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BACKGROUND AND AIMS Acute interstitial nephritis (AIN) is a common cause of acute renal failure affecting between 5% and 27%. It is characterized by the presence of interstitial inflammatory infiltrate, tubulitis and edema. A considerable number of cases develop chronic kidney disease (CKD), with a linear relationship observed with the diagnosis delay. There are different etiologies, most importantly those secondary to drug exposure and those related to immunological diseases. To the date, there are few studies comparing both etiologies. In this regard, the aim of this study is to determine difference between both etiologies by comparing clinical, histological and renal prognosis. METHOD A retrospective, observational, single-center study was performed. Clinical and histological characteristics of patients with a first episode of pharmacological or immunological AIN, confirmed by renal biopsy between 1998 and 2020, were compared. Histological analysis was measured by semi-quantitative methods. RESULTS A total of 67 patients have been described, with a mean age of 68 ± 13 years, 56% were women. The baseline creatinine was 93.8 umol/L with an eGFR (CKD-EPI) of 67 mL/min/1.73 m2; mean follow-up time was 63 ± 55 months. A total of 46 patients presented pharmacological AIN, being NSAIDs and antibiotics the most frequent agents, 21 patients with AIN associated to immunological diseases, being Sjögren’s syndrome the most frequent. Previous CKD was present in both groups, with 42% in immunological AIN versus 32% in pharmacological AIN, of which stage 3a CKD was more frequent in drug-mediated AIN (69% versus 33%) as opposed to stage 3b CKD was more frequent in immunological AIN (67% versus 19%). However, no significant differences were observed in the estimated glomerular filtration rate when comparing both groups. A longer diagnostic delay was observed in patients with immunological, defined as the elapsed time from renal function deterioration to the performance of renal biopsy, 93 ± 210 versus 13 ± 15 days (P = .021). However, creatinine at the time of diagnosis was higher in patients with pharmacological cause (380 ± 199 versus 252 ± 246 umol/L; P = .0002), leukocyturia was more frequent in the pharmacological AIN group without differences in the percentage of hematuria or proteinuria. In histological analysis, there were no significant differences in interstitial infiltrate, renal fibrosis or tubular atrophy. Once the biopsy was performed, treatment was started in all patients before the 5th day. In pharmacological AIN, the causative drug was withdrawn and corticosteroids were administered to the majority of patients. Out of 46 patients, 7 (15%) patients of the pharmacological AIN group, the drug was withdrawn with no additional treatment, 4 of them progressed to end-stage kidney disease (ESKD). In the immunological AIN group, most of patients were treated with corticosteroids or immunosuppressants. Out of 21 patients, 3 patients (14%) were not treated and progressed to ESKD. Treatment time was longer in patients with immunologic AIN (290 ± 195 versus 141 ± 168 days; P = .004). No differences were observed in creatinine or glomerular filtration rate at 6, 12 months, end of treatment or last control. The recovery of renal function was also analyzed, observing a higher percentage of complete recovery in patients with AIN associated with immunological diseases at 6 months (43% versus 24%) and at 12 months of follow-up (58% versus 29%); however, did not reach statistical significance. During follow-up, 2/46 (4%) recurrences were recorded in patients with pharmacological AIN and 6/21 (28%) in the immunological AIN group. CONCLUSION Despite the fact that patients with AIN associated with immunologic disease have a higher rate of previous CKD related to diagnostic delay and a higher rate of relapses, we observed that the evolution/progression of renal function was similar to the patients with pharmacological AIN. This could suggest that immunological AIN has a more favorable clinical course or better response to the treatment.

BACKGROUND AND AIMS Fibrillary glomerulopathy (FGN) is a rare glomerular deposit disease accounting for less than 1% of annual native kidney biopsies. Its pathogenesis is still not fully understood. Immunofluorescence (IF) techniques in the vast majority of cases reveal the presence of smudgy polytypic IgG deposits associated with C3 and, anecdotally, of scarce IgM or IgA. The majority of cases are idiopathic, but up to one-third of patients may present with a secondary cause including monoclonal gammopathy, which in previously reported series ranged from 4% to 16% of the cases. The association of FGN and monoclonal gammopathy remains controversial, nonetheless monotypic cases in the absence of multiple myeloma, wäldestrom macroglobulinemia or high-grade lymphoma are currently included in the spectrum of monoclonal gammopathy of renal significance (MGRS). The aim of the study was to describe the role of IgM in FGN as a possible marker of an underlying MGRS. METHOD A single-center, retrospective and observational study of FGN cases diagnosed during the period of 2012–2019 was performed. Kidney biopsies were retrospectively reviewed. All cases had a confirmatory diagnosis made with electron microscopy (EM). Due to a lack of material and the novelty of the marker, DNAJB9 was not performed in all samples. IF on frozen tissue was done in all cases; digestion with proteinase K was done in cases of light chain restriction to unmask possible deposits. Demographics, clinical presentations, associated conditions and outcomes were reviewed. Data were expressed as mean standard deviation (SD). RESULTS Our cohort consisted of 17 patients, all but 2 caucasians, 9 males and 8 women, with a mean age of 63.1 ± 13.2. The mean follow-up was of 34.6 months. At the time of the diagnosis, most patients presented with hypertension 70% (12). All patients had proteinuria (mean 24-h protein excretion of 4.84 g ± 5.2) and renal impairment with a medium creatinine of 203.8 ± 202. Full nephrotic syndrome was present in 29% (5) of the cases and microhematuria in 52.9% (9); complement was normal in all cases. As for related medical conditions: 23% (4) had history of autoimmune diseases, 17% (3) had diagnosis of a solid tumor, 76.5% (13) were smokers (2 with diagnosed chronic obstructive pulmonary disease) and 29% (5) had diabetes mellitus. Monoclonal gammopathy was present in 35.3% (6/17) of the cases, all of which had an identified monoclonal component detected by electrophoresis with immunofixation (SPEPE/SIF). Three of them (50%) progressed (2 to multiple myeloma, 1 to amyloidosis AL) (Fig. 1). Light microscopic study showed three distinct patterns of glomerular injury, being mesangial pattern the most common 82% (14/17). Staining with congo red was negative in all cases, 17 cases. By immunofluorescence only 82% (13) showed glomerular positivity for IgG. Unexpectedly 23% (4) showed exclusively IgM deposits; three of them had monoclonal gammopathy. Looking in depth, 5/6 of the patients with monoclonal gammopathy showed IgM deposits in contrast to the non-associated FGN cases (3/10) (Fig. 2). No cases of GNF with IgM deposits had underlying cryoglobulinemia; there was one case of diabetes mellitus. A total of 41% (7) end up needing renal replacement therapy (RRT). No differences in the rate of RRT were observed between patients with monoclonal gammopathy and without. CONCLUSION IgM deposits were observed in patients with FGN cases associated with monoclonal gammopathy. IgM deposition is a finding rarely described in the literature up to the date. In this regard, we hypothesize that IgM monoclonal gammopathy due to a conformational alteration in the protein could generate deposits in the form of fibrils triggering a possible GNF. Thus, IgM deposition in the context of GNF could be a marker of a possible underlying MGRS. Future studies proving IgM conformational alterations in these patients could corroborate our hypothesis.

BACKGROUND AND AIMS Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis characterized by inflammation of small blood vessels, being the kidney one of the most frequently affected organs. AAV has a high morbidity and mortality, developing rapidly progressive renal failure that could lead to end-stage renal disease (ESRD). The pathogenesis is complex and multifactorial; macrophages have turned out to be a key element in inflammation and also in fibrosis. As already described in previous publications, PR3-AAV and MPO-AAV show clinical-demographic differences and different renal phenotypes on kidney biopsy. Histopathological subgrouping into four classes (focal, crescentic, mixed and sclerotic, as defined by Berden et al.) was proposed to predict long-term renal survival rates, poorest in the sclerotic class. This classification, validated by our group and multiple others, is still under review. The aim of this study is to demonstrate whether interstitial fibrosis in AAV is at least as important as glomerular sclerosis in renal prognosis, being a differentiating element between MPO and PR3 vasculitis. METHOD We performed a retrospective single-center study of 95 AAV-patients (78 MPO-AAV and 17 PR3-AAV) diagnosed by renal biopsy from 1991 to 2021 and at least 1-year follow-up. Clinical and laboratory variables, presence and type of ANCA, immunosuppressant therapy and renal/patient survival were evaluated. Sixty-two kidney biopsy samples have been analyzed: histomorphometric quantification has been carried out using MetaMorph® software on trichrome-stained slides in order to measure the degree of fibrosis. Continuous variables were described using measures of central tendency and dispersion (mean and standard deviation), and categorical variables using frequency tables and percentages. Student's t-tests or Mann–Whitney U tests, as appropriate, were performed to evaluate differences in mean values, and chi-squared tests were used to evaluate differences in qualitative variables. Statistical significance was defined as P-values RESULTS PR3-AAV population was predominantly male (70%) with a mean age at diagnosis of 62 years and a mean follow-up of 54 months, while MPO-AAV population was mainly female (65.8%), mean age 66 years and follow-up 65 months. There were no statistically significant differences in renal function between MPO and PR3-AAV at diagnosis. However, our data showed that MPO-AAV had worse renal function than PR3-AAV at the end of follow-up (P = .01). Furthermore, it should be highlighted that renal function improved throughout the follow-up (P < .01 and P = .05 in MPO and PR3-AAV, respectively). From a histological point of view: MPO-AAV manifests more interstitial fibrosis at diagnosis than PR3-AAV (P = .01). However, there were no statistically differences in the amount of glomerular sclerosis. It is noteworthy that PR3-AAV showed more crescentic proliferation at diagnosis (P = .03) but less fibrotic crescents than MPO-AAV (not reaching statistical significance). CONCLUSION The method we used allows a quantitative assessment of renal fibrosis. Our data confirm that renal prognosis is better in PR3-AAV than in MPO-AAV, which could be explained by a greater interstitial fibrosis, as well as more fibrotic crescentic in MPO-AAV at diagnosis.

The current gold-standard diagnostic technique for IgA nephropathy (IgAN), the leading form of primary glomerulonephritis, is renal biopsy. CD89 (the main IgA receptor) is expressed on the surface of monocytes and plays a role in disease pathogenesis. Immunocomplexes formed by sCD89 (soluble form) and Gd-IgA1 are related to disease prognosis. We hypothesize that reduced CD89 surface expression on monocytes may be a marker of disease severity. We aimed to analyze leukocyte subpopulations in peripheral blood and CD89 surface expression on monocytes in a prospective study of 22 patients and 12 healthy subjects (HS). Leukocyte subpopulations and CD89 expression were analyzed by flow cytometry. IgAN patients had a higher percentage of activated and effector memory CD4+ and CD8+ T lymphocytes, a lower percentage of transitional B lymphocytes and plasmablasts, and a higher percentage of CD56dimCD16+ NK cells and myeloid dendritic cells compared with HS. Correlations between reduced CD89 expression levels on nonclassical monocytes, histological findings of a poor prognosis on renal biopsy and baseline renal function were observed. IgAN patients show a characteristic immunological pattern in peripheral blood. A reduced expression level of CD89 on nonclassical monocytes identifies patients with a worse renal prognosis.

Resumen La enfermedad renal cronica (ERC) se asocia a un incremento de la morbimortalidad. En la actualidad, a los factores de riesgo tradicionales se han unido otros no tradicionales, como las alteraciones del metabolismo mineral, como posible factor contribuyente a dicho aumento desproporcionado de mortalidad. Estas alteraciones oseominerales asociadas a la ERC han sido definidas con la presencia de uno o mas de los siguientes factores: 1) alteraciones bioquimicas (calcio, fosforo, parathormona y/o vitamina D); 2) presencia de anormalidades en la biopsia osea, y/o 3) calcificaciones vasculares (CV) o en otros tejidos blandos. En los ultimos anos se han disenado nuevas terapias para el control de las alteraciones bioquimicas, entre ellas destacan sevelamer, carbonato de lantano, activadores selectivos del receptor de la vitamina D y los calcimimeticos. La importancia del sevelamer recae en la atenuacion de la progresion de las CV y en la mejoria de la supervivencia en ciertos grupos de pacientes en programa cronico de hemodialisis. El carbonato de lantano disminuye efectivamente los niveles sericos de fosforo, pero debido a su corta experiencia, los resultados a largo plazo aun son poco conocidos. No obstante, existen datos preliminares retrospectivos sobre beneficios de supervivencia con su uso. Los activadores selectivos del receptor de la vitamina D, como el paricalcitol, poseen efectos diferenciales sobre las CV respecto al calcitriol, y se asocian tambien a un aumento de la supervivencia de los pacientes con ERC. Los calcimimeticos son muy utiles para alcanzar los propositos de las guias de practica clinica y sus resultados a largo plazo se estan evaluando en varios estudios prospectivos pendientes de finalizar. De hecho, resulta importante considerar que el tratamiento de las alteraciones oseominerales asociadas a la ERC deberia ser evaluado idealmente mediante estudios prospectivos con los distintos farmacos antedichos, y es posible que la combinacion de varios farmacos para el tratamiento de dicha entidad pueda ser superior a la monoterapia.