Complement-Mediated Thrombotic Microangiopathy after Kidney Transplant: Should Treatment with C5 Inhibitor Be Lifelong?

Complement-mediated thrombotic microangiopathy (CM-TMA) is a rare and life-threatening complication that can occur in kidney transplant recipients, with various potential triggers including immunosuppressive medications. The optimal management and duration of treatment with C5 inhibitors (C5i) for CM-TMA in this patient population remain areas of ongoing investigation. We present the case of a 38-year-old female with a history of IgA nephropathy who underwent preemptive living-related kidney transplantation and subsequently developed CM-TMA 7 years post-transplant. Treatment with ravulizumab led to a rapid hematologic response and stabilized platelet counts. Serial measurements of complement functional tests and clinical stability guided the discontinuation of C5i therapy. The case highlights the complexity of managing CM-TMA in kidney transplant recipients, particularly in determining the appropriate duration of C5i therapy. The absence of an established protocol for discontinuation necessitates a personalized approach based on clinical and laboratory stability, absence of complement gene variants, and serial complement functional tests. Further prospective investigations are warranted to define the optimal strategies for monitoring and safely discontinuing C5i therapy in this unique patient population. This case underscores the importance of individualized care in the management of CM-TMA post-kidney transplantation, offering insights into potential criteria for therapy discontinuation.

Case report: Thrombotic thrombocytopenic purpura in a pregnant woman with lupus membranous nephropathy: a diagnostic challenge.

A 27-year-old female at 20th week of pregnancy was admitted with edema, foamy urine, but normal blood pressure. Her blood count was normal, she had proteinuria of 3 g/day, creatinine 0.4 mg/dl, albumin 2.4 g/dl, and cholesterol 355 mg/dl. Antinuclear antibodies 1/160, but Anti-DNA, anticardiolipin antibodies and lupus anticoagulant were negative, with normal serum C3 and C4. A renal biopsy showed secondary membranous glomerulopathy, most likely lupus class V pure. Steroids, azathioprine, and aspirin were initiated, up to 28 weeks of pregnancy, when she developed severe hypertension, photopsia, headache, anasarca, extensive bruising of the extremities, severe anemia, thrombocytopenia, and creatinine rose to 2.09 mg/dl with preserved diuresis. A female infant, 1045 grams, was delivered by emergency caesarean section. Following the surgery, she experienced diplopia, dysarthria, bradypsychia, and sensory alterations in the lower extremities, necessitating emergency hemodialysis due to pulmonary congestion. Blood smear revealed schistocytes, LDH elevated at 1148 IU/L, while transaminases and liver function remained normal, suggesting thrombotic thrombocytopenic purpura. ADAMTS13 revealed 6% activity with the presence of inhibitor. Mycophenolate and daily plasmapheresis with fresh frozen plasma replacement yielded unsatisfactory response, unaffected by the addition of methylprednisolone pulses and rituximab. Eventually, intravenous cyclophosphamide was introduced, resulting in complete hematological remission and normalization of ADAMTS13, however dialysis-dependence persisted and four years later, right renal cancer prompted bilateral nephrectomy. After a total follow-up of six years, she remained free of neoplastic recurrence and lupus activity, receiving prednisone and hydroxychloroquine. The differential diagnosis of microangiopathic syndrome in a pregnant lupus patient is discussed.

Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common complications of diabetes, and currently the first end-stage renal disease worldwide. New strategies to treat DN using agents that target inflammatory pathways have attracted special interest. Recent pieces of evidences suggest a promising effect of IL-17A, the Th17 effector cytokine. Among experimental DN models, mouse strain BTBR ob/ob (leptin deficiency mutation) develops histological features similar to human DN, which means an opportunity to study mechanisms and novel therapies aimed at DN regression. We found that BTBR ob/ob mice presented renal activation of the factors controlling Th17 differentiation. The presence of IL-17A-expressing cells, mainly CD4+ and γδ lymphocytes, was associated with upregulation of proinflammatory factors, macrophage infiltration and the beginning of renal damage. To study IL-17A involvement in experimental DN pathogenesis, treatment with an IL-17A neutralizing antibody was carried out starting when the renal damage had already appeared. IL-17A blockade ameliorated renal dysfunction and disease progression in BTBR ob/ob mice. These beneficial effects correlated to podocyte number restoration and inhibition of NF-κB/proinflammatory factors linked to a decrease in renal inflammatory-cell infiltration. These data demonstrate that IL-17A takes part in diabetes-mediated renal damage and could be a promising therapeutic target to improve DN.

Lesiones renales en el lupus eritematoso diseminado: ausencia de relación entre datos clínicos e histológicos / Kidney injury in systemic lupus erythematosus: lack of correlation between clinical and histological data

ANTECEDENTES: La presencia y patrón morfológico del compromiso renal afecta el pronóstico del lupus eritematoso sistémico, información que puede ser indispensable para tomar decisiones terapéuticas apropiadas. OBJETIVO: Evaluar relación estadística entre datos clínicos e histológicos en pacientes con nefropatía lúpica biopsiada. MÉTODOS: Revisión de información clínica en solicitudes de biopsias renales de adultos, informadas entre 2002 y 2014, con diagnóstico clínico e histopatológico inequívoco de compromiso renal por lupus eritematoso sistémico. RESULTADOS: Ciento treinta y cuatro casos (86% mujeres), edad 15-59 años. Cuadro clínico: 30% alteraciones urinarias asintomáticas, 9% proteinuria nefrótica sin hipoalbuminemia, 19% síndrome nefrótico y 40% por insuficiencia renal, existiendo 2 casos sin manifestaciones clínicas renales. Las lesiones más frecuentes fueron proliferativas puras (68%). De los que tenían alteraciones urinarias asintomáticas, 35% eran clase IV, 30% clase III, 23% mixtas, 10% clase V y 2% clase II. Entre los de proteinuria nefrótica, 75% clase IV, 17% mixtas y 8% III. De los de síndrome nefrótico, 46% clase IV, 27% V, 19% mixtas y 8% clase III. Entre los de insuficiencia renal, el 67% eran IV, 22% mixtas, 7% III y 4% V. Estas proporciones no fueron estadísticamente diferentes. Aunque la peor función renal fue observada en la clase IV, casi la mitad (44%) de aquellos sin insuficiencia renal eran de esta misma clase. CONCLUSIÓN: No se demuestra una relación clínico-histológica consistente que permita predecir los patrones ni la gravedad de los hallazgos histológicos a partir del cuadro clínico en el lupus eritematoso sistémico con manifestaciones renales. Esos resultados refuerzan la importancia de la biopsia como herramienta diagnóstica fundamental en esta enfermedad

BACKGROUND: The existence and type of renal involvement influences the prognosis of systemic lupus erythematosus and this information may be critical when it comes to taking appropriate therapeutic decisions. OBJECTIVE: To evaluate statistical correlations between clinical and histological data in patients with biopsied lupus nephropathy. METHODS: Review of clinical information in adult kidney biopsy requests reported between 2002 and 2014 with a definitive clinical and histopathological diagnosis of renal involvement in systemic lupus erythematosus. RESULTS: 134 cases (86% women), aged 15-59 years. Indication for renal biopsy: asymptomatic urinary abnormalities (30%), nephrotic proteinuria without hypoalbuminaemia (9%), nephrotic syndrome (19%), renal failure (40%) and two cases without clinical renal manifestations. The most common lesions were purely proliferative (68%). In patients with asymptomatic urinary abnormalities, 35% were class IV, 30% class III, 23% mixed, 10% class V and 2% class II. In subjects with nephrotic proteinuria, 75% were class IV, 17% mixed and 8% class III. In nephrotic syndrome patients, 46% were class IV, 27% class V, 19% mixed and 8% class III. In renal failure subjects, 67% were class IV, 22% mixed, 7% class III and 4% class V. These proportions were not statistically different. Although class IV showed the worst renal function, almost half (44%) of those without renal failure belonged to this class. CONCLUSION: We could not demonstrate a consistent clinical-pathological relationship that predicts patterns or severity of histological findings based on the clinical profile in patients with systemic lupus erythematosus and renal manifestations. These results highlight the importance of biopsy as a key diagnostic tool in this disease

Kidney injury in systemic lupus erythematosus: lack of correlation between clinical and histological data. / Lesiones renales en el lupus eritematoso diseminado: ausencia de relación entre datos clínicos e histológicos.

BACKGROUND: The existence and type of renal involvement influences the prognosis of systemic lupus erythematosus and this information may be critical when it comes to taking appropriate therapeutic decisions. OBJECTIVE: To evaluate statistical correlations between clinical and histological data in patients with biopsied lupus nephropathy. METHODS: Review of clinical information in adult kidney biopsy requests reported between 2002 and 2014 with a definitive clinical and histopathological diagnosis of renal involvement in systemic lupus erythematosus. RESULTS: 134 cases (86% women), aged 15-59 years. Indication for renal biopsy: asymptomatic urinary abnormalities (30%), nephrotic proteinuria without hypoalbuminaemia (9%), nephrotic syndrome (19%), renal failure (40%) and two cases without clinical renal manifestations. The most common lesions were purely proliferative (68%). In patients with asymptomatic urinary abnormalities, 35% were class IV, 30% class III, 23% mixed, 10% class V and 2% class II. In subjects with nephrotic proteinuria, 75% were class IV, 17% mixed and 8% class III. In nephrotic syndrome patients, 46% were class IV, 27% class V, 19% mixed and 8% class III. In renal failure subjects, 67% were class IV, 22% mixed, 7% class III and 4% class V. These proportions were not statistically different. Although class IV showed the worst renal function, almost half (44%) of those without renal failure belonged to this class. CONCLUSION: We could not demonstrate a consistent clinical-pathological relationship that predicts patterns or severity of histological findings based on the clinical profile in patients with systemic lupus erythematosus and renal manifestations. These results highlight the importance of biopsy as a key diagnostic tool in this disease.

Recomendaciones sobre el manejo del compromiso renal del lupus eritematoso sistémico: Documento de Consenso de las Sociedades Chilenas de Nefrología y Reumatología / A consensus of the Chilean Nephrology and Rheumatology Societies on renal involvement in systemic lupus erythematosus

Renal involvement affects over one half of patients with Systemic Lupus Erythematosus increasing their mortality and morbidity, including chronic renal disease and the need of renal replacement therapies. Aiming to achieve a consensus in the most relevant topics on diagnosis, therapy and follow-up of patients with lupus renal disease, the Chilean Societies of Nephrology and Rheumatology constituted a workgroup that, based on a critical review of the available literature and their experience, raised and answered by consensus a set of relevant questions. This document includes aspects related to the clinical diagnosis, the importance of a suitable histological classification, therapeutic alternatives to induce and maintain disease remission, strategies for follow-up, additional therapies and ginecological-obstetric issues.

[A consensus of the Chilean Nephrology and Rheumatology Societies on renal involvement in systemic lupus erythematosus]. / Recomendaciones sobre el manejo del compromiso renal del lupus eritematoso sistémico: Documento de Consenso de las Sociedades Chilenas de Nefrología y Reumatología.

Renal involvement affects over one half of patients with Systemic Lupus Erythematosus increasing their mortality and morbidity, including chronic renal disease and the need of renal replacement therapies. Aiming to achieve a consensus in the most relevant topics on diagnosis, therapy and follow-up of patients with lupus renal disease, the Chilean Societies of Nephrology and Rheumatology constituted a workgroup that, based on a critical review of the available literature and their experience, raised and answered by consensus a set of relevant questions. This document includes aspects related to the clinical diagnosis, the importance of a suitable histological classification, therapeutic alternatives to induce and maintain disease remission, strategies for follow-up, additional therapies and gynecological-obstetric issues.

Podocyte-specific overexpression of wild type or mutant trpc6 in mice is sufficient to cause glomerular disease.

Mutations in the TRPC6 calcium channel (Transient receptor potential channel 6) gene have been associated with familiar forms of Focal and Segmental Glomerulosclerosis (FSGS) affecting children and adults. In addition, acquired glomerular diseases are associated with increased expression levels of TRPC6. However, the exact role of TRPC6 in the pathogenesis of FSGS remains to be elucidated. In this work we describe the generation and phenotypic characterization of three different transgenic mouse lines with podocyte-specific overexpression of the wild type or any of two mutant forms of Trpc6 (P111Q and E896K) previously related to FSGS. Consistent with the human phenotype a non-nephrotic range of albuminuria was detectable in almost all transgenic lines. The histological analysis demonstrated that the transgenic mice developed a kidney disease similar to human FSGS. Differences of 2-3 folds in the presence of glomerular lesions were found between the non transgenic and transgenic mice expressing Trpc6 in its wild type or mutant forms specifically in podocytes. Electron microscopy of glomerulus from transgenic mice showed extensive podocyte foot process effacement. We conclude that overexpression of Trpc6 (wild type or mutated) in podocytes is sufficient to cause a kidney disease consistent with FSGS. Our results contribute to reinforce the central role of podocytes in the etiology of FSGS. These mice constitute an important new model in which to study future therapies and outcomes of this complex disease.