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.

SARS-CoV-2-Spike Antibody and T-Cell Responses Elicited by a Homologous Third mRNA COVID-19 Dose in Hemodialysis and Kidney Transplant Recipients.

The effect of a third vaccine dose (3D) of homologous mRNA vaccine on blood levels of SARS-CoV-2-receptor binding domain (RBD)-total antibodies was assessed in 40 hemodialysis patients (HD) and 21 kidney transplant recipients (KTR) at a median of 46 days after 3D. Anti-RBD antibodies were detected in 39/40 HD and 19/21 KTR. Overall, 3D boosted anti-RBD antibody levels (median: 58-fold increase). Neutralizing antibodies (NtAb) against the Wuhan-Hu-1, Delta, and Omicron variants were detected in 14, 13, and 11 out of 14 HD patients, and in 5, 5, and 4 out of 8 KTR patients, respectively. The median fold increase in NtAb titers in HD patients was 77, 28, and 5 and 56, 37, and 9 in KTR patients for each respective variant. SARS-CoV-2-S S-IFN-γ-producing CD8+ and CD4+ T-cell responses were detected in the majority of HD (35 and 36/37, respectively) and all KTR (16/16) patients at 3D. Overall, the administration of 3D boosted T-cell levels in both population groups. In conclusion, a homologous mRNA COVID-19 vaccine 3D exerts a booster effect on anti-RBD antibodies, NtAb binding to Wuhan-Hu-1, Delta, and Omicron variants, and SARS-CoV-2-S-IFN-γ-producing T cells in both HD and KTR patients. The magnitude of the effect was more marked in HD than KTR patients.

Renal Histologic Findings in Necropsies of Type 2 Diabetes Mellitus Patients.

Background: Very few studies have analyzed early histologic lesions of diabetic nephropathy (DN) in patients without signs of clinical involvement (microalbuminuria). In this study, we analyzed renal histologic lesions in necropsies of diabetic patients with or without previous signs of DN. Methods: Histological material was analyzed from 21 autopsies of type 2 diabetes mellitus (T2DM) patients (9 with albuminuria and 12 without albuminuria) and 4 controls. Histologic lesions were evaluated according to the Tervaert classification. Results: Kidneys of diabetic patients presented significantly higher scores in most histologic indices analyzed (glomerular basal membrane thickening, mild and severe mesangial expansion, nodular sclerosis, interstitial fibrosis, and tubular atrophy) than in nondiabetic controls (p < 0.01 in all cases). In contrast, no significant differences were detected between histologic scores when comparing the 21 diabetic patients with and without albuminuria. A significant percentage of cases without albuminuria showed moderate to severe histologic lesions, particularly severe mesangial expansion and severe glomerular vascular lesions. No significant differences were found in age, blood pressure, diabetes vintage, BMI, HbA1c, cholesterol, triglycerides, or treatments between the two (albuminuric vs. nonalbuminuric) T2DM patient groups. Conclusions: Our data suggest that histologic lesions of DN are present in the early stages of the disease, even without albuminuria presence. More precise and earlier metabolic control is recommended in T2DM, and monitoring of risk factors can play a role in DN development.

Dynamics of SARS-CoV-2-Spike-reactive antibody and T-cell responses in chronic kidney disease patients within 3 months after COVID-19 full vaccination.

Background: Little is known regarding the dynamics of antibody and T-cell responses in chronic kidney disease (CKD) following coronavirus disease 2019 (COVID-19) vaccination. Methods: Prospective observational cohort study including 144 participants on haemodialysis (HD) (n = 52) or peritoneal dialysis (PD) (n = 14), those undergoing kidney transplantation (KT) (n = 30) or those with advanced CKD (ACKD) not on dialysis and healthy controls (n = 18). Anti-Spike (S) antibody and T-cell responses were assessed at 15 days (15D) and 3 months (3M) after complete vaccination schedule. HD, PD and KT patients received mRNA vaccines (mRNA-123 and BNT162b2). Most ACKD patients received BNT162b2 (n = 23), or Ad26.COV.2.S (4). Most controls received BNT162b2 (n = 12), or Ad26.COV.2.S (n = 5). Results: Anti-S antibodies at 15D and 3M were detectable in 95% (48/50)/98% (49/50) of HD patients, 93% (13/14)/100% of PD patients, 67% (17/26)/75% (21/28) of KT patients and 96% (25/26)/100% (24/24) of ACKD patients. Rates for healthy controls were 81% (13/16)/100% (17/17). Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2-S) infection was documented in four (7.7%) HD patients, two (14.3%) PD patients, two (6.7%) KT patients, one (5.55%) healthy control and in no ACKD patient. Antibody levels decreased at 3M in HD (P = .04), PD (P = .008) and ACKD patients (P = .0009). In KT patients, levels increased (P = .04) between 15D and 3M, although they were low at both time points.T-cell responses were detected in HD patients in 37 (80%) at baseline, 35 (70%) at 15D and 41 (91%) at 3M. In PD patients, T-cell responses appeared in 8 (67%) at baseline, 13 (93%) at 15D and 9 (100%) at 3M. In KT patients, T-cell responses were detected in 12 (41%) at baseline, 22 (84%) at 15D and 25 (96%) at 3M. In ACKD patients, T-cell responses were detected in 13 (46%) at baseline, 20 (80%) at 15D and 17 (89%) at 3M. None of healthy controls showed T-cell response at baseline, 10 (67%) at 15D and 8 (89%) at 3M. Conclusions: Most HD, PD and ACKD patients develop SARS-CoV-2-S antibody responses comparable to that of healthy controls, in contrast to KT recipients. Antibody waning at 3M was faster in HD, PD and ACKD patients. No differences in SARS-CoV-2 T-cell immunity responses were noticed across study groups.

Oxidative Stress in Non-Dialysis-Dependent Chronic Kidney Disease Patients.

BACKGROUND: Cardiovascular complications are the leading cause of morbidity and mortality at any stage of chronic kidney disease (CKD). Moreover, the high rate of cardiovascular mortality observed in these patients is associated with an accelerated atherosclerosis process that likely starts at the early stages of CKD. Thus, traditional and non-traditional or uremic-related factors represent a link between CKD and cardiovascular risk. Among non-conventional risk factors, particular focus has been placed on anaemia, mineral and bone disorders, inflammation, malnutrition and oxidative stress and, in this regard, connections have been reported between oxidative stress and cardiovascular disease in dialysis patients. METHODS: We evaluated the oxidation process in different molecular lines (proteins, lipids and genetic material) in 155 non-dialysis patients at different stages of CKD and 45 healthy controls. To assess oxidative stress status, we analyzed oxidized glutathione (GSSG), reduced glutathione (GSH) and the oxidized/reduced glutathione ratio (GSSG/GSH) and other oxidation indicators, including malondialdehyde (MDA) and 8-oxo-2'-deoxyguanosine (8-oxo-dG). RESULTS: An active grade of oxidative stress was found from the early stages of CKD onwards, which affected all of the molecular lines studied. We observed a heightened oxidative state (indicated by a higher level of oxidized molecules together with decreased levels of antioxidant molecules) as kidney function declined. Furthermore, oxidative stress-related alterations were significantly greater in CKD patients than in the control group. CONCLUSIONS: CKD patients exhibit significantly higher oxidative stress than healthy individuals, and these alterations intensify as eGFR declines, showing significant differences between CKD stages. Thus, future research is warranted to provide clearer results in this area.

IgA-Dominant Infection-Associated Glomerulonephritis Following SARS-CoV-2 Infection.

The renal involvement of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported. The etiology of kidney injury appears to be tubular, mainly due to the expression of angiotensin-converting enzyme 2, the key joint receptor for SARS-CoV-2; however, cases with glomerular implication have also been documented. The multifactorial origin of this renal involvement could include virus-mediated injury, cytokine storm, angiotensin II pathway activation, complement dysregulation, hyper-coagulation, and microangiopathy. We present the renal histological findings from a patient who developed acute kidney injury and de novo nephrotic syndrome, highly suggestive of acute IgA-dominant infection-associated glomerulonephritis (IgA-DIAGN) after SARS-CoV-2 infection, as evidenced by the presence of this virus detected in the renal tissue of the patient via immunohistochemistry assay. In summary, we document the first case of IgA-DIAGN associated to SARS-CoV-2. Thus, SARS-CoV-2 S may act as a super antigen driving the development of multisystem inflammatory syndrome as well as cytokine storm in patients affected by COVID-19, reaching the glomerulus and leading to the development of this novel IgA-DIAGN.

Onco-Nephrology: Cancer, chemotherapy and kidney. / Onco-Nefrología: cáncer, quimioterapia y riñón.

Chronic kidney disease (CKD), cancer and haematological diseases share areas of reciprocal influence. Cancer can affect the kidney either as glomerular lesions or as a result of the toxic effects of medication or radiation with acute (thrombotic microangiopathy, acute kidney injury, interstitial nephropathies among others) or chronic processes (worsening of CKD after nephrectomy due to renal cancer, interstitial fibrosis, hydroelectrolytic disorders). On the other hand, patients who require renal replacement therapy with dialysis and particularly with kidney transplantation are at high risk of onset of cancer due to the immunosuppression situation that they generate. In addition to conventional chemotherapy, innovative treatments have been developed: target agents against growth factors and their receptor; anti-angiogenic drugs; immunoregulatory proteins; cell cycle regulators; and enzyme inhibitors. Other immunotherapeutic approaches have also been developed, such as vaccines, adoptive cell therapy (CAR T cells) or development of antibodies. All these therapeutic advances will improve the outcomes against cancer and haematological diseases, but they are not free from secondary renal problems. Onco-Nephrology is already an important area for the Spanish Society of Nephrology with a large number of inter-consultations. Nephrologists need a better understanding of rapidly evolving areas of cancer biology and its treatment in order to become valued members of the cancer care team and to provide the best nephrology care possible.

Learning and Memory Impairments in Patients with Minimal Hepatic Encephalopathy are Associated with Structural and Functional Connectivity Alterations in Hippocampus.

Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with alterations in attentional and executive networks. There are no studies evaluating the relationship between memory in MHE and structural and functional connectivity (FC) changes in the hippocampal system. This study aimed to evaluate verbal learning and long-term memory in cirrhotic patients with (C-MHE) and without MHE (C-NMHE) and healthy controls. We assessed the relationship between alterations in memory and the structural integrity and FC of the hippocampal system. C-MHE patients showed impairments in learning, long-term memory, and recognition, compared to C-NMHE patients and controls. Cirrhotic patients showed reduced fimbria volume compared to controls. Larger volumes in hippocampus subfields were related to better memory performance in C-NMHE patients and controls. C-MHE patients presented lower FC between the L-presubiculum and L-precuneus than C-NMHE patients. Compared to controls, C-MHE patients had reduced FC between L-presubiculum and subiculum seeds and bilateral precuneus, which correlated with cognitive impairment and memory performance. Alterations in the FC of the hippocampal system could contribute to learning and long-term memory impairments in C-MHE patients. This study demonstrates the association between alterations in learning and long-term memory and structural and FC disturbances in hippocampal structures in cirrhotic patients.

Urinary Klotho measured by ELISA as an early biomarker of acute kidney injury in patients after cardiac surgery or coronary angiography.

BACKGROUND: Acute kidney injury (AKI) is a common complication after cardiac surgery and percutaneous coronary interventions which markedly worsens prognosis. In recent years, new early biomarkers of AKI have been identified, but many important aspects still remain to be solved. Klotho is a pleiotropic protein that acts as a paracrine and endocrine factor in multiple organs. Reduced renal Klotho levels have been show in several animal models of AKI. No study has been published in which Klotho was tested in humans as an early marker of AKI. The aim of this work is to assess the usefulness of measuring urinary Klotho for the early diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography. METHODS: Urinary Klotho was measured 12 hours after intervention in 60 patients admitted to the Intensive Care Unit with acute coronary syndrome or heart failure secondary to coronary or valvular conditions, who underwent coronary angiography (30 patients) or cardiac bypass surgery or heart valve replacement (30 patients). The primary endpoint used was the onset of AKI according to the RIFLE classification system. Human Klotho levels were measured using an ELISA assay. RESULTS: We found no differences in urinary Klotho levels between AKI patients and those who did not develop AKI. Moreover, there was not significant correlation between urinary Klotho levels and the presence of AKI. CONCLUSION: Urinary Klotho measured by ELISA does not seem to be a good candidate to be used as an early biomarker of AKI.

Urinary KIM-1, NGAL and L-FABP for the diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing coronary angiography.

Acute kidney injury (AKI) is a common complication after coronary angiography. Early biomarkers of this disease are needed since increase in serum creatinine levels is a late marker. To assess the usefulness of urinary kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL) and liver-type fatty acid-binding protein (uL-FABP) for early detection of AKI in these patients, comparing their performance with another group of cardiac surgery patients. Biomarkers were measured in 193 patients, 12 h after intervention. In the ROC analysis, AUC for KIM-1, NGAL and L-FABP was 0.713, 0.958 and 0.642, respectively, in the coronary angiography group, and 0.716, 0.916 and 0.743 in the cardiac surgery group. Urinary KIM-1 12 h after intervention is predictive of AKI in adult patients undergoing coronary angiography, but NGAL shows higher sensitivity and specificity. L-FABP provides inferior discrimination for AKI than KIM-1 or NGAL in contrast to its performance after cardiac surgery. This is the first study showing the predictive capacity of KIM-1 for AKI after coronary angiography. Further studies are still needed to answer relevant questions about the clinical utility of biomarkers for AKI in different clinical settings.

Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

Study of oxidative stress in patients with advanced renal disease and undergoing either hemodialysis or peritoneal dialysis.

Oxidative stress (OS) is directly involved in the formation of atheroma plaque and has been shown to be present since the early stages of Chronic Kidney Disease (CKD); however, the net role that dialytica techniques may play in OS process is yet to be determined. We studied three groups: hemodialysis (HD, n = 30), peritoneal dialysis (PD, n = 31), predialysis (pre-D, n = 32), and one control group (C, n = 67). Using highresolution liquid chromatography columns (HPLC), the superoxide dismutase (SOD), glutathione oxidized/reduced ratio (GSSG/GSH), and nuclear, as well as mitochondrial 8-oxo-dG (8-oxo-dG mit) were measured in lymphocytes. Protein carbonyls and F2-isoprostanes were measured in plasma. The antioxidant enzyme activity was evaluated by a spectrophotometric assay of catalase, glutathione peroxidase (GPX), glutathione reductase (GSR), and superoxide dismutase (SOD). Compared to the control group, all groups had significantly higher levels of products derived from molecular oxidation with a significant decrease in antioxidant enzymes. Patients in the pre-D group showed higher values for most of the oxidized molecules. The PD group showed a better oxidative balance, with no significant differences in levels of mitochondrial 8-oxo-dG when compared to the control group. We speculated that the better control of OS observed in patients receiving PD might be explained by the fact that this technique is more biocompatible, and this might help reduce the risk of cardiovascular events.

Echocardiographic impact of hydration status in dialysis patients.

INTRODUCTION: Cardiovascular disease is the main cause of death in Chronic Kidney Disease patients. Left ventricular hypertrophy is the most common manifestation and it is linked to arterial hypertension and overhydration. The goal of this paper is to stratify dialyzed patients according to hydration status and to make an evaluation about the possible echocardiography alterations of the different groups. METHODS: A transversal study was carried out with 117 patients: 65 were on hemodialysis and 52 on peritoneal dialysis. We performed the following tests: multifrequency bioimpedance with the BCM-Body Composition Freesenius' Monitor system, transthoracic echocardiography, and blood tests. If ECW/TBW (extracellular water vs total body water) normalization ratio for age and gender was > 2.5% SD, the patient was considered overhydrated. RESULTS: HD patients are significantly overhydrated before HD (67.1%) compared to DP patients (46.1%), and almost half of the overhydrated population presents arterial hypertension. However, after an HD session, a better control of the hydration status is reached (26.1%). DP patients frequently present high arterial pressure and/or are under antihypertensive treatment (DP 76.9% vs HD 49.2%). Left ventricular hypertrophy is much more common in HD overhydrated patients, eccentric LVH being more prevalent. Overhydrated patients present significantly high values of LAVI, ILVM, OH/ECW. CONCLUSIONS: Bioimpedance technique allows for the detection of a large number of overhydrated patients. Echocardiographic alterations in dialyzed patients show a high correlation between the hydration stage by ECW/TBW normalized ratio for age and gender and the LAVI and ILVM.

Early biomarkers of acute kidney failure after heart angiography or heart surgery in patients with acute coronary syndrome or acute heart failure.

BACKGROUND: Acute kidney injury (AKI) is a common complication in cardiac surgery and coronary angiography, which worsens patients' prognosis. The diagnosis is based on the increase in serum creatinine, which is delayed. It is necessary to identify and validate new biomarkers that allow for early and effective interventions. AIMS: To assess the sensitivity and specificity of neutrophil gelatinase-associated lipocalin in urine (uNGAL), interleukin-18 (IL-18) in urine and cystatin C in serum for the early detection of AKI in patients with acute coronary syndrome or heart failure, and who underwent cardiac surgery or catheterization. METHODS: The study included 135 patients admitted to the intensive care unit for acute coronary syndrome or heart failure due to coronary or valvular pathology and who underwent coronary angiography or cardiac bypass surgery or valvular replacement. The biomarkers were determined 12 hours after surgery and serum creatinine was monitored during the next six days for the diagnosis of AKI. RESULTS: The area under the ROC curve (AUC) for NGAL was 0.983, and for cystatin C and IL-18 the AUCs were 0.869 and 0.727, respectively. At a cut-off of 31.9 ng/ml for uNGAL the sensitivity was 100% and the specificity was 91%. CONCLUSIONS: uNGAL is an early marker of AKI in patients with acute coronary syndrome or heart failure and undergoing cardiac surgery and coronary angiography, with a higher predictive value than cystatin C or IL-18.

Estimated Glomerular Filtration Rate in Short-Risk Stratification in Acute Myocardial Infarction.

BACKGROUND/AIMS: Renal dysfunction is associated with a higher risk of cardiovascular disease in patients with acute myocardial infarction (AMI). The aim of this study was to investigate the independent prognostic value of renal dysfunction and its incremental predictability risk after adjusting for well-known clinical factors in patients with AMI. METHODS: 751 consecutive patients with AMI admitted to the Coronary Care Unit (CCU) were included. Patients were grouped into 2 categories according to the baseline estimated glomerular filtration rate (eGFR) on admission (eGFR <60 vs. eGFR ≧60 ml/min/1.73 m2). C-reactive protein and white blood cell count (WBC) as well as clinical prognostic variables were assessed. The endpoint was mortality during CCU stay. The discriminatory power was estimated by the C-index. RESULTS: The patient group with an eGFR <60 ml/min/1.73 m2 was older, had more cardiovascular risk factors, a lower left ventricular ejection fraction and higher cardiovascular mortality during CCU stay (13 vs. 3%). Logistic regression analysis revealed the following predictors of mortality: degree of renal impairment (eGFR <60 ml/min/1.73 m2), hazard ratio (HR) = 2.2 (95% CI 1.1-4.3; p = 0.028); WBC >11,000 × 106/l, HR = 2.3 (95% CI 1.2-4.5; p = 0.017); Killip class on admission, HR = 3.8 (95% CI 1.7-8.5; p = 0.001), and New York Heart Association Functional Classification, HR = 3.6 (95% CI 1.7-7.4; p = 0.001). The adjusted C-index was 0.78 for baseline clinical variables and 0.84 for eGFR. CONCLUSIONS: In patients with AMI, decreased eGFR is an important prognostic factor for impaired cardiac function and mortality in the short-term follow-up. The eGFR may be reliably used in the risk stratification of patients with AMI.

New mutation in female patient with renal variant of Fabry disease and HIV.

We describe the case of a 27-year-old woman with a family history of Anderson-Fabry disease (AFD). Urinary sediment presented microhematuria and 0.9 g/24 hours proteinuria. The alpha-galactosidase A measurement in fibroblasts showed partial deficit of the enzyme, which was compatible with being a carrier of the illness. Renal biopsy gave evidence of kidney lesions from Fabry disease. Genetic study revealed mutation C52Y or Cys52Tyr, which has not been previously described and had also been detected in the father of the patient. During follow-up, the presence of hypergammaglobulinemia revealed an underlying HIV disease. She is now awaiting enzymatic substitution treatment.