Recurrence of Immunotactoid Glomerulopathy with Monoclonal IgG3κ Deposits after Kidney Transplant

Immunotactoid glomerulopathy (ITG), fi rst reported by Korbet et al. in 1985 as a glomerular deposition disease in which immunoglobulin-derived protein fi laments deposit in the glomeruli and cause a range of nephritis [1], is a rare renal disease found in fewer than 1% of all kidney biopsies [2,3]. It exhibits pathological manifestations ranging from mesangial proliferative glomerulonephritis to membranoproliferative glomerulonephritis (MPGN). Immunostaining is frequently positive for immunoglobulin G (IgG) κ or λ light chains and complement C3. Different from amyloidosis, Congo red staining is negative in ITG [4]. Although some patients reportedly respond to steroid therapy [5], the treatment is ineffective in up to half of all cases. These patients develop end-stage renal failure within a few years after onset.


Introduction
Immunotactoid glomerulopathy (ITG), fi rst reported by Korbet et al. in 1985 as a glomerular deposition disease in which immunoglobulin-derived protein fi laments deposit in the glomeruli and cause a range of nephritis [1], is a rare renal disease found in fewer than 1% of all kidney biopsies [2,3]. It exhibits pathological manifestations ranging from mesangial proliferative glomerulonephritis to membranoproliferative glomerulonephritis (MPGN). Immunostaining is frequently positive for immunoglobulin G (IgG) κ or λ light chains and complement C3. Different from amyloidosis, Congo red staining is negative in ITG [4]. Although some patients reportedly respond to steroid therapy [5], the treatment is ineffective in up to half of all cases. These patients develop end-stage renal failure within a few years after onset.
Few reports of kidney transplantation have been made for patients with ITG. Although ITG has a high rate of recurrence after kidney transplantation, loss of graft function reportedly progresses slowly. Some reports describe successful long-term graft survival after treatment for ITG recurrence. Therefore, kidney transplantation was not contraindicated for ITG [6].
Our patient with ITG experienced immediate recurrence after kidney transplantation. His recurrent ITG did not respond

Abstract
We report a case of rapid recurrence of immunotactoid glomerulopathy (ITG) with monoclonal IgG3κ deposits in a transplanted renal graft. A 55-year-old hemodialysis male patient due to ITG underwent an ABO-incompatible living-donor kidney transplantation. Proteinuria (3.11 g/day) and increased serum creatinine (2.52 mg/dL) were detected on postoperative day (POD) 4 due to acute antibody-mediated rejection (aAMR). Even after treatment for aAMR, proteinuria increased again to 4.5 g/day because of a recurrent ITG with IgG3κ subclass deposits. He returned to maintenance hemodialysis 9 months after transplantation.
This case underlines the importance of preoperative monoclonal paraproteinuria test to predict an ITG recurrence in the renal graft.
to steroid pulse therapy. Although plasmapheresis was effective initially, renal function deteriorated gradually and maintenance hemodialysis started 9 months after transplantation. We herein report the clinical course of this case and review the relevant literature.

Case Report
A 55-year-old man who developed nephrotic syndrome was diagnosed with ITG, proven by kidney biopsy in July (0.1 mg/kg/day) and mycophenolate mofetil (2 g/day) were started on preoperative day 6. In addition, 20 mg of anti-CD25 antibody, basiliximab (BXM) was administered twice on POD 0 and 4. The titer of anti-blood group A antibodies (Anti-A Ab) before admission was as low as 8 in both of IgG and IgM. Therefore, preoperative plasmapheresis was not done. The operation was conducted without any event. Immediate renal graft function was achieved. The serum creatinine (s-Cr) level decreased to 1.4 mg/dL at a nadir. Suffi cient urine volume was maintained for a few days. On POD 4, proteinuria (3.11 g/day) was detected with hematuria (≥100 red blood cells in a high power fi eld). On POD 11, s-Cr level was elevated to 2.52 mg/ dL. A transplanted kidney biopsy was conducted, revealing acute antibody-mediated rejection (aAMR). Plasmapheresis with steroid pulse therapy was performed for aAMR. Then s-Cr level was lowered and the amount of proteinuria also decreased to 0.85 g/day, while the microscopic hematuria persisted.
Although the biopsy showed aAMR and electron deposition, the latter of which suggested ITG recurrence, the main cause of elevation of s-Cr level was regarded as a result of aAMR at that time.
On POD 22, the s-Cr level increased again. A second renal biopsy was performed, the diagnosis of which was ITG recurrence. MPGN-like appearance was detected using light microscopy, which was similar to specimen of native kidney with ITG ( Figure 1 Although RXM and BXM were administered in accordance with our protocol for ABOI-KTx, and although plasmaphereses were also frequently conducted postoperatively, the transplanted kidney function deteriorated progressively. Finally, the recurred ITG advanced to a stage where it did not effectively respond to any conventional treatment for aAMR.

Discussion
This rare disease, ITG that is found in fewer than 1% of all kidney biopsies has characteristic electron-dense deposits Figure 1: Kidney biopsy showed a membranoproliferative glomerulonephritis-like appearance, although Congo red staining for amyloidosis was negative (b), which was similar to that of the patient's native kidney (a). ITG recurrence was therefore suspected in the transplanted kidney.  with a microtubular structure in the glomeruli visualized using electron microscopy, but appearing negative with Congo red staining [2]. Actually, ITG can be distinguished pathologically from other types of glomerulopathies accompanied with fi brillary deposits, such as fi brillary gromerulonephritis, lupus nephritis, cryoglobulinemia and light-chain deposition disease. The deposits in ITG appear as hollow, regularly arranged microtubulars, with diameter greater than 30 nm [7].
Clinically, ITG can engender proteinuria (often in the nephrotic range), microscopic hematuria and often hypertension, which might result in end stage renal disease necessitating renal replacement therapy in the long run [2].
ITG and other deposition diseases are well known for their frequent recurrences after KTx [8]. Although the rate of ITG recurrence is as high as 47-64% [7,9], kidney transplantation in patients with ITG is not contraindicated because of the presence of successful cases [10].
Korbet et al. reported a successful case of KTx for ITG [10].
Azathioprine, prednisolone and anti-lymphocytoglobulin were used as immunosuppressive agents. The graft function was stable for about fi ve years with no recurrence. Neither monoclonal proteinemia nor hypocomplementemia was detected. In the other three cases, ITG recurred within 1.5-19 months [11][12][13]. Prednisolone, cyclosporine, azathioprine, tacrolimus, mycophenolate mofetil and thymoglobulins were administered as immunosuppressants. Prednisolone pulse therapy, cyclophosphamide, rituximab and plasma exchange were added as treatment for recurrence. After these therapies, each graft function recovered and lasted more than 1 year.
Neither monoclonal proteinemia nor hypocomplementemia was detected in these cases.
Korbet et al. reported another case which resulted in graft loss [10]. In this case, ITG recurred about 4.5 years after transplantation. Although the treatment for recurrence was initially effective, the graft function deteriorated gradually within a year, with no evidence of monoclonal proteinemia or of hypocomplementemia. Although immunostaining was positive for IgG, λ, κ and C3 IgG subclass were not described in their report.
In our case, ITG recurred within a month and caused graft loss at the earliest timing after transplant when compared with previous reports, i.e. only 9 months after transplantation.
Comparison to other cases [11][12][13][14], revealed that IgG3 subclass and hypocomplementemia were detected only in our case (Table 1). Although no report described the association between IgG subclasses and ITG recurrence, IgG3 subclass is well known to have strong affi nity for complement and inducement of its activation [15].