Sixteen patients developed AKI while on CPIs and required renal biopsies over the past 10 years at our institution. The characteristics of these patients, urine findings, AKI category, and associated renal pathology are summarized in Table 1.Tab1

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

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, 38–77 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.

The median time to development of AKI after starting a CPI was 14 weeks (range: 6–56 weeks). However, AKI occurred within 9 weeks with the use of the CTLA-4 inhibitor tremelimumab or the combination of 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, 10–56 weeks) with nivolumab alone and 13.5 weeks (range: 8–18 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 0–31. 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 one.

Summary of observed other irAEs in patients who developed CPI related nephrotoxcity and their outcome are included in Table 2.Tab2

Observed irAEs in patients who developed CPI related nephrotoxcity and their outcome

CPIs were discontinued in 15 cases and held for 6 weeks in one case of the studied cases at the time of AKI diagnosis. Most of the patients received steroids at the time of AKI diagnosis except two patients. One who had mild nephritis, in whom CPI was held, and another who had severe kidney disease and poor residual renal function (seen in interstitial fibrosis with tubular atrophy (IFTA) > 90% on biopsy). Additional immunosuppressant agents were used as indicated by the associated glomerulonephritis in the pathology. The dose, form, or duration of steroid treatment did not follow any guideline. The initial used dose of prednisone ranged from 0.5–4 mg/kg/day. The prednisone was tapered off over 4–24 weeks depending on the renal pathology and recurrence of renal disease.

Three of the 5 ATIN cases all had partial renal recovery after prednisone and one of which had also infiliximab (2 doses). The 2 cases with no renal response, one had poor residual renal function from severe chronic kidney disease with associated IFTA > 90%, CPI was held, and no steroids were given, and the other case had associated acute tubular necrosis and remained hemodialysis dependent as of 12 weeks post AKI diagnosis despite prednisone therapy.

In our glomerulonephritis cases, membranous nephropathy, granulomatous with C3 glomerular deposition, and focal segmental glomerulosclerosis, and one of the 2 cases of CPI-related IgA nephropathy had complete or partial recovery after starting prednisone (0.5 mg/kg-3 mg/kg). The two ANCA negative pauci-immune glomerulonephritis patients had complete recovery of renal function after discontinuing CPI and starting prednisone and rituximab for treatment of pauci immune GN. The 3rd patient with ANCA positive pauci immune GN underwent treatment with steroids, plasmapheresis, and rituximab as indicated for creatinine > 4.0 mg/dl and possible lung involvement. The patient with AA amyloid had partial renal recovery after steroid treatment and due to continued colitis received infliximab and later progressed to AKI due to sepsis. The second IgA case had partial renal response after steroids, mycophenolate mofetil and then one dose of infliximab due to failure of initial response.

Three of the 16 cases died because of disease progression. All 13 surviving patients continued treatment, with 5 being on active therapy and 8 staying on surveillance.

We included the disease progression free survival (PFS) of the 16 patients in Table 1. However, we are not able to conclude a disease response or PFS benefit in these patients since we do not have in this current population patients who were treated with CPIs and didn’t develop nephrotoxicity to make such comparison.

Patients with other irAEs may have also undergone treatment with steroids or other forms of immunosuppression that further ameliorate the renal dysfunction prior to the renal biopsy. In addition, because of the retrospective nature of the study we do lack baseline urinalysis prior to use of CPI and therefore cannot completely exclude the presence of underlying renal pathologies prior to CPI use. In addition, although majority of our cases with renal pathologies were treated with anti-PD-1 agents we cannot conclude that ATIN was more prevalent in this class of medications since out of the 6412 patients identified more than half (3608) were treated with anti-PD1 agents. Needed are prospective studies with urinalysis, proteinuria evaluation at baseline, during CPI and pre-toxicity, at time of toxicity and at the time of toxicity resolution to more accurately identify and characterize renal irAEs and response to immune suppression, in addition to obtaining early renal consult and renal biopsy when indicated.