Characteristics of the patients who developed CPI-related renal manifestations and their laboratory and microscopic findings associated with the CPI-related renal manifestations, initial therapies and the outcomes

NoAge, yearsSexRaceCancer typeCPI durationComorbiditiesPotentially nephrotoxic home medication(dose; mg/day)Baseline Cr mg/dLPrior UAPeakCr mg/dLSeverity of AKIUrine SedimentCells/HPFProteinuriaKidney biopsyInitial ManagementRenal outcomePFSCancer status
Acute tubulointerstitial nephritis
165MWSmoldering myelomaPembrolizumab6 cycles (14 weeks)HTN, dyslipidemia, RA, GERDLosartan, 50 Omeprazole, 200.8N/A4.83G33 WBC,1 RBC,UPC:1• Acute TIN with eosinophils • Acute mild tubular epithelial injury with tubulitis• 5% IFTACPI discontinued Dexamethasone (0.6 mg/kg)Partial recovery17 weeksprogressed to MM, started on CYBORD
274MWUrothelial bladder cancerNivolumab 60 cycles (24 weeks)CKD stage 4, stable, attributed to prior chemotherapy-related nephrotoxicityIbuprofen, PRN2.5N/A7.48G311 WBC,eosinophil0 RBC,UPC: 0.8• Acute TIN with neutrophils and eosinophils• Moderate hypertensive nephroscleosis• No immune complex deposition• 48% global glomerular sclerosis• 50% IFTACPI discontinued Prednisone (1 mg/kg)Partial recovery followed by AKI(sepsis) dialysis-dependent32 monthsMinimal residual disease
368MWMetastatic melanomaNivolumab and dabrafenib and trametinib 9 cycles (9 months)HTN,CKD stage 2, hypophysitis; hypothyroidism and adrenal insufficiencyFosinopril, 40Hydralazine, 30Hydrocortisone, 601.3N/A5.38G348 WBC,7 RBC,UPC:0.36• Acute tubuloepithelial injury• Acute tubulointerstitial nephritis• Arterial and arteriolar sclerosis• IFTA 30% and global sclerosis 23%CPI discontinued Methylprednisolone (1.1 mg/kg)Infliximab (2 doses 8 weeks apart)Partial recovery15 months with no evidence of progression under observation
477MWPapillary urothelialcancer ofurinary bladderPembrolizumab for 10 weeks3 dosesDMCKD stage 3Obstructive uropathy (S/p left nephrostomy)-1.5Protein (+ 1)7.8G4> 182 WBC9 RBCeosinophil+ 1 proteinATIN with eosinophil and few multinucleated giant cellsATNGlobal sclersosis 50% and IFTA 50%CPI discontinued. Methyprednisone 1 mg/kg BIDintiated on HD and steroid dose was taperedPersistent AKI dialysisdepenedent2 months with no evidence of progression under observatoin
555MBTransitional cell bladder cancerAtezolizumabaround 6 monthsObstructive uropathy s/p bilateral nephrostomy tubesCKD stage 4GERDPantoprazole, 403.3UPC 1.25.8G327 WBC8 RBCeosinophilUPC:2.7Acute and chronic tubulointerstitial nephritis with neutrophils and eosinophilsDiffuse (> 95%) IFTACPI renal recovery. CKD stage 59 months had progression of metastasis. Deceased
Acute tubulointersitial Nephritis with Glomerulonephritis
641MWSquamous cell cancer of the lungNivolumab4 cycles (14 weeks)AsthmaIbuprofen daily for 2 weeks0.8N/A4.52G319 WBC,320 RBC,UACR:1025 mg/g• Acute focal segmental necrotizing pauci-immune GN (no crescents or global sclerosis): ANCA-negative• Mild interstitial nephritis without atrophyCPI discontinued Prednisone(1 mg/kg)Rituximab (1 dose)Complete recovery14 weeks patient deceased owe to progression of cancer
775MWMetastatic RCCTremelimumab 2 doses (6 weeks)HTN and CKD stage 3Amoxicillin/clavulanate, 500 mg daily for 5 daysHydralazine, 751.8N/A4.75G35 WBC,67 RBC,UPC:1.43• Acute focal segmental pauci-immune necrotizing GN• Mild acute tubulointerestitial nephritis with eosinophils• Acute tubular epithelial injury• Arterial and arteriolar sclerosis• IFTA 5% and global sclerosis 38%CPI discontinued Methylprednisolone (2 mg/kg)Rituximab (weekly for 4 doses)Plasmapheresis (daily for 5 sessions)Partial recovery11 months with no evidence of progression under observatoin
869WWUveal MelanomaNivolumab and Ipilimumab (3 cycles) 9 weeksHTN, DM, StrokeCKD stage 3GERDOmeprazole, 40 Valsartan, 801.4No protein4.9G315 WBC7 RBCUPC:0.4Granulomatous necrotizing vasculitishypertensive nephrosclerosisPatchy moderate to severe interstitial inflammation50% global glomeulosclerosis and 30% IFTANegative ANCACPI discontinued. Prednisone 1 mg/kg daily followed by rituximab x1 after one weekCompleterecovery8 months with no evidence of progression under observatoin
969MWMelanomaIpilimumab and Nivolumab 2 cycles (6 weeks)GERD, HTN, CKD stage 3Olmesartan, 40Furosemide, 20Omeprazole, 201.4N/A2.40G27 WBC,11 RBC,UPC: 7.7• IgA nephropathy with focal segmental endocapillary hypercellularity and sclerosis• Acute mild TIN with eosinophils• 40% global glomerular sclerosis, 20% IFTA• Mild arterial and arteriolar sclerosisCPI discontinued Prednisone(0.5 mg/kg)Complete recovery followed by relapse19 months with no evidence of disease on observation
1050FWMelanomaPembrolizumabcompleted 5 doses (12 weeks)Asthma, GERD, HTNNaproxen, 250 PRNOmeprazole, 10HCTZ, 12.50.8N/A3.08G36 WBC,2 RBC,negative dipstickDone 5 weeks after AKI:• low-grade tubulointerstitial injury• IgA nephropathy (without pathologic indication of active disease)• FSGS, NOS• Very mild interstitial inflammationCPI discontinued Prednisone(2 mg/kg)Mycophenolate Mofetil 1 g BID Infliximab (one dose)Partial recovery followed by AKI attributed to Vemurafenib4 weeks progression of metastasis
1160FHRCCNivolumab6 cycles (16 weeks)GERD, and dyslipidemiaEsomeprazole, 400.8Negative dipstickN/A2 WBC,3 RBC,UPC: 9.7• PLA2R negative early membranous GN• Focal T-cell–rich crescent-like inflammation• Acute tubulocentric TIN with T cells positive for CD3, CD4, CD8CPI discontinued Prednisone(1 mg/kg)Completerecovery20 weeks then had disease progression started on axitinib
1261FWSmoldering myelomaPembrolizumab 2 cycles (8 weeks)Hypothyroidism,HTN, dyslipidemiaGERDLansoprazole, 300.6N/A2.86G332 WBC,1 RBC,UPC: 0.3• Granulomatous TIN• C3 deposition (possible early GN)• Rare subepithelial deposits• 5–10% IFTA • Arterial and arteriolar sclerosisCPI discontinued Prednisone(1 mg/kg)Partial recovery12 months with no progression under observation
1374MWRCCCMLNivolumab with Axitinib (for 14 months) and Imatinib (for 20 months)HTNCKD stage 3GERDOmeprazole, 401.6N/A2.73G21 WBC,0 RBC,UPC: 0.38• Acute tubuloepithelial injury• Acute tubulointerestitial nephritis with eosinophils• FSGS (preservation of foot process) likely secondary (HTN and post-nephrectomy)• Arterial and arteriolar sclerosis (moderate)• IFTA 20% and global sclerosis 9%CPI discontinued Predisone(0.8 mg/kg)Partial recovery12 months with evidence of progression
1463MWChondromaPembrolizumab 6 cycles (18 weeks)Coronary artery disease, hypothyroidism, neurogenic bladder0.5N/A2.25G321 WBC,11 RBC, UPC: 31• AA type amyloidosis,• Acute tubular epithelial injury• 28%global glomerular sclerosis• 5% IFTACPI discontinued Methylprednisolone (1 mg/kg)Infliximab 440 mg one dosePartial recovery followed by AKI(sepsis)26 weeksPatient deceased owing to bowel perforation
Cases with suspected CPI toxicity
1538MWHodgkin LymphomaNivolumab and LAG-3 antibody2 cycles (10 weeks)Cardiomyopathys/p SCT (9 months ago)Sulfamethoxazole and trimethoprim (800/160 mg) 3 times per weekValacyclovir, 500Pantoprazole, 400.8–0.9N/A1.63G111 WBC,1 RBC,UPC: 0.05Done 4 weeks after AKI (first biopsy was inadequate):• No evidence of acute glomerular or tubular injury or inflammation• IFTA 5% and global sclerosis 5%CPI was held then resumed after 6 weeks along with proton pump inhibitor without recurrence of AKIComplete recovery13 months remains with complete response then patient declined further therapy
1658MWNon-small cell lung cancerCarboplatin and Pemetrexed for 3 cycles (7 weeks added to Pembrolizumab (13 weeks)HTNCOPDAmoxicillin and Clavulanate, 875–125 mg BIDLisinopril 200.5Protein (+ 1)7.1G3No pyuria or hematuriaUPC 0.6ATNNo Glomerulosclerosis15% IFTACPI discontinued. Prednisone 1 mg/kgPersistent AKI dialysisdependent depenedent9 months with no recurrence (withdrew from further therapy)

PFS progression-free survival, M male, F female, W white, B black, LAG-3 lymphocyte activation gene 3, HTN hypertension, GERD gastroesophageal reflux disease, MM multiple myeloma, RA rheumatoid arthritis, DM diabetes mellitus, COPD chronic obstructive pulmonary diseases, SCT stem cell transplant, CKD chronic kidney disease, WBC white blood cells, RBC red blood cells, UA urinalysis, UPC urine protein to creatinine ratio, WNL within normal limit, ANA anti-nuclear antibody, ANCA antineutrophil cytoplasmic antibody, RF rheumatoid factor, CCP cyclic citrullinated peptide, MPO myeloperoxidase, CK creatine kinase, N/A not available, dsDNA double-stranded DNA, GN glomerulonephritis, TIN tubulointerstitial nephritis, IFTA interstitial fibrosis/tubular atrophy, AA amyloid A, UACR urine albumin to creatinine ratio, PET positron emission tomography, FSGS focal segmental glomerulosclerosis, CPI immune checkpoint inhibitor, BID twice daily, Cr creatinine, RRT renal replacement therapy