End-Stage Renal Disease Following Carboplatin Chemotherapy for a Nasopharyngeal Carcinoma

Abstract

Renal failure secondary to carboplatin therapy is due to acute tubular necrosis and is usually reversible. However, acute renal failure with rapid progression to end-stage renal disease is an exceedingly rare complication of carboplatin therapy. The authors report a case of definitive renal failure secondary to carboplatin chemotherapy for a nasopharyngeal carcinoma. The mechanisms that give rise to the chronic nephropathy are discussed.

Keywords:

• carboplatin
• cortical necrosis
• end-stage renal disease
• hemodialysis

INTRODUCTION

Carboplatin, a new analogue of cisplatin used in the treatment of various solid tumors, has been demonstrated to be less nephrotoxic than its predecessor.[1–3] To date, hundreds of cycles of therapy have been given without a significant incidence of renal failure.[4–6] We report herein a case of definitive end-stage renal failure due to renal cortical necrosis in a patient receiving carboplatin as chemotherapy for a nasopharyngeal carcinoma.

CASE REPORT

A 43-year-old male was diagnosed as having nasopharyngeal carcinoma in January 2004. The histology report was poorly differentiated epidermoid cell carcinoma, clinical staging T₄N₀M₀, stage IV according to Ho's classification.[7] CT scan of the nasopharynx and skull base showed a large right-sided abnormal soft tissue density in the nasopharynx involving the right maxillary, ethmoid, and sphenoid sinuses, with bony destruction of the right pterygoid plate, roof of the nasal cavity, and floor of the sphenoid sinus. Carboplatin therapy was initiated at a dose of 400 mg/m² (1h intravenous infusion) on day 1 every four weeks. The patient did not receive irradiation or prior cisplatin treatment. Six days after the second course of carboplatin, the patient suddenly developed anuria and azotemia (BUN 68 mg/dL, serum creatinine 6.9 mg/dL). His coagulation profile was normal (bleeding time, 3 min; prothrombin time, 13.1 s; partial thromboplastin time, 35 s; fibrin split products, 10 mg/mL; fibrinogen, 550 mg/dL; protein C, 50%; protein S, 87%). No schistocytes were found on a peripheral blood smear. Anti-DNA, ANA, ANCA, and cryoglobulin were all negative. Renal ultrasonography and cardiac echocardiogram showed normal findings. To investigate the etiology of acute renal failure, renal biopsy was performed. Light microscopy showed an almost complete cortical necrosis, with enlarged acellular glomeruli containing microthrombi, necrosis of arterioles, and extensive tubular lesions (see Figure 1). There was no specific immunofluorescent deposit on the glomerulus. The patient did not recover renal function, and chronic hemodialysis was needed.

Figure 1. Renal biopsy specimen shows a widespread area of cortical necrosis. Glomerulis shows congestion and thrombosis of capillaries and tubules are necrotic. (Masson's trichrome; original magnification  ×  125)

DISCUSSION

Carboplatin is a second-generation platinum-containing anticancer drug.[8] Like cisplatin, it contains a platinum atom surrounded in a plane by two ammonia groups and two other ligands in the cis position. The other two ligands in carboplatin are present in a ring structure rather than as two chloride atoms in cisplatin. This difference makes carboplatin more stable and has less nephrotoxicity, neurotoxicity, ototoxicity, and hematogenesis.[8]

High-dose carboplatin chemotherapy can cause renal injury in cancer patients.[6],[9–11] The incidences of abnormal renal function tests reported are 6% for serum creatinine and 14% for blood urea nitrogen (10% and 22%, respectively, in pre-treated ovarian cancer patients). Most of these reported abnormalities have been mild, and about one-half of them were reversible.[10],[12] Carboplatin-induced acute renal failure generally includes damage to vasculature or structures of the kidneys, hemolytic uremic syndrome, and pre-renal perfusion deficits (see Table 1).[4],[6],[13],[14] However, rapid progression to ESRD, as seen in this case, is highly unusual and has only been reported once before in a child.[13]

Table 1 Report of renal failure after carboplatin therapy

Author	Number	Condition	Baseline, serum creatinine	Predisposing condition to renal failure	Carboplatindose	Etiologyof renal failure	Treatment	Outcome
Butani, 2003	1	Stem cell transplantation for a metastatic Ewing's sarcoma	0.9 mg/dl	Left nephrectomy for recurrent Ewing's sarcoma	667 mg/m^2/day for three days	Atrophy of a single kidney+ no biopsy was performed	Continuous cycler PD	ESRD
Karim, 2002	1	Grade III, stage IIb carcinoma of the left ovary with peritoneal nodules and metastases to the right fallopian tube	Normal	New-onset features of scleroderma in association with carcinoma of the ovary	Carboplatin at monthly intervals, five doses in all	Thromboticmic roangiopathy	Plasma exchange+hemodialysis	Impaired renal function, died following a lung hemorrhagia
Agraharkar, 1998	1	Chemotherapy with paclitaxel and carboplatin for a stage IC ovarian carcinoma	Normal	Hemorrhagic cystitis, presumably by toxicity to transitional epithelium of the bladder	753 mg/m^2(AUC  =  7.5 mg/mL)	Bilateral ureteral obstruction and hydronephrosis resulting in gross hematuria and blood clots	Spontaneously resolved with a brisk diuresis, presumably due to clot lysis	ARF spontaneously resolved in 24H
McDonald, 1991	2	Advanced ovarian carcinoma	0.9 mg/dl,1.1 mg/dl	Extensive previous treatment with cisplatin	Four cycles of intraperitoneal carboplatin in patient 1and five cycles of IP carboplatin in patient 2	Acute interstitial nephritis in both cases	Prednisone 1 mg/kg/day	Rapid recovery of renal function over four weeks in both cases
Present study, 2004	1	Metastatic nasopharyngeal carcinoma	0.6 mg/dl	None	400 mg/m^2, two courses in all	Acute cortical necrosis	Hemodialysis	ESRD, chronic hemodialysis

The mechanisms that give rise to the chronic nephropathy are conjectural. Carboplatin is known to be eliminated largely through the kidneys.[15] Platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of five days.[12] This may lead to direct and indirect toxic injuries on renal structures and vasculature, in analogy to the toxic effects of other heavy metals. Carboplatin further causes a substantial decrease in median glomerular filtration rate and effective renal plasma flow, perhaps via an indirect vasomotorica effect that results in increased vascular resistance.[12],[13] The combined vascular and tubular alterations may result in parenchymal atrophy, interstitial inflammation, and probably irreversible interstitial fibrosis. The reasons of the rapid deterioration and the self-perpetuation of the renal damage in our patient are unknown.

In summary, this case highlights multiple relevant clinical aspects of carboplatin renal toxicity. First, it may be profound, irreversible, and occur outside the context of other complicating medical circumstances such as sepsis or deshydratation. Second, normal serum creatinine is not a reliable negative predictor for future carboplatin nephrotoxicity. Third, the present case lacks the complicating effect of many confounding variable,s such as prior cisplatinum or radiation therapy.