Introduction: Zoledronic acid (ZA) is a widely used bisphosphonate compound for the prevention of skeletal metastasis-associated osteolysis and treatment of post-menopause osteoporosis. Acute kidney injury is one of the commonly described renal complications. Electrolyte disorder has also been reported relevant to ZA exposure and nephrotoxicity. Syndrome of persistent hypophosphatemia, hypokalemia, and metabolic acidosis is regarded as the initial signs of acute kidney injury. Case Presentation: We reported a 64-year-old female with bone metastasis from lung adenocarcinoma who received a 5-year history of 4-week cycle of ZA infusion. She initially presented with symptomatic severe hypophosphatemia and was finally identified with ZA-induced generalized tubular dysfunction as Fanconi’s syndrome and distal renal tubular acidosis. Renal pathological findings revealed toxic renal tubular necrosis. The ZA infusion was thus extended to an 8-week cycle with oral phosphate supplementation and alfacalcidol. Although periodic changes pre- and post-ZA infusion existed yet, hypophosphatemia was effectively improved, and the rapid decline of eGFR was partially delayed. We reviewed the literature and mainly summarized the characteristics of bisphosphonate-associated hypophosphatemia. Moderate hypophosphatemia was more frequently mentioned in contrast to severe cases being predisposed to be reported. Progressive hypophosphatemia serves as an early sign of kidney injury. Conclusion: Progressive electrolyte disorders and CKD were the long-term renal outcomes of the current patient. We would like to arouse more attention to electrolyte imbalance related to early ZA-induced kidney injury and emphasize the significance of close monitoring.
Zoledronic acid (ZA) is a long-acting bisphosphonate (BP) compound that specifically binds to bone minerals and increases density . It is widely used for the prevention of skeletal metastasis-associated osteolysis and the treatment of post-menopause osteoporosis . Acute kidney injury (AKI) or insidious increase of serum creatinine (sCr) is commonly described as ZA-induced renal complications, and electrolytes disorder has also been reported relevant to ZA exposure; however, it is underestimated because most of them were asymptomatic . Some patients manifested severe hypophosphatemia, hypokalemia, and metabolic acidosis as the initial signs of acute kidney injury. The risk of AKI was increased, especially in patients at higher doses, with long-term BP use, heavy tumor burden, and when combined with other nephrotoxic medications [4, 5]. Here we report a 64-year-old female with a 5-year history of 4-week 4 mg ZA infusion and icotinib for lung adenocarcinoma, who initially presented with symptomatic hypophosphatemia and was identified with ZA-induced renal Fanconi’s syndrome, distal renal tubular acidosis, rapidly progressive kidney injury, and biopsy-proven tubular injury.
A 64-year-old female patient complained of severe nausea and fatigue for the past month with unremarkable weight loss. Severe hypophosphatemia was detected when she was admitted to the hospital for investigation, with mild hypokalemia and metabolic acidosis. The patient had a history of well-controlled type 2 diabetes with glimepiride, osteopenia, and lung adenocarcinoma treated with icotinib. A 4-week ZA cycle infusion was administrated for almost 5 years to a cumulative dosage of around 160 mg. She received the last cycle 10 days before hospital admission. We reviewed her past laboratory tests and found that the sCr was increased from the baseline 59 μmol/L (5 years ago) to 109 μmol/L 12 days before admission and deteriorated to 138 μmol/L at admission, with uncharacteristically hypouricemia, hypophosphatemia, hypokalemia, and hyperchloremia after these years (Fig. 1; Table 1). On admission, the physical examination revealed a blood pressure of 125/65 mmHg. Examination of the heart, lungs, and abdomen showed no abnormalities. As listed in Table 1, the serum phosphorus was 0.29 mmol/L, potassium was 3.2 mmol/L, and the levels of sodium, calcium, and magnesium were normal. Urinalysis showed negative urine glucose, elevated albumin/creatinine at 454.05 mg/g, and renal loss of phosphorus, potassium, and uric acid; the excretion fractions of phosphorus and uric acid were both high at 42.8% and 65.9% respectively. Despite acidemia indicated by the low blood pH, standard base excess −11.5 mmol/L, and HCO3−15.8 mmol/L at the arterial blood gas, we detected alkalized urine at a pH 6.8, with reduced titrated acid and normal bicarbonate. The urine anion gap was 22–26 mmol/L, and osmolality was 452 mOsm/kg, with urine sodium at 44 mmol/L (which is required >25 mmol/L when interpreting urinary acidification analysis results). The relevant markers of bone turnover were displayed in Table 1. We observed increased intact parathormone and decreased levels of 25-OH-vitamin D, osteocalcin, and type I collagen amino propeptide. The blood alkaline phosphatase level was normal (71 IU/L, 60–135 IU/L). Ultrasonography revealed multiple kidney stones. In summary, Fanconi’s syndrome and distal renal tubular acidosis were diagnosed. The severe hypokalemia was “masked” by chronic metabolic acidosis. Urine osmolality above 400 indicated the presence of elevated urinary ammonium.
Renal pathology found 41 glomeruli under light microscopy observation, all negative by immunofluorescence staining. Ischemic glomerular sclerosis was apparent, accounting for 22.0% of glomeruli; diffuse tubular necrosis; segmental bare tubular basement membrane; and locally infiltrated lymphocytes and monocytes (Fig. 1). The pathological diagnosis of toxic renal tubular necrosis was made. The sCr self-restored days after admission and was maintained at 113 μmol/L (the estimated glomerular filtration rate, eGFR, 43 mL/min/1.73 m2) before the next cycle of ZA infusion. After calculation, the 5-year annual rate of eGFR decline was around 10.3 mL/min/1.73 m2. The patient received a combination of oral phosphate mixture, potassium citrate, and alfacalcidol. Symptoms were relieved apparently. The ZA infusion was thus extended to an 8-week cycle, and icotinib was kept. Although periodic changes of sCr and phosphorus pre- and post-ZA infusion existed yet (Fig. 1), the estimated eGFR decline was retarded to a rate of 4.8 mL/min/1.73 m2 in the following year. Moreover, the recovery of serum uric acid (Fig. 1a) and satisfactory correction of phosphorus and potassium confirmed the improved kidney injury.
Generalized renal tubular dysfunction is the typical presentation of drug-induced toxic tubular injury . This might lead to renal loss of electrolytes reabsorbed in renal tubules, causing hypokalemia, hypophosphatemia, and hyperchloraemic metabolic acidosis. The main clinical symptoms include nausea, fatigue, anorexia, and palpitation from advanced kidney injury, severe electrolyte disorders, metabolic acidosis, and nephrolithiasis. In the patient reported in this article, the decrease in calcium level by ZA initiated the secretion of parathormone. Therefore, renal phosphorus wasting and symptomatic hypophosphatemia were also attributed to secondary hyperparathyroidism and vitamin D deficiency. As we have known, some nephrotoxic medications (i.e. adefovir) induce generalized tubular dysfunction. History of concurrent ZA and Icotinib administration in this patient should be considered. Icotinib is an epidermal growth factor receptor (EGFR) inhibitor. The EGFRs are mainly expressed in distal tubules and collecting ducts and participate in magnesium ion reabsorption. It has been reported that EGFR inhibitors can cause hypomagnesemia , concurrent hypokalemia , and a rare case of renal tubular acidosis reported in Cetuximab . The finding of the normal magnesium did not support tubular injury induced by an EGFR inhibitor. For ZA, there have been some relevant reports of hypophosphatemia and studies focusing on kidney injury. According to the partial remission after adjusting the administration interval of ZA from a 4-week to 8-week cycle, we confirmed ZA is the culprit of tubular injury.
ZA is a BP compound having an affinity for calcium ions and calcium-containing hydroxyapatite , specifically inhibiting bone resorption by inhibiting the activity of osteoclasts besides direct chelation . ZA was excreted unchanged renally, with 39–45% of a dose . ZA uptake into renal tubular cells took place by fluid phase endocytosis . It is widely used and recommended every 4–12 weeks by 2021 NCCN guidelines for breast and prostate cancers, multiple myeloma, B cell lymphoma, and pediatric acute lymphoblastic leukemia to relieve malignancy-related recurrent fractures and severe bone mass loss. Compared with hypocalcemia, transient hypophosphatemia is a more common characteristic clinical manifestation after the use of BPs as the result of intracellular redistribution , but persistent hypophosphatemia is mostly caused by excessive intestinal or renal phosphorus loss . Previous research works suggested that ZA-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway. Metabolomic and proteomic assays showed that ZA triggered multiple dysregulated pathways including TGFβ/smad3-mediated profibrotic processes, abnormal fatty acid metabolism, and small GTPase signaling . Overexpression of fatty acid transporter SLC27A2 and defective fatty acid β-oxidation following ZA treatments were significant factors contributing to its nephrotoxicity. ZA-induced perturbations in glutathione biosynthesis and the tricarboxylic acid cycle, further causing ROS overproduction, oxidative stress, and cellular inflammation, thereby led to nephrotoxicity . Other BPs-associated adverse reactions described in research articles included fever, pain (myalgia and headache, aggravation of bone pain), gastrointestinal symptoms (nausea, vomiting, and diarrhea), jaw necrosis, etc.
We used PubMed to search for results on “BP” or “zoledronate” or “pamidronate disodium” or “alendronate sodium” and “hypophosphatemia.” There were 144 results, 46 English literature that reported BP-related adverse reactions, 24 case reports, and 22 research articles (Fig. 2), [4, 5, 17‒60].
As shown in Table 2,  patients developed electrolyte disorder after BP use at ages ranging from newborn to 76 years old. ZA and pamidronate acid accounted for 42.9% and 32.1% of the whole cohort respectively. Other BPs were alendronic acid and etidronic acid. There were 19 patients having bone metastasis or tumor-related hypercalcemia (8 with hematological malignancies, 5 with breast cancer), and another 9 patients diagnosed with non-malignant diseases (3 with osteoporosis, 3 with infantile arterial calcification, each one of Duchenne muscular dystrophy, Crohn’s disease, and parathyroid adenoma). Twenty-four patients (24/28, 85.7%) developed hypophosphatemia, with concurrent hypocalcemia in 58.3% and secondary PTH elevation in 20.8% of the total. The percentage of hypocalcemia, hyponatremia, magnesium and potassium disorders was 60.7%, 3.6%, 21.4%, and 17.9%. 64.3% of the above-mentioned electrolyte disorder was found within 7 days after BP administration. One patient with bone metastases from breast cancer withdrew ZA after a 5-year course (4 mg/month) of treatment because of jaw necrosis; however, rechallenging ZA led to severe hypophosphatemia and hypokalemia. The symptom was relieved after symptomatic supplementation . Among 28 patients with electrolyte disorder, 8 patients (28.6%) developed AKI (with ZA in 7 and with pamidronate in one), averaging 7 days (3–14 days) after ZA infusion, mainly characterized as renal tubular injury. The percentage of concurrent hypophosphatemia, hypokalemia, hypocalcemia, and hypomagnesemia were 87.5%, 62.5%, 50.0%, and 25% successively. Fanconi’s syndrome was identified in only 2 patients [4, 5]. Similar as our reported case, most patients (75.0%) undertook regular dosage of BPs (ZA <4 mg or pamidronate <90 mg per month ).
In contrast to a 62.5% percentage of severe hypophosphatemia in these case reports, the prevalence of severe hypophosphatemia was rare, accounting for 1.4% and 4.9% of patients receiving ZA and pamidronate in clinical studies; moderate hypophosphatemia was found in 51.4% of patients treated with 4 mg ZA . The potential nephrotoxicity of BPs is related to the rapid excretion from the kidneys, especially in patients with malignancies and chronic kidney disease who receive high-dose or chronic drug exposure . Moreover, ZA-associated tubular injury led to an aggravation of vitamin D deficiency because of impaired renal tubular reabsorption of 25-OH-vitamin D due to decreased renal megalin expression . In severely ill cases, BPs must be discontinued to avoid critical complications of cardiac accidents, combination therapy with the prolonged supplement of phosphorus and/or vitamin D was more effective to relieve symptomatic hypophosphatemia . From our case, we could finger out that repeated accident of AKI induced by ZA would result in irreversible renal function and progressive CKD [65, 66]. The patient experienced rapidly progressive kidney injury during the previous years of ZA infusion, however, was expected to benefit from decreasing the frequency of therapy the following year.
This current case is a typical ZA-induced kidney injury presenting a clinical syndrome of renal Fanconi’s syndrome with distal tubular acidosis and tubular injury in renal pathology. Most importantly, rapid progression of CKD could be delayed after decreasing the frequency of ZA infusion. We would like to arouse more attention to electrolyte imbalance related to early signs of ZA-induced kidney injury and emphasize the significance of close monitoring.
Statement of Ethics
This case report was in adherence with the Declaration of Helsinki and approved by the Ethics Committee of Peking University First Hospital, approval number 2017(1280). The authors declared that written informed consent was obtained from the patient for publication of this case report and accompanying images.
Conflict of Interest Statement
The authors declare that they have no relevant financial interests.
This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2019-I2M-5-046).
Yujia Wu, Tiantian Ma, Xiaojuan Yu, and Tao Su contributed to patient diagnosis, management, and clinical data analysis. Xiaojuan Yu contributed to the patient’s pathological diagnosis and took and edited pathological pictures. Yujia Wu and Tao Su wrote the manuscript draft and contributed to data analysis, interpretation, and intellectual content of critical importance to the work described. All authors had the opportunity to revise the manuscript.
Data Availability Statement
The patient was regularly followed up, and the clinical data are traceable. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.