TACROLIMUS, MYH9-RELATED, DISORDERS,MYH9-related disorders, angiotensin receptor blockers,Tacrolimus

MYH9-related disorders (MYH9RD) belong to a group of inherited diseases caused by mutations of MYH9 gene, which encodes non-muscle myosin heavy chain IIA. The aim of the study is to report a patient with MYH9RD with progressive proteinuria (PU) treated with combination therapy of ACE inhibitors (ACEi), angiotensin receptor blockers (ARB) and Tacrolimus (TAC). We report a girl with macrothrombocytopenia, Döhle like bodies in leukocytes, deafness, cataracts, hypertension, hematuria and continually increasing PU since 4 years of age reaching nephrotic level with generalized edemas at the age of 15 years. DNA analysis showed 7 known MYH9RD polymorphisms. Despite therapy with ACEi (Ramipril 0.1 mg/kg/d) and ARB (Losartan 1.0 mg/kg/d) since the age of 10 years, PU has been worsening to nephrotic range (5.4 g/24 h). The therapy with TAC has been started (TAC through level 2.8–4.0 μg/l) and has led to partial remission. After 3 month of combination therapy with TAC, ACEi and ARB, the ACEi was reduced (0.05 mg/kg/d) due to hypotension. This has led to a relapse of PU (6 g/24 h), which prompted re-increase of ACEi to the initial dosing (0.1 mg/kg/d); this combination therapy has then improved PU to 2.1 ± 0.59 g/24 h. The slopes of PU were significantly different when analyzed before TAC, on TAC + ACEi + ARB before PU relapse and on TAC + ACEi + ARB after PU relapse (+0.03,-0.74, −0.54 g/24 h/month; respectively, p = 0.019) suggesting a favorable effect of combination therapy with TAC and higher dose of ACEi and ARB. At the same time periods, the slopes of eGFR were not significantly different (−0.001, 0.037, 0.026 ml/s/1.73 m2/month; respectively, p = 0.75). The combination therapy with ACEi, ARB and TAC may lead to a significant improvement of proteinuria while preserving renal function in children with MYH9RD. We hypothesize that the therapy is effective not only via its hemodynamic changes, but also due to the TAC interaction with synaptopodin.