Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Nephrotoxicity: A Position Statement from the American Society of Onco-nephrology.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer and are now the backbone of therapy for several malignancies. However, ICIs can cause a spectrum of renal immune-related adverse events including acute kidney injury (AKI), most commonly manifesting as acute interstitial nephritis (AIN), though glomerular disease and electrolyte disturbances have also been reported. In this position statement by the American Society of Onco-nephrology (ASON), we summarize the incidence and risk factors for ICI-AKI, pathophysiological mechanisms and clinicopathological features of ICI-AKI. We also discuss novel diagnostic approaches and promising biomarkers for ICI-AKI. From expert panel consensus, we provide clinical practice points for the initial assessment and diagnosis of ICI-AKI, management and immunosuppressive therapy, and consideration for re-challenge with ICI following AKI episodes. In addition, we explore ICI use in special populations such as kidney transplant recipients and propose key areas of focus for future research and clinical investigation.

Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI.

BACKGROUND: Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. METHODS: We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29-84 days). RESULTS: Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). CONCLUSION: A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

Anemia Management in the Cancer Patient With CKD and End-Stage Kidney Disease.

Anemia is a common medical problem among patients with cancer and chronic kidney disease (CKD). Although anemia in patients with CKD is often treated with iron and erythropoietin-stimulating agents, there are controversies with regard to the use of erythropoietin-stimulating agents in cancer patients. In this article, we review the treatment of anemia in patients with cancer and CKD, in addition to summarizing the current guidelines in treatment of anemia in these patients.

The Role of Kidney Biopsy in Immune Checkpoint Inhibitor-Associated AKI.

AKI in the setting of immune checkpoint inhibitors.Need for kidney biopsy for diagnosis of immune checkpoint inhibitors.Importance of pathology in diagnosis of immune checkpoint inhibitor-induced AKI.

IgA nephropathy relapse following COVID-19 vaccination treated with corticosteroid therapy: case report.

BACKGROUND: The flare of immune-mediated disease following coronavirus disease of 2019 (COVID-19) vaccination is a rare adverse event following immunization. De novo, as well as relapsing IgA nephropathy (IgAN) cases, have been reported following either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) vaccination. To our knowledge, the majority of IgAN relapses did not result in severe acute kidney injury (AKI) and resolved spontaneously. CASE PRESENTATION: This is a case of a 54-year-old female with a previous diagnosis of IgAN who developed IgAN relapse following the second dose of Moderna vaccine. Gross hematuria developed 2 days after vaccination, which was accompanied by significant AKI. Kidney biopsy showed mild tubular atrophy and IgA staining in mesangium without crescent formation. Significant improvement in serum creatinine (Cr) was observed on day 10 after initiating prednisone. Cr came back to normal within 3 months after initiating corticosteroid. CONCLUSION: COVID-19 vaccination is associated with a flare of IgAN that may cause significant AKI. Steroid therapy is associated with recovery. IgAN flare after COVID-19 vaccination should be closely monitored to elucidate any adverse effect associated with the novel vaccine.

Immune Checkpoint Inhibitor-Associated AKI: Debates in Diagnosis, Management, and Rechallenge.

Immune checkpoint inhibitors (ICIs) are now established treatments for advanced cancer and their use is now ubiquitous. The high upside of ICIs is tempered by their toxicity profile affecting almost every organ, including the kidneys. Although acute interstitial nephritis is the major kidney-related adverse effect of checkpoint inhibitors, other manifestations such as electrolyte abnormalities and renal tubular acidosis have been described. With increasing awareness and recognition of these events, the focus has shifted to non-invasive identification of ICI-acute interstitial nephritis, with sophisticated approaches involving biomarkers and immunologic signatures being studied. Although the management of immune-related adverse events with corticosteroids is straightforward, there now are more data to help guide immunosuppressive regimens, ICI rechallenge, and delineate risk and efficacy in special populations such as individuals on dialysis or those who have received a transplant.

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.

Serum amyloid A-type amyloidosis of the kidney and immune complex-mediated glomerulopathy in the setting of hyperimmunoglobulin E (Job's) syndrome.

Hyperimmunoglobulin E syndrome (HIES) is a rare immunodeficiency syndrome with characteristic features of pulmonary infections, eczema, recurrent skin abscesses and elevated serum IgE. We present a case of an HIES patient referred for nephrology consultation with elevated serum creatinine and nephrotic-range proteinuria. The subsequent kidney biopsy revealed AA-type amyloidosis and a separate and distinct inactive immune complex-mediated glomerulopathy with frequent glomerular capillary wall and mesangial polyclonal deposits. Potential kidney pathology in the setting of HIES has not been well described previously, and this case provides insight into associated renal comorbidities faced by patients with this rare syndrome.

Serum electrolyte dynamics in multiple myeloma patients undergoing autologous haematopoietic stem cell transplantation.

AIM: High-dose melphalan followed by autologous haematopoietic cell transplantation remains the standard-of-care therapy for multiple myeloma (MM). Gastrointestinal toxicity concomitant with electrolyte derangement is a primary cause of morbidity from transplant. Here, we assessed the dynamics of electrolyte imbalances and its role in hematologic counts and engraftment. Ω Patients and Methods One hundred and eighteen MM patients that received transplant were studied. RESULTS: Engraftment speed (ES) was calculated as the period between the first rise in the absolute neutrophil count (ANC) and full engraftment defined as the first of three consecutive days with ANC > 500 × 106 /L. The defined median ES was 2 days (range 0-5 days) and 40 patients had ES ≤2 days. Engraftment occurred at a median of 10 days. The median time-to-nadir for phosphorus and potassium was 10 and 4.28 days, respectively. The drop in phosphorus and potassium serum level was statistically greater in patients with an ES ≤2 days compared to patients with ES ≥2 days. Magnesium level were not significantly affected and there was no significant difference between the drop in serum phosphorus and potassium based on severity of nausea or oral mucositis. CONCLUSION: Our results indicate that there is a significant correlation between the magnitude of drop in potassium and phosphorous levels and a steep rise in neutrophil counts around the engraftment period following stem cell transplant. These events indicate a "genesis syndrome" characterized by a rapid, massive transfer of electrolytes into proliferating cells as has been previously described after HCT for certain high-grade lymphomas and leukemias.

The effect of iron-vitamin C co-supplementation on biomarkers of oxidative stress in iron-deficient female youth.

There is no study that assessed the effect of co-supplementation of iron and vitamin C on biomarkers of oxidative stress in non-anemic iron-deficient females. We investigated the effects of iron vs. iron + vitamin C co-supplementation on biomarkers of oxidative stress in iron-deficient girls. In a double-blind randomized controlled clinical trial, performed among 60 non-anemic iron-deficient girls, participants were randomly assigned to receive either 50 mg/day elemental iron supplements or 50 mg/day elemental iron + 500 mg/day ascorbic acid for 12 weeks. Fasting blood samples were taken at baseline, weeks 6 and 12 for assessment of biomarkers of oxidative stress. Compared with the baseline levels, both iron and iron + vitamin C supplementation resulted in a significant reduction in serum malondialdehyde (MDA) levels (P time < 0.001) and remarkable elevation in serum total antioxidant capacity (TAC; P time < 0.001) and vitamin C levels (P time = 0.001); however, comparing the two groups we failed to find an additional effect of iron + vitamin C supplementation to that of iron alone on serum TAC and MDA levels (P group was not statistically significant). Iron + vitamin C supplementation influenced serum vitamin C levels much more than that by iron alone (P group < 0.01). We also found a significant interaction term between time and group about serum vitamin C levels while this interaction was not significant about serum TAC and MDA levels. In conclusion, we found that iron supplementation with/without vitamin C improve biomarkers of oxidative stress among non-anemic iron-deficient females and may strengthen the antioxidant defense system by decreasing reactive oxygen species. Co-supplementation of iron + vitamin C has no further effect on oxidative stress compared with iron alone.

Immunoglobulin A nephropathy associated with mesothelioma.

Immunoglobulin A nephropathy (IgAN) has been identified in patients with various malignancies. Although membranous glomerulonephritis and minimal change disease have been described in patients with mesothelioma, to our knowledge IgAN associated with mesothelioma has not been reported. We present a case of IgAN, characterized by progressive deterioration of renal function from normal and confirmed by kidney biopsy. Despite improvement of renal function following treatment with cyclophosphamide and prednisone, the patient succumbed to acute respiratory failure 8 months later. We conclude that IgAN may be a potential complication of mesothelioma.

The case for chronic kidney disease, diabetes mellitus, and myocardial infarction being equivalent risk factors for cardiovascular mortality in patients older than 65 years.

The objective of the study was to determine whether chronic kidney disease (CKD) is as important a risk as either diabetes mellitus (DM) or previous myocardial infarction (MI). CKD and DM are important coronary artery disease risk factors. We hypothesized that the risk of cardiovascular mortality in elderly patients with CKD is equivalent to that for patients with either DM or previous MI. The CHS limited-access database was used to identify a cohort of patients with a baseline history of MI, DM, or CKD (estimated glomerular filtration rate <60 ml/min). Subjects were categorized in 1 of 3 groups as group 1, patients with DM (no CKD or MI); group 2, patients with previous MI (no DM or CKD); and group 3, patients with CKD (no DM or MI). Patients were followed up for a mean of 8.6 years, and rates of cardiovascular mortality were compared using proportional hazards regression. There were 789, 443, and 667 people in the MI, DM, and CKD groups, respectively. During follow-up, 124 patients (15.7%) died of cardiovascular causes in the MI group, and 69 (15.8%) and 87 (13%), in the DM and CKD groups, respectively. After adjusting for age, race, gender, smoking, hypertension, and total, high-density lipoprotein, and low-density lipoprotein cholesterol, the hazard ratio (HR) for cardiovascular mortality was similar between the DM (HR 1.0, 95% confidence interval 0.8 to 1.4)) and CKD cohorts (HR 0.8, 95% confidence interval 0.6 to 1.1) compared with the MI group. In conclusion, the risk of cardiovascular mortality in patients with moderate CKD was as high as that in patients with a history of MI or DM. Designation of CKD as a cardiovascular risk equivalent in patients >65 years of age appears justified.

Does absolute neutrophilia predict early congestive heart failure after acute myocardial infarction? A cross-sectional study.

BACKGROUND: Acute myocardial infarction (AMI) is usually associated with increased neutrophil count. However, it has not clearly been defined whether neutrophilia can cause myocardial injury. In this study, we hypothesized that absolute neutrophilia can predict the occurrence of congestive heart failure (CHF) after AMI. METHODS: A cross-sectional study was carried out on 312 patients with a diagnosis of AMI. Patients with a history of chest pain for more than 12 hours before admission, heart failure with Killip class III and IV, history of recent gastrointestinal bleeding, major trauma, infection, malignancy, renal failure and corticosteroid consumption were excluded. A blood sample was drawn for leukocyte count and an echocardiogram was obtained 4 days after admission. Congestive heart failure was defined as an ejection fraction less than 40% on echocardiogram or clinical heart failure according to the Framingham's criteria for diagnosis of heart failure. RESULTS: After excluding 19 patients, data for 293 patients were analyzed. Among them, 152 (51.9%) patients developed new onset CHF. Two hundred and two patients (68.9%) had neutrophilia (neutrophil count >7500/mic/lit). The risk of developing heart failure was higher in patients with neutrophilia (OR = 2.32; 95% CI = 1.33-4.03, P = 0.000). There was a negative correlation between ejection fraction and neutrophil count (r = -0.191, P = 0.000). After adjustment for age, sex, serum creatinine level, peak enzyme CK-MB level and MI location, the relationship between the absolute neutrophil count and the presence of congestive heart failure remained significant (OR = 2.14; 95% CI = 1.19-3.84, P = 0.011). CONCLUSIONS: The study shows that the presence of absolute neutrophilia during the first 12 hours after AMI can predict the occurrence of CHF. This association may help identify high-risk individuals, who might benefit from more aggressive interventions.

Is chronic kidney disease comparable to diabetes as a coronary artery disease risk factor?

BACKGROUND: Chronic kidney disease (CKD) is one of the known risk factors for coronary heart disease (CHD). Though electrocardiograms (ECGs) have limited accuracy in determining the true prevalence of CHD, we wondered whether CKD and diabetes mellitus (DM) controlled for hypertension (HTN), had similar prevalences of ECG abnormalities that could reflect underlying coronary heart disease. METHOD: Data were collected for 5,942 men and women aged 30 to 69 years in the Tehran Lipid and Glucose Study (TLGS), a crosssectional phase of a large epidemiologic study first initiated in 1999. ECG findings of all subjects were coded according to Minnesota ECG coding criteria. The Whitehall criteria for abnormal ECG findings that could represent ischemia were utilized. Creatinine clearance (Crcl) was estimated using the Cockroft-Gault equation and diabetes was defined according to the American Diabetic Association (ADA) criteria. Subjects with moderate CKD and without DM were compared with the patients with DM without CKD. HTN prevalence was similar. The analysis was performed for all Whitehall ECG ischemia abnormalities combined, and separately for pathologic Q waves. RESULTS: In spite of an overall similar prevalence of smoking, and a lower incidence of dyslipidemia and HTN, moderate CKD patients had a higher prevalence of Whitehall criteria abnormal ECG findings compared with the patients with DM. Over 19% of patients with CKD had abnormal ECG findings while 14.7% of diabetic patients had abnormal ECGs (P = 0.02). The prevalence of Q waves was 11.5% in patients with CKD and 10.8% in patients with DM. In an age-matched subgroup of patients with DM and no CKD, the prevalence of ECG abnormalities was 19.3%, similar to the patients with moderate CKD and no DM (19.7%) (P = 0.9). The prevalence of pathologic Q waves in an age-matched group was 11.45%, compared with 11.5%, respectively. CONCLUSION: Moderate CKD is a major risk factor for the development of the Whitehall ECG criteria which have been associated with ischemic heart disease. The importance of CKD as a risk factor for ECG abnormalities is comparable with DM. Patients with moderate CKD probably are candidates for aggressive CHD risk modification.

Height and weight of urban preschool children in relation to their mothers' educational levels and employment status in Rasht City, northern Iran.

This study determined the relationship between anthropometric status of 3-5-year-old urban children and theirs mothers' educational levels and employment status in Rasht City, northern Iran. A total of 1319 children (638 girls and 681 boys) at the ages of 3 and 6 years in all day-care centres in Rasht City were studied, using a cross-sectional design. Height and weight of the children were measured, and data on mothers' educational levels, employment status and duration of any breastfeeding were collected. Height for age, weight for age and weight for height of the children were compared with the National Center for Health Statistics (NCHS) reference population of the United States, and z-values 12 years of schooling, OR = 1.87; 95% CI: 1.08-2.4) had higher relative risk for underweight than children of mothers with an intermediate level of education (5-12 years of schooling). Children of mothers with college education were also more at risk for development of stunting (OR = 1.41; 95% CI: 1.14-4.22). In addition, children of employed mothers were more likely to be underweight (OR = 1.52; 95% CI: 1.05-2.31), stunted (OR = 2.42; 95% CI: 1.21-6.35) and wasted (OR = 3.35; 95% CI: 1.21-5.58) than children of non-employed mothers. The relative risk for undernutrition was higher in the children of both less and highly educated mothers compared with children of mothers with an intermediate level of education. Mothers' employment was also negatively related to nutritional status of these children in day-care centres in Rasht City.