Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study.

BACKGROUND: Subclinical inflammation, including borderline lesions (BL), is very common (30-40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function. METHODS: The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression. DISCUSSION: This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL. TRIAL REGISTRATION: clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1 . Protocol Version 2 of 21 January 2022. SPONSOR: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org .

C3 glomerulonephritis associated with monoclonal gammopathy of renal significance: case report.

BACKGROUND: Morbidity associated with monoclonal gammopathy of renal significance is high due to the severe renal lesions and the associated systemic alterations. Accordingly, early diagnosis is fundamental, as is stopping the clonal production of immunoglobulins using specific chemotherapy. CASE PRESENTATION: A 75-year-old man with chronic renal disease of unknown origin since 2010 experienced rapid worsening of renal function over a period of 6 mos. Bone marrow biopsy showed monoclonal gammopathy of undetermined significance. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence and a membranoproliferative pattern on light microscopy. Skin biopsy showed endothelial deposition of complement. Given both the renal and cutaneous involvement the patient was considered to have monoclonal gammopathy of renal significance. We considered an underlying pathogenic mechanism for the renal alteration secondary to activation of the alternative complement pathway by the anomalous immunoglobulin. Despite treatment with plasmapheresis, bortezomib and steroids, advanced chronic kidney disease developed. CONCLUSIONS: The possible underlying cause of the monoclonal gammopathy of renal significance suggests that monoclonal gammopathy should be considered in adult patients with membranoproliferative glomerulonephritis.

Time-Dependent Changes of Klotho and FGF-23 Levels after Kidney Transplantation: Role of Cold Ischemia Time, Renal Function and Graft Inflammation.

We investigated the evolution of serum klotho (s-Kl) and FGF-23 during the first two years post-kidney transplantation (KT), considering the cold ischemia time (CIT), glomerular filtration rate (GFR) and graft subclinical inflammation (SCI). We undertook a prospective, cohort, multicenter study of consecutive patients between April 2018 and January 2021 (with follow-up at 24 months). Subgroups were analyzed according to the median CIT (<14 vs. ≥14 h), the median GFR (≤40 vs. >40 mL/min/1.73 m2) and the presence of SCI at month 3. A total of 147 patients were included. s-Kl and fibroblast growth factor-23 (FGF-23) levels were measured at baseline and at months 3, 12 and 24. Graft biopsies (n = 96) were performed at month 3. All patients had low s-Kl levels at month 3. Patients with CIT < 14 h exhibited a significant increase in s-Kl at month 24. In patients with CIT ≥ 14 h, s-Kl at month 3 fell and lower s-Kl levels were seen at month 24. Patients with a GFR > 40 had a lesser decrease in s-Kl at month 3. FGF-23 fell significantly at months 3 and 12 in both GFR groups, a reduction maintained during follow-up. There were significant inter-group differences in s-Kl from months 3 to 24. CIT, GFR at 3 months and SCI were significantly associated with s-KI at month 3. A reduction in s-Kl at month 3 post-KT could be explained by longer CIT and delayed graft function as well as by impaired graft function. Early SCI may regulate s-Kl increase post-KT.

Monoclonal gammopathy of renal significance: Early diagnosis is key.

Monoclonal gammopathy of renal significance is a clinical-pathological entity grouping renal disorders secondary to the secretion of a monoclonal immunoglobulin synthesized by a B-cell-derived clone and/or plasma cells in a patient with no diagnostic criteria for multiple myeloma. This term applies to a concept recently introduced owing to the need to differentiate this entity from monoclonal gammopathy of undetermined significance, given the negative prognostic impact of its high morbidity and mortality resulting from both renal and systemic involvement, occasionally even progressing to advanced chronic kidney disease. The renal damage occurs via both direct pathogenic mechanisms, with the deposition of the monoclonal protein in different renal structures, as well as indirect mechanisms, acting as an autoantibody provoking dysregulation of the alternative complement pathway. The detection of this monoclonal protein and an early hematologic study are essential, as is the need for a kidney biopsy to establish the associated nephropathological diagnosis. Consequently, this then leads to the start of specific hematologic treatment to detain the production of the monoclonal protein and minimize renal and systemic injury.

Decrease in CD14++CD16+ Monocytes in Low-Immunological-Risk Kidney Transplant Patients with Subclinical Borderline Inflammation.

We determined the association between CD14++CD16+ monocytes and subclinical infiltrates that do not reach the histological threshold for rejection (≥Banff IA). We studied low-immunological-risk kidney-transplant recipients in a clinical trial (NCT02284464; EudraCT 2012-003298-24) whose protocol biopsy in the third month showed no significant changes or borderline lesions (BL). Flow cytometry was used to analyze the percentage of CD14++CD16+ monocytes in peripheral blood (PB) and blood from a fine-needle-aspiration biopsy (FNAB). A protocol biopsy was performed in 81 low-immunological-risk patients, of whom 15 were excluded (BK polyomavirus and rejection). The 28 (42.4%) with borderline lesions had significantly low levels of CD14++CD16+ in PB compared to patients with normal biopsies (7.9 ± 5.4 vs. 13.0 ± 12.8; p = 0.047). Patients without significant changes had similar percentages of CD14++CD16+ monocytes in the graft blood (GB) and FNAB blood. The percentage of these monocytes in the patients with an interstitial infiltrate, however, increased significantly in the FNAB blood compared to the GB: 16.9 ± 16.6 vs. 7.9 ± 5.4; p = 0.006. A difference of 50% in CD14++CD16+ in the GB versus the PB was a significant risk factor (p = 0.002) for BL, increasing the risk seven times. A decrease in CD14++CD16+ in the PB could be associated with the recruitment of these cells to the graft tissue in cases of subclinical BL inflammatory infiltrates below the threshold for rejection.

Clinical Relevance of Corticosteroid Withdrawal on Graft Histological Lesions in Low-Immunological-Risk Kidney Transplant Patients.

The impact of corticosteroid withdrawal on medium-term graft histological changes in kidney transplant (KT) recipients under standard immunosuppression is uncertain. As part of an open-label, multicenter, prospective, phase IV, 24-month clinical trial (ClinicalTrials.gov, NCT02284464) in low-immunological-risk KT recipients, 105 patients were randomized, after a protocol-biopsy at 3 months, to corticosteroid continuation (CSC, n = 52) or corticosteroid withdrawal (CSW, n = 53). Both groups received tacrolimus and MMF and had another protocol-biopsy at 24 months. The acute rejection rate, including subclinical inflammation (SCI), was comparable between groups (21.2 vs. 24.5%). No patients developed dnDSA. Inflammatory and chronicity scores increased from 3 to 24 months in patients with, at baseline, no inflammation (NI) or SCI, regardless of treatment. CSW patients with SCI at 3 months had a significantly increased chronicity score at 24 months. HbA1c levels were lower in CSW patients (6.4 ± 1.2 vs. 5.7 ± 0.6%; p = 0.013) at 24 months, as was systolic blood pressure (134.2 ± 14.9 vs. 125.7 ± 15.3 mmHg; p = 0.016). Allograft function was comparable between groups and no patients died or lost their graft. An increase in chronicity scores at 2-years post-transplantation was observed in low-immunological-risk KT recipients with initial NI or SCI, but CSW may accelerate chronicity changes, especially in patients with early SCI. This strategy did, however, improve the cardiovascular profiles of patients.

Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients.

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.

Monoclonal gammopathy of renal significance: Early diagnosis is key / Gammapatía monoclonal de significado renal: la clave es el diagnóstico precoz

Monoclonal gammopathy of renal significance is a clinical–pathological entity grouping renal disorders secondary to the secretion of a monoclonal immunoglobulin synthesized by a B-cell-derived clone and/or plasma cells in a patient with no diagnostic criteria for multiple myeloma. This term applies to a concept recently introduced owing to the need to differentiate this entity from monoclonal gammopathy of undetermined significance, given the negative prognostic impact of its high morbidity and mortality resulting from both renal and systemic involvement, occasionally even progressing to advanced chronic kidney disease. The renal damage occurs via both direct pathogenic mechanisms, with the deposition of the monoclonal protein in different renal structures, as well as indirect mechanisms, acting as an autoantibody provoking dysregulation of the alternative complement pathway. The detection of this monoclonal protein and an early hematologic study are essential, as is the need for a kidney biopsy to establish the associated nephropathological diagnosis. Consequently, this then leads to the start of specific hematologic treatment to detain the production of the monoclonal protein and minimize renal and systemic injury. (AU)

La gammapatía monoclonal de significado renal es una entidad clínico-patológica que agrupa los trastornos renales secundarios a la secreción de una inmunoglobulina monoclonal sintetizada por un clon derivado de células B y/o células plasmáticas en un paciente sin criterios de diagnóstico de mieloma múltiple. Este término se aplica a un concepto introducido recientemente debido a la necesidad de diferenciar esta entidad de la gammapatía monoclonal de significado incierto, teniendo en cuenta el impacto pronóstico negativo de su alta morbilidad y mortalidad a causa de la afectación tanto renal como sistémica, llegando en ocasiones a progresar a una enfermedad renal crónica avanzada. El daño renal se produce tanto por mecanismos patogénicos directos, con el depósito de la proteína monoclonal en diferentes estructuras renales, como por mecanismos indirectos, actuando como un autoanticuerpo que provoca la desregulación de la vía alternativa del complemento. La detección de esta proteína monoclonal y un estudio hematológico precoz son imprescindibles, así como la necesidad de una biopsia renal para establecer el diagnóstico nefropatológico asociado. En consecuencia, esto lleva al inicio de un tratamiento hematológico específico para detener la síntesis de la proteína monoclonal y minimizar la lesión renal y sistémica. (AU)

Clinicopathologic correlations of renal microthrombosis and inflammatory markers in proliferative lupus nephritis.

INTRODUCTION: Microthrombosis is often observed in lupus nephritis (LN) lesions, but its clinical significance is unknown. We evaluated the clinicopathologic correlations of renal microthrombosis and inflammatory markers in LN. METHODS: Kidney biopsies from 58 patients with systemic lupus erythematosus (SLE) proliferative nephritis were analyzed with immunohistochemistry (IHC) for intravascular platelet aggregates (CD61), macrophagic infiltration (CD68), and activated complement deposition (C4d). Clinical data at the time of kidney biopsy and follow-up were analyzed with regard to pathologic IHC data. RESULTS: Microthrombosis was present in 52% of the tissues. It was significantly more prevalent in patients with antiphospholipid antibodies (aPLs) (62% versus 42%). The presence of microthrombosis significantly correlated with higher macrophagic infiltration. Macrophagic infiltration but not microthrombosis was significantly correlated with C4d deposition. Only macrophagic infiltration showed a correlation with SLE and renal activity (proteinuria and active sediment), whereas neither the presence of CD61+ microthrombi nor the extent of C4d deposition correlated with LN severity or outcome. CONCLUSIONS: Microthrombosis is associated with higher macrophagic infiltration in LN but does not seem to increase independently the severity of renal damage. Macrophagic infiltration was the best marker of SLE and renal activity in this LN series.

Dislipemia y lipodistrofia en niños uruguayos VIH positivos en tratamiento antirretroviral / Dyslipidemia and lipodistrophy in HIV Uruguayan children under anti-retroviral therapy (HAART)

La sobrevida de los pacientes infectados por el virus de la inmunodeficiencia humana (VIH) ha mejorado con el tratamiento antirretroviral de alta eficacia. Nuevos problemas han surgido, como la aparición de efectos adversos.El objetivo del siguiente trabajo fue describir la prevalencia de lipodistrofia y dislipemia en niños infectados tratados y determinar si el estadio de la enfermedad y la duración del tratamiento se asocian con estas alteraciones.Material y método: estudio descriptivo de corte transversal. Se definió lipoatrofia al niño con índice de masa corporal (IMC) normal y pliegue tricipital <5percentil (p) o mejillas hundidas, o ambos; lipohipertrofia al IMC normal y pliegue subescapular >90p o grasa de disposición central, o ambos; lipodistrofia combinada, la que incluye ambos tipos. Se definieron hipertrigliceridemia e hipercolesterolemia a los valores >90p según tablas de referencia. Se clasificó la duración del tratamiento en menor e igual a cinco años y el estadio de la enfermedad. Los resultados se expresaron como porcentajes con sus intervalos de confianza de 95 p/ ciento. Se utilizó el test de c2.Resultados: se incluyeron 60 niños con una edad media de 6,8 años ± 3,3. Trece presentaron lipodistrofia (21,7p/ciento, IC95p/ciento,12,5-34,5) y 33 dislipemia (55 p/ciento, IC95 p/ciento, 41,7-67,7). Ni la dislipemia ni la lipodistrofia se asociaron al estadio de la enfermedad. La dislipemia mixta predominó en los niños con cinco años o más de tratamiento a diferencia de la hipertrigliceridemia. La lipodistrofia no se asoció a la duración del tratamiento.Conclusiones: la lipodistrofia y la dislipemia son alteraciones frecuentes. El monitoreo de los lípidos y de la composición corporal son imprescindibles para lograr niños más saludables.

Participación del laboratorio en el diagnóstico de mieloma múltiple: análisis de 16 casos / Participation of the laboratory in the diagnosis of multiple myeloma: analysis of 16 cases

Se analizan las características de laboratorio en 16 casos de Mieloma Múltiple, presentados en los últimos seis años. Se encontró que un 62,5% de los pacientes fueron mujeres. Un 56,3% de los casos tenían entre 51 y 70 años. Encontramos que un 75% de los casos presentó sólo anemia como alteración hematológica en sangre periférica. En un 83,3% de los pacientes, se encontró sobre un 30% de células plasmáticas en médula ósea. Un 57,1% de los Mielomas analizados, fueron IgG, y 28,6% IgA. El nivel promedio de Inmunoglobulinas, en los casos IgG, fue 8.574 mgr/dl y 5.135 mgr/dl en los IgA. Además, se presentan otras características hematológicas, inmunológicas y químicas observadas. La tasa de incidencia(1,1 al año, por cada 100 mil habts.), es baja en relación a lo descrito en la literatura. Se sugiere buscar más esta patología e implementar la técnica de Electroforesis de Proteínas en orina