Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects

Here, we present cases of biopsy proven acute tubulointerstitial nephritis (ATIN) and glomerulonephritis (GN) induced by CPIs and discuss potential mechanisms of these adverse effects. Study design, setting, & participants We retrospectively reviewed all cancer patients from 2008 to 2018 who were treated with a CPI and subsequently underwent a kidney biopsy at The University of Texas MD Anderson Cancer Center. Results We identified 16 cases diagnosed with advanced solid or hematologic malignancy; 12 patients were male, and the median age was 64 (range 38 to 77?years). (14 of 16) and presented in almost all cases as either the major microscopic finding or as a mild form of interstitial inflammation in association with other glomerular pathologies (pauci-immune glomerulonephritis, membranous glomerulonephritis, C3 glomerulonephritis, immunoglobulin A (IgA) nephropathy, or amyloid A (AA) amyloidosis). CPIs were discontinued in 15 out of 16 cases. Steroids and further immunosuppression were used in most cases as indicated for treatment of ATIN and glomerulonephritis (14 of 16), with the majority achieving complete to partial renal recovery. Conclusions Our data demonstrate that CPI related AKI occurs relatively late after CPI therapy. Our biopsy data demonstrate that ATIN is the most common pathological finding; however it can frequently co-occur with other glomerular pathologies, which may require immune suppressive therapy beyond corticosteroids. In the lack of predictive blood or urine biomarker, we recommend obtaining kidney biopsy for CPI related AKI. progression-free survival, male, female, white, black, lymphocyte activation gene 3, hypertension, gastroesophageal reflux disease, multiple myeloma, rheumatoid arthritis, diabetes mellitus, chronic obstructive pulmonary diseases, stem cell transplant, chronic kidney disease, white blood cells, red blood cells, urinalysis, urine protein to creatinine ratio, within normal limit, anti-nuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, cyclic citrullinated peptide, myeloperoxidase, creatine kinase, not available, double-stranded DNA, glomerulonephritis, tubulointerstitial nephritis, interstitial fibrosis/tubular atrophy, amyloid A, urine albumin to creatinine ratio, positron Adrenalone HCl emission tomography, focal segmental glomerulosclerosis, immune checkpoint inhibitor, twice daily, creatinine, renal replacement therapy Most cases identified were white men (1 case was a Hispanic man, and 4 cases were women), with a median age of 64?years (range, 38C77?years). Renal cell carcinoma, urothelial bladder cancer and melanoma were the most common malignancies (3 cases of RCC and 3 urothelial bladder cancer and 4 cases of melanoma), followed by multiple myeloma (2 cases) and 1 case each of chondroma, squamous cell cancer of the lung, adenocarcinoma of the lung, and Hodgkin lymphoma. Most cases occurred in the setting of nivolumab (anti-PD-1) and pembrolizumab (anti-PD-1) use (6 cases each), a combination of nivolumab and ipilimumab (anti-CTLA-4) (2 cases), tremelimumab(anti-CTLA-4) (1 case), and atezolizumab (anti-PD-L1) (1 case). 7 patients had chronic kidney disease (CKD) at baseline:5 had CKD stage 3, and 2 had CKD stage 4. Clinical features The median time to development of AKI after starting a CPI was 14?weeks (range: 6C56?weeks). However, Adrenalone HCl AKI occurred within 9?weeks with the use of the CTLA-4 inhibitor Adrenalone HCl tremelimumab or the combination of NEU the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab. All other patients on PD-1 inhibitors had longer durations to development of AKI: a median of 20?weeks (range, 10C56?weeks) with nivolumab alone and 13.5?weeks (range: 8C18?weeks) with pembrolizumab alone. The most common urine finding was sub-nephrotic proteinuria at time of acute kidney injury diagnosis (urine studies were done within 48?h of diagnosis in 13 out of 16 cases). The median urine protein-to-creatinine (UPC) ratio was 0.8?g/g with a range of 0C31. 3 cases had 0.3?g/g protein in the urine. 10 cases had proteinuria ranging from 0.3 to 3?g/g, and 3 cases had nephrotic-range proteinuria and hypoalbuminemia consistent with nephrotic syndrome and associated with renal pathologies of AA amyloidosis, membranous glomerulonephritis, or IgA nephropathy (one case each). Prior urinalysis was not available in most of the cases (11 out of 16) to compare the acuity of reported proteinuria. Pyuria ( ?5 white blood cells [WBC]/high-power field [HPF]) with associated biopsy finding of tubulointerstitial inflammation was present in 7 patients but was absent in four patients despite histological evidence of tubulointerstitial nephritis in those patients, there was no clear association with type of CPI or use of steroids. Microscopic hematuria ( ?3 red blood cells [RBC]/HPF) was present in eight of the patients in our series, two patients had ?50 RBC/HPF with a renal pathology of pauci-immune glomerulonephritis. Among non-renal irAEs that developed during therapy with CPI (both Anti-PD-1 and Anti -CTLA-4), the most common irAE was hypothyroidism. Other irAEs were dermatitis, pnemonitis, colitis, esophagitis, adrenal insufficiency, and myositis. Majority of the non renal irAEs developed nephrotoxicity after or at the time of non renal irAE diagnosis. No correlation was observed between the severity and recovery of non-renal irAE with the renal.