Adverse renal effects of check-point inhibitors (ICI) in cancer patients: Recommendations of the Onco-nephrology Working Group of the Spanish Society of Nephrology.

The most widely used approach in the immunotherapy treatment of cancer is the administration of monoclonal antibodies directed against regulatory molecules of immune control that inhibit the activation of T cells, the so-called check point inhibitors (ICI). ICI nephrotoxicity epidemiology and pathology; its diagnosis with or without kidney biopsy; the type and duration of treatment; the possibility of rechallenging after kidney damage; and its indication in patients with cancer and renal transplantation are certainly controversial. In the absence of definitive studies, this document is intended to specify some recommendations agreed by the group of Onconephrology experts of the Spanish Society of Nephrology in those areas related to ICI nephrotoxicity, in order to help decision-making in daily clinical practice in Onconephrology consultations.

Efectos renales adversos por inhibidores del check-point (ICP) en pacientes con cáncer. Recomendaciones del grupo de Onconefrología de la Sociedad Española de Nefrología (SEN) / Adverse renal effects of check-point inhibitors (ICI) in cancer patients: Recommendations of the Onco-nephrology Working Group of the Spanish Society of Nephrology

El enfoque más utilizado en el tratamiento inmunoterápico del cáncer es la administración de anticuerpos monoclonales dirigidos contra moléculas reguladoras del control inmunitario que inhiben la activación de las células T, los llamados inhibidores del check-point (ICP). La epidemiología y patología de la nefrotoxicidad por los ICP, su diagnóstico con o sin biopsia renal, el tipo y la duración del tratamiento, la posibilidad de retratar después del daño renal, y su indicación en pacientes con cáncer y trasplante renal son ciertamente controvertidas. En ausencia de estudios definitivos, este documento está destinado a concretar unas recomendaciones consensuadas por el grupo de expertos de Onconefrología de la SEN en aquellas áreas relacionadas con la nefrotoxicidad por los ICP, con la finalidad de ayudar en la toma de decisiones en la práctica clínica diaria de las consultas de Onconefrología. (AU)

The most widely used approach in the immunotherapy treatment of cancer is the administration of monoclonal antibodies directed against regulatory molecules of immune control that inhibit the activation of T cells, the so-called check point inhibitors (ICI). ICI nephrotoxicity epidemiology and pathology; its diagnosis with or without kidney biopsy; the type and duration of treatment; the possibility of rechallenging after kidney damage; and its indication in patients with cancer and renal transplantation are certainly controversial. In the absence of definitive studies, this document is intended to specify some recommendations agreed by the group of onconephrology experts of the Spanish Society of Nephrology in those areas related to ICI nephrotoxicity, in order to help decision-making in daily clinical practice in onconephrology consultations. (AU)

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. METHODS: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. FINDINGS: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). INTERPRETATION: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. FUNDING: F Hoffmann-La Roche.

Octogenarians with chronic kidney disease in the nephrology clinic: Progressors vs. non-progressors.

Background: The current definition of chronic kidney disease applied to patients over the age of 80 has increased the number of referrals to Nephrology. However not all of these patients may benefit from its assessment. This study aims to analyze the evolution of ≥80 years old patients referred to Nephrology. Methods: Single-center study including patients ≥80 years old with eGFR <60 mL/min/1,73m2 who were referred to Nephrology consultation for the first time. Clinical and analytical parameters were collected retrospectively 12 months before the visit, and prospectively at baseline, and 12 and 24 months after the initial visit. We divided patients into two groups based on annual eGFR loss: progressors (>5 mL/min/1.73m2) and non-progressors (≤5 mL/min/1,73m2). Results: A total of 318 patients were included, mean age was 84,9 ± 4 (80-97) years. Baseline serum creatinine was 1,65 ± 0,62 mg/dL, eGRF 35 (28-42) mL/min/1,73, and albumin/creatinine ratio 36 (7-229) mg/g. 55,7% of the patients met the definition of progressor at baseline (initial-progressors), 26,3% were progressors after a 12-month follow-up and 13,4% after 24 months. 21,2% and 11,4% of initial-progressors met this definition at 12 and 24 month follow up. The main risk factor for progression was albuminuria. No relationship was found between the nephrologist intervention and the evolution of renal function among initial non-progressors. Conclusion: Elderly patients who have stable renal function at the time of referral will continue to have stable renal function over the subsequent 24 months and thus may not need to be referred to a nephrologist.

Subacute cutaneous lupus erythematosus following ribociclib therapy for metastatic breast cancer.

INTRODUCTION: Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) has been associated with drugs with different mechanisms of action, including anti-hypertensives, tumour necrosis factor-α inhibitors and even some chemotherapy medicines. In the last years, a few reports have been described in patients treated with cyclin-dependent kinase (CDK) 4/6 inhibitors, palbociclib and abemaciclib. CASE REPORT: Here, we describe a case of DI-SCLE in association with ribociclib and exemestane in a woman diagnosed with metastatic breast cancer. MANAGEMENT AND OUTCOME: Topical mometasone was prescribed for two weeks with complete resolution of lesions, also abemaciclib was substituted for ribociclib, and the patient had stable disease with no relapse of DI-SCLE. DISCUSSION: To our knowledge, this is the first report of ribociclib-induced SCLE but based on the DI-SCLE reported cases associated others CDK4/6 inhibitors, the role of this family of drugs in dermatopathology must be further investigated.

Thrombotic microangiopathy in patients with malignant hypertension.

BACKGROUND: Thrombotic microangiopathy (TMA) is a complication of malignant hypertension (mHTN) attributed to high blood pressure (BP). However, no studies have investigated in patients with mHTN of different aetiologies whether the presence of TMA is associated with specific causes of mHTN. METHODS: We investigated the presence of TMA (microangiopathic haemolytic anaemia and thrombocytopenia) in a large and well-characterized cohort of 199 patients with mHTN of different aetiologies [primary HTN 44%, glomerular diseases 16.6%, primary atypical haemolytic uraemic syndrome (aHUS) 13.1%, renovascular HTN 9.5%, drug-related HTN 7%, systemic diseases 5.5%, endocrine diseases 4.5%]. Outcomes of the study were kidney recovery and kidney failure. RESULTS: Patients with TMA [40 cases (20.1%)] were younger, were more likely female and had lower BP levels and worse kidney function at presentation. Their underlying diseases were primary aHUS (60%), drug-related mHTN (15%), glomerular diseases [all of them immunoglobulin A nephropathy (IgAN); 10%], systemic diseases (10%) and primary HTN (5%). The presence of TMA was 92.3% in primary aHUS, 42.9% in drug-related HTN, 36.4% in systemic diseases, 12.1% in glomerular diseases and 2.3% in primary HTN. No patient with renovascular HTN or mHTN caused by endocrine diseases developed TMA, despite BP levels as high as patients with TMA. A higher proportion of TMA patients developed kidney failure as compared with patients without TMA (56.4% versus 38.9%, respectively). CONCLUSIONS: The presence of TMA in patients with mHTN should guide the diagnosis towards primary aHUS, drug-related mHTN, some systemic diseases and IgAN, while it is exceptional in other causes of mHTN.

Rational use of eculizumab in secondary atypical hemolytic uremic syndrome.

Background: Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in secondary aHUS, since the two main series that investigated this subject showed discrepant results. Our work aims to reassess the efficacy of eculizumab in treating secondary aHUS. Methods: Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 23 patients diagnosed with secondary aHUS who received treatment with eculizumab and compared them with a control cohort of 14 patients. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets. Results: We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 52.3% of patients and partial in 23.8%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (90.9% in the eculizumab cohort and 85.7% in the control cohort). Conclusion: Early and short-term use of eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, assuring better renal recovery compared to patients who do not receive complement blockade.

Cardiac monitoring during trastuzumab therapy in metastatic breast cancer: early incidence of cardiac dysfunction.

Trastuzumab therapy has dramatically changed breast cancer prognosis. Consensus documents recommend a close monitoring during therapy, not always feasible, especially in metastatic breast cancer. The purpose of this study is to describe trastuzumab cardiotoxicity in metastatic breast cancer patients to understand how to improve cardiovascular monitoring. We retrospectively studied metastatic breast cancer patients scheduled for trastuzumab therapy (2001-2018). All patients underwent a baseline evaluation and monitoring during therapy. Cardiotoxicity was defined as symptomatic heart failure or asymptomatic decrease in left ventricular ejection fraction > 10% from baseline and < 53%. Ninety-two women were included, mean age 61 years (±14.43), median follow-up 42.5 months (IQR 26-74). Fourteen percent developed cardiotoxicity:  two heart failure with preserved left ventricular ejection fraction, three heart failure with reduced left ventricular ejection fraction, and eight asymptomatic decreased in left ventricular ejection fraction. Eighty-one percent of cardiac dysfunction cases occurred within the first 4 years and on median of 31 months from trastuzumab initiation. Thus, in metastatic breast cancer patients, trastuzumab-mediated cardiotoxicity occurred more frequently during the first 4 years. These data should be considered to optimize follow-up protocols.

Cardiovascular risk factors during cancer treatment. Prevalence and prognostic relevance: insights from the CARDIOTOX registry.

AIMS: The actual usefulness of cardiovascular (CV) risk factor assessment in the prognostic evaluation of cancer patients treated with cardiotoxic treatment remains largely unknown. Prospective multicentre study in patients scheduled to receive anticancer therapy related with moderate/high cardiotoxic risk. METHODS AND RESULTS: A total of 1324 patients underwent follow-up in a dedicated cardio-oncology clinic from April 2012 to October 2017. Special care was given to the identification and control of CV risk factors. Clinical data, blood samples, and echocardiographic parameters were prospectively collected according to protocol, at baseline before cancer therapy and then at 3 weeks, 3 months, 6 months, 1 year, 1.5 years, and 2 years after initiation of cancer therapy. At baseline, 893 patients (67.4%) presented at least one risk factor, with a significant number of patients newly diagnosed during follow-up. Individual risk factors were not related with worse prognosis during a 2-year follow-up. However, a higher Systemic Coronary Risk Estimation (SCORE) was significantly associated with higher rates of severe cardiotoxicity (CTox) and all-cause mortality [hazard ratio (HR) 1.79 (95% confidence interval, CI 1.16-2.76) for SCORE 5-9 and HR 4.90 (95% CI 2.44-9.82) for SCORE ≥10 when compared with patients with lower SCORE (0-4)]. CONCLUSIONS: This large cohort of patients treated with a potentially cardiotoxic regimen showed a significant prevalence of CV risk factors at baseline and significant incidence during follow-up. Baseline CV risk assessment using SCORE predicted severe CTox and all-cause mortality. Therefore, its use should be considered in the evaluation of cancer patients.

Consulta monográfica de onconefrología. Justificación y puesta en marcha / Monographic consultation of onconephrology. Rationale and implementation

El incremento de la demanda asistencial por afección renal asociada a enfermedades neoplásicas es una realidad en la mayoría de los servicios de nefrología. Para dar respuesta a esta situación, debe considerarse la creación de modelos asistenciales como consultas monográficas y desarrollar programas de formación en onconefrología que permitan optimizar la atención de estos pacientes. A través de un estudio exploratorio y descriptivo, identificamos cuál es la situación actual de la afectación renal en pacientes con cáncer. El objetivo del presente estudio es establecer los criterios para la asistencia específica en el ámbito de la onconefrología. Para ello hemos revisado aspectos clave y analizado la situación actual en nuestro entorno, mediante una encuesta dirigida a todos los nefrólogos a través de la SEN, junto a la experiencia de 2 centros españoles. A partir de esta información hemos establecido una serie de requisitos y recomendaciones para la puesta en marcha de estas consultas

The increase in demand for medical care for renal complications associated with neoplastic diseases is a reality in most nephrology departments. In response to this overall situation, the creation of healthcare models such as monographic consultations and develop training programs in onconephrology could improve the care of these patients. Through an exploratory and descriptive study, we identified current situation of kidney involvement in cancer patients. The objective of the present study is to establish the criteria for specific assistance in the field of onconephrology. For this, we have reviewed key aspects and analyzed the current situation in our country, through a survey addressed to all nephrologists through the Spanish Society of Nephrology, together with the experience of 2 Spanish centers. From this information, we have established some requirements and recommendations for the start-up of these consultations

Pre-emptive rituximab in focal and segmental glomerulosclerosis patients at risk of recurrence after kidney transplantation.

BACKGROUND: The recurrence of proteinuria after kidney transplantation (KT) is a characteristic complication of focal segmental glomerulosclerosis (FSGS). It has been suggested that pre-emptive rituximab might prevent recurrences in patients at risk, but there is no agreement about which factors might help to identify such patients. METHODS: We studied 93 kidney transplants with biopsy-proven idiopathic FSGS in order to analyse if preventive rituximab treatment could decrease recurrences in patients at risk. RESULTS: Fifteen patients (16.1%) presented a recurrence after KT, but when we restricted the analysis to the 34 patients presenting nephrotic syndrome at primary disease onset, the recurrence diagnosis rate increased to 44.1%. All patients with recurrence had complete nephrotic syndrome at the time of diagnosis. After multivariate adjustment, the only significant risk factor for recurrence was the presence of complete nephrotic syndrome at diagnosis. Twelve of the 34 patients at risk for recurrence received rituximab at the time of transplantation. Clinical and analytical characteristics were similar in all patients at risk. The number of recurrences was similar among treated (50%) and non-treated patients (40.9%). CONCLUSIONS: Nephrotic syndrome with hypoalbuminaemia at diagnosis is the most important feature to identify patients at risk of recurrence. Our data suggest that pre-emptive rituximab is not effective to prevent FSGS recurrences.

Monographic consultation of onconephrology. Rationale and implementation.

The increase in demand for medical care for renal complications associated with neoplastic diseases is a reality in most nephrology departments. In response to this overall situation, the creation of healthcare models such as monographic consultations and develop training programs in Onconephrology could improve the care of these patients. Through an exploratory and descriptive study, we identified current situation of kidney involvement in cancer patients. The objective of the present study is to establish the criteria for specific assistance in the field of Onconephrology. For this, we have reviewed key aspects and analyzed the current situation in our country, through a survey addressed to all nephrologists through the Spanish Society of Nephrology., together with the experience of two Spanish centers. From this information, we have established some requirements and recommendations for the start-up of these consultations.

Monographic consultation of onconephrology. Rationale and implementation. / Consulta monográfica de onconefrología. Justificación y puesta en marcha.

The increase in demand for medical care for renal complications associated with neoplastic diseases is a reality in most nephrology departments. In response to this overall situation, the creation of healthcare models such as monographic consultations and develop training programs in onconephrology could improve the care of these patients. Through an exploratory and descriptive study, we identified current situation of kidney involvement in cancer patients. The objective of the present study is to establish the criteria for specific assistance in the field of onconephrology. For this, we have reviewed key aspects and analyzed the current situation in our country, through a survey addressed to all nephrologists through the Spanish Society of Nephrology, together with the experience of 2 Spanish centers. From this information, we have established some requirements and recommendations for the start-up of these consultations.

Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.

AIM: Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking. METHODS AND RESULTS: We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P < 0.001). CONCLUSIONS: The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

Microangiopatía trombótica como recidiva de síndrome antifosfolípido en trasplante renal / Primary antiphospholipid syndrome presented as thrombotic microangiopathy in renal transplantation

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First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial.

PURPOSE: The phase 3 MONALEESA-2 study demonstrated that addition of ribociclib (RIB) to letrozole (LET) significantly improved progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Here, we evaluated duration of response (DoR), tumor shrinkage, PFS by treatment-free interval (TFI), and health-related quality of life (HRQoL). METHODS: Postmenopausal women (N = 668) with HR+ , HER2- ABC and no prior systemic therapy for ABC were randomized to RIB (600 mg/day; 3 weeks on/1 week off) plus LET (2.5 mg/day; continuous) or placebo (PBO) plus LET. Primary end point was PFS; HRQoL was the secondary end point; DoR was exploratory end point and PFS by TFI was post hoc analysis. RESULTS: Of 501 pts with measurable disease and confirmed complete or partial response, median DoR was 26.7 months (95% CI, 24.0-NR) in the RIB arm versus 18.6 months (95% CI, 14.8-23.1) in the PBO arm. At 8 weeks, more pts in the RIB arm (32%) versus the PBO arm (17%) experienced best percentage change ≥ 60%. The average pain reduction was greater in the RIB arm (26%) versus the PBO arm (15%). PFS benefit was seen with RIB vs PBO, irrespective of TFI. CONCLUSION: RIB plus LET versus PBO plus LET is associated with earlier and more durable tumor response, greater degree of tumor shrinkage and pain reduction, and PFS benefit irrespective of TFI. These data further support RIB plus LET as a first-line treatment option for postmenopausal women with HR+ , HER2- ABC.