Focal segmental glomerulosclerosis: a very unusual complication of allogeneic hematopoietic cell transplantation (HCT)

Nephrotic syndrome (NS) is an extremely rare complication of hematopoietic cell transplantation (HCT) that usually occurs in association with chronic GVHD.1, 2, 3 Glomerular histology comprises mainly membranous nephropathy (MN) and minimal change disease. Conversely, focal segmental glomerulosclerosis (FSGS) is a very uncommon etiology of NS in patients undergoing HCT.4, 5, 6 Here, we report the case of a 49-year-old white man with the diagnosis of AML-M1 with no chromosome abnormalities who received an allogeneic PBSC transplantation from his HLA-identical brother at the Department of Hematology of our Hospital, 4 months after achieving CR with chemotherapy (mitoxantrone, 12 mg/m2; cytarabine, 500 mg/m2; etoposide, 200 mg/m2). A reduced intensity conditioning (RIC) regimen consisting of fludarabine (30 mg/m2/day, 5 days), anti-thymocyte globulin (2 mg/kg/day, 5 days), prednisone (2 mg/kg/day, 5 days) and melphalan (60 mg/m2/day, days −3 and −2) was used. In addition, he received cyclosporin (5 mg/kg/day, b.i.d.) and mycophenolate mofetil (2 g/day) for the prophylaxis of GVHD. Cyclosporin and mycophenolate mophetil were continued for 4 and 3 months, respectively. Asymptomatic CMV reactivation controlled with ganciclovir, limited acute GVHD with skin involvement, and septic shock with pulmonary origin, occurring within the first 2 weeks, were the most remarkable events in the post-HCT period. Eight months later, the patient presented with a rash on his face, on both forearms and on both lower limbs consistent with skin involvement of chronic GVHD. Coincidentally, he noticed edema of the lower limbs and weight gain (15% of body weight) for 1 month. Physical examination showed pitting edema of the lower limbs, and erythema of the face, forearms, as well as of lower limbs, with multiple areas of desquamation on both forearms and lower limbs. Laboratory findings showed hypoalbuminemia (21 g/L) and nephrotic-range proteinuria (8.3 g/day). There was no hematuria and renal function was normal (creatinemia, 0.8 mg/dl). Serology for lupus, as well as for human immunodeficiency virus types 1 and 2, hepatitis B and hepatitis C, was negative. Hematologically, recurrence of AML was not observed. Renal ultrasound revealed normal-sized and normoechoic kidneys, normal differentiation, and no hydronephrosis. The patient was referred to the Department of Nephrology of our Hospital. A renal biopsy was performed and revealed segmental sclerosis at the origin of the tubular pole in 3 of the 16 glomeruli observed; the remaining glomeruli had no changes (Figure 1). According to these findings, the diagnosis of FSGS (tip lesion) was established. The edema resolved with furosemide and spironolactone, and prednisone (1 mg/kg/day), cyclosporin (2 mg/kg/day, b.i.d.) and enalapril (5 mg/day) were started. Five months later, he was asymptomatic and proteinuria decreased to non-nephrotic range (300 mg/24 h). Serum albumin was 36 g/L and renal function remained stable (creatinemia, 1.0 mg per 100ml). Skin manifestations were no longer present. FSGS is an extremely rare complication of HCT. To our knowledge, to date there are only three previous reports linking FSGS to HCT, all of them occurring in myeloablative HCT.4, 6, 7 To our knowledge, the present case constitutes the first description of FSGS after nonmyeloablative HCT. The influence of the conditioning regimen on NS occurrence is controversial. A cohort study identified nonmyeloablative HCT as a risk factor for NS, because 7 of 163 patients developed this complication as opposed to none of 118 patients after myeloablative HCT, with comparable rates of chronic GVHD. Renal biopsy was performed in four cases and revealed MN.8 Because the vast majority (80%) of all cases reviewed in this study, aside from the mentioned cohort study, were myeloablative (data not shown) and the preparative regimen was not reported in several of the remaining cases, other authors claimed that a greater risk for NS posed by RIC than myeloablative preparation cannot be supported by this analysis, and hence follow-up of larger cohorts is warranted.1 In the present case, the patient coincidentally presented with cutaneous manifestations consistent with skin involvement by chronic GVHD, and NS. This suggests the possibility that NS may be a renal manifestation of chronic GVHD in an HCT patient. In fact, in almost half of the patients a concomitant temporal relationship between GVHD and NS can be observed, as NS appears simultaneously with chronic GVHD.1 The exact pathophysiology of NS associated with GVHD post-HCT remains as yet unknown and it is likely to be a consequence of the combination of complex interactions between allo-reactive T-cells, the nature of HLA mismatches, the cytokine milieu, the preparative regimen, B-cell dysregulation and perhaps even the underlying disease.2 In the case described here, NS and skin involvement by chronic GVHD occurred 8 months after cessation of prednisone and cyclosporin, and they did substantially improve 2 months after the reintroduction of the immunosuppressive medication. This finding is in line with the observation that in 58% of the cases NS occurred within 9 months after discontinuation of immunosuppression.1 Therefore, the time course between cessation of immunosuppression and onset of NS suggests the former as a risk factor. To the best of our knowledge, the occurrence of FSGS following HCT has only been reported in four individuals to date (including the one described here), but should be considered in the differential diagnosis of a patient with NS following HCT. The authors declare no conflict of interest. We thank Dr Fernanda Carvalho, Dr Helena Viana and Dr Lurdes Correia for providing the histological microphotographs.