Abatacept in B7-1–Positive Proteinuric Kidney Disease

Yu, Chih Chuan; Fornoni, Alessia; Weins, Astrid; Hakroush, Samy; Maiguel, Dony; Sageshima, Junichiro; Chen, Linda; Ciancio, Gaetano; Faridi, Mohd Hafeez; Behr, Daniel; Campbell, Kirk N.; Chang, Jer Ming; Chen, Hung Chun; Oh, Jun; Faul, Christian; Arnaout, M. Amin; Fiorina, Paolo; Gupta, Vineet; Greka, Anna; Burke, George W.; Mündel, Peter

doi:10.1056/nejmoa1304572

Cited by 336 publications

(330 citation statements)

References 15 publications

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“…Sirolimus may accelerate progression of FSGS and should be avoided (93). Ongoing and recently completed phase 3 trials have shown some efficacy with sparsentan, an irbesartan-like molecule that also antagonizes endothelin receptor, and abatacept, a CD80 antagonist (121).…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

378

308

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Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies arenow recognized asdrivers of FSGS: high-penetrance geneticFSGSdue to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g., to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

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Section: Therapeutic Approachesmentioning

confidence: 99%

Focal Segmental Glomerulosclerosis

Rosenberg

Kopp

2017

CJASN

378

308

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“…There have been isolated case reports documenting resolution of recurrent FSGS in patients who received abatacept in doses that have been utilized for the treatment of systemic lupus erythematosus [81]. However, this observation has not been replicated by other investigators who failed to achieve permanent remission in patients with recurrent FSGS [82].…”

Section: Treatmentmentioning

confidence: 99%

Recurrent focal segmental glomerulosclerosis after kidney transplantation

2015

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Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents and nearly 50 % of affected patients will progress to endstage kidney disease over a 5 to 10-year period. Unfortunately, there is no established treatment for disease in the native kidney. Moreover, up to 55 % of patients develop recurrent disease after receiving a kidney transplant, with a substantially higher risk in patients who have already experienced recurrent disease in a prior transplant. A number of clinical and laboratory factors have been identified as risk factors for this complication. In addition, new investigations into podocyte biology and circulating permeability factors have shed light on the cause of recurrent the disease. While a number of novel therapeutic agents have been applied in the management of this problem, there still is no proven treatment. In this review, we summarize recent advances in the epidemiology, pathophysiology, and treatment of recurrent FSGS in pediatric patients who have received a kidney transplant.

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“…Serum and urinary CTLA-4 levels tend to be low in MCD patients in relapse, and the urinary CTLA-4 level returns to higher levels during remission [95]. Yu et al described the use of abatacept in inducing remission in five patients with FSGS based on positive staining for CD80 in glomerular podocytes, reporting a clinically significant reduction in proteinuria in all patients [96]. However, the validity of these findings were questioned by other researchers [97,98].…”

Section: Abataceptmentioning

confidence: 99%

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Müller-Deile

Schiffer

2015

Pediatr Nephrol

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Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active insideout signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.

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Abatacept in B7-1–Positive Proteinuric Kidney Disease

Cited by 336 publications

References 15 publications

Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis

Recurrent focal segmental glomerulosclerosis after kidney transplantation

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

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