Optimization of Rituximab Therapy in Adult Patients With PLA2R1-Associated Membranous Nephropathy With Artificial Intelligence.

Introduction: Rituximab is a first-line treatment for membranous nephropathy. Nephrotic syndrome limits rituximab exposure due to urinary drug loss. Rituximab underdosing (serum level <2 µg/ml at month-3) is a risk factor for treatment failure. We developed a machine learning algorithm to predict the risk of underdosing based on patients' characteristics at rituximab infusion. We investigated the relationship between the predicted risk of underdosing and the cumulative dose of rituximab required to achieve remission. Methods: Rituximab concentrations were measured at month-3 in 92 sera from adult patients with primary membranous nephropathy, split into a training (75%) and a testing set (25%). A forward-backward machine-learning procedure determined the best combination of variables to predict rituximab underdosing in the training data set, which was tested in the test set. The performances were evaluated for accuracy, sensitivity, and specificity in 10-fold cross-validation training and test sets. Results: The best variables combination to predict rituximab underdosing included age, gender, body surface area (BSA), anti-phospholipase A2 receptor type 1 (anti-PLA2R1) antibody titer on day-0, serum albumin on day-0 and day-15, and serum creatinine on day-0 and day-15. The accuracy, sensitivity, and specificity were respectively 79.4%, 78.7%, and 81.0% (training data set), and 79.2%, 84.6% and 72.7% (testing data set). In both sets, the algorithm performed significantly better than chance (P < 0.05). Patients with an initial high probability of underdosing experienced a longer time to remission with higher rituximab cumulative doses required to achieved remission. Conclusion: This algorithm could allow for early intensification of rituximab regimen in patients at high estimated risk of underdosing to increase the likelihood of remission.

Rare Variants in Complement Gene in C3 Glomerulopathy and Immunoglobulin-Mediated Membranoproliferative GN.

BACKGROUND: C3 glomerulopathy and idiopathic immunoglobulin-mediated membranoproliferative GN (Ig-MPGN) are rare complement-mediated kidney diseases. Inherited forms of C3 glomerulopathy/Ig-MPGN are rarely described. METHODS: Three hundred ninety-eight patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102) from a national registry were screened for three complement genes: factor H ( CFH ), factor I ( CFI ), and C3 . Patients with rare variant (minor allele frequency <0.1%) were included. Epidemiologic, clinical, and immunologic data at diagnosis and kidney outcomes of patients were retrospectively collected. RESULTS: Fifty-three different rare variants, including 30 (57%), 13 (24%), and ten (19%) in CFH , CFI , and C3 variants, were identified in 66/398 (17%) patients. Thirty-eight (72%) variants were classified as pathogenic, including 20/30 (66%) and 11/13 (84%) variants in CFH and CFI , respectively, impairing synthesis of factor H or factor I regulators. Fifteen of 53 (27%) variants were of unknown significance. At diagnosis, 69% of patients were adult (median age of 31 years). With the exception of biologic stigma of thrombotic microangiopathy, which was more frequent in patients with CFI variants (5/14 [36%] versus 1/37 [3%] and 0% in the CFH group and C3 group, respectively, P < 0.001), the clinical and histologic features were similar among the three variants groups. The kidney outcome was poor regardless of the age at onset and treatment received. Sixty-five percent (43/66) of patients with rare variant reach kidney failure after a median delay of 41 (19-104) months, compared with 28% (55/195) after a median delay of 34 (12-143) months in the nonvariant group. Among 36 patients who received a kidney transplant, 2-year recurrence was frequent, occurring in 39% (12/31), without difference between variant groups, and led to graft failure in three cases. CONCLUSIONS: In our cohort, 17% of C3 glomerulopathy/Ig-MPGN cases were associated with rare variants in the CFH , CFI , or C3 genes. In most cases, a quantitative deficiency in factor H or factor I was identified. The presence of a rare variant was associated with poor kidney survival. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_08_CJN0000000000000252.mp3.

Low baseline IFN-γ response could predict hospitalization in COVID-19 patients.

The SARS-CoV-2 infection has spread rapidly around the world causing millions of deaths. Several treatments can reduce mortality and hospitalization. However, their efficacy depends on the choice of the molecule and the precise timing of its administration to ensure viral clearance and avoid a deleterious inflammatory response. Here, we investigated IFN-γ, assessed by a functional immunoassay, as a predictive biomarker for the risk of hospitalization at an early stage of infection or within one month prior to infection. Individuals with IFN-γ levels below 15 IU/mL were 6.57-times more likely to be hospitalized than those with higher values (p<0.001). As confirmed by multivariable analysis, low IFN-γ levels, age >65 years, and no vaccination were independently associated with hospitalization. In addition, we found a significant inverse correlation between low IFN-γ response and high level of IL-6 in plasma (Spearman's rho=-0.38, p=0.003). Early analysis of the IFN-γ response in a contact or recently infected subject with SARS-CoV-2 could predict hospitalization and thus help the clinician to choose the appropriate treatment avoiding severe forms of infection and hospitalization.

Toxic Occupational Exposures and Membranous Nephropathy.

BACKGROUND AND OBJECTIVES: Membranous nephropathy is a rare autoimmune kidney disease whose increasing prevalence in industrialized countries pleads for the involvement of an environmental factor in the development of the disease. In addition, the predominance of men in membranous nephropathy, classically attributed to biologic or genetic differences between men and women, could also be due to different occupational exposures. To support this hypothesis, we sought to describe the toxic occupational exposures of patients with membranous nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational epidemiologic study, we compared the occupations and toxic occupational exposures of 100 patients with membranous nephropathy with those of the general population, consisting of two cohorts of 26,734,000 and 26,500 French workers. We then compared the characteristics of patients exposed to an occupational toxic substance with those of unexposed patients. RESULTS: Patients with membranous nephropathy worked more frequently in the construction sector than the general population (33% versus 7%, P<0.001). This difference remained significant by age and sex. They were also more frequently exposed to toxic substances, such as asbestos (16% versus 5%, P<0.001), lead (9% versus 1%, P<0.001), or organic solvents (37% versus 15%, P<0.001), than the general population. The predominance of men in the subgroup of patients occupationally exposed to toxic substances was not observed in unexposed individuals (organic solvents: 80% men versus 41%, P<0.001; asbestos: 90% men versus 55%, P=0.004). In addition, patients with phospholipase A2 receptor 1 (PLA2R1) epitope spreading were more frequently exposed to asbestos and organic solvents than patients without epitope spreading (32% versus 7%, P=0.02 and 74% versus 43%, P=0.02, respectively), with a dose-dependent effect. CONCLUSIONS: Patients with membranous nephropathy were more frequently exposed to certain occupational toxic substances, such as asbestos and organic solvents, than the general population. This occupational exposure was more frequent in men and in patients with PLA2R1 epitope spreading. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Immunopathological Analysis in a French National Cohort of Membranous Nephropathy (IHMN), NCT04326218. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_10_25_CJN02930322.mp3.

Air pollution exposure induces a decrease in type II interferon response: A paired cohort study.

BACKGROUND: While air pollution is a major issue due to its harmful effects on human health, few studies focus on its impact on the immune system and vulnerability to viral infections. The lockdown declared following the COVID-19 pandemic represents a unique opportunity to study the large-scale impact of variations in air pollutants in real life. We hypothesized that variations in air pollutants modify Th1 response represented by interferon (IFN) γ production. METHODS: We conducted a single center paired pilot cohort study of 58 participants, and a confirmation cohort of 320 participants in Nice (France), with for each cohort two samplings at six months intervals. We correlated the variations in the production of IFNγ after non-specific stimulation of participants' immune cells with variations in key regulated pollutants: NO2, O3, PM2.5, and PM10 and climate variables. Using linear regression, we studied the effects of variations of each pollutant on the immune response. FINDINGS: In the pilot cohort, IFNγ production significantly decreased by 25.7% post-lockdown compared to during lockdown, while NO2 increased significantly by 46.0%. After the adjustment for climate variations during the study period (sunshine and temperature), we observed a significant effect of NO2 variation on IFNγ production (P=0.03). In the confirmation cohort IFNγ decreased significantly by 47.8% and after adjustment for environmental factors and intrinsic characteristics we observed a significant effect of environmental factors: NO2, PM10, O3, climatic conditions (sunshine exposure, relative humidity) on variation in IFNγ production (P=0.005, P<0.001, P=0.001, P=0.002 and P<0.001 respectively) but not independently from the BMI at inclusion and the workplace P=0.007 and P<0.001 respectively). INTERPRETATION: We show a weakening of the antiviral cellular response in correlation with an increase of pollutants exposition. FUNDING: Agence Nationale de la Recherche, Conseil Départemental des Alpes-Maritimes and Region Sud.

Risk factors associated with immune checkpoint inhibitor-induced acute kidney injury compared with other immune-related adverse events: a case-control study.

Background: Immune checkpoint inhibitors (ICIs) foster anti-cancer immune responses. Their efficacy comes at the cost of immune-related adverse events (IRAEs). The latter affects various organs, including kidneys, mostly as acute tubulointerstitial nephritis, the pathophysiology of which remains unclear. We conducted a multicentre case-control study to compare the characteristics of patients with renal IRAEs (ICI-AKI) with those of patients diagnosed with other IRAEs. Methods: We queried the French pharmacovigilance database for all adverse events involving ICIs. Reports were classified as ICI-AKI or extrarenal IRAE. For each ICI-AKI report, four reports of extrarenal IRAEs were randomly included (control group, 4:1 ratio). Variables showing an association with a P < 0.05 were included as covariates in a multivariate analysis. Results: Therefore, 167 ICI-AKI reports were compared with 668 extrarenal IRAEs. At least one concomitant extrarenal IRAE was mentioned in 44.3% of ICI-AKI reports. Patients with ICI-AKI were significantly older than patients with extrarenal IRAEs (69.1 versus 64.6 years; P = 0.0135), and chronic kidney disease was significantly more prevalent (12.0% versus 3.3%; P = 0.0125). Patients with ICI-AKI were significantly more likely to be treated with fluindione [adjusted odds ratio (OR) 6.53, 95% confidence interval (95% CI) 2.21-19.31; P = 0.0007], a non-steroidal anti-inflammatory drug (NSAID, OR 3.18, 95% CI 1.07-9.4; P = 0.0368) or a proton-pump inhibitor (PPI, OR 2.18, 95% CI 1.42-3.34; P = 0.0004). Conclusion: This study is limited by a lack of data, preventing confirmation of numerous reports therefore not included in the analysis. We are unable to draw definite pathophysiological conclusions from our data. Nonetheless, we suggest that ICIs may be a 'second-hit' that precipitates acute kidney injury caused by another concomitant drug (fluindione, NSAID or PPI).

New Strategies for Volume Control in Patients with Diabetes Mellitus, a Narrative Review.

Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure.

Advances in the Management of Primary Membranous Nephropathy and Rituximab-Refractory Membranous Nephropathy.

Primary membranous nephropathy (pMN) is an auto-immune disease characterized by auto-antibodies targeting podocyte antigens resulting in activation of complement and damage to the glomerular basement membrane. pMN is the most common cause of nephrotic syndrome in adults without diabetes. Despite a very heterogeneous course of the disease, the treatment of pMN has for many years been based on uniform management of all patients regardless of the severity of the disease. The identification of prognostic markers has radically changed the vision of pMN and allowed KDIGO guidelines to evolve in 2021 towards a more personalized management based on the assessment of the risk of progressive loss of kidney function. The recognition of pMN as an antibody-mediated autoimmune disease has rationalized the use immunosuppressive drugs such as rituximab. Rituximab is now a first line immunosuppressive therapy for patients with pMN with proven safety and efficacy achieving remission in 60-80% of patients. For the remaining 20-40% of patients, several mechanisms may explain rituximab resistance: (i) decreased rituximab bioavailability; (ii) immunization against rituximab; and (iii) chronic glomerular damage. The treatment of patients with rituximab-refractory pMN remains controversial and challenging. In this review, we provide an overview of recent advances in the management of pMN (according to the KDIGO 2021 guidelines), in the understanding of the pathophysiology of rituximab resistance, and in the management of rituximab-refractory pMN. We propose a treatment decision aid based on immunomonitoring to identify failures related to underdosing or immunization against rituximab to overcome treatment resistance.

Low T Cell Responsiveness in the Early Phase of COVID-19 Associates with Progression to Severe Pneumonia in Kidney Transplant Recipients.

Kidney transplant (KT) recipients are at increased risk of developing severe forms of COVID-19. Little is known about the immunological mechanisms underlying disease severity in these patients receiving T-cell targeting immunosuppressive drugs. We investigated the relationship between T cell responsiveness at the beginning of the infection and the risk of subsequent progression to respiratory failure. We performed a multicentric prospective study in KT recipients with a positive RT-PCR COVID-19 test and only mild symptoms at inclusion. Blood samples were collected at baseline in a cell culture system containing T cell stimuli. We assessed T cell responsiveness by computing the ratio between the levels of Th1, Th2, Th17 and Treg cytokines produced after polyclonal stimulation and the number of blood lymphocytes. We then used an unsupervised classification approach to stratify patients into low and high T cell responders and a penalized logistic regression to evaluate the association between T cell responsiveness and progression to severe pneumonia. Forty-five patients were included. All patients who progressed to severe pneumonia (24.4%, n = 11) were low T cell responders at baseline (p = 0.01). In multivariate analysis, low T cell responsiveness at baseline was the main risk factor for subsequent progression to severe pneumonia. This study provides novel insights into the mechanisms underlying COVID-19 severity in organ transplant recipients and data of interest to clinicians managing immunosuppressive drugs in these patients.

Long-term health-related quality of life outcomes of adults with pediatric onset of frequently relapsing or steroid-dependent nephrotic syndrome.

BACKGROUND: Long-term psychosocial outcomes and health-related quality of life (HRQOL) in adults with pediatric onset of frequently relapsing or steroid-dependent idiopathic nephrotic syndrome (FRNS or SDNS) remain to be determined. METHODS: In this prospective cohort study, 59 adults with pediatric onset of FRNS/SDNS and persistent active glomerular disease in adulthood completed the GEDEPAC-2 questionnaire exploring 11 well-being domains. Data were compared to the French general population (FGP) with standardized incidence ratio ([SIR]; adjusted for period, age, gender). Regression models were performed to identify predictive factors of psychosocial well-being. RESULTS: In 82% of cases, the questionnaire was completed while the participants (n = 59; 47 men; median age = 32 years; median number of relapses = 13) were in complete remission (under specific therapy in 76% of cases). Participants had higher educational degree than in the FGP (SIR = 6.3; p < 0.01) and more frequently a managerial occupation (SIR = 3.1; p < 0.01). Social integration was acceptable with regard to marital status and experience of sexual intercourse, but experiences of discrimination were far more frequent (SIR = 12.5; p < 0.01). The SF-12 mental component summary (MCS) score was altered (Z-score = - 0.6; p < 0.01) and mean multidimensional fatigue inventory (MFI-20) global fatigue score appeared high (12). Transfer from pediatric to adult healthcare was followed by a period of discontinued care for 33% of participants. Multivariate analysis revealed a close relationship between MFI-20, physical health, and MCS. CONCLUSIONS: This study shows that pediatric onset FRNS and SDNS may have a long-term negative impact on mental HRQOL and highlights the impact of fatigue, which is often not adequately considered in routine care.

Rituximab Immunomonitoring Predicts Remission in Membranous Nephropathy.

Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%-80% of cases. For the remaining 20%-40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19+ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.

Safety and cross-variant immunogenicity of a three-dose COVID-19 mRNA vaccine regimen in kidney transplant recipients.

BACKGROUND: The immunogenicity of a two-dose mRNA COVID-19 vaccine regimen is low in kidney transplant (KT) recipients. Here, we provide a thorough assessment of the immunogenicity of a three-dose COVID-19 vaccine regimen in this population. METHODS: We performed a prospective longitudinal study in sixty-one KT recipients given three doses of the BNT162b2 COVID-19 vaccine. We performed semi-structured pharmacovigilance interviews and monitored donor-specific antibodies and kidney function. We compared levels of anti-spike IgG, pseudo-neutralization activity against vaccine homologous and heterologous variants, frequency of spike-specific interferon (IFN)-γ-secreting cells, and antigen-induced cytokine production 28 days after the second and third doses. FINDINGS: Reactions to vaccine were mild. One patient developed donor-specific anti-HLA antibodies after the second dose which could be explained by non-adherence to immunosuppressive therapy. Spike-specific IgG seroconversion raised from 44·3% (n=27) after the second dose to 62·3% (n=38) after the third dose (p<0·05). The mean level of spike-specific IgG increased from 1620 (SD, 3460) to 8772 (SD, 16733) AU/ml (p<0·0001). Serum neutralizing activity increased after the third dose for all variants of concern tested including the Delta variant (p<0·0001). The frequency of spike-specific IFN-γ-secreting cells increased from 19·9 (SD, 56·0) to 64·0 (SD, 76·8) cells/million PBMCs after the third dose (p<0·0001). A significant increase in IFN-γ responses was also observed in patients who remained seronegative after three doses (p<0·0001). INTERPRETATION: A third dose of the BNT162b2 vaccine increases both cross-variant neutralizing antibody and cellular responses in KT recipients with an acceptable tolerability profile. FUNDING: Nice University Hospital, University Cote d'Azur.

Cohort study: "Outcomes of kidney transplantation in patients with prosthetic heart valves".

The number of kidney transplant candidates with prosthetic heart valves (PHVs) is increasing. Yet, outcomes of kidney transplantation in these patients are still unclear. This is the first report of post-transplant outcomes in patients with PHVs at time of kidney transplantation. We conducted a matched cohort study among recipients from the multicentric and prospective DIVAT cohort to compare the outcomes in patients with left-sided PHVs at time of transplantation and a group of recipients without PHV matched according to age, dialysis time, initial disease, pretransplant DSA, diabetes, and cardiovascular events. Of 23 018 patients, 92 patients with PHVs were included and compared to 276 patients without PHV. Delayed graft function and postoperative bleeding occurred more frequently in patients with PHVs. Kidney graft survival was similar between groups. 5-year overall survival was 68.5% in patients with PHV vs. 87.9% in patients without PHV [HR, 2.72 (1.57-4.70), P = 0.0004]. Deaths from infection, endocarditis, and bleeding were more frequent in patients with PHV. Mechanical valves, but not bioprosthetic valves, were independent risk factors for mortality [HR, 2.89 (1.68-4.97), P = 0.0001]. Patients with PHV have high mortality rates after kidney transplantation. These data suggest that mechanical valves, but not biological valves, increase risks of post-transplant mortality.

Extracellular fluid volume: A suitable indexation variable to assess impact of bariatric surgery on glomerular filtration rate in patients with chronic kidney disease.

BACKGROUND: Bariatric surgery (BS) might be a nephroprotective treatment in obese patients with chronic kidney disease (CKD), and the non-linear relation between body surface area (BSA) and extracellular fluid volume (ECFV) in obese people raises the question of the most relevant way to scale glomerular filtration rate (GFR) for assessing renal function changes after BS. METHODS: We screened 1774 BS candidates and analysed 10 consecutive participants with CKD stage 3. True GFR (mGFR), measured by the renal clearance of 51Cr-ethylenediaminetetraacetic acid (EDTA), was scaled either to BSA (mGFRBSA) or to ECFV measured by 51Cr-EDTA distribution volume (mGFRECFV) before and one year after BS. RESULTS: The 10 candidates for BS had a mean body mass index of 43.3 ± 3.6 kg/m2 and a mean GFR of 48 ± 8 mL/min/1.73 m2. Six participants had a sleeve gastrectomy and four had a Roux-en-Y gastric bypass. One year after BS, ECFV decreased (23.2 ± 6.2 to 17.9 ± 4.3 L, p = 0.001), absolute mGFR was not significantly modified (74 ± 23 versus 68 ±19 mL/min), mGFRBSA did not change significantly (53 ± 18 versus 56 ± 17 mL/min/1.73 m2) whereas mGFRECFV significantly increased (42 ± 13 versus 50 ± 14 mL/min/12.9 L, p = 0.037). The relation between mGFRECFV and mGFRBSA was different from the identity line before (p = 0.014) but not after BS (p = 0.09). CONCLUSION: There is a difference between mGFRBSA and mGFRECFV following BS and the latter might better reflect the adequacy between renal function and corpulence.

Regulation of Monocytes/Macrophages by the Renin-Angiotensin System in Diabetic Nephropathy: State of the Art and Results of a Pilot Study.

Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin-angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2.