Acute kidney injury in patients treated with immune checkpoint inhibitors

Antígeno CTLA-4; InmunoterapiaAntigen CTLA-4; ImmunoteràpiaCTLA-4 antigen; ImmunotherapyBackground Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors

NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease

The type and the extent of tissue damage inform the prognosis of chronic kidney disease (CKD), but kidney biopsy is not a routine test. Urinary tests that correlate with specific histological findings might serve as surrogates for the kidney biopsy. We used immunoblots and ARCHITECT-NGAL assays to define the immunoreactivity of urinary neutrophil gelatinase–associated lipocalin (NGAL) in CKD, and we used mass spectroscopy to identify associated proteins. We analyzed kidney biopsies to determine whether specific pathological characteristics associated with the monomeric NGAL species. Advanced CKD urine contained the NGAL monomer as well as novel complexes of NGAL. When these species were separated, we found a significant correlation between the NGAL monomer and glomerular filtration rate (r=-0.53, P<0.001), interstitial fibrosis (mild vs. severe disease; mean 54 vs. 167μg uNGAL/g Cr, P<0.01), and tubular atrophy (mild vs. severe disease; mean 54 vs. 164μg uNGAL/g Cr, P<0.01). Monospecific assays of the NGAL monomer demonstrated a correlation with histology that typifies progressive, severe CKD

Acute kidney injury in patients treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Sofosbuvir-based hepatitis C therapies in patients with chronic and end-stage kidney disease

Sofosbuvir (SOF), a nucleotide inhibitor of the hepatitis C virus (HCV) polymerase, is a component of several all-oral HCV therapies. GS-331007, SOF's predominant metabolite, is renally eliminated and accumulates 5- to 20-fold in patients with advanced chronic kidney disease (CKD) or undergoing hemodialysis (HD), respectively. Preclinical data did not determine whether these exposures represented a risk for toxicity. Therefore subjects with advanced CKD were not included in registrational studies and SOF was not initially approved for use in advanced CKD. Nevertheless, after initial licensing, off-label use of SOF at full or reduced doses was reported in patients with kidney disease. Two clinical trials of SOF-containing therapies were conducted in patients with end-stage kidney disease, demonstrating safety and efficacy. These led to expanded US Food and Drug Administration approval in 2019 for the use of SOF-containing regimens in patients with advanced CKD, including dialysis dependence. Even so, given the availability of protease inhibitor-containing direct-acting antiviral regimens, there was a reluctance by some practitioners to use SOF-containing regimens in moderate to severe kidney disease. Here we review the existing data on SOF's pharmacokinetics, toxicology, efficacy and safety in patients with kidney disease. Data from both clinical trials and real-world practice settings indicate that in patients with moderate to severe kidney disease, full-dose SOF-based regimens have high rates of efficacy and acceptable safety and tolerability profiles, without increased risk for cardiac adverse events or clinically meaningful changes in kidney function. SOF-based regimens are safe and effective in patients who have moderate to severe kidney disease, including those undergoing HD

Acute Renal Dysfunction

Acute renal dysfunction is a common complication in hospitalized patients that is associated with significant morbidity and mortality. Patients with acute renal dysfunction often require admission to the intensive care unit, dialysis initiation, and prolonged hospitalization. While a combination of vascular, tubular, and inflammatory factors has been known to underlie most cases of acute kidney injury (AKI), several cohort studies have attempted to define risk factors for the development of AKI and to place cellular factors in the context of clinical presentations. Distinguishing prerenal AKI from intrinsic AKI is more difficult; however, it is important given the significant increase in morbidity and mortality in the latter. Prerenal causes of AKI include volume depletion from dehydration, blood loss, and diuretics. Causes of intrinsic renal failure commonly encountered on surgical service include ischemic and nephrotoxic acute tubular necrosis, contrast-induced nephropathy, and allergic interstitial nephritis. Renal replacement therapy is the definitive treatment for complications of AKI that are intractable to medical management

Race, Education, and Gender Disparities in Transplantation of Kidneys From Hepatitis C Viremic Donors

Transplantation of kidneys from hepatitis C virus (HCV)-viremic donors into HCV-negative patients followed by direct-acting antiviral therapy was an important breakthrough to increase the number of life-saving kidney transplants. Data suggest that these transplants offer several benefits; however, it is unknown whether adoption of this practice has been shared equitably, especially among disadvantaged groups. We evaluated United Network for Organ Sharing data on HCV-seronegative adult deceased-donor kidney transplant recipients from January 1, 2017, to June 12, 2020. We compared recipients of a kidney from an HCV antibody- (Ab-)/nucleic acid test- (NAT-), HCV Ab+/NAT-, and HCV NAT+ donor. The primary covariates were as follows: (1) race/ethnicity; (2) female sex; and (3) highest level of education. Models included variables associated with being offered an HCV NAT+ kidney. We fit mixed-effects multinomial logistic regression models with the center as a random effect to account for patient clustering. Of 48 255 adult kidney-alone deceased-donor kidney transplant HCV-seronegative recipients, 1641 (3.4%) donors were HCV NAT+-, increasing from 0.3% (January 2017-June 2017) to 6.9% (January 2020-June 2020). In multivariable models, racial/ethnic minorities, women, and those with less education were significantly less likely to receive a kidney from an HCV NAT+ donor relative to an HCV Ab-/NAT- and HCV Ab+/NAT- donor. The disparities were most pronounced among Hispanic and Asian patients with less educational attainment (grade school, high school, or some college/tech school). Despite an increase in transplants from HCV NAT+ donors, we found substantial racial/ethnic disparities in transplantation of these kidneys. These data highlight how the benefits of a scientific breakthrough are often made less available to disadvantaged patients

KDOQI US Commentary on the 2018 KDIGO Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C

The first KDIGO (Kidney Disease: Improving Global Outcomes) guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection was published in 2008. The ensuing decade bore witness to remarkable advances in the treatment of HCV infection following the approval of direct-acting antiviral (DAA) agents that deliver cure rates routinely >95%. In this context, the KDIGO organization correctly recognized the need for an updated HCV guideline that would be relevant to the treatment of HCV-infected patients with kidney disease in the DAA era. The current NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) commentary provides an in-depth review and perspective on the 2018 KDIGO guideline. Of note, the KDIGO work group made significant updates to guideline chapters 2 and 4 as a direct result of the availability of DAAs. The intent of this commentary is to provide useful interpretation for nephrologists and other practitioners caring for HCV-infected patients with chronic kidney disease, including dialysis patients and kidney transplant recipients. The availability of DAA agents that are safe and highly effective has created new opportunities, such as the transplantation of kidneys from HCV-infected kidney donors. The ability to treat HCV infection in patients with kidney disease will have a significant impact on the care of our patients and should favorably influence long-term outcomes as well

Short and long-term effects of telaprevir on kidney function in patients with hepatitis C virus infection: a retrospective cohort study.

Recent reports suggest that telaprevir, a protease inhibitor used to treat hepatitis C infection, is associated with decline in kidney function during therapy, particularly in patients with baseline renal impairment.Patients treated with telaprevir in a single healthcare network were retrospectively reviewed. Kidney function was determined at baseline, during therapy, and twelve weeks and twelve months after telaprevir discontinuation. Significant creatinine rise during therapy was defined as an increase in serum creatinine ≥ 0.3mg/dL from baseline during treatment with telaprevir.Between July 2011 to January 2013,seventy-eight patients began treatment. The majority completed the prescribed twelve weeks of telaprevir therapy; 32% discontinued due to side effects. The average rise in serum creatinine during therapy was 0.22mg/dL (standard deviation 0.22mg/dL). Thirty-one percent experienced a significant creatinine rise during therapy. Decline in estimated glomerular filtration rate (eGFR) was lower in those with baseline eGFR < 90 mL/min/1.73m2 compared to the group with baseline eGFR ≥ 90 mL/min/1.73m2 (12 vs. 18 mL/min/1.73m2, P = 0.047). Serum creatinine fully normalized by twelve weeks after cessation of telaprevir in 83% of patients, however experiencing a significant creatinine rise during telaprevir use was associated with a 6.6mL/min/1.73m2 decrease in estimated glomerular filtration rate at twelve months in an adjusted model.Decline in kidney function during therapy with telaprevir is common and is not associated with baseline eGFR < 90mL/min/1.73m2 as previously reported