Recurrent or De Novo IgA Nephropathy with Crescent Formation after Renal Transplantation

Abstract

IgA nephropathy is the most common glomerular disease in China, accounting for 38.8% of primary glomerular disease. It has been reported that 20.8% patients of IgA nephropathy had a different degree of crescent formation. From January 1995 to December 2004, 1000 patients had undergone cadaveric renal transplantation, and 1742 allograft renal biopsies were reviewed in the Department of Nephrology at Jinling Hospital, Nanjing University. Among them, 18 cases were found with crescent formation, in which 10 patients were diagnosed as recurrent or de novo IgA nephropathy because their immunofluorescence showed strong IgA deposition in mesangial area and capillary. The initial treatment protocol was CsA+Azp+Pred, except in two cases of CsA+MMF+Pred. There were 8 males and 2 females, with ages from 25 to 69 (mean of 37.1) years old. All of them showed progressive renal dysfunction with increasing level of serum creatinine ranged from 1.48 to 6.25 mg/dL. Seven cases presented edema with an increasing level of proteinuria (1.36 to 3.58 g/24hr), and nine cases presented with hematuria ranging from 50 to 1250 × 10⁴/mL (one showed gross hematuria). In pathological examinations, they showed mesangial proliferation and matrix expansion with 10% to 66.7% crescents (mean of 37.5%) in their allograft renal biopsy's samples. All patients changed their immunosuppressive regimens; however, nine of them eventually advanced to ESRD and returned to hemodialysis after 6 to 36 months. Two cases received second renal transplantation after six months to five years, and one kept stable renal function with 2.5 mg/dL of serum creatinine after three years of follow-up. IgA nephropathy with crescentic formation was not rare in renal allografts or native glomerulonephritis in Chinese patients. These patients showed rapidly progressive renal dysfunction, and most of them lost graft function and needed hemodialysis therapy.

Keywords:

• recurrent IgA nephropathy
• kidney transplantation
• crescent

INTRODUCTION

IgA nephropathy is the most common form of glomerular disease in Chinese, accounting for 39.9% of primary glomerulopathy.[1],[2] It has been reported that 20.8% of cases of IgA nephropathy was found with crescent formation in renal histological examinations.[3] As is well known, many glomerular diseases may be recurrent after renal transplantation; however, recurrent IgA nephropathy after kidney allograft was also the most common form. It has been estimated that approximately 20–24.3% of Chinese,[4],[5] as well as 50–60% of western renal transplant recipients, with IgA nephropathy as the cause of their original kidney disease will develop recurrent disease.[6],[7] Clinically, the manifestation of recurrent IgA nephropathy is often associated with microscopic hematuria and intermittent proteinuria, a benign prognosis.[8] Though rare, patients with recurrent IgA nephropathy can present with rapidly progressive glomerulonephritis and subsequent graft loss, characterized by a various degree of crescent formation in histological examination.[9–12]

In this study, we retrospectively analyzed our ten kidney transplanting patients who had renal biopsy proven IgA nephropathy with a different degree of crescentic formation in order to investigate their clinical and pathological features and renal outcome.

PATIENTS AND METHODS

Patients

Between January 1995 and December 2004, a total of 1,000 patients with a history of cadaveric kidney transplantation were followed up at the Center of Kidney Transplantation, Department of Nephrology, at Jinling Hospital, Nanjing University School of Medicine, in Nanjing, China. In all, 1,742 allograft renal biopsies were performed on those 1,000 recipients. In histology, we studied all renal allograft biopsy specimens and found that 18 patients presented with some degree of crescent formation. The cellular crescents were defined according to widely accepted WHO definition as two or more layers of proliferative cells and inflammatory cells within bowman's space (see Figure 1).[13] Among them, ten cases were diagnosed as recurrent or de novo IgA nephropathy according to immunopathological examination, of which eight were confirmed previously by native kidney biopsies on the initial glomerular disease presentation (see Table 1).

Table 1 Histological changes and immunohistological findings

	Crescent (%)	Cellular crescent(%)	Glomerular sclerosis (%)	Mesangial proliferation	Tubularatrophy	Interstitialfibrosis	Infiltrating cells	IgA mesangial area deposition	Disease in native kidney
1	60	40	30	++	+++	+++	++	++	IgAN
2	20	20	15	++	++	+	+	+	IgAN
3	50	100	25	++	++	++	+++	+	No data
4	66.7	100	20	+	+++	+++	+++	++	IgAN
5	20	50	50	++	++	++	++	++	No data
6	20	100	15	++	++	++	+	+	MPGN I
7	35.5	15	25	+	+++	++	++	++	IgAN
8	40	50	10	++	+	++	++	++	IgAN
9	10	50	20	+	+	+	+	+	Vasculitis
10	50	20	40	++	++	+	++	++	APKD

Figure 1. Cellular crescent in PAS (×400).

Diagnosis of Recurrence or De Novo

The diagnosis of recurrent or de novo IgA nephropathy was based on an allograft biopsy showing deposits of immunoglobin A (IgA) on immunofluorescence (see Figure 2). In our patients, five cases confirmed as IgA nephropathy previously by native renal biopsy was diagnosed with certain recurrence; three cases confirmed as type I of membranous proliferative glomerulonephritis (MPGN I), autosomal polycystic kidney disease (APKD), and vasculitis previously by native renal biopsy were labeled de novo IgA nephropathy; while renal biopsy on native kidney was not performed in two cases. In patients with a biopsy-proven diagnosis of IgA nephropathy, the features of microscopic hematuria or proteinuria more than 0.4 g per 24 hours with or without graft dysfunction that were not attributable to other causes were considered the first sign of recurrent or de novo IgA nephropathy.

Figure 2. IgA deposition on mesangial area in IF.

Histological Examinations

In this study, the allograft renal biopsies contained 10 to 46 glomeruli per specimens. All of specimens in those cases of recurrent IgA nephropathy were re-examined by another pathologist. The glomerular histological changes, including globe or focal sclerosis, mesangial proliferation, and crescent formation, were determined. The tubular and interstitial lesions including tubular atrophy and interstitial fibrosis were semi-quantitatively grade mild (+), moderate (++), or severe (+++). Immunofluorescence microscopy was performed using fluorescent-labeled rabbit antihuman IgG, IgA, IgM, C3, and C4.

Immunosuppressive Regimens

Before September 1997, there were eight patients who were administered the old triple immunosuppressive regimen (i.e., cyclosporine [CsA, initially 6–7 mg/kg/day], azathioprine [Azp, 1 mg/kg/day], and prednisolone [Pred, initially 80 mg/day, with gradual taper]). After October 1997, two patients received a new triple immunosuppressive regimens (i.e., CsA [initially 6–7 mg/kg/day], mycophenolate mofetil [MMF, 0.75–1.0 twice/day], and Pred [initially, 80 mg/day, with gradual taper]).

RESULTS

General Conditions

From 1994 to 2004, a duration of 10 years, cadaveric kidney transplantation was performed for 1,000 patients. Among them, 243 cases were confirmed recurrent or de novo IgA nephropathy, and 10 recipients were diagnosed as recurrent or de novo IgA nephropathy with crescent formation.

These 10 patients, eight male and two female, were 25 to 69 years old. The duration from beginning kidney transplantation to diagnosing recurrent or de novo IgA nephropathy was three to seven years.

Clinical Manifestations and Laboratory Findings

All of patients represented rapidly progressive glomerulonephritis syndrome. The level of serum creatinine was sharply increased (1.45 to 6.25 mg/dL), accompanied by the appearance of microscopic hematuria (38 to 1250 × 104/mL) and an increase of urinary protein excretion (1.36 to 3.20 gm/24 hours; see Table 2). There was gross hematuria in one, oliguria in two, severe edema in four, nocturia in six, severe anemia (Hg < 9.0gm/dL) in seven, and hypertension in eight cases.

Table 2 Clinical manifestations and laboratory findings

	Y/Sex	Time from Tx	Hypertension	Upro(g/d)	URBC (10^4/mL)	HB (<90g/L)	Scr (mg/dL)	Initial treatment	Changing treatment	Follow-up
1	26/M	4y	+	3.2	1500	+	3.56	CsA+Azp+Pred	MP, Azp to MMF	Re-transplant after 6 mo
2	25/M	5y	+	1.8	245	−	1.79	CsA+Azp+Pred	MP, Azp to MMF	Return to HD after 6 mo.
3	28/M	4y	+	+++	126	+	4.68	CsA+Azp+Pred	MP, CsA to FK506	Return to HD after 1 yr
4	28/M	6.5y	+	3.14	420	+	3.73	CsA+Azp+Pred	MP, Azp to MMF	Return to HD after 2 yr
5	31/M	6.5y	+	1.50	110	+	6.25	CsA+Azp+Pred	MP+CRRT	Return to HD after 2 mo
6	32/M	6y	−	1.88	56	+	2.83	CsA+Azp+Pred	MP, Azp to MMF	Return to HD after 6 mo
7	28/M	3y	+	2.05	68	+	2.94	CsA+MMF+Pred	MP, CsA to FK506	Return to HD after 3 yr
8	48/M	4y	+	++	672	+	2.65	CsA+Azp+Pred	MP, FK506+MMF	Re-transplant after 5 yr
9	69/F	7y	−	1.54	536	−	1.45	CsA+Azp+Pred	MP, CsA to FK506	SCr kept stable (2.5mg/dL) for 3 yr
10	45/F	4.5y	+	1.36	123	−	3.80	CsA+MMF+Pred	MP, CsA to FK506	Return to HD after 8 mo

Abbreviations: M = male, F = female, Y = years, y = years, Tx = transplantation, Upro = urinary protein, URBC = urinary red blood cell, Scr = serum creatinine, HD = hemodialysis

Light Microscopy Examinations

All of cases showed diffuse mesangial proliferation and matrix expansion in the glomeruli associated with a varying degree of crescent formation from 10–66.7% (see Table 1). All patients had a different degree of focal and globe glomerulosclerosis from 10–40%. We found vasculitis in two, tubulitis in three, moderate or severe interstitial fibrosis in seven, and moderate or severe tubular atrophy in eight cases. In all cases, a varying degree of infiltrating cells, including CD4- and CD8-positive cells and monocytes in the interstitium, was observed.

Treatment and Outcomes

After making a diagnosis of recurrent or de novo IgA nephropathy with crescent formation, all cases were administered methylprednisolone pulse therapy (0.5 g intravenous injection per day for three times). Except for five cases, the other nine patients changed their immunosuppressive protocol (CsA+MMF+Pred in seven and FK506+MMF+Pred in two cases; see Table 2). However, these nine patients eventually advanced to ESRD and returned to hemodialysis after 2, 6, 6, 6, 8, 12, 28, 39, and 60 months, of which two cases received second renal transplantation after six months to five years, and only one (case 9) kept stable renal function with 2.5 mg/dL of serum creatinine after three years of follow-up.

DISCUSSION

IgA nephropathy, which is the most common form of primary glomerulonephritis disease worldwide as well as of recurrent glomerular disease, has a recurrent rate of approximately 50% in kidney allograft.[6–8] It has been reported that recurrent IgA nephropathy occurred more frequently in living, related recipients, and in one series, a recurrence rate of up to 83% was found.[14] In this study, we first reported 10 Chinese cases of recurrent or de novo IgA nephropathy with crescent formation from 10–66.7%, accounting for 0.1% of our patients with kidney transplantation, 4.12% of patients who diagnosed recurrent or de novo IgA nephropathy,[4] and 55.6% of allograft kidney with crescent formation.

As early as 1975, Berger et al.[15] observed 12 patients with kidney transplantation, of which 58% were histologically proven with recurrent IgA nephropathy in the transplant allograft 6 to 48 months after transplantation. Recently, Kowalewska[12] has reported eight cases of renal biopsy diagnosed as recurrent or de novo IgA nephropathy with crescent formation from 1.75 to 20 years post-renal transplantation. In our patients, recurrent or de novo IgA nephropathy with crescent formation was confirmed three to seven years after kidney transplantation. Clinically, as with primary IgA nephropathy, the majority of patients with recurrent IgA nephropathy showed microscopic hematuria and intermittent proteinuria and had a benign prognosis.[8] However, a small group of patients presented a rapidly progressive glomerulonephritis, and subsequent allograft loss was proven severe pathological changes with a various degree of crescent formation in histology.[9–12] We reported 10 cases that were diagnosed as recurrent or de novo IgA nephropathy with crescent formation. They aged from 25 to 65 years old, and 80% were male. Clinically, all of our patients presented rapid graft function loss, associated with severe hematuria and heavy proteinuria.

Recently, Floege[8] has completed a review about 1200 cases of recurrent IgA nephropathy. They showed an average of five years in follow-up. Eventually, only 13% of the patients would exhibit some recurrence-related renal graft dysfunction and approximately 5% would have lost their graft as a result of recurrent nephropathy. These patients with recurrent IgA nephropathy often presented crescent formation in histology with rapidly progressive renal failure.[9–12] In this study, we found that our patients had no response or just short time response to intensive immunosuppressive therapy. All of our patients changed their initial immunosuppressive regimens; however, six advanced to renal graft loss within 2 to 12 months, three of them eventually developed ESRD and returned to hemodialysis therapy within two years after kidney transplantation, and only one kept stable graft function for more than three years of follow-up. Those results were similar to Kowalewska's report.[12] He had eight cases confirmed as recurrent or de novo IgA nephropathy with crescent formation from only 7% to 30%. Four patients lost their graft renal function, developed ESRD, and needed hemodialysis therapy within 1 to 12 months; three patients kept their stable graft function for follow-up for 4 to 6 years; and one case was lost at follow-up.

Until now, no immunosuppressive drug, including newer agents such as mycophenolate mofetil (MMF) or rapamycin, can prevent recurrent IgA nephropathy.[7] However, some pilot data suggested that MMF could affect the clinical course of recurrent IgA nephropathy.[16] Our study found that of these patients who had been diagnosed as IgA nephropathy before 2000, the majority of them were administered the triple regimens of CsA+Azp+Pred, and only two cases received the regimen of CsA+MMF+Pred. Similar to Kowalewska's patients,[12] there was only one who received MMF therapy of eight recurrent IgA nephropathy patients with crescent formation. As is well known, MMF, a new immunosuppressive agent, is unlike other immunosuppressive drugs in that it has an inhibiting effect on the proliferation of B lymphocytes in addition to T lymphocytes, thereby reducing the exaggerated IgA production in patients with IgA nephropathy, and it also has a direct anti-proliferative effect on mesangial cells.[17],[18] Recently, many preliminary studies and clinical trials have proven that MMF is effective and safe in the induction of remission as well as in long-term maintenance therapy for patients with severe lupus nephritis, renal limited vasculitis, and native IgA nephropathy[19–21] who had suffered from glomerular capillary necrosis and crescent in histology. In our patients, as well as in Kowalewska's data, the different immunosuppressive regimens for patients with kidney transplantation could result from different pathological changes, such as crescent formation in recurrent IgA nephropathy; it remains to be determined whether or not this suggests that MMF can prevent crescent formation. However, it is difficult to assess the role of MMF in renoprotection because of small number of cases. The effective protocol for recurrent IgA nephropathy patients with crescent formation remains a further prospective randomized and controlled study.

In summary, IgA nephropathy with crescentic formation was not rare in renal allografts or native glomerulonephritis in Chinese patients. These patients showed rapidly progressive renal dysfunction, and most of them lost graft function to return hemodialysis therapy. MMF could affect on the clinical course of recurrent IgA nephropathy, which may contribute to having a direct anti-proliferative effect on mesangial cells and preventing capillary necrosis and crescent formation.

Notes

4. Ji SM, Tang Z, Chen JS, Chen HP, Liu ZH, Li LS. Clinical and pathological spectrums of recurrent IgA nephropathy after renal transplantation. In press.