Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.

BACKGROUND AND AIMS The development and massive use of mRNA COVID-19 vaccine BNT162b2 has raised new concerns on triggering de novo immune-mediated diseases, in particular rare diseases as glomerulonephritis (GN), even if the security profile is excellent and severe reactions have been rare. In literature few similar cases were recently described [1, 2]. We report six cases of newly diagnosed GN after a two-dose regimen of SARS-CoV-2 vaccine, from a single tertiary care institution in Northern Italy. METHOD We described six cases of de novo GN occurring after massive use of Pfizer-BioNTech BNT162b2 COVID-19 vaccine from March 2021 to December 2021. All cases were biopsy proven. Baseline characteristics and laboratory findings, treatments and outcomes were based on review of medical records. RESULTS From April 2021, we observed two IgA nephropathies (IgA-N), one membranous nephropathy (MN), one membranoprolipherative GN (MPGN), one acute interstitial nephritis (aTIN) and one minimal change disease (MCD). Of note, one IgA-N presented with diffuse purpura as in IgA-vasculitis. The median age at vaccination was 52.8 years (min–max 18–67) and three (50%) were female; arterial hypertension was the most common comorbidity (50%). Only one subject contracted COVID-19 before vaccine (16.6%). None of the points showed any sign of renal disease before vaccine; at the time of disease onset, the median creatinine was 1.49 mg/dL (min–max 0.6–10.5 mg/dL) and proteinuria 3.0 g/24 h (min–max 0.9–13.8 g/24 h). All cases presented after the second dose (1 day to 6 months thereafter) and three (50%) were within 3 weeks from the vaccine. Of note, the aTIN developed after the vaccine during a long-time therapy with statins and relapsed after a rechallenge with a statin few months later. All the nephropathies were treated as per center practice, with an overall good response (four partial remissions and one complete remission). Given a target population of about 100 000–200 000 residents in our area, we could estimate an incidence rate of 4–8 cases/100 000 patient-years. CONCLUSION This small series has a lot of limitations including the small number of patients and we probably missed some cases in our area. Furthermore, we could not investigate a causal association, even if the timing of disease onset might be suspicious in three cases and the incidence seemed to be almost twice as the expected in Europe (about 2–4/100.000 patient-years). As for SARS-CoV-2 vaccines, it is likely that the mRNA vaccine will result in a more potent inflammatory stimulus than the one observed after inactivated virus-vaccine: maybe some patients had already a subclinical GN and the vaccine constituted a flare leading to the full-blown disease [3].

BACKGROUND AND AIMS AKI is the most frequent complication after respiratory failure in COVID-19. AKI increases mortality risk, length of hospital stay and healthcare costs, with possible progression towards CKD. Study aims: (1) evaluation of AKI incidence in 1020 COVID-19 hospitalized patients; (2) comparison of AKI incidence in COVID-19 versus pre-pandemic period; (3) establishment of out-patient follow-up for monitoring kidney, lung, motor and immune function; (4) creation of a biobank for biomarker discovery studies. METHOD AKI incidence was calculated matching laboratory and administrative data of 26 214 hospitalized patients in 2018–2019 and in 1020 COVID-19 patients in 2020–2021: KDIGO algorithms were applied for AKI grading. After 12 months from discharge, 232 COVID AKI patients and relative controls matched for age and gender were evaluated for kidney (eGFR, biomarkers of tubular damage NGAL, CCl-14, DKK-3), lung (DLCO, CT scan) and neuro-motor (SPPB, 2-min walking test, post-traumatic stress test-IES) function. RESULTS Before the pandemic, in-hospital AKI incidence was 18% (10% KDIGO 1, 5% KDIGO 2, 3% KDIGO 3): median age of AKI patients was 69. In-hospital mortality was 3.5% in non-AKI group versus 15% in AKI group in accordance with KDIGO stages. In COVID patients, AKI incidence increased to 37% (20% KDIGO 1.11% KDIGO 2, 6% KDIGO 3): median age of patients was 54. In-hospital mortality was 31% in the AKI group; AKI is an independent risk factor for death. After 12 months from hospital discharge, COVID AKI patients showed a persistent reduction of respiratory function (severe DLCO impairment < 60%) related to the extent of CT scan abnormalities. AKI patients also presented the motor function impairment and a worse post-traumatic stress response. GFR reduction was 1.8 mL/min in non-AKI patients versus 9.7 mL/min in AKI COVID patients not related to age. Urinary DKK-3 and CCL-14 were also higher in the AKI group. Last, IgG response after SARS-CoV-2 vaccination was significantly lower in the AKI group. CONCLUSION AKI incidence was significantly increased during COVID-19 in respect to the pre-pandemic period, with an association with higher mortality in class 2–3 KDIGO. In the post-COVID follow-up, AKI was associated with lung and neuro-motor function impairment, a defective antibody response and a sudden GFR decline concomitant to the persistence of tubular injury biomarkers. These results suggest the importance of nephrological and multidisciplinary follow-up of frail patients who developed AKI during hospitalization for COVID-19.

BACKGROUND AND AIMS The mass vaccination for COVID-19 has raised new concerns for patients with immune-mediated nephropathies: there is a small but growing literature of case-reports linking SARS-CoV-2 vaccines with heightened off-target immune responses leading to de novo or relapsing glomerular diseases [1, 2]. Aim of this study was to evaluate how many and how severe were the relapses of immune-mediated nephropathies after the SARS-CoV-2 vaccine in a single center. METHOD This is a retrospective study held in Italy from the start of the vaccination campaign (late December 2020) to December 31st 2021. We included all patients with an immune-mediated nephropathy (either on or off immunosuppressive therapy—IS), excluding patients with an end-stage renal disease or kidney transplant. In Italy we used mRNA (Comirnaty by Pfizer-BioNTech or Spikevax by Moderna) or adenoviral vector vaccines (Vaxzevria by AstraZeneca or Janssen), without any preference for patients with kidney disease, but those on active IS were given preferentially an mRNA vaccine. There was no active surveillance of lab tests after vaccination and post-vaccine tests were either concomitant to programmed visits or suggested on a patient by patient basis. Recurrence was defined as relapse of nephrotic or nephritic syndrome, doubling of urinary proteins with a max value > 1 g/24h, acute kidney injury with an active urinary sediment, or positivization or 5-fold increase of serological markers of disease activity (i.e.: ANCA in AAV). RESULTS A total of 38 patients (M: F 28:10, age at vaccine 45.9 ± 19.1 years) completed the vaccination protocol: among them, the most common nephropathy was membranous nephropathy (n = 12, 31.6%), followed by IgA nephropathy (n = 7, 18.4%), minimal change disease (n = 6, 15.8%) and ANCA-associated vasculitis (n = 6, 15.8%); 26 patients (68.4%) had at least one other comorbidity. We observed six relapses (4 MN, 1 IgA, 1 AAV), of which only one (MN) developed a mild oedema. The mean time from the first vaccine dose to the relapse was 101 ± 71 days (5–199 days) and only two episodes occurred within 4 weeks from a vaccine dose. We could not find an association between recurrences and maintenance IS at the time of vaccine or any other variable. The overall post-vaccine incidence rate of relapses was 35.8/100 patient-years, as compared with 14.0/100 patient-years historically observed in the same cohort [IRR 2.55, 95% confidence interval (CI) 0.89–5.97]. CONCLUSION Relapses of immune-mediated nephropathies are not common after SARS-CoV-2 vaccine and we did not observe any clinically relevant relapse. However the overall rate of relapse seems to be a little higher than prior vaccination [3], but only 2/6 patients recurred soon after a vaccine dose. As these relapses seem to be self-limiting, a post-vaccine monitoring could be useful in patients at high risk of severe disease.