Factor B Inhibition with Iptacopan in Recurrent C3 Glomerulopathy Following Kidney Transplant: A Report of Two Cases.

C3 glomerulopathy is a rare disease caused by fluid phase dysregulation of the alternative complement pathway. Currently, treatment depends on clinical and histological severity and includes nephroprotection, unspecific immunosuppression, and terminal complement blockers (C5), without having an etiological treatment approved. C3 glomerulopathy has high recurrence rates after kidney transplantation with a high risk of graft loss. Fortunately, new molecules are being developed that specifically target the proximal alternative complement pathway, such as iptacopan, a factor B inhibitor that showed promising results in native kidneys and cases of transplant recurrence in a phase 2 clinical trial. We present 2 "real-world" cases of C3 glomerulopathy recurrence in kidney allografts treated with iptacopan, with initial excellent clinical response and safety profile, especially with early introduction. We also present follow-up biopsies that showed no C3 deposition during factor B inhibition. Our cases suggest that proximal blockade of the alternative complement pathway can be effective and safe in the treatment of C3 glomerulopathy recurrence in kidney transplantation, bringing other questions such as dual blockade (eg, in C3 and C5), the optimal patient profile to benefit from factor B inhibition or treatment duration and its potential use in other forms of membranoproliferative glomerulonephritis (eg, immune complex-mediated).

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.

Tubulo-interstitial inflammation increases the risk of graft loss after the recurrence of IgA nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) is the most frequent recurrent disease in kidney transplant recipients and its recurrence contributes to reducing graft survival. Several variables at the time of recurrence have been associated with a higher risk of graft loss. The presence of clinical or subclinical inflammation has been associated with a higher risk of kidney graft loss, but it is not precisely known how it influences the outcome of patients with recurrent IgAN. Methods: We performed a multicentre retrospective study including kidney transplant recipients with biopsy-proven recurrence of IgAN in which Banff and Oxford classification scores were available. 'Tubulo-interstitial inflammation' (TII) was defined when 't' or 'i' were ≥2. The main endpoint was progression to chronic kidney disease (CKD) stage 5 or to death censored-graft loss (CKD5/DCGL). Results: A total of 119 kidney transplant recipients with IgAN recurrence were included and 23 of them showed TII. Median follow-up was 102.9 months and 39 (32.8%) patients reached CKD5/DCGL. TII related to a higher risk of CKD5/DCGL (3 years 18.0% vs 45.3%, log-rank 7.588, P = .006). After multivariate analysis, TII remained related to the risk of CKD5/DCGL (HR 2.344, 95% CI 1.119-4.910, P = .024) independently of other histologic and clinical variables. Conclusions: In kidney transplant recipients with IgAN recurrence, TII contributes to increasing the risk of CKD5/DCGL independently of previously well-known variables. We suggest adding TII along with the Oxford classification to the clinical variables to identify recurrent IgAN patients at increased risk of graft loss who might benefit from intensified immunosuppression or specific IgAN therapies.

Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis.

BACKGROUND: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management glomerular/systemic autoimmune diseases with proteinuria in real-world clinical settings is unclear. METHODS: This is a retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-h proteinuria from SGLT2i initiation to 3, 6, 9 and 12 months. Secondary outcomes included percentage change in estimated glomerular filtration rate (eGFR), proteinuria reduction by type of disease and reduction of proteinuria ≥30% from SGLT2i initiation. RESULTS: Four-hundred and ninety-three patients with a median age of 55 years and background therapy with renin-angiotensin system blockers were included. Proteinuria from baseline changed by -35%, -41%, -45% and -48% at 3, 6, 9 and 12 months after SGLT2i initiation, while eGFR changed by -6%, -3%, -8% and -10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. A correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up. By mixed-effects logistic regression model, serum albumin at SGLT2i initiation emerged as a predictor of ≥30% proteinuria reduction (odds ratio for albumin <3.5 g/dL, 0.53; 95% CI 0.30-0.91; P = .02). A slower eGFR decline was observed in patients achieving a ≥30% proteinuria reduction: -3.7 versus -5.3 mL/min/1.73 m2/year (P = .001). The overall tolerance to SGLT2i was good. CONCLUSIONS: The use of SGLT2i was associated with a significant reduction of proteinuria. This percentage change is greater in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

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)

Diagnosis and treatment of lupus nephritis: a summary of the Consensus Document of the Spanish Group for the Study of Glomerular Diseases (GLOSEN).

Lupus nephritis (LN) is the most frequent serious manifestation of patients with systemic lupus erythematosus (SLE). Up to 60% of SLE patients develop LN, which has a significant impact on their quality of life and prognosis. Recent advances have improved the diagnostic approach to LN, and new drugs that block specific pathways and kidney damage progression have been developed. Several randomized and well-powered clinical trials have confirmed the efficacy of these agents in terms of proteinuria remission and preservation of kidney function in the medium and long term, with an acceptable safety profile and good tolerance. The combination of different therapies allows for reduction of the dose and duration of corticosteroids and other potentially toxic therapies and leads to an increase in the number of patients achieving complete remission of the disease. This consensus document carried out by the Spanish Group for the Study of Glomerular Diseases (GLOSEN) provides practical and updated recommendations, based on the best available evidence and clinical expertise of participating nephrologists.

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.

Effect of Immunosuppressive Treatments on Kidney Outcomes After Gross Hematuria-Related Acute Kidney Injury in Older Patients With IgA Nephropathy.

Introduction: Macroscopic hematuria (MH) bouts, frequently accompanied by acute kidney injury (AKI-MH) are one of the most common presentations of IgA nephropathy (IgAN) in the elderly. Immunosuppressive therapies are used in clinical practice; however, no studies have analyzed their efficacy on kidney outcomes. Methods: This is a retrospective, multicenter study of a cohort of patients aged ≥50 years with biopsy-proven IgAN presenting with AKI-MH. Outcomes were complete, partial, or no recovery of kidney function at 1 year after AKI-MH, and kidney survival at 1, 2, and 5 years. Propensity score matching (PSM) analysis was applied to balance baseline differences between patients treated with immunosuppression and those not treated with immunosuppression. Results: The study group consisted of 91 patients with a mean age of 65 ± 15 years, with a mean follow-up of 59 ± 36 months. Intratubular red blood cell (RBC) casts and acute tubular necrosis were found in all kidney biopsies. The frequency of endocapillary hypercellularity and crescents were low. Immunosuppressive therapies (corticosteroids alone or combined with mycophenolate mofetil or cyclophosphamide) were prescribed in 52 (57%) patients, whereas 39 (43%) received conservative treatment. There were no significant differences in the proportion of patients with complete, partial, or no recovery of kidney function at 1 year between patients treated with immunosuppression and those not treated with immunosuppression (29% vs. 36%, 30.8% vs. 20.5% and 40.4 % vs. 43.6%, respectively). Kidney survival at 1, 3, and 5 years was similar among treated and untreated patients (85% vs. 81%, 77% vs. 76% and 72% vs. 66%, respectively). Despite the PSM analysis, no significant differences were observed in kidney survival between the two groups. Fourteen patients (27%) treated with immunosuppression had serious adverse events. Conclusions: Immunosuppressive treatments do not modify the unfavorable prognosis of patients with IgAN who are aged ≥50 years presenting with AKI-MH, and are frequently associated with severe complications.

From systemic lupus erythematosus to lupus nephritis: The evolving road to targeted therapies.

Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage.

Ex vivo confocal microscopy detects basic patterns of acute and chronic lesions using fresh kidney samples.

Background: Ex vivo confocal microscopy is a real-time technique that provides high-resolution images of fresh, non-fixed tissues, with an optical resolution comparable to conventional pathology. The objective of this study was to investigate the feasibility of using ex vivo confocal microscopy in fusion mode (FuCM) and the haematoxylin and eosin (H&E)-like digital staining that results for the analysis of basic patterns of lesion in nephropathology. Methods: Forty-eight renal samples were scanned in a fourth-generation ex vivo confocal microscopy device. Samples were subjected to confocal microscopy imaging and were then processed using conventional pathology techniques. Concordance between the techniques was evaluated by means of the percentage of agreement and the κ index. Results: Agreement between conventional microscopy and H&E-like digital staining was strong (κ = 0.88) in the evaluation of acute tubular damage and was substantial (κ = 0.79) in the evaluation of interstitial fibrosis, interstitial inflammation, arterial and arteriolar lesions. H&E-like digital staining also allows rapid identification of extracapillary proliferation (κ = 0.88), necrosis and segmental sclerosis (κ = .88) in the glomerular compartment, but the results reported here are limited because of the small number of cases with these glomerular findings. Conclusions: FuCM proved to be as effective as conventional techniques in evaluating the presence of acute tubular necrosis and interstitial fibrosis changes, but in fresh tissue. The ease of acquisition of ex vivo confocal microscopy images suggests that FuCM may be useful for rapid evaluation of kidney biopsies and to restructure the clinical workflow in renal histopathology.

Anti-dsDNA B-Cell ELISpot as a Monitoring and Flare Prediction Tool in SLE Patients.

Anti-dsDNA autoantibodies quantification and complement levels are widely used to monitor disease activity in systemic lupus erythematosus (SLE). However, better biomarkers are still needed. We hypothesised whether the dsDNA antibody-secreting B-cells could be a complementary biomarker in disease activity and prognosis of SLE patients. Fifty-two SLE patients were enrolled and followed for up to 12 months. Additionally, 39 controls were included. An activity cut-off (comparing active and non-active patients according to clinical SLEDAI-2K) was established for SLE-ELISpot, chemiluminescence and Crithidia luciliae indirect immunofluorescence tests (≥11.24, ≥374.1 and ≥1, respectively). Assays performances together with complement status were compared regarding major organ involvement at the inclusion and flare-up risk prediction after follow-up. SLE-ELISpot showed the best performance in identifying active patients. High SLE-ELISpot results were associated with haematological involvement and, after follow-up, with an increased hazard ratio for disease flare-up (3.4) and especially renal flare (6.5). Additionally, the combination of hypocomplementemia and high SLE-ELISpot results increased those risks up to 5.2 and 32.9, respectively. SLE-ELISpot offers complementary information to anti-dsDNA autoantibodies to evaluate the risk of a flare-up in the following year. In some cases, adding SLE-ELISpot to the current follow-up protocol for SLE patients can improve clinicians' personalised care decisions.

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.

Kidney biopsy in lupus nephritis after achieving clinical renal remission: paving the way for renal outcome assessment.

The role of repeat kidney biopsy in lupus nephritis (LN) with renal remission is unclear. The aim of this study was to assess this role in a real-life scenario. This retrospective, single-centre study included 56 patients with LN diagnosed from 1998 to 2019, with an initial kidney biopsy (KB1) at the onset of LN and a second kidney biopsy (KB2) after achieving renal remission. A total of 51 (91.1%) patients were women with a median age of 29.9 years [interquartile range (IQR) 23.4-40.6] at the time of LN diagnosis. KB2s were performed after 41.1 months (IQR 30.1-52.5) of KB1. At the time of KB2, complete renal response was achieved in 51 (91.1%) patients. The median activity index decreased from a baseline value of 6.5 (IQR 2.8-11) to 0 (IQR 0-2) (P < .001). The chronicity index worsened from 1 (IQR 0-2) to 2 (IQR 1-3) (P = .01). In patients with proliferative/mixed forms at KB2, the chronicity index median value increased to 3 (IQR 1.5-4), as well as interstitial fibrosis and tubular atrophy [Formula: see text]25%, from 5.4% to 13.5%. Persistent histological active LN (activity index ≥2) was present in 11 (19.6%) KB2s. There were no differences when comparing immunological parameters between both groups (activity index ≥2 versus <2) at KB2, nor in the percentage of patients who presented renal flare. Immunosuppressive treatment was withdrawn in 35 (62.5%) patients and maintained/switched in 21 (37.5%). Afterward, new renal flare occurred in 9 patients per group (25.7% and 43%, respectively), after a median time of 39 months (IQR 6.5-55) and 7 months (IQR 6-30), respectively. There was no difference in the number of patients who developed chronic kidney disease [n = 14 (25%)] according to the treatment. In conclusion, KB2 provides valuable information to guide immunosuppressive maintenance therapy.