An Unusual Case: Pauci-immune Necrotizing Glomerulonephritis
By Anna M. Lamb, DO
ABSTRACT: Rapidly progressive glomerulonephritis (RPGN) is an uncommon presentation of acute renal failure in the primary care office. Pauci-immune glomerulonephritis in a young person is even less common. A high index of suspicion in patients with fatigue, edema or urinary complaints can lead to the diagnosis. RPGN can progress over days to months. It can be seen as a primary glomerular disease or as part of a systemic vasculitis. The following discussion illustrates a case of pauci-immune glomerulonephritis, outlines the pathophysiology of rapidly progressive glomerulonephritis and demonstrates how the primary care physician can play an active role in the health of their patient.
Introduction
Pauci-immune glomerulonephritis is a form of rapidly progressive glomerulonephritis (RPGN). While not a common presentation in the primary care physician’s office, the diagnosis can be made by urinalysis, renal biopsy and evaluation for antineutrophil cytoplasmic antibodies.1 The clinical course is unpredictable and the need for dialysis or kidney transplantation varies by patient. While the primary care physician may not be managing the kidney disease, it is important to maintain a high index of suspicion to help make the diagnosis. Knowledge of the various types and presentations of rapidly progressing glomerulonephritis will also help osteopathic family physicians serve their patients in identifying relapses and extra renal symptoms of the disease. Following is a case presentation of pauci-immune glomerulonephritis and a review of RPGN.
Case Presentation
RS is a 23-year-old white female student who presented to the office complaining of a three-week history of joint pain and stiffness in her hands, feet and shoulders. She stated that the stiffness lasted two to three hours in the morning. She had been using naproxen with minimal relief. She reported no recent illnesses but did report a similar episode approximately one year previous which resolved without treatment. The patient’s past medical history was significant for mastoiditis and deafness. Basic laboratory studies at the time of presentation in the office revealed mild anemia, a normal sedimentation rate, a negative rheumatoid factor and a normal serum creatinine level.
A rheumatology consultation was obtained to evaluate her joint symptoms. Prior to the consultation, which was approximately three months after the presentation, RS started to gain weight and develop edema in her hands and legs. She also began to complain of increased fatigue and a general sense of being unwell. The patient’s joint pain and stiffness did ultimately resolve, prior to her seeing the rheumatologist, and the edema improved with a small dose of hydrochlorothiazide. RS was given a working diagnosis of palindromic rheumatism and she was sent for further laboratory testing.
Laboratory studies done approximately three months after her initial presentation in the office revealed a sedimentation rate of 111 mm/hr, a C-reactive protein of 27.9 mg/L, a complement C4 of 48 mg/dL , a creatinine of 3.7 mg/dL, and an elevated complement C3 of 229 mg/dL. Peripheral antinuclear cytoplasmic antibodies (P-ANCA) and central antinuclear cytoplasmic antibodies (C-ANCA) were negative. A 24-hour urine revealed oliguric renal failure with a urine protein of 925 mg. An urgent nephrology consult was obtained and renal biopsy performed.
Renal biopsy revealed a diagnosis of pauci-immune necrotizing glomerulonephritis. The patient was immediately started on high dose prednisone and cyclophosphamide. Approximately four months after her initial diagnosis and one month after beginning chemotherapy her kidney function worsened, with her creatinine increasing to 6.5 mg/dL. This required admission to the hospital and dialysis. Since that admission her kidney function has improved and remained stable. She has completed more than six months of immunosuppressive therapy and is weaning off prednisone. Her sedimentation rate and C-Reactive Protein have returned to normal, but she is now positive for anti-myeloperoxidase antibodies. Approximately one year after her diagnosis, following a significant hiatus due to her medical issues, RS has returned to school to complete her education. The patient has no more joint symptoms, and she is overall feeling well.
Discussion
Pauci-immune glomerulonephritis is a rare and heterogeneous disorder. It is one type of rapidly progressive glomerulonephritis (RPGN). RPGN is characterized by the development of renal failure, proteinuria and hematuria which progresses over days to months.2 It can be seen as a renal limited vasculitis or can occur in the presence of other diseases, including Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. The clinical course is variable with some patients experiencing rapid renal failure and death, and others developing a chronic renal failure leading to end-stage renal disease. Most patients have circulating antineutrophil cytoplasmic antibodies which are specific for either proteinase 3 or myeloperoxidase.5
Rapidly progressive glomerulonephritis can be divided into the following primary groupings: RPGN associated with infectious disease, RPGN associated with multisystem disease, RPGN caused by medications, and finally, primary glomerular disease.1
The first category is infectious disease. The classic illustration of this category is post streptococcal glomerulonephritis. In children, this disease is self limited and is managed by treating fluid and electrolyte abnormalities. In adults, the disease does not have as favorable a prognosis. Glomerulonephritis due to infections can also be seen in HIV, infective endocarditis, hepatitis B and sepsis. RPGN may be seen after any viral or bacterial infection.1
RPGN can also be seen as a component of other systemic diseases. It can be seen with small vessel vasculitis such as Henoch-Schonlein purpura and microscopic polyangiitis. Henoch-Schonlein purpura is a disease of children, characterized by the deposition of IgA containing immune complexes in the vessel walls. Henoch-Schonlein purpura generally resolves with supportive care. Microscopic polyangiitis affects men in the fourth and fifth decades of life. Although few immune complexes are deposited at the site of the necrotizing vasculitis, this disease has the potential for severe end-organ damage. RPGN can also be seen with medium vessel vasculitis such as Wegener’s granulomatosis and Churg-Strauss syndrome.6 Both Wegener’s and Churg Strauss are associated with circulating antineutrophil cytoplasmic antibodies. The significance of these circulating antibodies is unknown. Both conditions affect persons in their 40s and 50s and are treated with steroids and immunosuppressive therapy.2
Glomerulonephritis can also be seen with the use of certain medications. Rifampin, penicillamine, and hydralazine can all cause a rapidly progressive glomerulonephritis.1
The last category of RPGN is idiopathic or primary glomerular disease. These conditions can be limited to the kidney or can have extra-renal manifestations. Primary glomerular disease is divided into three types.
Each type of primary glomerular disease is characterized by the observation of crescents on renal biopsy. Crescents are extracapillary proliferations composed of parietal epithelial cells and inflammatory cells. On immunoflourescent staining the biopsy can reveal linear deposits of anti-glomerular basement membrane antibodies or granular deposits of immune complexes. These are Types I and II respectively. Type III shows relatively few or no immune complex deposition and thus is “pauci-immune”.3
Primary glomerular disease or renal-limited vasculitis is present in one-third of patients with RPGN. These patients may experience fatigue, fever and myalgias, even though no other sign of systemic illness is present. In older adults, pauci- immune glomerulonephritis is the most common category of RPGN. Treatment consists of steroids and cyclophosphamide.
As previously mentioned, vasculitis can be associated with the presence of circulating antineutrophil cytoplasmic antibodies (ANCA). These are autoantibodies to cytoplasmic components. ANCA can be specific for either proteinase 3 or myeloperoxidase, and can be used to aid in the diagnosis of vasculitis. A high percentage of patients with Wegener’s granulomatosis have circulating ANCA.2
A study by Vizjak, et.al. in 2003 set out to determine the importance of the different types of ANCA, looking at a selection of patients with various types of vasculitides, including pauci-immune glomerulonephritis.7 Antibodies to myeloperoxidase are found predominately in pauci-immune glomerulonephritis. Also noted were a female predominance, and that patients present with a higher than expected initial creatinine.
The pathological lesions for myeloperoxidase and proteinase 3 are the same. There are active lesions and there are lesions which show a large degree of sclerosis. Those patients with ANCA to myeloperoxidase tend to have a less favorable kidney survival than those with antibodies to proteinase 3. A percentage of patients who had renal limited vasculitis did go on to develop a systemic vasculitis in the six-month to ten-year follow up period.
Because the clinical course of pauci-immune glomerulonephritis is variable, researchers have attempted to identify factors which may predict a more rapid progression to end-stage renal disease. A study published in 2000 by Cohen and Clark was a retrospective review of medical records which looked at the presenting signs and symptoms and also the treatment given to 94 patients.4 Advanced age, male sex, respiratory tract involvement and a greater relapse rate were all predictive of an unfavorable outcome. Female sex and the use of an angiotensin-converting enzyme inhibitor indicated a more favorable outcome. End points examined were the need for dialysis or death.
Epilogue
The eventual clinical outcome for our patient remains unknown. RS has already required dialysis, although she has had some return of her renal function. She had a high creatinine at presentation and now has circulating anti-myeloperoxidase antibodies. It is thought that her joint symptoms on this most recent occasion were an extra-renal manifestation of her glomerulonephritis. She has not yet had a relapse, although this would likely be anticipated. RS will be monitored closely over the next ten years for the development of a systemic vasculitis. Any respiratory, musculoskeletal or cardiac symptoms must be fully investigated to determine whether or not they are manifestations of her renal disease.
Conclusion
Although rapidly progressive glomerulnephritis is a rare presentation in a primary care practice, a high index of suspicion will help to make the diagnosis. Renal function should be assessed in any patient who presents with fatigue, edema and urinary complaints. The presence of hematuria, proteinuria and elevated creatinine should be fully investigated. Initial work up can be undertaken by the primary care physician, but timely referral to a nephrologist remains paramount. Once the diagnosis has been made and treatment begun, the primary care physician may be asked to evaluate other symptoms to determine if they are part of the vasculitis. An osteopathic family physician’s working knowledge of the presentation of the vasculitides will aid in making a timely diagnosis, thus potentially improving the clinical outcome for these patients.
Dr. Lamb is a 1996 graduate of Kirksville College of Osteopathic Medicine. She is board certified in Family Medicine and is currently in private practice in Batavia, New York.
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