A 38-year-old Caucasian male was diagnosed with a stage IIIc (TX, N3, M1a) malignant melanoma. The patient had no known risk factors for melanoma. He was treated with interferon alpha in an adjuvant setting; however, three years later he experienced an episode of gastrointestinal bleeding. After an enterectomy, this proved to be due to metastatic melanoma in the jejunum. The lesions were found positive for the V600E mutation of the BRAF gene. A CT scan performed a month later revealed two enlarged mesenteric lymph nodes; the patient was started on vemurafenib at 960 mg, twice daily and cobimetinib at 60 mg, once daily, for 21 days, followed by 7 days off, in the context of a phase III, randomized, blinded clinical trial (ClinicialTrials.gov identifier: CO39262/IMspire 150).   As per protocol, atezolizumab at 840 mg every two weeks was added to the regimen after the first 4 weeks of treatment with vemurafenib and cobimetinib. Four months after treatment initiation, the patient achieved a complete remission (CR).
Fifteen months since treatment initiation, the patient experienced a gradual decline of his renal function, evidenced by a decrease of his estimated glomerular filtration rate (eGFR), along with subtle proteinuria (0.34 g/24h) with no arterial pressure changes. His serum creatinine level was 1.81 mg/dl (baseline value being 0.75 mg/dl) corresponding to an eGFR of 44 ml/min/1.73 m2. The patient's hemoglobin level also decreased to 10.2 g/dl from a baseline of 12.4 g/dl. No metabolic acidosis was found. His erythrocyte sedimentation rate was 65 mm/h, with no c-reactive protein increase. There was no increase in urine leukocytes and a urine culture was found negative. A kidney and renal arteries ultrasound revealed no findings, while a positron emission tomography (PET)-CT scan confirmed a sustained CR of his advanced melanoma. Treatment with vemurafenib and cobimetinib was temporarily withheld and his renal function improved; however, upon re-initiation of treatment, his eGFR declined once again (serum creatinine of 2.70 g/dl, eGFR 31 ml/min/1.73 m2) and the drugs were once more discontinued. Atezolizumab was also temporarily discontinued and a renal biopsy was performed. The histologic evaluation revealed the presence of non-necrotizing granulomas in the interstitial space (Figure 2), findings indicative of a granulomatous nephritis. In addition, a tuberculin skin test was negative, as was a urine culture for Mycobacterium tuberculosis. Vemurafenib and cobimetinib were permanently discontinued and the patient was started on methylprednisolone at 0.75 mg/kg/day for a week, with rapid tapering during the following month. After the first week of corticosteroids, the patient's eGFR normalized, while treatment with atezolizumab was resumed. Twenty-nine months after resuming treatment, the patient is still in CR under atezolizumab, without any renal function impairment.