Hair cortisol and changes in cortisol dynamics in chronic kidney disease.

Objective: We compared hair cortisol (HC) with classic tests of the hypothalamic-pituitary-adrenal (HPA) axis in chronic kidney disease (CKD) and assessed its association with kidney and cardiometabolic status. Design and methods: A cross-sectional study of 48 patients with CKD stages I-IV, matched by age, sex, and BMI with 24 healthy controls (CTR) was performed. Metabolic comorbidities, body composition, and HPA axis function were studied. Results: A total of 72 subjects (age 52.9 ± 12.2 years, 50% women, BMI 26.2 ± 4.1 kg/m2) were included. Metabolic syndrome features (hypertension, dyslipidaemia, glucose, HOMA-IR, triglycerides, waist circumference) and 24-h urinary proteins increased progressively with worsening kidney function (p < 0.05 for all). Reduced cortisol suppression after 1-mg dexamethasone suppression (DST) (p < 0.001), a higher noon (12:00 h pm) salivary cortisol (p = 0.042), and salivary cortisol AUC (p = 0.008) were seen in CKD. 24-h urinary-free cortisol (24-h UFC) decreased in CKD stages III-IV compared with I-II (p < 0.001); higher midnight salivary cortisol (p = 0.015) and lower suppressibility after 1-mg DST were observed with declining kidney function (p < 0.001). Cortisol-after-DST cortisol was >2 mcg/dL in 23% of CKD patients (12.5% in stage III and 56.3% in stage IV); 45% of them had cortisol >2 mcg/dL after low-dose 2-day DST, all in stage IV (p < 0.001 for all). Cortisol-after-DST was lineally inversely correlated with eGFR (p < 0.001). Cortisol-after-DST (OR 14.9, 95% CI 1.7-103, p = 0.015) and glucose (OR 1.3, 95% CI 1.1-1.5, p = 0.003) were independently associated with eGFR <30 mL/min/m2). HC was independently correlated with visceral adipose tissue (VAT) (p = 0.016). Cortisol-after-DST (p = 0.032) and VAT (p < 0.001) were independently correlated with BMI. Conclusion: Cortisol-after-DST and salivary cortisol rhythm present progressive alterations in CKD patients. Changes in cortisol excretion and HPA dynamics in CKD are not accompanied by significant changes in long-term exposure to cortisol evaluated by HC. The clinical significance and pathophysiological mechanisms explaining the associations between HPA parameters, body composition, and kidney damage warrant further study.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Impact of cardiac surgery associated acute kidney injury on 1-year major adverse kidney events.

Background: The incidence of acute kidney injury following cardiac surgery (CSA-AKI) is up to 30%, and the risk of chronic kidney disease (CKD) has been found to be higher in these patients compared to the AKI-free population. The aim of our study was to assess the risk of major adverse kidney events (MAKE) [25% or greater decline in estimated glomerular filtration rate (eGFR), new hemodialysis, and death] after cardiac surgery in a Spanish cohort and to evaluate the utility of the score developed by Legouis D et al. (CSA-CKD score) in predicting the occurrence of MAKE. Methods: This was a single-center retrospective study of patients who required cardiac surgery with cardiopulmonary bypass (CPB) during 2015, with a 1-year follow-up after the intervention. The inclusion criteria were patients over 18 years old who had undergone cardiac surgery [i.e., valve substitution (VS), coronary artery bypass graft (CABG), or a combination of both procedures]. Results: The number of patients with CKD (eGFR < 60 mL/min) increased from 74 (18.3%) to 97 (24%) within 1 year after surgery. The median eGFR declined from 85 to 82 mL/min in the non-CSA-AKI patient group and from 73 to 65 mL/min in those with CSA-AKI (p = 0.024). Fifty-eight patients (1.4%) presented with MAKE at the 1-year follow-up. Multivariate logistic regression analysis showed that the only variable associated with MAKE was CSA-AKI [odds ratio (OR) 2.386 (1.31-4.35), p = 0.004]. The median CSA-CKD score was higher in the MAKE cohort [3 (2-4) vs. 2 (1-3), p < 0.001], but discrimination was poor, with a receiver operating characteristic curve (AUC) value of 0.682 (0.611-0.754). Conclusion: Any-stage CSA-AKI is associated with a risk of MAKE after 1 year. Further research into new measures that identify at-risk patients is needed so that appropriate patient follow-up can be carried out.

Autosomal dominant polycystic kidney disease in young adults.

Background: The clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD) usually appear in adulthood, however pediatric series report a high morbidity. The objective of the study was to analyze the clinical characteristics of ADPKD in young adults. Methods: Family history, hypertension, albuminuria, estimated glomerular filtration rate (eGFR) and imaging tests were examined in 346 young adults (18-30 years old) out of 2521 patients in the Spanish ADPKD registry (REPQRAD). A literature review searched for reports on hypertension in series with more than 50 young (age <30 years) ADPKD patients. Results: The mean age of this young adult cohort was 25.24 (SD 3.72) years. The mean age at diagnosis of hypertension was 21.15 (SD 4.62) years, while in the overall REPQRAD population was aged 37.6 years. The prevalence of hypertension was 28.03% and increased with age (18-24 years, 16.8%; 25-30 years, 36.8%). Although prevalence was lower in women than in men, the age at onset of hypertension (21 years) was similar in both sexes. Mean eGFR was 108 (SD 21) mL/min/1.73 m2, 38.0% had liver cysts and 3.45% of those studied had intracranial aneurysms. In multivariate analyses, hematuria episodes and kidney length were independent predictors of hypertension (area under the curve 0.75). The prevalence of hypertension in 22 pediatric cohorts was 20%-40%, but no literature reports on hypertension in young ADPKD adults were found. Conclusions: Young adults present non-negligible ADPKD-related morbidity. This supports the need for a thorough assessment of young adults at risk of ADPKD that allows early diagnosis and treatment of hypertension.

Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage kidney disease. Currently, tolvaptan is the only treatment that has proven to delay disease progression. The most notable side effect of this therapy is drug-induced liver injury; however, recently, there have been two reports of creatine kinase (CK) elevation in ADPKD patients on tolvaptan treatment. We set out to monitor and determine the actual incidence of CK elevation and evaluate its potential association with other clinical factors. METHODS: This is an observational retrospective multicenter study performed in rapidly progressive ADPKD patients on tolvaptan treatment from Barcelona, Spain. Laboratory tests, demographics, treatment dose, and reported symptoms were collected from October 2018 to March 2021. RESULTS: Ninety-five patients initiated tolvaptan treatment during follow-up. The medication had to be discontinued in 31 (32.6%) patients, primarily due to aquaretic effects (12.6%), elevated liver enzymes (8.4%), and symptomatic or persistently elevated CK levels (3.2%). Moreover, a total of 27 (28.4%) patients had elevated CK levels, with most of them being either transient (12.6%), mild and asymptomatic (4.2%), or resolved after dose reduction (3.2%) or temporary discontinuation (2.1%). CONCLUSION: We pre-sent the largest cohort that has monitored CK levels in a real-life setting, finding them elevated in 28.4% of patients. More research and monitoring will help us understand the clinical implications and the pathophysiological mechanism of CK elevation in this population.

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.

Management of acute renal replacement therapy in critically ill cirrhotic patients.

Renal replacement therapy (RRT) in cirrhotic patients encompasses a number of issues related to the particular characteristics of this population, especially in the intensive care unit (ICU) setting. The short-term prognosis of cirrhotic patients with acute kidney injury is poor, with a mortality rate higher than 65% in patients with RRT requirement, raising questions about the futility of its initiation. Regarding the management of the RRT itself, there is still no consensus with respect to the modality (continuous versus intermittent) or the anticoagulation required to improve the circuit life, which is shorter than similar at-risk populations, despite the altered haemostasis in traditional coagulation tests frequently found in these patients. Furthermore, volume management is one of the most complex issues in this cohort, where tools used for ambulatory dialysis have not yet been successfully reproducible in the ICU setting. This review attempts to shed light on the management of acute RRT in the critically ill cirrhotic population based on the current evidence and the newly available tools. We will discuss the timing of RRT initiation and cessation, the modality, anticoagulation and fluid management, as well as the outcomes of the RRT in this population, and provide a brief review of the albumin extracorporeal dialysis from the point of view of a nephrologist.

Complement Mediated Endothelial Damage in Thrombotic Microangiopathies.

Thrombotic microangiopathies (TMA) constitute a group of different disorders that have a common underlying mechanism: the endothelial damage. These disorders may exhibit different mechanisms of endothelial injury depending on the pathological trigger. However, over the last decades, the potential role of the complement system (CS) has gained prominence in their pathogenesis. This is partly due to the great efficacy of complement-inhibitors in atypical hemolytic syndrome (aHUS), a TMA form where the primary defect is an alternative complement pathway dysregulation over endothelial cells (genetic and/or adquired). Complement involvement has also been demonstrated in other forms of TMA, such as thrombotic thrombocytopenic purpura (TTP) and in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), as well as in secondary TMAs, in which complement activation occurs in the context of other diseases. However, at present, there is scarce evidence about the efficacy of complement-targeted therapies in these entities. The relationship between complement dysregulation and endothelial damage as the main causes of TMA will be reviewed here. Moreover, the different clinical trials evaluating the use of complement-inhibitors for the treatment of patients suffering from different TMA-associated disorders are summarized, as a clear example of the entry into a new era of personalized medicine in its management.

The Density of Renal Lymphatics Correlates With Clinical Outcomes in IgA Nephropathy.

Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) worldwide. The disease course fluctuates, and the most important challenge is the considerable variation in the time lag between diagnosis and the development of a hard clinical end point, such as end-stage kidney disease (ESKD). The reaction of renal tissue to damage resembles the common wound-healing response. One part of this repair in IgAN is the expansion of lymphatic vessels known as lymphangiogenesis. The aim of this work was to establish the prognostic value of the density of lymphatic vessels in the renal biopsy at the time of diagnosis, for predicting the risk of ESKD in a Spanish cohort of patients with IgAN. Methods: We performed a retrospective multicenter study of 76 patients with IgAN. The end point of the study was progression to ESKD. The morphometric analysis of lymphatic vessels was performed on tissue sections stained with antipodoplanin antibody. Results: Density of lymphatic vessels was significantly higher in patients with IgAN with mesangial hypercellularity >50%, segmental sclerosis, higher degrees of interstitial fibrosis, and tubular atrophy. Patients with more lymphatic vessels had significantly higher values of proteinuria and lower estimated glomerular filtration rate (eGFR). A density of lymphatic vessels ≥8 per mm2 was associated with a significantly higher rate of progression to ESKD at 3 years from biopsy. After adjustment for the International IgAN prediction score, at the multivariate logistic regression, high density of lymphatic vessels (≥8 per mm2) remained significantly associated with a higher rate of early progression to ESKD. Conclusion: This study contributes to the understanding of the natural history of the progression to ESKD in patients with IgAN revealing the density of lymphatics vessels may optimize the prognostic value of the International IgA predicting tool to calculate the risk of ESKD, favoring the evaluation of new targeted therapies.

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.

Risk Factors for Acute Kidney Injury Following Cardiac Surgery and Performance of Leicester Score in a Spanish Cohort.

The incidence of acute kidney injury following cardiac surgery (CSA-AKI) is up to 30%, and it places patients at an increased risk of death. The Leicester score (LS) is a new score that predicts CSA-AKI of any stage with better discrimination compared to previous scores. The aim of this study was to identify risk factors for CSA-AKI and to assess the performance of LS. A unicentric retrospective study of patients that required cardiac surgery with cardio-pulmonary bypass (CPB) in 2015 was performed. The inclusion criteria were patients over 18 years old who were operated on for cardiac surgery (valve substitution (VS), Coronary Artery Bypass Graft (CABG), or a combination of both procedures and requiring CPB). CSA-AKI was defined with the Kidney Disease Improving Global Outcomes (KDIGO) criteria. In the multivariate analysis, hypertension (odds ratio 1.883), estimated glomerular filtration rate (EGFR) <60 mL/min (2.365), and peripheral vascular disease (4.66) were associated with the outcome. Both discrimination and calibration were better when the LS was used compared to the Cleveland Clinic Score and Euroscore II, with an area under the curve (AUC) of 0.721. In conclusion, preoperative hypertension in patients with CKD with or without peripheral vasculopathy can identify patients who are at risk of CSA-AKI. The LS was proven to be a valid score that could be used to identify patients who are at risk and who could benefit from intervention studies.

Results of a multidisciplinary strategy to improve the management of cardiovascular risk factors after liver transplantation.

Although liver transplantation (LT) recipients are at high cardiovascular risk (CVR), the management of CVR factors (CVRF) after LT is far from optimal and needs to be improved. For this reason, we developed a multidisciplinary protocol to standardize the identification, risk stratification, management, and targets of therapy of CVRF during the first post-LT year. The grade of identification and control of CVRF 12 months after LT in the postintervention cohort (LT January 2018-January 2020, n = 150) were compared with a control cohort who underwent LT between July 2015 and December 2016 (n = 100). Before LT, the prevalence of metabolic-associated fatty liver disease as the indication of LT and the presence of obesity were significantly higher in the postintervention cohort, whereas the prevalence of other CVRF and renal dysfunction tended to be higher. Cyclosporine A was used less frequently in the postintervention cohort, whereas everolimus tended to increase. At 12 months after LT, the proportion of patients with measured blood pressure (88% vs. 56%), glycosilated hemoglobin (HbA1c; 96% vs. 72%), and high-density lipoprotein/low-density lipoprotein cholesterol (67% vs. 33%) was higher in the postintervention than in the control cohort (all p < 0.001). Blood pressure (64% vs. 36%, p = 0.02) and HbA1c (85% vs. 70%, p = 0.1) were within target in more individuals with hypertension and diabetes mellitus, respectively, in the postintervention cohort. Median total cholesterol levels were lower in the postintervention (184 mg/dl; interquartile range [IQR], 160-210 mg/dl) than in the control cohort (212 mg/dl; IQR, 186-240 mg/dl; p = 0.02). At 2 years after LT, the incidence of cardiovascular events was 14% in the control cohort and 6% in the postintervention cohort (p = 0.063). In conclusion, a multidisciplinary, multiprofessional strategy can achieve a higher grade of assessment and management of post-LT CVR despite a worsening metabolic profile of LT recipients.

Cloudy fluid, cloudy diagnosis.

Here, we report a case of a patient with cloudy effluent that was initially diagnosed as bacterial peritonitis. The persistence of a cloudy effluent despite antibiotic therapy led to an extensive peritoneal dialysis (PD) effluent analysis, with the final diagnosis being high-grade B-cell lymphoma. This case will increase the awareness of this rare presentation of a lymphoproliferative disorder reminding clinicians to consider this diagnosis as a part of the differential diagnosis PD effluent.

The Interplay between Pathophysiological Pathways in Early-Onset Severe Preeclampsia Unveiled by Metabolomics.

INTRODUCTION: Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. The precise pathogenesis of this complex disorder is still unrevealed. METHODS: We examined the pathophysiological pathways involved in early-onset preeclampsia, a specific subgroup representing its most severe presentation, using LC-MS/MS metabolomic analysis based on multi-level extraction of lipids and small metabolites from maternal blood samples, collected at the time of diagnosis from 14 preeclamptic and six matched healthy pregnancies. Statistical analysis comprised multivariate and univariate approaches with the application of over representation analysis to identify differential pathways. RESULTS: A clear difference between preeclamptic and control pregnancies was observed in principal component analysis. Supervised multivariate analysis using orthogonal partial least square discriminant analysis provided a robust model with goodness of fit (R2X = 0.91, p = 0.002) and predictive ability (Q2Y = 0.72, p < 0.001). Finally, univariate analysis followed by 5% false discovery rate correction indicated 82 metabolites significantly altered, corresponding to six overrepresented pathways: (1) aminoacyl-tRNA biosynthesis; (2) arginine biosynthesis; (3) alanine, aspartate and glutamate metabolism; (4) D-glutamine and D-glutamate metabolism; (5) arginine and proline metabolism; and (6) histidine metabolism. CONCLUSION: Metabolomic analysis focusing specifically on the early-onset severe form of preeclampsia reveals the interplay between pathophysiological pathways involved in this form. Future studies are required to explore new therapeutic approaches targeting these altered metabolic pathways in early-onset preeclampsia.

Antiphospholipase A2 receptor antibody-positive membranous nephropathy in the kidney donor: Lessons from a serendipitous transplantation.

Primary membranous nephropathy (PMN) is an autoimmune disease limited to the kidney that is characterized by the presence of circulating PLAR2 antibodies in 70% of the cases and usually positivity for PLA2R and IgG4 by immunohistochemistry (IHC) staining. We report the first documented case of PMN (PLA2R positive) in a deceased kidney donor, transplanted to two different recipients and their clinical and immunological evolution through serial biopsies. Recipient A's first allograft biopsy (Day 26) was compatible with a MN with both positive PLA2R and IgG4 subepithelial deposits in IHC. The donor's preimplantation kidney biopsies were retrieved and reexamined, revealing MN, with high intensity for PLA2R and IgG4 in IHC. Recipient B's protocol allograft biopsy, performed later at 3 months, also revealed histology compatible with MN but without the presence of PLA2R nor IgG4 in IHC. At 1-year follow-up, both recipients maintain graft function. Serial protocol biopsies were performed in both patients showing disappearance of IgG4 in recipient A but the persistence of PLA2R in IHC. We can conclude that, given the reversal of PMN changes in the grafts, it could be considered to transplant a patient from an asymptomatic deceased donor with PMN as long as he maintains unaltered renal function.

Assessing and counteracting fibrosis is a cornerstone of the treatment of CKD secondary to systemic and renal limited autoimmune disorders.

Chronic kidney disease (CKD) is an increasing cause of morbidity and mortality worldwide. Besides the higher prevalence of diabetes, hypertension and aging worldwide, immune mediated disorders remain an important cause of kidney disease and are especially prevalent in young adults. Regardless of the initial insult, final pathway to CKD and kidney failure is always the loss of normal tissue and fibrosis development, in which the dynamic equilibrium between extracellular matrix synthesis and degradation is disturbed, leading to excessive production and accumulation. During fibrosis, a multitude of cell types intervene at different levels, but myofibroblasts and inflammatory cells are considered critical in the process. They exert their effects through different molecular pathways, of which transforming growth factor ß (TGF-ß) has demonstrated to be of particular importance. Additionally, CKD itself promotes fibrosis due to the accumulation of toxins and hormonal changes, and proteinuria is simultaneously a manifestation of CKD and a specific driver of renal fibrosis. Pathways involved in renal fibrosis and CKD are closely interrelated, and although important advances have been made in our knowledge of them, it is still necessary to translate them into clinical practice. Given the complexity of this process, it is highly likely that its treatment will require a multi-target strategy to control the origin of the damage but also the mechanisms that perpetuate it. Fortunately, rapid technology development over the last years and new available drugs in the nephrologist's armamentarium give reasons for optimism that more personalized assistance for CKD and renal fibrosis will appear in the future.

Thrombotic microangiopathies assessment: mind the complement.

When faced with microangiopathic haemolytic anaemia, thrombocytopenia and organ dysfunction, clinicians should suspect thrombotic microangiopathy (TMA). The endothelial damage that leads to this histological lesion can be triggered by several conditions or diseases, hindering an early diagnosis and aetiological treatment. However, due to systemic involvement in TMA and its low incidence, an accurate early diagnosis is often troublesome. In the last few decades, major improvements have been made in the pathophysiological knowledge of TMAs such as thrombotic thrombocytopenic purpura [TTP, caused by ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13) deficiency] and atypical haemolytic uraemic syndrome (aHUS, associated with dysregulation of the alternative complement pathway), together with enhancements in patient management due to new diagnostic tools and treatments. However, diagnosis of aHUS requires the exclusion of all the other entities that can cause TMA, delaying the introduction of terminal complement blockers, which have shown high efficacy in haemolysis control and especially in avoiding organ damage if used early. Importantly, there is increasing evidence that other forms of TMA could present overactivation of the complement system, worsening their clinical progression. This review addresses the diagnostic and therapeutic approach when there is clinical suspicion of TMA, emphasizing complement evaluation as a potential tool for the inclusive diagnosis of aHUS, as well as for the improvement of current knowledge of its pathophysiological involvement in other TMAs. The development of both new complement activation biomarkers and inhibitory treatments will probably improve the management of TMA patients in the near future, reducing response times and improving patient outcomes.