Recurrent Pauci-immune Necrotizing Crescentic Glomerulonephritis in a Kidney Transplant Patient
Article Outline
Index Words: Antineutrophil cytoplasmic antibody (ANCA) vasculitis, kidney transplant, disease recurrence
Glomerulonephritis is the primary cause of end-stage renal disease (ESRD) in a substantial proportion of patients and includes antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis. Although recognition and treatment of ANCA-associated vasculitis (AAV) has improved, the diagnosis can be difficult to make. In 1 study, the diagnosis was missed (before ANCA testing was performed) in 43% of patients.1 It is estimated that 20%-40% of patients with AAV will progress to kidney failure requiring replacement therapy.2 It is important to be aware of the diagnosis before transplant to provide patient counseling and monitor allograft function closely in the postoperative period because the relapse rate can be significant. In a pooled analysis by Nachman et al,3 the overall recurrence rate was 17%. We present a case of a patient with reported “focal sclerosing nephropathy” and an acute increase in serum creatinine level shortly after transplant who was noted to have crescentic glomerulonephritis with the absence of immune complexes on allograft biopsy. This case shows the importance of confirming the cause of ESRD before transplant and the role of allograft biopsy in identifying the causes of decreased kidney function.
Case Report
Clinical History and Initial Laboratory Data
A 31-year-old African American man presented to his primary care physician in May 2002 with a sore throat, and streptococcal pharyngitis was diagnosed. Serum creatinine level on laboratory evaluation was 3.3 mg/dL (291.7 μmol/L; estimated glomerular filtration rate [eGFR], 28 mL/min/1.73 m2 [0.47 mL/s/1.73 m2]). An ultrasound showed normal kidneys without masses, obstruction, or hydronephrosis. Antistreptolysin O titer was normal. A presumptive diagnosis of acute poststreptococcal glomerulonephritis or chronic glomerulonephritis was made.
During outpatient follow-up, the patient underwent a percutaneous biopsy because of ongoing decreased kidney function. The native kidney biopsy specimen showed “focal sclerosing nephropathy, active, moderately advanced” (Fig 1) with no crescentic or necrotizing lesions noted, and he was treated with high-dose steroid therapy.
Figure 1.
The native kidney biopsy specimen shows numerous segmental scars with broad-based adhesions typical of the sclerosis ensuing from healed aggressive necrotizing crescentic lesions (Jones silver stain; original magnification, ×400).
In November 2003, the patient presented with increasing malaise, fever, hemoptysis, epigastric pain, nausea, and vomiting. Creatinine level was 4.6 mg/dL (406.6 μmol/L; eGFR, 19 mL/min/1.73 m2 [0.32 ml/s/1.73 m2]), and a chest radiograph showed bilateral diffuse pulmonary infiltrates. He was treated for pneumonia and initiated on hemodialysis therapy. Serologic work-up included normal complement levels, negative hepatitis B and C serologic test results, negative antinuclear antibodies, and negative anti–glomerular basement membrane (anti-GBM) antibody. Perinuclear ANCA was positive (titer, 1:512) with markedly increased antimyeloperoxidase (anti-MPO) antibody.
In April 2004, the patient was admitted with Gram-positive sepsis related to his dialysis catheter. ANCA titer was 1:4,096 with markedly increased anti-MPO antibody. Reviewing the original kidney biopsy, the patient's nephrologist believed that the most likely cause of the “focal sclerosing nephropathy” was pauci-immune glomerulonephritis, not primary focal segmental glomerular sclerosis (FSGS). The pulmonary infiltrates never recurred, and he did not receive additional steroids or chemotherapeutic agents.
When the patient presented for transplant evaluation, the presumptive diagnosis of FSGS was made based on the outside biopsy report. The slides were not requested for review, and the primary nephrologist was not contacted for confirmation. The patient underwent a 2-antigen match (HLA-A1, HLA-B0, and HLA-DR1) living related donor kidney transplant in September 2004. Posttransplant, he had immediate allograft function with a decrease in serum creatinine level from 13.9 mg/dL (1,228.8 μmol/L) pretransplant to 5.4 mg/dL (477.4 μmol/L) on postoperative day 1. Induction immunosuppression included basiliximab and methylprednisolone with maintenance tacrolimus, mycophenolate mofetil, and prednisone.
On posttransplant day 2, the patient became markedly oliguric, serum creatinine level was 9.2 mg/dL (813.3 μmol/L), and he required acute hemodialysis for pulmonary edema. An ultrasound of the allograft with Doppler flow showed normal echogenicity, no hydronephrosis, and normal arterial and venous flow. He underwent a percutaneous allograft biopsy that showed acute cellular rejection (Cooperative Clinical Trials in Transplantation [CCTT] type I), acute vascular rejection (CCTT type II), and moderate acute tubular necrosis. There also were unusual fibrinoid lesions without karyorrhexis associated with GBM breaks within 3 glomeruli, suspicious for pauci-immune glomerulonephritis (Fig 2). There was no evidence of recurrent FSGS. Intravenous thymoglobulin, 175 mg/d, was administered for 10 days for rejection, with improvement in allograft function to a nadir creatinine level of 2.9 mg/dL (256.4 μmol/L; eGFR, 32 mL/min/1.73 m2 [0.53 mL/s/1.73 m2]).
Figure 2.
In the first transplant biopsy specimen, there was a single small segmental glomerular basement membrane break with fibrinoid material within Bowman space. There also were red blood cells within Bowman space and in the surrounding interstitium (Jones silver stain; original magnification, ×200).
Two weeks after hospital discharge (posttransplant day 20), the patient developed periumbilical abdominal pain, nonbloody diarrhea, nausea, and vomiting. Creatinine level was 3.2 mg/dL (282.9 μmol/L; eGFR, 29 mL/min/1.73 m2 [0.48 mL/s/1.73 m2]). Urinalysis showed trace albumin, 5-10 white blood cells per high power field, and 11-20 red blood cells per high power field. Urinary sediment showed few red blood cell casts with proteinuria quantified at protein excretion of 500 mg/24 h. A second allograft biopsy was performed.
Kidney Biopsy
Twenty glomeruli were present, none of which were globally sclerosed. There was no segmental sclerosis, hyalinosis, mesangial, or endocapillary proliferation. Twelve glomeruli showed fibrin deposition within the glomerular tufts, 4 with frank fibrinoid necrosis, karyorrhexis, and GBM breaks. Three of these glomeruli also featured cellular crescents, 1 of which showed Bowman capsule rupture (Fig 3). There was interstitial edema with minimal lymphoplasmacytic infiltrate and occasional eosinophils involving < 5% of intact tissue, but without tubulitis. Less than 5% interstitial fibrosis with proportional tubular atrophy was present. There were frequent red blood cell casts. Interlobular arteries were unremarkable. There was no vasculitis, endothelialitis, or viral cytopathic changes.
Figure 3.
In the second transplant biopsy specimen, widespread segmental necrotizing lesions through the glomerular basement membrane breaks were present. The remaining part of the glomerular tufts did not show endocapillary proliferative lesions, and immunofluorescence study results were negative, indicative of pauci-immune necrotizing crescentic glomerulonephritis (Jones silver stain; original magnification, ×100).
Immunofluorescence showed no significant staining, including C4d negativity. Electron microscopy showed a segmental increase in lamina rara interna and segmental corrugation without immune complex deposits. Podocytes showed ∼40% foot-process effacement with focal microvillous transformation. Endothelial cells were swollen without reticular aggregates. There were multiple medium to large fibrin tactoids within the expanded subendothelial space and capillary loops.
Diagnosis
Pauci-immune necrotizing crescentic glomerulonephritis with moderate to severe activity and minimal chronicity. No acute cellular or vascular rejection.
Clinical Follow-up
Given the findings on allograft biopsies, ANCA and anti-GBM antibody tests were ordered: perinuclear ANCA was positive with an anti-MPO level of 41.3 EU/mL (normal, <4.0 EU/mL), anti–proteinase 3 (PR3) was negative at < 4.0 EU/mL, and anti-GBM antibody was negative at 4 EU (normal, 0-20 EU). The patient was treated with intravenous methylprednisolone, 3.5 g total, during 6 days and oral cyclophosphamide, 1.5 mg/kg/d. Mycophenolate mofetil therapy was discontinued. He was discharged from the hospital on tacrolimus, cyclophosphamide, and high-dose prednisone (1 mg/kg/d) therapy. He received oral cyclophosphamide for 6 months, with a decrease in anti-MPO titers to negative (<4.0 EU/mL). Four years later, renal allograft function remains stable with a creatinine level of 1.8 mg/dL (159.1 μmol/L; eGFR, 55 mL/min/1.73 m2 [0.92 mL/s/1.73 m2]). He is maintained on tacrolimus, mycophenolate mofetil, and prednisone therapy with no systemic manifestations of vasculitis.
Discussion
Pauci-immune glomerulonephritis is the most common cause of rapidly progressive glomerulonephritis.4 The 2 major subtypes, associated with circulating ANCA and renal histologic type characterized by glomerular necrosis and crescent formation,5 include Wegener granulomatosis and microscopic polyangiitis. Despite improved recognition and treatment of these disorders, 20%-40% of patients will develop ESRD requiring renal replacement therapy.2
Surprisingly, little information about the long-term outcomes of dialysis patients with AAV is available in the literature. This may be caused by difficulty making the diagnosis in patients who present with ESRD, evidenced by our patient. Despite this, there is evidence that the diagnosis of AAV does not adversely affect patient mortality, with survival rates on dialysis therapy equal to those of age-matched controls with other causes of ESRD.6
For the timing of kidney transplant, most would agree that patients may proceed when clinical remission is achieved,3 even in the presence of ongoing circulating ANCAs. Several groups have reported successful transplant in patients with AAV with positive antibody titers.7, 8 Although the presence of ANCAs at the time of transplant does not appear to increase the risk of relapse, it is common practice to monitor ANCA titers after transplant in an attempt to identify patients who might be at higher risk of disease relapse. However, this phenomenon has been difficult to show across studies and may be caused by differences in study design and the absence of a universally accepted method of testing for ANCA.9, 10
The reported risk of AAV disease recurrence after transplant is estimated to be ∼17%, with an average time to relapse of 31 months.3 With regard to our patient who presented 20 days after surgery, he likely had ongoing active disease that was not recognized at the time of transplant until clinical symptoms of vasculitis and biopsy findings of crescentic necrotizing glomerulonephritis appeared soon thereafter. Despite a substantial risk of disease recurrence, recent registry data from Australia indicate that AAV is associated with a very low risk of allograft loss in this situation.11
In those who experience recurrence, treatment should include oral cyclophosphamide for 6 months, after which an antimetabolite agent should be substituted. Mycophenolate mofetil was used in our patient. Recurrences can be differentiated from new cases of glomerulonephritis, acute rejection, and toxic effects of medications only on the basis of kidney biopsy. It obviously is important to review the cause of ESRD before transplant. In many cases, biopsy is not performed and the diagnosis is presumed to be caused by a particular disease process, for example, diabetes or hypertension. We were fortunate that our patient underwent native kidney biopsy, although at the time of transplant evaluation, the report was misinterpreted as FSGS. The biopsy report and original slides were reviewed after the first transplant biopsy and additional available clinical history were obtained. Although the complete outside report was technically correct in diagnosing chronic sclerosing nephropathy and suggested possible secondary causes, the unfortunate descriptive line diagnosis noting focal and segmental sclerosing lesions led to miscommunication of the actual process. Review of the biopsy specimen at our institution not only confirmed the presence of broad-based scars in the pattern seen in this patient (Fig 1) that was highly suggestive of healed previous aggressive necrotizing lesions, but also revealed rare acute necrotizing lesions (Fig 4). This illustrates the importance of clear communication between the referring and transplant nephrologists and, if possible, direct review of key diagnostic material before transplant.
Figure 4.
The native kidney biopsy specimen shows a small area of segmental disruption of the glomerular tuft with surrounding extracapillary proliferation adjacent to an area of nonspecific segmental sclerosis. There is surrounding interstitial fibrosis and atrophy of tubules. Immunofluorescence study results were negative, and the glomerular tuft shows no proliferation (Jones silver stain; original magnification, ×100).
This case also shows the difficulty diagnosing AAV, even with positive ANCA titers and a native kidney biopsy, as well as the importance of allograft biopsy in the diagnosis and treatment of acute kidney injury posttransplant in the early follow-up period. With appropriate therapy, recurrent AAV responds with good long-term outcomes.7, 12, 13, 14
Acknowledgements
Support: None.
Financial Disclosure: None.
References
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Originally published online as doi:10.1053/j.ajkd.2009.07.019 on September 27, 2009.
PII: S0272-6386(09)01074-9
doi:10.1053/j.ajkd.2009.07.019
Published by Elsevier Inc.
