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Table 1 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

From: Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience

No Age, years Sex Race Cancer type CPI duration Comorbidities Potentially nephrotoxic home medication
(dose; mg/day)
Baseline Cr mg/dL
Prior UA
Peak
Cr mg/dL
Severity of AKI
Urine Sediment
Cells/HPF
Proteinuria
Kidney biopsy Initial Management Renal outcome PFS
Cancer status
Acute tubulointerstitial nephritis
1 65 M W Smoldering myeloma Pembrolizumab
6 cycles (14 weeks)
HTN, dyslipidemia, RA, GERD Losartan, 50 Omeprazole, 20 0.8
N/A
4.83
G3
3 WBC,
1 RBC,
UPC:1
• Acute TIN with eosinophils • Acute mild tubular epithelial injury with tubulitis
• 5% IFTA
CPI discontinued Dexamethasone (0.6 mg/kg) Partial recovery 17 weeks
progressed to MM, started on CYBORD
2 74 M W Urothelial bladder cancer Nivolumab 60 cycles (24 weeks) CKD stage 4, stable, attributed to prior chemotherapy-related nephrotoxicity Ibuprofen, PRN 2.5
N/A
7.48
G3
11 WBC,
eosinophil
0 RBC,
UPC: 0.8
• Acute TIN with neutrophils and eosinophils
• Moderate hypertensive nephroscleosis
• No immune complex deposition
• 48% global glomerular sclerosis
• 50% IFTA
CPI discontinued Prednisone (1 mg/kg) Partial recovery followed by AKI(sepsis) dialysis-dependent 32 months
Minimal residual disease
3 68 M W Metastatic melanoma Nivolumab and dabrafenib and trametinib 9 cycles (9 months) HTN,
CKD stage 2, hypophysitis; hypothyroidism and adrenal insufficiency
Fosinopril, 40
Hydralazine, 30
Hydrocortisone, 60
1.3
N/A
5.38
G3
48 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 recovery 15 months with no evidence of progression under observation
4 77 M W Papillary urothelial
cancer of
urinary bladder
Pembrolizumab for 10 weeks
3 doses
DM
CKD stage 3
Obstructive uropathy (S/p left nephrostomy)
- 1.5
Protein (+ 1)
7.8
G4
> 182 WBC
9 RBC
eosinophil
+ 1 protein
ATIN with eosinophil and few multinucleated giant cells
ATN
Global sclersosis 50% and IFTA 50%
CPI discontinued. Methyprednisone 1 mg/kg BID
intiated on HD and steroid dose was tapered
Persistent AKI dialysis
depenedent
2 months with no evidence of progression under observatoin
5 55 M B Transitional cell bladder cancer Atezolizumab
around 6 months
Obstructive uropathy s/p bilateral nephrostomy tubes
CKD stage 4
GERD
Pantoprazole, 40 3.3
UPC 1.2
5.8
G3
27 WBC
8 RBC
eosinophil
UPC:2.7
Acute and chronic tubulointerstitial nephritis with neutrophils and eosinophils
Diffuse (> 95%) IFTA
CPI discontinued. no renal recovery. CKD stage 5 9 months had progression of metastasis. Deceased
Acute tubulointersitial Nephritis with Glomerulonephritis
6 41 M W Squamous cell cancer of the lung Nivolumab
4 cycles (14 weeks)
Asthma Ibuprofen daily for 2 weeks 0.8
N/A
4.52
G3
19 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 atrophy
CPI discontinued Prednisone
(1 mg/kg)
Rituximab (1 dose)
Complete recovery 14 weeks patient deceased owe to progression of cancer
7 75 M W Metastatic RCC Tremelimumab 2 doses (6 weeks) HTN and CKD stage 3 Amoxicillin/clavulanate, 500 mg daily for 5 days
Hydralazine, 75
1.8
N/A
4.75
G3
5 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 recovery 11 months with no evidence of progression under observatoin
8 69 W W Uveal Melanoma Nivolumab and Ipilimumab (3 cycles) 9 weeks HTN, DM, Stroke
CKD stage 3
GERD
Omeprazole, 40 Valsartan, 80 1.4
No protein
4.9
G3
15 WBC
7 RBC
UPC:0.4
Granulomatous necrotizing vasculitis
hypertensive nephrosclerosis
Patchy moderate to severe interstitial inflammation
50% global glomeulosclerosis and 30% IFTA
Negative ANCA
CPI discontinued. Prednisone 1 mg/kg daily followed by rituximab x1 after one week Complete
recovery
8 months with no evidence of progression under observatoin
9 69 M W Melanoma Ipilimumab and Nivolumab 2 cycles (6 weeks) GERD, HTN, CKD stage 3 Olmesartan, 40
Furosemide, 20
Omeprazole, 20
1.4
N/A
2.40
G2
7 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 sclerosis
CPI discontinued Prednisone
(0.5 mg/kg)
Complete recovery followed by relapse 19 months with no evidence of disease on observation
10 50 F W Melanoma Pembrolizumab
completed 5 doses (12 weeks)
Asthma, GERD, HTN Naproxen, 250 PRN
Omeprazole, 10
HCTZ, 12.5
0.8
N/A
3.08
G3
6 WBC,
2 RBC,
negative dipstick
Done 5 weeks after AKI:
• low-grade tubulointerstitial injury
• IgA nephropathy (without pathologic indication of active disease)
• FSGS, NOS
• Very mild interstitial inflammation
CPI discontinued Prednisone
(2 mg/kg)
Mycophenolate Mofetil 1 g BID Infliximab (one dose)
Partial recovery followed by AKI attributed to Vemurafenib 4 weeks progression of metastasis
11 60 F H RCC Nivolumab
6 cycles (16 weeks)
GERD, and dyslipidemia Esomeprazole, 40 0.8
Negative dipstick
N/A 2 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, CD8
CPI discontinued Prednisone
(1 mg/kg)
Complete
recovery
20 weeks then had disease progression started on axitinib
12 61 F W Smoldering myeloma Pembrolizumab 2 cycles (8 weeks) Hypothyroidism,HTN, dyslipidemia
GERD
Lansoprazole, 30 0.6
N/A
2.86
G3
32 WBC,
1 RBC,
UPC: 0.3
• Granulomatous TIN
• C3 deposition (possible early GN)
• Rare subepithelial deposits
• 5–10% IFTA • Arterial and arteriolar sclerosis
CPI discontinued Prednisone
(1 mg/kg)
Partial recovery 12 months with no progression under observation
13 74 M W RCC
CML
Nivolumab with Axitinib (for 14 months) and Imatinib (for 20 months) HTN
CKD stage 3
GERD
Omeprazole, 40 1.6
N/A
2.73
G2
1 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 recovery 12 months with evidence of progression
14 63 M W Chondroma Pembrolizumab 6 cycles (18 weeks) Coronary artery disease, hypothyroidism, neurogenic bladder 0.5
N/A
2.25
G3
21 WBC,
11 RBC, UPC: 31
• AA type amyloidosis,
• Acute tubular epithelial injury
• 28%global glomerular sclerosis
• 5% IFTA
CPI discontinued Methylprednisolone (1 mg/kg)
Infliximab 440 mg one dose
Partial recovery followed by AKI(sepsis) 26 weeks
Patient deceased owing to bowel perforation
Cases with suspected CPI toxicity
15 38 M W Hodgkin Lymphoma Nivolumab and LAG-3 antibody
2 cycles (10 weeks)
Cardiomyopathy
s/p SCT (9 months ago)
Sulfamethoxazole and trimethoprim (800/160 mg) 3 times per week
Valacyclovir, 500
Pantoprazole, 40
0.8–0.9
N/A
1.63
G1
11 WBC,
1 RBC,
UPC: 0.05
Done 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 AKI Complete recovery 13 months remains with complete response then patient declined further therapy
16 58 M W Non-small cell lung cancer Carboplatin and Pemetrexed for 3 cycles (7 weeks added to Pembrolizumab (13 weeks) HTN
COPD
Amoxicillin and Clavulanate, 875–125 mg BID
Lisinopril 20
0.5
Protein (+ 1)
7.1
G3
No pyuria or hematuria
UPC 0.6
ATN
No Glomerulosclerosis
15% IFTA
CPI discontinued. Prednisone 1 mg/kg Persistent AKI dialysis
dependent depenedent
9 months with no recurrence (withdrew from further therapy)
  1. 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