Allogenic and autologous types of hematopoietic stem cell transplantation (HSCT) are globally established strategies for treating malignant diseases (1). Short- and long-term survival has become prolonged, which in turn has increased the incidence of renal complications. Thus, nephropathy associated with HSCT should be carefully considered. Acute renal failure is caused during early HSCT by nephrotoxic agents, bacterial sepsis or hepatic veno-occlusive disease (VOD). However, late-onset HSCT-related renal complications defined as azotemia that occurs over 100 days after HSCT with concurrent hypertension and anemia in the absence of identifiable nephrotoxins, are not well understood (2, 3). Lawton et al (2) and Cohen (3) et al claimed from histological findings of humans and other animals that this type of complication is a result of total body irradiation (TBI). Therefore this condition is recognized as acute radiation nephritis, since it is primarily the endothelial cells which are damaged. Nephrotic syndrome (NS) is a rare type of late-onset nephropathy that occurs after HSCT. Suehiro et al (4) described one patient with NS and their review of the literature found only 12 others. Although most of these patients had membranous nephropathy, a few had minimal change disease (MCD). In general, proteinuria disappears soon with corticosteroid or cyclosporine (CsA) treatment in patients of idiopathic MCD. In the present patient, incomplete remission was achieved by long administration of CsA. Here, we describe a patient who developed late-onset NS after HSCT that was probably caused not only by chronic graft versus host disease (GVHD) but also by TBI.

An 18-year-old man noticed conjunctival bleeding and high fever in 1996 and he was diagnosed with acute lymphocytic leukemia (ALL). First and second remissions were achieved by chemotherapy. He underwent related identical allogenic peripheral blood stem cell transplantation (PBSCT) in August 2000. At that time, he received TBI (2 Gy ×2 for 3 consecutive days), cytarabine/cyclophosphamide as a conditioner and short-term methotrexate plus cyclosporine (CsA) as GVHD prophylaxis. Around the same time, he was also administered acyclovir, ceftazidime and amikacin. His laboratory data at the time of PBSCT showed serum albumin 4.8 g/dl, serum creatinine 0.5 mg/dl and normal urinalysis. From day 41 after PBSCT, low-grade fever, lip swelling and stomatitis gradually appeared. A lip biopsy indicated early chronic GVHD, but these signs were reduced without corticosteroid. Serum creatinine did not increase and urinalysis remained normal around or after PBSCT.

Proteinuria that had been asymptomatic had gradually increased according to a dipstick test 12 months after PBSCT. In March 2002, at the age of 24, he was admitted to our hospital for further evaluation of proteinuria. Upon admission (18 months after PBSCT), his blood pressure was 110/60 mmHg and edema of the lower extremities was absent. Urinalysis showed proteinuria (++), occult blood (–) and no casts. Laboratory data revealed 0.3 mg/dl creatinine, 3.91 g/dl albumin, WBC 7,300/μl, Hb 14.0 g/dl, Plt 28.4 ×10⁴/μl and positive anti-nuclear antibody. Urinary protein excretion was 1.6 g/day and creatinine clearance was 260 ml/min. Plasma renin activity was 4.0 ng/ml/h and the plasma aldosterone concentration was 91.7 pg/ml. A specimen of renal cortical tissue contained 20 glomeruli. Mesangial matrix expansion without apparent mesangial hypercellularity was either absent or very mild in all of the glomeruli, except in two that were obsolescent (Fig. 1A). Figure 1B shows the obvious focal double contour of the GBM. This mesangial interposition-like appearance was identified by electron microscopy (Fig. 1C). The GBM was irregularly thickened and the subendothelium had apparently loosened (Fig. 1D). An immunofluorescence study did not confirm deposition.

Follow-up proceeded on an outpatient basis and enalapril (5 mg/day) was prescribed. Proteinuria and hypoalbuminemia gradually developed. Prednisolone (30 mg/day) was started on September 2002 (24 months after PBSCT), but the proteinuria did not improve. The patient was re-admitted to our hospital on December 2002 with blood pressure of 130/88 mmHg, urinary protein excretion 4.0 g/day, serum albumin 2.03 g/dl and total cholesterol 315 mg/dl with normal renal function. Lip, oral mucosa and head skin lesions indicated chronic GVHD. Prednisolone (30 mg/day) for 2 months and methyl-prednisolone pulse therapy (1,000 mg/day intravenous drip infusion for 3 days) did not affect the proteinuria. This nephrotic syndrome was considered as steroid resistant. Therefore, we selected the next treatment modality using CsA (3–5 mg/kg/day) plus LDL (low density lipoprotein)-apheresis, but proteinuria remained. However, 12 months of CsA (2 mg/kg/day) improved not only proteinuria and hypoalbuminemia but also chronic GVHD reactions (Fig. 2).

Various renal complications can arise after HSCT. Hepatic VOD or sepsis and nephrotoxic antibiotics are often involved in acute renal failure that develops within 30 days after HSCT. Renal insufficiency, characterized as hemolytic-uremic syndrome, may result from large doses of cyclosporine or tacrolimus within the first 100 days after HSCT. On the other hand, late-onset renal failure occurs in up to 20% of HSCT survivors. Acute radiation nephritis caused by TBI can occur between 6 and 12 months after HSCT (2, 3) and chronic radiation nephritis can appear over 5 years thereafter (5). Nephrotic syndrome is another late-onset renal complication of HSCT. Suehiro et al (4) described a patient who became nephrotic after HSCT and their review of the literature revealed 12 others who developed nephrotic syndrome after HSCT. Their pathological diagnoses were membranous nephropathy (n=8), minor glomerular abnormalities (n=3) and diffuse proliferative glomerulonephritis (n=1). Almost all of these conditions were considered to be due to chronic GVHD.

Nephrotic syndrome after HSCT is rare. The present patient is similar to those summarized in Table 1 who were all clinically diagnosed with minimal change nephrotic syndrome (6–9). Five patients showed a chronic GVHD reaction and four of them received TBI. Although the glomerular abnormalities revealed by light microscopy and by immunofluorescence staining were apparently minor, electron microscopy revealed intramembranous or subepithelial dense deposits on the GBM from 4 patients. Three patients achieved complete remission with corticosteroids and/or immunosuppressants. The positive response to these agents might have involved cytokines released by donor T-lymphocytes that increased glomerular permeability (6–9). Chronic GVHD was considered to be the main cause of nephrotic syndrome in our patient, because of positive anti-nuclear antibody, electron-dense deposits on the glomerular basement membrane, and a positive response to immunosuppressants in parallel with the subsidence of the skin lesions caused by chronic GVHD.

A recent case report showed an increased production of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) from T cells concomitant with the onset of minimal change nephrotic syndrome in a patient who received HSCT (9). LDL-apheresis might absorb glomerular permeability factors (e.g. TNF-α, IFN-γ) in addition to LDL and help decrease proteinuria in patients with steroid-resistant nephrotic syndrome (10). Our patient also underwent therapy with LDL-apheresis, but nephrotic syndrome did not go into remission during the short term.

Nephrotic syndrome remained resistant to intensive treatment in the short time, irrespective of the minimal changes observed by light microscopy in glomeruli from our patient. Electron microscopy revealed a focal double contour with mesangial interposition, focal subepithelial deposits and subendothelial loosening. These findings showed endothelial cell damage that was unrelated to chronic GVHD in addition to immune complex-mediated immunity. Anti-cancer drugs and calcineurin inhibitors could have damaged endothelial cells during the 6 months of HSCT and after HSCT, respectively. Late endothelial damage is thought to arise because of TBI, and the GBM has a double contour in the kidney of irradiated patients (11). Drug-resistant nephrotic syndrome that persists after HSCT seems to be related to the effect of TBI. However, we supposed that chronic GVHD caused by an immunological mechanism was the main cause of nephrotic syndrome in this patient.

The frequency of HSCT as a treatment modality for malignant diseases has increased all over the world, including Japan. Renal complications after HSCT, particularly those of late onset, might also be increased along with the prolonged survival of patients undergoing HSCT. Documenting late-onset renal diseases after HSCT and improved understanding of their features are necessary to achieve a better prognosis for patients with nephropathies associated with HSCT.