An Elderly Man with Fatigue, Dyspnea, and Kidney Failure

Introduction

For most American Society of Nephrology (ASN) Kidney Week attendees, case-based clinical nephrology talks are one of the most exciting venues. The Nephrology Quiz and Questionnaire (NQQ) is the essence of clinical nephrology and represents what drew all of us into the field of nephrology. This year’s NQQ in surprisingly temperate Chicago, with full-house attendance, was no exception. The expert discussants prepared vignettes of puzzling patients, which illustrated some topical, challenging, or controversial aspect of the diagnosis or management of key clinical areas of nephrology. These eight interesting patients were presented and eloquently discussed by our four expert ASN faculty. Subsequently, each discussant prepared a manuscript summarizing his or her case discussions, which serves as the text of this article (Mark A. Perazella and Michael Choi, comoderators).

Patient Presentation

A 76-year-old man reports to his primary care physician that he has been feeling more fatigued than usual. He also complains of feeling cold and having chills (“like I have the flu”) and has an unintentional 15-pound weight loss over the previous month. In the last week, he has developed a new cough and some shortness of breath with exertion. His medical history includes coronary artery disease requiring percutaneous coronary intervention, systolic heart failure (ejection fraction of 45%), chronic obstructive pulmonary disease, hypertension, and hyperlipidemia. His medications have not changed recently and include lisinopril 2.5 mg daily, hydralazine 25 mg three times daily, carvedilol 6.25 mg twice daily, aspirin 81 mg daily, and atorvastatin 80 mg daily. His primary care physician sends him to the emergency room for further evaluation.

In the emergency room, his examination is notable for normal BP, mild conjunctival injection, decreased breath sounds at bilateral bases, and trace nonpitting edema. A chest radiograph shows bilateral hazy opacities. Laboratory tests reveal serum creatinine of 3.8 mg/dl, hemoglobin 6.0 g/dl, and urinalysis with 3+ blood and 2+ protein. A renal ultrasound shows no evidence of hydronephrosis. After repeat laboratory values confirm these abnormal results, he is transfused 2 U packed red blood cells, and a number of serologic tests are sent to work up the kidney failure. A kidney biopsy is performed the following day, with most of these tests pending. The biopsy shows a pauci-immune necrotizing and crescentic GN.

Question 1

If hydralazine-induced vasculitis is suspected, what serology result would you expect to find in this patient?

1. Positive proteinase3 (PR3)-ANCA, high titer

2. Positive myeloperoxidase (MPO)-ANCA, high titer

3. Negative MPO-ANCA and negative PR3-ANCA

4. Positive antidouble-stranded DNA (anti-dsDNA) antibody

5. Positive antihistone antibody

Discussion of Question 1

Patients with a drug-induced ANCA-associated vasculitis usually manifest very high titers of MPO-ANCA (answer B is correct). Drug-induced ANCA-associated vasculitis has been reported with a number of agents (Table 1), with the strongest associations found in patients using hydralazine, minocycline, and antithyroid drugs (propylthiouracil, methimazole, and carbimazole). Of these, hydralazine is the most commonly reported agent to induce ANCA-associated vasculitis (1,2). In a series from the Massachusetts General Hospital of 30 patients with ANCA-associated vasculitis and the highest anti-MPO titers (ranging from 3087 to 141,409 AU/ml), ten had been exposed to hydralazine, three had been exposed to propylthiouracil, two had been exposed to penicillamine, two had been exposed to allopurinol, and one had been exposed to sulfasalazine (3). A small number of patients with drug-induced vasculitis present with PR3-ANCAs, although these antibodies are more commonly seen in conjunction with significantly higher titers of anti-MPO antibodies.

Table 1.

Drugs reported to induce ANCA-associated vasculitis

Stronger Evidence Base	Weaker Evidence Base
Hydralazine	Penicillamine
Minocycline	Allopurinol
Propylthiouracil	Sulfasalazine
Methimazole	Rifampicin
Carbimazole	Cefotaxime
Levamisole (CC)	Isoniazid
	Indomethacin
	Clozapine
	Phenytoin

Strength of evidence is on the basis of the number of published cases in the medical literature. CC, cocaine contaminant.

Hydralazine can also induce a lupus syndrome with antibodies to dsDNA and antihistone antibodies, and patients with overlap cases of hydralazine-induced necrotizing and crescentic lupus nephritis with (+)MPO-ANCA serologies have been reported (4). These patients, however, do not have pauci-immune staining on immunofluorescence microscopy but rather, stain positive for Ig and complement typical of lupus nephritis. Positive antihistone antibodies have been detected in patients with hydralazine-induced ANCA vasculitis, but this is not common.

A review of the literature, performed by Yokogawa and Vivino (2) in 2009, found 68 reported patients with hydralazine-associated vasculitis. GN was a presenting feature in >80% of patients. In terms of additional serologies, 96% of these reported patients were antinuclear antibody positive, but only 26% were anti-dsDNA positive. The mean duration of drug exposure was 4.7 years, and patients were taking an average dose of 142 mg/d, suggesting that drug-induced vasculitis can occur even after longstanding use of the offending agent and at relatively low doses. In the case presented here, the patient had been on hydralazine for over 3 years on a current dose of only 75 mg/d.

Pendergraft and Niles (5) recently proposed an epigenetic explanation for the mechanism underlying hydralazine-induced ANCA vasculitis. Recognizing the role in nondrug-induced ANCA-associated vasculitis of abnormal epigenetic modifications necessary for gene silencing around MPO and PR3 loci (6), they noted a similarity in how hydralazine can act as a synthetic non-nucleoside DNA methylation inhibitor to reverse epigenetic silencing of tumor-suppressor genes in cancer cells (7). Hydralazine may, therefore, reverse epigenetic silencing of PR3 and MPO, resulting in increased expression of both autoantigens in neutrophils to break tolerance and induce formation of disease-causing anti-MPO and anti-PR3 antibodies.

The MPO-ANCA titer in this patient returned very high (971 AU/ml; reference range 0–19), and PR3-ANCA was also positive at low levels (60 AU/ml; reference range 0–19), confirming a diagnosis of drug-induced vasculitis. Anti-dsDNA and antihistone antibodies returned negative. Hydralazine was discontinued. Bronchoscopy with alveolar lavage revealed diffuse alveolar hemorrhage. The patient was started on pulse steroids and plasmapheresis.

Question 2

What, if any, further therapy would you recommend for this patient?

1. No additional immunosuppression

2. Mycophenolate mofetil

3. Cyclophosphamide (intravenous or orally)

4. Rituximab

5. Azathioprine

Discussion of Question 2

This patient should be treated with an immunosuppressive therapy in addition to the treatments already received, and cyclophosphamide has the strongest evidence base for induction therapy in this setting (answer C is correct). Hydralazine-induced ANCA-associated vasculitis is frequently associated with kidney involvement—a necrotizing and crescentic GN with pauci-immune staining on immunofluorescence as in this patient—with similar outcomes seen in nondrug-associated forms of ANCA-associated crescentic GN. Therefore, in addition to withdrawal of the offending drug, immunosuppressive therapy is required to maximize kidney and overall survival. In the above-mentioned series from the Massachusetts General Hospital, of the ten patients with hydralazine-associated ANCA vasculitis, over a 6-month follow-up period, two died, and three required dialysis (of which one remained dialysis dependent).

The choice of immunosuppressive therapy in drug- and nondrug-induced ANCA-associated GN is the same. Many centers will only use induction phase therapy without maintenance immunosuppression if remission is achieved given that relapse of disease would not be expected as long as the patient is not re-exposed to the offending drug. Of the four treatment choices offered for induction therapy of ANCA-associated GN, cyclophosphamide is the regimen supported by both the Kidney Disease Outcomes Quality Initiative and the Kidney Disease Improving Global Outcomes in practice guidelines (8,9). The guidelines do not specifically endorse intravenous versus oral cyclophosphamide, and the choice is generally center specific. A randomized clinical trial, conducted in 42 centers in 12 European countries, showed similar efficacy between these regimens, with reduced cumulative doses and lower rates of neutropenia using an intravenous regimen (10), but relapse rates were approximately twice as high in subjects treated with intravenous cyclophosphamide compared with subjects treated with oral cyclophosphamide in a subsequent report with long-term follow-up data from this trial (11).

Mycophenolate mofetil and azathioprine, alone or in conjunction with steroids, are not induction regimens for ANCA-associated GN but rather are used as maintenance therapies for patients who have achieved remission. Rituximab, an mAb against CD20, is an approved induction therapy for ANCA-associated GN on the basis of results from the Randomized Trial of Rituximab Versus Cyclophosphamide in ANCA-Associated Vasculitis (RITUXVAS) and the Rituximab in ANCA-Associated Vasculitis (RAVE) Trials(12,13). However, the current guideline recommendations are for use of this drug in patients without severe disease or with clear contraindications to cyclophosphamide (8,9), neither of which apply to our patient. Indeed, the subjects in the RAVE Trial, which compared rituximab with oral cyclophosphamide as induction therapy for ANCA-associated GN (compare with intravenous cyclophosphamide given with rituximab in the RITUXVAS), had a mean age of 53 years old and mean creatinine clearance of 62 ml/min at the time of enrollment (13). In a subgroup analysis from the RAVE Trial looking only at the 52% (102 of 197) of the enrolled subjects with kidney involvement at entry, the mean age was 56 years old, and mean serum creatinine was 2.02 mg/dl (eGFR=41.4 ml/min per 1.73 m²) (14). Extending the very encouraging results from the RAVE Trial participants to a 76-year-old man with a creatinine approaching 4 mg/dl is not preferred to using a more standard cyclophosphamide-based regimen. In addition, rituximab has, to date, not been reported as an effective therapy for drug-induced ANCA-associated vasculitis, whereas there are rare reports of rituximab-associated vasculitides (15).

Disclosures

None.