant part of sodium chloride and water reabsorption in the proximal tubule. In the present study the effects of acetazolamide on proximal tubule water and electrolyte excretion were examined in 6 normal dogs and 10 chronic ammonium chloride-loaded dogs during distal blockade produced by ethacrynic acid and chlorothiazide administration. During distal blockade control urine/plasma osmolality and urine/plasma sodium were close to unity in all experiments. Urine/plasma chloride and urine/plasma bicarbonate were 1.21+/-0.02 and 0.75+/-0.07 in normal and 1.24+/-0.01 and 0.04+/-0.01 in acidotic dogs, respectively. After the administration of acetazolamide (20 mg/kg i.v.), there was a significant increase in urine flow, absolute and fractional excretion of sodium, bicarbonate, and chloride in all animals. Associated with these effects, urine/plasma osmolality and urine/plasma sodium remained unchanged but urine/plasma chloride decreased significantly to 1.15+/-0.01 in normal and to 1.19+/-0.01 in acidotic dogs. In acidotic dogs there was a significant correlation between the increase in bicarbonate, sodium, or chloride excretion after acetazolamide and the plasma bicarbonate level (range 6.8-12.5 meq/liter). These data demonstrate a significant effect of acetazolamide on bicarbonate, sodium, and chloride reabsorption in the proximal tubule even in the face of severe acidosis. Moreover, the data suggest that the decrease in chloride reabsorption (and accompanying sodium) after acetazolamide is related to the decrease in bicarbonate reabsorption and the associated decrease in the transtubular chloride gradient.

High-dose leucovorin as sole therapy for methotrexate toxicity.

PURPOSE: Hemodialysis, hemoperfusion, thymidine, and carboxypeptidase have been recommended together with high-dose (HD) leucovorin (LV) to treat patients at risk for methotrexate (MTX) toxicity. To elucidate the efficacy of high LV rescue as the sole salvage modality for severe MTX intoxication, we studied 13 patients who were treated in this fashion at Memorial Sloan-Kettering Cancer Center (New York, NY). PATIENTS AND METHODS: To identify patients at high risk for severe MTX toxicity, we performed a retrospective review of all patients with MTX levels greater than 100 micromol/L at 24 hours and greater than 10 micromol/L at 48 hours after HD MTX. RESULTS: A total of 13 patients were identified. The median MTX concentration was 164 micromol/L at 24 hours (range, 102 to 940 micromol/L), 16.3 micromol/L at 48 hours (range, 10.5 to 190 micromol/L), and 6.2 micromol/L at 72 hours (range, 1.35 to 39 micromol/L). MTX levels remained greater than 0.1 micromol/L for an average of 11 +/- 3 days (mean +/- SD) (range, 7 to 17 days). In addition to supportive treatment with hydration and sodium bicarbonate administration, all patients were treated solely with HD LV, which was started within the first 24 hours in nine patients, 48 hours in three patients, and 72 hours in one patient in doses that varied from 0.24 to 8 g/d. Significant neutropenia (neutrophil count < 1,000/ microL) occurred in eight patients and lasted for 1 to 5 days. Thrombocytopenia (platelet count < 100,000/microL) occurred in seven patients and lasted for 5 to 10 days. Other toxic manifestations included mucositis of varying degrees, diarrhea, and neutropenic fever, but all patients recovered. CONCLUSION: In the range of MTX levels observed, HD LV can be used as a sole therapy for MTX toxicity without the need for extracorporeal removal and with tolerable morbidity.

Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients.

PURPOSE: To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood-derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] x minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison. PATIENTS AND METHODS: Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m(2) plus ifosfamide 6 g/m(2) were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1, 200 mg/m(2), and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) x min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC. RESULTS: Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula. CONCLUSION: Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.

Treatment of acute obstructive renal failure with high-dose methylprednisolone.

High-dose methylprednisolone sodium succinate (Solu-Medrol) therapy was administered to two patients with acute renal failure and anuria secondary to cancer-related urinary tract obstruction. Following the administration of intravenous methylprednisolone, obstruction was relieved, as evidenced by increased urinary flow and improvement of renal function. The salutary effect of methylprednisolone is probably related to the relief of obstruction secondary to a decrease in tumor-associated edema similar to the effect obtained in patients with brain tumors and spinal cord compression by epidural metastases. The temporary improvement in renal function allowed time for more definitive therapy to be instituted under more favorable clinical conditions.

TPN-induced catch-up of growth in a 22-y-old male with radiation enteritis.

Nutritional rehabilitation of malnourished children with growth arrest is generally associated with a catch-up of growth but the occurrence of this compensatory phenomenon in adulthood is not well recognized. We investigated a case of maturation and growth acceleration secondary to nutritional intervention in a 22-y-old patient. After treatment for a rhabdomyosarcoma of the bladder at age 7 y, the patient developed severe malabsorption secondary to radiation enteritis and short bowel syndrome. As a result of profound malnutrition, growth and maturation were severely impaired. Initiation of home total parenteral nutrition at age 22 y led to an increase in height, substantial weight gain, advancement of bone age, and sexual maturation evidenced by appearance of secondary sex characteristics and normalization of hormone concentrations. The development of signs of puberty and a growth spurt appearing at this late age clearly show the potential for maturation and growth once malnutrition is corrected.

Selected ultratrace elements in total parenteral nutrition solutions.

Ultratrace elements are potentially essential (eg. boron, molybdenum, nickel, and vanadium) or toxic (eg, aluminum and cadmium) in humans. Long-term total parenteral nutrition (TPN) patients can inadvertently receive significant amounts of ultratrace elements present as contaminants in TPN solutions. We determined the intake of selected ultratrace elements from a standard TPN solution and compared it with the amount reported to be absorbed from food in normal subjects. Contamination of TPN solutions with ultratrace elements was widespread and variable. The daily intakes of Mo, Ni, V. and Cd from this contamination were comparable to the amounts reported to be absorbed through the gastrointestinal tract in normal subjects. Al intake was high; B intake was low, approximately 10% of the amount absorbed by normal subjects. Thus, TPN solutions are contaminated with significant amounts of ultratrace elements. The biological significance of the intravenous infusion of these ultratrace elements is unclear and requires further investigation, particularly in home TPN patients.

Bone disease in prolonged parenteral nutrition: osteopenia without mineralization defect.

A metabolic bone disease characterized by a mineralization defect, low plasma 1,25(OH)2D, and hypercalciuria has been described in patients receiving prolonged total parenteral nutrition (TPN). Because the practice of TPN differs from center to center, we investigated 13 home TPN patients to determine whether they had similar or different bone abnormalities. They had received TPN for a mean period of 51 +/- 38 mo. Bone pain occurred in six patients and two had multiple vertebral and rib fractures (with trauma in one patient). Bone pain was mild to moderate and not incapacitating. Bone histomorphometry showed reduced bone volume, reduced osteoid with normal resorption and calcification rates. These abnormalities were associated with hypercalciuria, but the plasma levels of 1,25(OH)2D were normal. Abnormalities in bone metabolism in this group of patients suggest a fundamental decrease in bone matrix-formation rather than a mineralization defect as the underlying mechanism.

Metabolic emergencies in the cancer patient.

The acute tumor lysis syndrome (ATLS) is characterized by the rapid development of hyperuricemia, hyperkalemia, hyperphosphatemia, and acute renal failure (ARF). Hematologic malignancies are responsible for most cases of ATLS. Control of hyperuricemia and the achievement of a high urine flow are the mainstays of prevention. Urinary alkalinization should be performed only when hyperuricemia is present. Hypercalcemia occurs in 10% to 20% of patients with cancer at some time during the disease course. Parathyroid hormone-related protein (PTHrP) is the most common mediator of humoral hypercalcemia of malignancy (HHM), while local osteolysis is the principal mechanism in patients with bone metastasis. Hydration with saline and administration of pamidronate control hypercalcemia in most patients. Hyponatremia with an increase in total-body salt and water content, manifested as edema and/or ascites, is the most common electrolyte abnormality in cancer patients. Hyponatremia due to salt depletion may occur in patients who receive cisplatin. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur in association with cancer of the lung, after high-dose cyclophosphamide, and during vigorous fluid administration in patients with chemotherapy-associated emesis. Lactic acidosis without tissue hypoperfusion may be seen in patients with extensive liver metastasis or with certain hematologic malignancies. In the latter cases, lactate levels parallel disease activity and chemotherapy often leads to resolution of the lactic acidosis. Idiopathic hyperammonemia has been described after intensive chemotherapy for hematological malignancies and following bone marrow transplantation.

Carboplatin-based chemotherapy with pharmacokinetic analysis for patients with hemodialysis-dependent renal insufficiency.

Three patients with renal insufficiency requiring hemodialysis were treated with carboplatin at 100 mg/m2 in combination with etoposide for advanced germ-cell tumor (GCT, two cases) or Adriamycin + vinblastine for a transitional-cell carcinoma of the ureter (one case). Hemodialysis was performed 24 h after the administration of carboplatin. Both patients with GCT achieved a complete response, and the patient with transitional-cell carcinoma of the ureter was inevaluable for response but his disease has not progressed. The dose of carboplatin was increased in one patient as renal function improved on therapy. In two patients, the pharmacokinetics of carboplatin were determined; the pre-dialysis half-lives, AUC, and total body clearances of free carboplatin-derived platinum were estimated to be 32 and 18.3 h, 4.93 and 6.17 mg ml-1 min, and 18.2 and 18.7 ml/min, respectively. The dialysis elimination half-lives (t1/2 beta) of 2 and 3 h, respectively, for these two patients were markedly lower than the predialysis values, indicating that carboplatin was dialyzed. In summary, carboplatin can be given to patients with severe renal insufficiency. Adequate AUCs were achieved and dialysis limited systemic exposure to free carboplatin.

Safety of pamidronate in patients with renal failure and hypercalcemia.

Pamidronate (APD) is a drug widely used for the treatment of hypercalcemia of malignancy. Renal impairment has been associated with the use of other bisphosphonates in humans, and nephrotoxicity has been described after APD administration in animals. We retrospectively evaluated the safety and efficacy of APD administration in 31 patients with underlying renal insufficiency who received 33 courses of APD in doses of 60-90 mg. Hypercalcemia resolved or improved in 91% of the patients and only 1 case had severe hypocalcemia. A transient deterioration in renal function was observed in 8 courses but this was unrelated to APD administration. No systemic ill effects were observed. APD appears to be a safe drug in patients with underlying renal failure.

Acute renal failure and dialysis in cancer patients.

Acute renal failure continues to be a common occurrence in critically ill cancer patients. It frequently results from a combination of risk factors, which include the following: hemodynamic alterations associated with renal ischemia; exposure to nephrotoxic drugs; urinary tract obstruction; and specific abnormalities related to cancer itself. Recent advances in the techniques of hemodialysis, nutritional support, and the recent introduction of continuous arteriovenous hemofiltration have improved the care of these patients.

Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis.

To improve the efficacy of risk-adapted melphalan (MEL) in patients with amyloidosis (AL), we conducted a phase II trial using bortezomib and dexamethasone (BD) as consolidation. Forty untreated patients with renal (70%), cardiac (65%), liver/gastrointestinal (15%) or nervous system (13%) AL were assigned MEL 100, 140 or 200 mg/m(2) based on age, renal function and cardiac involvement. Hematological response was assessed at 3 months post stem cell transplant (SCT); patients with less than complete hematological response (CR) received BD consolidation. Four patients with advanced cardiac AL died within 100 days of SCT (10% treatment-related mortality). Survival at 12 and 24 months post treatment start was 88 and 82% overall and was 81 and 72% in patients with cardiac AL. At 3 months post SCT, 45% had ≥ partial response (PR) including 27% CR. Twenty-three patients received consolidation and in 86% response improved; all patients responded in one cycle. At 12 and 24 months, 79 and 60% had ≥ PR, 58 and 40% CR. Organ responses occurred in 55 and 70% at 12 and 24 months. Eight patients relapsed/progressed. One patient with serologic progression had organ impairment at time of progression. In newly diagnosed AL, BD following SCT rapidly and effectively improves responses resulting in high CR rates and maintained organ improvement.

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease.

The treatment of monoclonal Ig deposition disease (MIDD) is controversial and not standardized. We report our experience with high dose melphalan and auto-SCT (HDM/auto-SCT) in seven patients with MIDD associated with underlying Durie-Salmon stage IB multiple myeloma, including five with light chain deposition disease, one with light and heavy chain deposition disease and one with light chain crystal deposition disease. The median age of these patients was 50 years; six of them were male subjects. A monoclonal kappa-light chain was detected by Serum Free Light Chain Assay in all seven. The patients received melphalan 140 mg/m(2) followed by auto-SCT. All patients are alive and six remain in hematologic CR with a median follow up of 23.6 months (7.9-69.8 months). Renal function has improved compared to pre-HDSM/auto-SCT in five patients--two of whom had a renal transplant and became dialysis independent--remained stable in one and worsened in one leading to hemodialysis despite hematologic CR. Our results corroborate previous experience with HDM/auto-SCT in MIDD and argue in favor of kidney transplantation in patients who achieve hematologic CR after HDM/auto-SCT. Although this approach appears effective, multi-center studies are needed to define the optimal treatment for patients with MIDD.

Acute renal failure associated with the retinoic acid syndrome in acute promyelocytic leukemia.

All-trans-retinoic acid is an effective agent to induce remission in patients with acute promyelocytic leukemia (APL). Unlike conventional chemotherapy, this drug exerts its effect by inducing differentiation of immature leukemic cells. A distinctive clinical syndrome characterized by fever, dyspnea, effusions, weight gain, and organ failure (the "retinoic acid syndrome") can occur during treatment with this drug. Postmortem studies have shown extensive organ infiltration by leukemic cells, and the early administration of corticosteroids can result in prompt resolution of symptoms. We describe a patient with APL in whom acute renal failure developed during treatment with all-trans-retinoic acid. Transient renal enlargement during a period of leukocytosis and a beneficial response to treatment with dexamethasone suggest that renal failure in this patient was probably related to the retinoic acid syndrome.

Case report 772. Stress fracture of the hip secondary to renal osteodystrophy and erosion of ischium due to amyloid deposition.

We have reported the case history of a 72-year-old woman who was on hemodialysis for 15 years. Her course was marked by many of the musculoskeletal complications of ESRD including CTS, stromal amyloid deposition of synovium, amyloid cystic degeneration of bone, and inflammation of the synovium due to the deposition of calcium oxalate and calcium pyrophosphate microcrystals. She also had evidence of metabolic bone disease: moderate osteoporosis related to secondary hyperparathyroidism and osteomalacia related to aluminum deposition at the mineralization front. The pathological and radiological findings associated with her bone disease are described.

Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine.

Three patients with pancreatic carcinoma treated with gemcitabine for 1 year developed clinical and laboratory findings compatible with an indolent form of the hemolytic-uremic syndrome. Renal biopsy specimens in two of these patients showed the characteristic features of thrombotic microangiopathy, and a skin biopsy specimen from the third patient, who presented with livedo reticularis, showed intravascular fibrin deposition. Thrombotic microangiopathy may represent a toxic effect of long-term gemcitabine therapy.

Lactic acidosis and renal enlargement at diagnosis and relapse of acute lymphoblastic leukemia.

Bilateral renal enlargement was noted on ultrasonography during an extensive renal evaluation for severe hypokalemic metabolic acidosis with an increased anion gap in a 12-year-old Hispanic boy who had normal results of a physical examination and complete blood count. The patient was found to have acute lymphoblastic leukemia. Resolution of the lactic acidosis and bilateral renal enlargement occurred with initiation of chemotherapy and recurred with each subsequent relapse.

Septicemia and septic shock in pediatric patients: 140 consecutive cases on a pediatric hematology-oncology service.

PURPOSE: This report describes the incidence of septic shock in pediatric hematology-oncology patients with positive blood cultures and investigates parameters of potential use in early diagnosis of gram-negative (GN) bacteremia and septic shock. PATIENTS: In a 12-month period, 140 consecutive episodes of septicemia (135 bacterial and 5 fungal) were seen in 100 patients. The absolute neutrophil count (ANC) was > 500/microl in 89 episodes (65%). RESULTS: Septic shock developed in patients with positive blood cultures with an overall incidence of approximately 19%. Of the 12 bacteremic patients who required transfer to the intensive care unit, 83% had a GN isolate recovered. The incidence of septic shock was not significantly lower in the group of patients with ANC > 500/microl. Low serum bicarbonate correlated with GN infection in patients with bacteremia. CONCLUSIONS: GN organisms were the major cause of septic shock in a group of pediatric hematology-oncology patients with positive blood cultures although they were recovered less frequently than gram-positive organisms. In our study, non-neutropenic patients with indwelling catheters were at approximately the same risk for GN shock as neutropenic patients. Monitoring blood carbon dioxide content may be useful in the early diagnosis of GN infection.