Transient acute kidney injury after chimeric antigen receptor T-cell therapy in patients with hematological malignancies.

Background: Acute kidney injury (AKI) occurs in 30% of patients infused with chimeric antigen receptor (CAR) T-cells. The purpose of this study was to identify risk factors and long-term outcomes after AKI in patients who received CAR T-cell therapy. Methods: Medical records of 115 adult patients with R/R hematological malignancies treated with CD19-targeted CAR T-cells at Vall d'Hebron University Hospital between July 2018 and May 2021. Baseline demographic data including age, gender, ethnicity, body mass index (BMI), and co-morbidities, as well as the type of hematological neoplasia and prior lines of therapy were collected. Laboratory parameters including serum creatinine and whole blood hemoglobin were retrospectively reviewed and values were gathered for days +1, +7, +14, +21, and +28 post-infusion. Results: A total of 24/115 (21%) patients developed AKI related to CAR T-cell therapy; 6/24 with AKI over chronic kidney disease (CKD). Two patients had AKI in the context of lymphodepleting (LD) chemotherapy and the other 22 after CAR T-cell infusion, starting at day+1 in 3 patients, day+7 in 13 patients, day +14 in 1 patient, day+21 in 2 patients, and day+28 in 3 patients. Renal function was recovered in 19/24 (79%) patients within the first month after infusion. Male gender, CKD, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with AKI. Male gender, CKD, ICANS grade ≥3 and CRS grade ≥2 were identified as independent risk factors for AKI on multivariable analysis. In terms of the most frequent CAR T-cell related complications, CRS was observed in 95 (82%) patients and ICANS in 33 (29%) patients. Steroids were required in 34 (30%) patients and tocilizumab in 37 (32%) patients. Six (5%) patients were admitted to the intensive care unit (1 for septic shock, 4 for CRS grade ≥2 associated to ICANS grade ≥2, and 1 for CRS grade ≥3). A total of 5 (4.4%) patients died in the first 30 days after CAR T-cell infusion for reasons other than disease progression, including 4 cases of infectious complications and 1 of heart failure. Conclusion: Our results suggest that AKI is a frequent but mild adverse event, with fast recovery in most patients.

The Presence of ANCA in IgA Crescentic Nephropathy Does Not Lead to Worse Prognosis with Intensive Rescue Treatment.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The concomitant presence of both crescentic proliferation and anti-neutrophil cytoplasmic autoantibodies (ANCA) in this pathology represents a rare coincidence. However, it is not clear to what extent the presence of ANCA (IgA or IgG) in these patients could have any clinical significance. The aim of the current work is to describe the presence of ANCA (IgA or IgG) in patients with IgAN and crescentic proliferation and its possible clinical implications. METHODS: We retrospectively recruited all patients in our center with a histological diagnosis of IgAN with crescentic proliferation between January 2013 and December 2020. The main demographic and clinicopathologic data, fundamental histological characteristics, as well as the treatments implemented and main kidney outcomes, were collected and analyzed at a 6 and 12-month follow-up. RESULTS: Between January 2013 and December 2020, a total of 17 adults were diagnosed with concomitant crescentic proliferation through a kidney biopsy of IgAN. Five (29.4%) patients showed ANCA, three (60%) showed IgA-ANCA and two (40%) showed IgG-ANCA. All ANCA-positive patients had some degree of crescentic proliferation. At diagnosis, the mean age of patients was 48 years old (range: 27-75). Nine of them were women (52%) and the most common clinical presentation was hypertension (71%). At the time of biopsy, the mean serum creatinine and proteinuria were 2.2 mg/dL (DS 1.42) and 3.5 g/mgCr (DS 1.22), respectively, with no statistical differences between ANCA-positive and -negative patients. Histological analyses showed that 11 out of the 12 (91%) ANCA-negative IgAN patients displayed less than 25% cellular crescents, whereas 100% of ANCA-positive IgAN patients displayed more than 25% cellular crescents (p = 0.04). Notably, five (30%) patients displayed fibrinoid necrosis, with four of them (80%) being IgAN-ANCA-positive (p = 0.01). Only one ANCA-negative patient needed renal replacement therapy (RRT) upon admission (5%). The mean serum creatinine and proteinuria were 1.94 mg/dL (DS 1.71) and 1.45 g/gCr (DS 1.78), respectively, within 6 months of immunosuppressive therapy. At 12-month follow-up, the mean creatinine was 1.57 mg/dL (DS 1). Four (23.5%) patients needed RRT at the end of the follow-up and four (23.5%) patients died. CONCLUSIONS: Probably due to the limited number of IgAN-ANCA-positive and IgAN-ANCA-negative patients, no significant differences were found between the clinical and laboratory characteristics. IgAN-ANCA-negative patients seemed to display less extracapillary proliferation than IgAN-ANCA-positive patients, who tended to show significantly higher fibrinoid necrosis. There were no differences regarding renal prognosis and patient survival after aggressive immunosuppressive therapy within 6 and 12 months when comparing the two samples.

Immunotherapy and the Spectrum of Kidney Disease: Should We Individualize the Treatment?

The new targeted cancer therapies including immune checkpoint inhibitors (ICIs) have been demonstrated to improve the survival of oncological patients, even in cases of metastatic cancer. In the past 5 years, several studies have revealed that ICI can produce several immune-mediated toxicities involving different organs, such as the skin, the gastrointestinal tract, the liver, and, of course, the kidney. The most frequent lesion of immunotoxicity in the kidney is acute interstitial nephritis (AIN), although other nephropathies have also been described as a consequence of the use of ICI, such as glomerulonephritis and acute thrombotic microangiopathy, among others. In addition, kidney rejection has also been reported in kidney transplant patients treated with ICI. Normally randomized clinical trials with ICI exclude patients with end-stage kidney disease, namely, patients undergoing dialysis and kidney transplant patients. Several important questions need to be addressed in relation to immunotherapy and patients with kidney disease: (a) when to start corticosteroid therapy in a patient with suspected acute kidney injury (AKI) related to ICI, (b) the moment of nephrologist referral and kidney biopsy indication, (c) management of ICI in patients undergoing dialysis, and (d) the effect of ICI in kidney transplantation, immunosuppressive personalized treatment, and risk of allograft rejection in kidney transplant patients. The objective of this review was to summarize the recently published literature on a wide spectrum of kidney disease patients with cancer and ICI. This review will address three main important groups of individuals with kidney disease and cancer immunotherapy, AKI associated with ICI, patients undergoing dialysis, and kidney transplant recipients. We believe that the information provided in this review will enlighten the personalized ICI treatment in individuals with a broader spectrum of kidney diseases.

Kidney Biopsy in Patients with Cancer along the Last Decade: A Multicenter Study.

BACKGROUND: Currently, following the new advances in cancer treatments and the increasing prevalence of kidney disease in the population, more kidney biopsies are being performed. The aim of our study is to analyze clinical and histological characteristics of patients with active solid organ malignancy who underwent kidney biopsy. This is a multi-center collaborative retrospective study supported by groups GLOSEN/Onconephrology from the Spanish Society of Nephrology. Clinical, demographical and histological data were collected. RESULTS: A total of 148 patients with cancer who underwent a kidney biopsy from 12 hospitals were included. 64.3% men and mean age of 66.9 years old. The indications for biopsy were acute renal injury (67.1%), proteinuria (17.1%), exacerbated chronic kidney disease (8.2%), and chronic kidney disease (7.5%). Most frequent malignances were lung (29.1%) and abdominal (25%), with 49.7% metastatic cancer. As oncospecific treatment, 28% received chemotherapy, 29.3% immunotherapy, 19.3% specific therapies, and 2.1% conservative treatment. At the time of kidney biopsy, median creatinine was of 2.58 mg/dL [1.81-4.1 (IQ 25-75)], median urine protein-to-creatinine ratio of 700 mg/g [256-2463 (IQ 25-75)] and 53.1% presented hematuria. The most frequent renal biopsy diagnoses were: acute interstitial nephritis (39.9%), acute tubular necrosis (8.8%), IgA nephropathy (7.4%) and membranous nephropathy (6.1%). Median follow-up was 15.2 months [5.7-31.4 (IQ 25-75)]. CONCLUSIONS: There is a new trend in kidney disease and cancer patients in terms of diagnosis and treatment. Acute interstitial nephritis has established itself as the most common kidney injury in patients with cancer who underwent a kidney biopsy. Renal biopsy is a valuable tool for diagnosis, treatment, and prognosis of solid organ cancer patients with kidney damage.

Safety of Obtaining an Extra Biobank Kidney Biopsy Core.

BACKGROUND AND OBJECTIVES: Kidney biopsy (KB) is the "gold standard" for the diagnosis of nephropathies and it is a diagnostic tool that presents a low rate of complications. Nowadays, biobank collections of renal tissue of patients with proven renal pathology are essential for research in nephrology. To provide enough tissue for the biobank collection, it is usually needed to obtain an extra kidney core at the time of kidney biopsy. The objective of our study is to evaluate the complications after KB and to analyze whether obtaining an extra core increases the risk of complications. MATERIAL AND METHODS: Prospective observational study of KBs performed at Vall d'Hebron Hospital between 2019 and 2020. All patients who accepted to participate to our research biobank of native kidney biopsies were included to the study. Clinical and laboratory data were reviewed and we studied risk factors associated with complications. RESULTS: A total of 221 patients were included, mean age 56.6 (±16.8) years, 130 (58.8%) were men, creatinine was 2.24 (±1.94) mg/dL, proteinuria 1.56 (0.506-3.590) g/24 h, hemoglobin 12.03 (±2.3) g/dL, INR 0.99 (±0.1), and prothrombin time (PT) 11.86 (±1.2) s. A total of 38 patients (17.2%) presented complications associated with the procedure: 13.1% were minor complications, 11.3% (n = 25) required blood transfusion, 1.4% (n = 3) had severe hematomas, 2.3% (n = 5) required embolization, and 0.5% (n = 1) presented arterio-venous fistula. An increased risk for complication was independently associated with obtaining a single kidney core (vs. 2 and 3 cores) (p = 0.021). CONCLUSIONS: KB is an invasive and safe procedure with a low percentage of complications. Obtaining an extra kidney core for research does not increase the risk of complications during the intervention, which remains low in concordance with previously published reports.

Corrigendum: Enteric Budesonide in Transplant and Native IgA Nephropathy: Real-World Clinical Practice.

[This corrects the article DOI: 10.3389/ti.2022.10693.].

Acute kidney injury as a risk factor for mortality in oncological patients receiving checkpoint inhibitors.

BACKGROUND: Checkpoint inhibitors (CPIs) have drastically improved metastatic cancer outcomes. However, immunotherapy is associated with multiple toxicities, including acute kidney injury (AKI). Data about CPI-related AKI are limited. Our aim was to determine risk factors for CPI-related AKI as well as its clinical characteristics and its impact on mortality in patients undergoing immunotherapy. METHODS: All patients under CPI at our centre between March 2018 and May 2019 and with a follow-up through April 2020 were included. Demographic, clinical and laboratory data were collected. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines. We performed a logistic regression model to identify independent risk factors for AKI and actuarial survival analysis to establish risk factors for mortality in this population. RESULTS: A total of 759 patients were included, with a median age of 64 years. A total of 59% were men and baseline median creatinine was 0.80 mg/dL. The most frequent malignancy was lung cancer and 56% were receiving anti-programmed death protein 1 (PD-1). About 15.5% developed AKI during the follow-up. Age and baseline kidney function were identified as independent risk factors for CPI-related AKI. At the end of follow-up, 52.3% of patients had died. The type of cancer (not melanoma, lung or urogenital malignance), type of CPI (not cytotoxic T-lymphocyte-associated protein 4, PD-1, programmed death-ligand 1 or their combination) and the presence of an episode of AKI were identified as risk factors for mortality. CONCLUSIONS: A total of 15.5% of patients under immunotherapy presented with AKI. A single AKI episode was identified as an independent risk factor for mortality in these patients and age and baseline renal function were risk factors for the development of AKI.

Acute interstitial nephritis associated with immune checkpoint inhibitors: a single-centre experience.

BACKGROUND: Checkpoint inhibitors (CPIs) are used to treat solid organ metastatic malignancies. They act by triggering a vigorous immune response against tumoural cells, preventing their proliferation and metastasis. However, this is not a selective response and can cause immune-related adverse events (irAEs). The kidney can potentially be damaged, with an incidence of irAEs of 1-4%. The most frequent type of toxicity described is acute interstitial nephritis (AIN). METHODS: We conducted a study of patients with solid organ metastatic malignancies treated with immunotherapy who developed acute renal injury and underwent kidney biopsy in the last 14 months at the Vall d'Hebron University Hospital. RESULTS: In all, 826 solid organ malignancies were treated with immunotherapy in our centre, 125 of them (15.1%) developed acute kidney injury (AKI), 23 (18.4% of AKI) visited the nephrology department and 8 underwent kidney biopsy. The most frequent malignancy was lung cancer, in five patients (62%), followed by two patients (25%) with melanoma and one patient (12%) with pancreatic cancer. Four patients (50%) had already received previous oncological therapy, and for the remaining four patients (50%), CPI was the first-line therapy. Five patients (62%) were treated with anti-programmed cell death protein 1, three patients (37%) received anti-programmed death ligand 1 and two (25%) patients were treated in combination with anti-cytotoxic T-lymphocyte antigen 4. The time between the start of CPI and the onset of the AKI ranged from 2 to 11 months. The most frequent urine findings were subnephrotic-range proteinuria, with a mean protein:creatinine ratio of 544 mg/g (standard deviation 147) and eosinophiluria. All patients were biopsied after being diagnosed with AIN. Three patients (37%) received treatment with pulses of methylprednisolone 250-500 mg/day and five patients (62%) received prednisone 1 mg/kg/day. Seven patients (87%) experienced recovery of kidney function and one patient (12%) progressed to chronic kidney disease. CONCLUSIONS: We report on eight patients with CPI-related AIN diagnosed in the last 14 months at our centre. The novel immunotherapy treatment of metastatic solid organ malignancies carries a higher risk of irAEs. The kidney is one of the most commonly affected organs, frequently presenting as an AIN and exhibiting a favourable response to steroid treatment.

Acute tubulointerstitial nephritis induced by checkpoint inhibitors versus classical acute tubulointerstitial nephritis: are they the same disease?

BACKGROUND: The incidence of acute tubulointerstitial nephritis (ATIN) related to drugs has dramatically increased over recent years. A new subtype of ATIN, apparently different from classical drug-related ATIN, has emerged that has been related to the administration of immune checkpoint inhibitors (ICIs). We investigated these differences between ICI-related ATIN (ICI ATIN) and non-ICI-related ATIN in terms of clinical features, response to treatment with steroids and the evolution of kidney function. METHODS: A total of 47 patients diagnosed with ATIN from two centres were recruited. Of these, 13 patients presented with ATIN during ICI treatment and 34 were diagnosed with ATIN attributed to other drugs. The main demographic, clinical and analytical variables such as gender, age and current medication were recorded. The type of malignancy, oncological treatment, ICI dose and presence of extrarenal immune-related adverse events were also reviewed. Renal biopsy diagnosis, time to drug withdrawal and ATIN-specific treatment, as well as laboratory data during follow-up, were also studied. RESULTS: Patients diagnosed with ICI ATIN presented with lower creatinine (ICI ATIN 3.8 ± 1.03 versus classical ATIN 5.98 ± 4.15 mg/dL, P = 0.007) at diagnosis and higher urinary leucocyte counts (ICI ATIN 263.2 ± 418.04 versus classical ATIN 133.55 ± 284.62, P = 0.048) compared with patients with non-ICI-related ATIN. Time from initiation of the culprit drug to ATIN diagnosis was longer in patients with ICI ATIN than in those with classical ATIN (197.07 ± 184.99 versus 114.4 ± 352.16 days, P = 0.006). In addition, during follow-up, the slope of decreasing creatinine over time was lower for ICI ATIN compared with non-ICI-related ATIN. CONCLUSIONS: In this study, we analysed differences between ICI ATIN and classical ATIN. We found that patients with ICI ATIN presented with a larger latency period after culprit drug initiation, milder acute kidney injury and slower creatinine amelioration compared with those with classical ATIN. These results may, in part, be ascribed to potential differences in the pathological mechanisms involved in ATIN development, suggesting that ICI and classical ATIN may be different diseases with similar renal histologies.

Biopsia renal transyugular. La alternativa a la biopsia percutánea en pacientes de alto riesgo / Utility of transjugular renal biopsy as an alternative to percutaneous biopsy

ANTECEDENTES Y OBJETIVOS: La biopsia renal transyugular (BTY) es una alternativa a la biopsia renal ecoguiada percutánea en caso de que existan contraindicaciones para su realización. En la actualidad, pocos centros realizan este procedimiento y la literatura acerca de las indicaciones, complicaciones y rentabilidad diagnóstica es limitada. El objetivo de este estudio es analizar las indicaciones, rendimiento diagnóstico, seguridad y complicaciones de la biopsia renal transyugular percutánea en los últimos 15 años en nuestro centro. MATERIAL Y MÉTODOS: Estudio descriptivo retrospectivo que revisa las biopsias renales transyugulares (BTY) realizadas en el Hospital Vall d'Hebrón de 2003 a 2018 para lo cual se ha llevado a cabo una revisión exhaustiva de las historias clínicas de los pacientes sometidos a este procedimiento durante el periodo de estudio. RESULTADOS: Durante el periodo de estudio se realizaron 56 BTY. Los pacientes fueron 31 hombres (55,4%) y 25 mujeres (44,6%), con una mediana de edad de 62 años (rango intercuartil (IQ) 25-75 [52,5-69,5]). La mediana de creatinina fue 2,69 mg/dL (IQ 25-75 [1,7-4,3]) y la de proteinuria (en 24 horas) de 2.000 mg (IQ 25-75[0,41-4,77]. Más de la mitad presentaban hematuria en el momento de la biopsia. La presión arterial media sistólica fue de 140 +/- 26 mmHg y diastólica 75 +/- 15 mmHg. La biopsia se realizó por insuficiencia renal aguda en 19 pacientes, enfermedad renal crónica en 12 y síndrome nefrótico en 10 casos; en 15 pacientes se realizó por otros motivos. Se decidió realización del procedimiento por vía transyugular por imposibilidad técnica ecoguiada en 16 de 56 casos (incluyendo riñones infracostales, obesidad y enfermedad pulmonar obstructiva crónica), alteraciones en hemostasia (n = 6), trombocitopenia (n = 5) y riñón único (n = 7). El 12,5% de las biopsias fueron hepato-renales. Se obtuvo diagnóstico histológico en dos tercios de las biopsias renales. La media de cilindros obtenidos fue de de 2,5 ± 1,3, y la media de glomérulos 6,6 ± 6,2. Los diagnósticos histológicos más frecuentes fueron nefropatía IgA, glomerulonefritis membranoproliferativa y microangiopatía trombótica. Se observaron tres complicaciones mayores: rotura de fórnix y dos requerimientos transfusionales por sangrado y hematoma subcapsular. CONCLUSIONES: En nuestro centro, la realización de BTY permitió el diagnóstico histológico en dos tercios de los pacientes que presentaban contraindicación para la realización de biopsia renal ecoguiada, permitiendo el diagnóstico y posterior tratamiento dirigido en dichos pacientes

BACKGROUND AND OBJECTIVES: Transjugular renal biopsies (TRB) are an alternative when percutaneous ultrasound renal biopsy is contraindicated. Few sites are currently carrying out this procedure, with limited literature existing on the indications, complications and diagnostic yield thereof. The aim of the study is to analyse the indications, diagnostic yield, safety and complications of percutaneous transjugular renal biopsies in our site over the last 15 years. MATERIAL AND METHODS: Retrospective descriptive study of all transjugular renal biopsies performed in our site, the Hospital Vall d'Hebron, between 2003 and 2018. For this, an exhaustive review of the clinical records of patients subjected to this procedure during the study period was conducted. RESULTS: 56 TRBs were performed during the study period. Out of the patients, 31 were men (55.4%) and 25 were women (44.6%), with a median age of 62 years (IQ range 25-75 [52.5-69.5]). More than half presented with haematuria at the time of biopsy, with a median creatinine of 2.69 mg/dL (IQ 25-75 [1.7-4.3]) and median proteinuria at 24 hours of 2000 mg (IQ 25-75 [0.41-4.77]).The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 140 +/- 26 mmHg and 75 +/- 15 mmHg, respectively. The biopsy was carried out owing to acute kidney failure in 19 patients, chronic kidney disease in 12 patients and nephrotic syndrome in 10 patients; in 15 patients it was carried out for other reasons. The most frequent TRB indication was technical impossibility in 16 of 56 cases (including infracostal kidneys, obesity and COPD), alterations in haemostasis (n = 6), thrombocytopenia (n = 5) and solitary kidney (n = 7). 12.5% of the biopsies were hepato-renal. Histological diagnoses were obtained in two thirds of the renal biopsies. The average number of cylinders obtained was 2.5 ± 1.3, with the average number of glomeruli being 6.6 ± 6.2. The most frequent histological diagnoses were IgA nephropathy, membranoproliferative glomerulonephritis and thrombotic microangiopathy. Three major complications were observed: fornix rupture and two transfusion requirements due to bleeding and subcapsular hematoma. CONCLUSIONS: In our site, TRB allowed for a histological diagnosis in 2/3 of patients for whom percutaneous ultrasound renal biopsy is contraindicated. This allowed us to diagnose and subsequently treat said patients

Utility of transjugular renal biopsy as an alternative to percutaneous biopsy. / Biopsia renal transyugular. La alternativa a la biopsia percutánea en pacientes de alto riesgo.

BACKGROUND AND OBJECTIVES: Transjugular renal biopsies (TRB) are an alternative when percutaneous ultrasound renal biopsy is contraindicated. Few sites are currently carrying out this procedure, with limited literature existing on the indications, complications and diagnostic yield thereof. The aim of the study is to analyse the indications, diagnostic yield, safety and complications of percutaneous transjugular renal biopsies in our site over the last 15 years. MATERIAL AND METHODS: Retrospective descriptive study of all transjugular renal biopsies performed in our site, the Hospital Vall d'Hebron, between 2003 and 2018. For this, an exhaustive review of the clinical records of patients subjected to this procedure during the study period was conducted. RESULTS: 56 TRBs were performed during the study period. Out of the patients, 31 were men (55.4%) and 25 were women (44.6%), with a median age of 62 years (IQ range 25-75 [52.5-69.5]). More than half presented with haematuria at the time of biopsy, with a median creatinine of 2.69 mg/dL (IQ 25-75 [1.7-4.3]) and median proteinuria at 24 hours of 2000 mg (IQ 25-75 [0.41-4.77]).The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 140 +/- 26 mmHg and 75 +/- 15 mmHg, respectively. The biopsy was carried out owing to acute kidney failure in 19 patients, chronic kidney disease in 12 patients and nephrotic syndrome in 10 patients; in 15 patients it was carried out for other reasons. The most frequent TRB indication was technical impossibility in 16 of 56 cases (including infracostal kidneys, obesity and COPD), alterations in haemostasis (n = 6), thrombocytopenia (n = 5) and solitary kidney (n = 7). 12.5% of the biopsies were hepato-renal. Histological diagnoses were obtained in two thirds of the renal biopsies. The average number of cylinders obtained was 2.5 ± 1.3, with the average number of glomeruli being 6.6 ± 6.2. The most frequent histological diagnoses were IgA nephropathy, membranoproliferative glomerulonephritis and thrombotic microangiopathy. Three major complications were observed: fornix rupture and two transfusion requirements due to bleeding and subcapsular hematoma. CONCLUSIONS: In our site, TRB allowed for a histological diagnosis in 2/3 of patients for whom percutaneous ultrasound renal biopsy is contraindicated. This allowed us to diagnose and subsequently treat said patients.