Acute renal failure during treatment with Zoledronate in cancer patients

Introduction

Since their discovery more than 5 decades ago, bisphosphonates have been used in the treatment of Paget's disease, malignant hypercalcemia, bone metastases and osteoporosis.^1,2 These drugs have a primary role in maintaining bone density and contribute to serum calcium homeostasis in these pathological situations.^2,3,4 They are incorporated into the bone matrix and absorbed by osteoclasts at resorption sites. They inhibit osteoclast activity and bone remodeling, increase bone mineral density and reduce bone mass loss and the risk of vertebral and non-vertebral fractures. ⁵ Currently, the standard treatment for bone metastases is based on intravenous bisphosphonates, including zoledronic acid. ⁶ Renal tolerance of zoledronic acid is a problem linked to its intrinsic toxicity and the cancer patient. ⁷ zoledronate more frequently induces tubular toxicity. The incidence of renal failure during Zoledronate varies between studies from 10 to 24%. ⁸ The objective of our study was to evaluate the incidence of acute renal failure during Zoledronate and to analyze the correlated factors.

Materials and methods

Results

Patient characteristics

48 patients were included. The average age of the patients was 56.9 ± 10.7 years with extremes ranging from 30 to 82 years. Patients aged less than 60 years represented 56.7% of cases (n = 27). Female patients represented 66.7% of cases (n = 32), the sex ratio was equal to 0.5. Four patients were hypertensive (8.3%) and two patients were diabetic (4.2%). The average weight of the patients was equal to 68.5 ± 16.4 kg with extremes ranging from 40 to 115 kg. 30 patients. 30 patients were followed for breast cancer, 6 had lung cancer and 6 had prostate adenocarcinoma. Forty-six patients had bone metastases. 2 patients received Zoledronic acid as an adjuvant in combination with Letrozole given the presence of osteoporosis. 41 of patients (85.5%) were treated with chemotherapy. Trastuzumab was indicated in 14.6% of cases. 16.7% of patients had received hormonal therapy.

The mean hemoglobin value before the start of treatment was equal to 11.5 ± 1.7 g/dl with extremes ranging from 6 to 15.1 g/dl. The mean value of platelets before the start of treatment was equal to 276.48 ± 93.3 *103 elements/mm3 with extremes ranging from 143 to 554 *103 elements/mm3. One patient had hypercalcemia. The mean serum creatinine before the start of treatment was equal to 74.3 ± 34.3 µmol/l (0.84 ± 0.11 mg/dl). The mean pre-therapeutic MDRD clearance was equal to 94.1 ± 40.2 ml/min with 5 cases of moderate renal insufficiency (10.5%). Table 1 summarizes the pre-therapeutic biological assessment.

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Table 1.

Pre-therapeutic biological assessment.

Complete blood count (n = 41)
Hemoglobin (g/dl)	11.5 ± .,7
Anemia (< 10 g/dl)	6 (14.6%)
Platelets (103 elements/mm3)	143 à 554
Thrombocytopenia (< 150*103 elements/mm3)	2 (4.9%)
Thrombocytosis (> 450*103 elements/mm3)	2 (4.9%)
Dyscalcemia
Absent	47 (97.9%)
Hypercalcemia	1 (2.1%)
Renal assessment (n = 48)
Creatinemia	74.3 ± 34.3 µmol/l (0.84 ± 0.11 mg/dl).
MDRD clearance (ml/min)	94.1 ± 40.2
Preserved (≥ 90 ml/min)	23 (47.9%)
Light (60–89 ml/min)	21 (43.8%)
Moderate (30–59 ml/min)	4 (8.3%)
COCKROFT clearance (ml/min)	91.1 ± 36.6
Preserved (≥ 90 ml/min)	21 (43.8%)
Light (60–89 ml/min)	22 (45.8%)
Moderate (30–59 ml/min)	5 (10.4%)

Zoledronate and acute renal failure

Five patients were treated with a dose of less than 4 mg/100 ml of Zoledronate (10.5%). The others were treated with a dose of 4 mg/100 ml (89.5%). The median cumulative dose was 30 mg (IQR = [24–48 mg]). Acute renal failure during Zoledronic acid was observed in 9 cases (18.8%) (Table 2), thus requiring a dose reduction. No cases of nephrotic syndrome or acute interstitial or tubulointerstitial nephropathy were observed. A single case of evolution to chronic renal failure was noted in a patient receiving Gemcitabine-Carboplatin-based chemotherapy for metastatic bladder cancer. Acute renal failure varied significantly depending on weight (p = 0.002), it was associated with a lower patient weight of 53.44 kg ± 7.35, initial clearance <60 ml/min (p = 0.002) and a dose of Zoledronate < 4 mg/100 ml (p = 0.032) (Table 3, 4, 5). In multivariate analysis, initial clearance <60 ml/min and lower weight were associated significantly with acute renal failure (p = 0.003 and p = 0.01 respectively).

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Table 2.

Characteristics of patients who developed acute renal failure.

	Clearance (ml/min)	Body weight (kg)	Dose of zoledronate (mg/ml)
1	61	53	4
2	54	64	3.5
3	52	68	3.5
4	68	52	4
5	51	70	3.5
6	65	51	4
7	62	53	4
8	58	69	3.5
9	48	72	3.3

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Table 3.

Epidemiological factors associated with acute renal failure.

	No renal failure (n = 39)	Acute renal failure (n = 9)	P
Age (years)	56.59 ± 10.9	58.44 ± 10.3	0.646
Gender
Male	11 (68.8%)	5 (31.3%)	0138
Feminine	28 (87.5%)	4 (12.5%)
Comorbidities
Hypertension	4 (100%)	0 (0%)	1
Diabetes	2 (100%)	0 (0%)	1
Initial weight (Kg)	72 ± 16.04	53.44 ± 7.35	0.002

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Table 4.

Biological factors associated with acute renal failure.

	No renal failure (n = 39)	Acute renal failure (n = 9)	P
Renal assessment
Initial creatinine (µmol/l) (mg/dl)	68.09 ± 17.730.77 ± 0.2	104.12 ± 65.241.17 ± 0.73	0.138
Initial clearance (ml/min)	98.83 ± 35.32	57.97 ± 21.1	0.002
≥ 60 ml/min	37 (86%)	6 (14%)	0.039
< 60 ml/min	2 (40%)	3 (60%)
Complete blood count
Initial hemoglobin (g/dl)	11.69 ± 1.72	10.71 ± 1.43	0.168
Anemia	4 (66.7%)	2 (33.3%)	0.268
Initial platelets (*103/mm3)	284.7 ± 97.51	236.57 ± 59.37	0.218
Thrombocytopenia	1 (50%)	1 (50%)	0.316
Thrombocytosis	2 (100%)	0 (0%)	1

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Table 5.

Acute renal failure according to the site of the cancer and associated treatment.

	No renal failure (n = 39)	Acute renal failure (n = 9)	P
Cancer site
Breast	26 (86.7%)	4 (13.3%)	0.265
Prostate	4 (66.7%)	2 (33.3%)	0.312
Lung	5 (83.3%)	1 (16.7%)	1
Cavum	1 (50%)	1 (50%)	0.343
Bladder	1 (50%)	1 (50%)	0.343
Associated treatment
Chemotherapy	33 (80.5%)	8 (19.5%)	1
Targeted therapies	5 (71.4%)	2 (28.6%)	0.601
Hormone therapy	7 (87.5%)	1 (12.5%)	1
Dose and rate of administration
Dose <4 mg/100 ml	0 (0%)	2 (100%)	0.032
Dose 4 mg/100 ml	39 (84.8%)	7 (15.2%)
Every 21 days	33 (80.5%)	8 (19.5%)	1
Every 6 months	1 (50%)	1 (50%)
Duration < 2 years	37 (80.4%)	9 (19.6%)	1
Duration ≥ 2 years	2 (100%)	0 (0%)
Total dose	36.61 ± 18.14	31.2 ± 25.15	0.55

Discussion

To the best of our knowledge, this is the first study of acute renal failure during zoledronate in Africa. Furthermore, there is no prospective data studying this entity in the overall literature. Our study concluded that the incidence of acute renal failure during zoledronate was 18.8%. Factors associated with this side effect were low weight and clearance less than 60 ml/min. In multivariate analysis we didn’t find the dose <4 mg/100 ml. This may be explained by a chance finding based on confounding by association of creatinine clearance < 60 mL/min being a risk factor for acute renal failure.

The incidence of renal failure during Zoledronate varies between studies from 10 to 24%. ⁸ In a recent published study, ⁹ the authors analyzed data from 3340 North American breast cancer patients and determined the frequency of occurrence of renal failure, defined as a decrease of 25% of the glomerular filtration rate estimated by the MDRD formula. This study included 3 groups: a group of patients treated with zoledronate (n = 312), a group of patients receiving pamidronate (n = 166), and a group of patients not treated with bisphosphonate (n = 2862). Patients in the zoledronate and pamidronate groups had comparable characteristics at inclusion and the frequency of occurrence of acute renal failure in these two groups was not statistically different: 24% and 27%, respectively. In the group of patients not receiving bisphosphonates, renal failure accounted for 14%.

In multivariate analysis, the risk of developing renal failure in patients with breast cancer receiving zoledronate or pamidronate was twice as high as for patients not receiving bisphosphonates.

In our series, acute renal failure according to KDIGO during treatment with Zoledronic acid (18.8%) required a dose reduction.

The individual risk of developing renal failure during treatment with Zoledronate depends on several patient-related factors ¹⁰ such as age over 65 years, the presence of diabetes or high blood pressure, the association with other nephrotoxic drugs, dehydration and pre-existing renal failure.

The treatment-related risk factors ¹¹ are the total dose delivered, the duration of infusion and the number of infusions.

Although the risk is reduced by administering the dose of zoledronic acid over 15 min, impairment of renal function may occur. ¹¹ Renal impairment, progression of renal failure and cases of dialysis have been reported in patients after an initial dose or a single dose of 4 mg Zoledronic acid. In a retrospective analysis of 3115 patients with myeloma and bone metastases from solid tumors who received Zoledronate, McDermott et al. reported worsening of renal function in 9.4% of patients. ¹² Predictors of the development of renal deterioration included patient age > 60 years, number of doses administered > 4, current or previous use of cisplatin, and myeloma or renal cancer. In multivariate analysis, the cumulative dose of Zoledronate was an independent predictive factor for developing renal failure. ¹² In our study, acute renal failure varied significantly depending on weight (p = 0.002), it was associated with a lower weight of patients 53.44 kg ± 7.35. It also varied significantly depending on initial clearance (p = 0.002). It was significantly more observed in cases of values lower than 60 ml/min (60% vs 14%; p = 0.039). Interestingly, we observed renal failure in the 5 patients treated at a dose < 4 mg/100 ml (p = 0.032). The result of this study shows different indications for zoledronic acid treatment (osteoporosis and bone metastasis). Zoledronate is administrated every 6 months in case of osteoporosis and every 21 days in case of bone metastasis. We didn’t find difference according indications. This may be explained by the low number of patients with osteoporosis included in our study. Our study has some limitations. On one hand, this is a retrospective study and on the other hand the number is limited. Prospective trials are necessary to confirm these results.