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 Table of Contents  
CLINICOPATHOLOGIC CONFERENCE
Year : 2021  |  Volume : 11  |  Issue : 6  |  Page : 291-294

A 65-year-old woman with fever and renal failure


1 Department of Medicine, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Histopathology, Sir Ganga Ram Hospital, New Delhi, India

Date of Submission23-Oct-2021
Date of Decision10-Nov-2021
Date of Acceptance26-Nov-2021
Date of Web Publication31-Dec-2021

Correspondence Address:
Dr. Atul Gogia
Senior Consultant, Department of Medicine, Sir Gangaram Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_113_21

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How to cite this article:
Batra T, Kakar A, Gogia A, Badwal S. A 65-year-old woman with fever and renal failure. Curr Med Res Pract 2021;11:291-4

How to cite this URL:
Batra T, Kakar A, Gogia A, Badwal S. A 65-year-old woman with fever and renal failure. Curr Med Res Pract [serial online] 2021 [cited 2022 Jan 17];11:291-4. Available from: http://www.cmrpjournal.org/text.asp?2021/11/6/291/334576




  Clinic Pathological Discussion Top


Dr Tanvi Batra: A 65-year-old female presented with chief complaints of decreased appetite, nausea and vomiting (1–2 episodes per day) for 10 days. She had low-grade fever on and off for 10 days, associated with malaise. The patient gave a history of black-coloured stools for 2 days before admission. There was no history of cough, sore throat, diarrhoea, bleeding from any other site, burning micturition, altered sensorium, dyspnoea or chest pain. She gave no history suggestive of COVID infection in the past. She had taken second dose of Covishield vaccine on 24 April 2021 (approximately 6 weeks before admission). She denied having any other co-morbidities. The patient was recently admitted in an outside hospital and treated with intravenous (I/V) antibiotics and other supportive therapy for possible complicated urinary tract infection. She was found to have low haemoglobin with a recent drop from 9.1 to 7 g/dL. She was then referred to our hospital for further management.

On examination, the patient was febrile and had tachycardia and severe pallor. Per-abdomen examination revealed hepatomegaly with no guarding, rigidity or tenderness. Rest of the systemic examination was essentially normal. Based on the clinical history and symptoms, our clinical diagnosis was acute febrile illness with severe anaemia. The differential diagnosis of this tropical fever which we considered was malaria, dengue, leptospirosis, enteric fever and scrub typhus, with acute kidney injury. On repeated questioning, she also gave a history of low backache for 2 months, for which she was taking analgesics such as paracetamol and diclofenac sodium frequently. We also included multiple myeloma and Pott's spine to the list of differentials.

Her laboratory parameters showed: haemoglobin 6 g/dL, total leucocyte count – 12,200 cumm, platelet count– 294 lac, erythrocyte sedimentation rate (ESR) – 143, sodium – 138 mmol/L, potassium – 4.22 mmol/L, BUN – 24 mg/dL, serum creatinine – 4.38 mg/dL, lactate dehydrogenase – 222 and serum calcium – 7.25. Her liver function tests were normal with international normalised ratio of 1.30. Peripheral smear and antigen test for malarial parasite were negative. Dengue NS1 antigen and IgM serology and leptospira IgM were negative. Serum procalcitonin was normal. Blood and urine cultures were sterile. TB quantiferon Gold and Montoux test were negative. C-reactive protein was 78. Urine routine/microscopic examination showed numerous RBCs, 5–10 WBCs/hpf, granular cast (+). Anaemia profile revealed severe iron deficiency; serum iron – 9 mcg/dL, ferritin – 507 ng/mL and Vitamin B12 – 2000 pg/mL. Stool for occult blood was negative on three different occasions. Urine spot protein and creatinine ratio was high (2.65). Peripheral smear showed normocytic normochromic anaemia with mild neutrophila and Rouleaux formation. Viral markers were negative (HIV, anti-HCV, and hepatitis B surface antigen [HbsAg]). Ultrasound abdomen was normal with normal-sized kidneys. Subsequently, computed tomography scan thorax, abdomen and spine was normal.

In view of negative screening for infective cause of fever, we further worked up for multiple myeloma and systemic vasculitis as the patient had high ESR, Rouleaux formation, normal size kidney and urine analysis showing casts. Bone marrow analysis was noncontributory. Urine for eosinophils and Bence Jones protein were negative. X-ray skull was grossly normal. Comprehensive myeloma panel and complement levels were normal. Anti nuclear antibody (ANA) was negative and extractable nuclear antibodies showed 1(+) SS-B. Anti-PR3 was negative. Anti - Myeloperoxidase Antibody (Anti-MPO) was found to be strongly positive (53.4 AU/ml).


  Dr Atul Gogia Top


This was a case worth discussing because the initial presentation of patient pointed towards infectious diseases. Keeping in mind her complaints and basic investigations, we worked her up for:

  1. Complicated urinary tract infection
  2. Malaria
  3. Leptospira
  4. Scrub typhus
  5. Dengue haemorrhagic fever
  6. Myeloma
  7. Autoimmune diseases.


The patient was thoroughly worked up for sepsis; however, her procalcitonin was normal and so were her cultures. Bone marrow examination was done which suggested reactive changes. As we ruled out majority of differential, the diagnosis of systemic vasculitis was entertained and we proceeded with kidney biopsy. There are few systemic infections which can mimic vasculitis which was also ruled out in our patient.


  Dr Jyoti Kotwal (Department of Hematology, SGRH) Top


For the patient in question, the clinical possibilities which the clinicians thought were to rule out infection and myeloma. Her bone marrow aspiration revealed that myeloid predominance with neutrophilic leucocytosis, monocytosis and 1.5% of all cells were plasma cells. These changes in the setting of her laboratory reports (severe anaemia, low Ret-He, raised ferritin) pointed towards functional iron deficiency/anaemia of inflammation. Bone marrow biopsy showed myeloid preponderance with plasma cells, most probably reactive changes. Vasculitis cannot be diagnosed by bone marrow examination.


  Dr Sonia Badwal Top


The renal biopsy was evaluated morphologically and by direct immunofluorescence (DIF). Microscopic features revealed active cellular circumferential crescents with fibrinoidnecrosis, focal disruptions of glomerular basement membrane and periglomerular inflammation. Acute tubular injury with interstitial nephritis was also observed along with capillaritis in medullary vasarecta. DIF was negative for immune deposits [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d. In view of the characteristic morphological features, negative DIF and P-ANCA positivity, a diagnosis of ANCA-associated necrotising crescentic glomerulonephritis was offered. There was no eosinophilic inflammatory component as well as granulomatous response with negative C-ANCA; hence, the favoured subset is microscopic polyangitis over Eosinophilic granulomatosis with polyangiitis (EGPA) and Granulomatosis with polyangiitis (GPA).
Figure 1: (a) H and E, ×100 and (b) PAS stain, ×200: Glomeruli showing cellular to fibrocellular crescents. H and E, ×400. (b) Glomerulus with fibrinoid necrosis and disruptions of glomerular basement membrane. (c) Capillaritis vasarecta

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  Dr Tanvi Batra Top


In view of persistently dropping haemoglobin, multiple blood transfusions were done and she was started on pulse therapy of methyl prednisolone along with I/V cyclophosphamide (750 mg). On 3rd day after methyl prednisolone, she had sudden onset dyspnoea for which she was thoroughly investigated and found to be in fluid overload. She was started on haemodialysis as her urine output began to decrease and serum creatinine was gradually rising. Plasmapheresis was initiated forehand; she underwent total 5 cycles of the same. Possible causes of worsening acute kidney injury at this point were thought to be sepsis, vasculitis or drug induced.


  Dr. Atul Kakar Top


This patient presented to us with both diagnostic and therapeutic challenge. Systemic vasculitis usually presents with multisystem involvement which was not seen in our patient. There was no history of weight loss, fatigue, joint pains, eye involvement and nasal crusting or any history suggestive of neuropathy in our patient.

She was an elderly woman who had anti-MPO–positive ANCA and required regular dialysis. The seminal question in this patient was to treat or not to treat the underlying vasculitis (anti-MPO positive and renal biopsy suggestive of vasculitis). The treatment[1] of ANCA-positive vasculitis includes corticosteroids, immunosupressants (cyclophosphamide, rituximab, and mycophenolate mofetil) and plasma exchange therapy. The therapy needs to be individualised for each patient so that it causes less risk, more benefit, especially while treating the elderly population.

“Advanced Medicine has converted every acutely fatal disease into a chronic relapsing disorder with accumulating morbidity.”

When to treat or when to take back seat is a question which we debated with our nephrologist.

In older individuals, large-vessel vasculitis shows peak incidence between 65 and 75 years of age. In a study by Langford,[2] it was seen that and this disease mainly has a predilection for older individuals with peak incidence between 65 and 7 years of age. Our patient was MPO-positive vasculitis which is medium-to-small vasculitis and the common mean age of presentation is 45 years. Such vasculitis above the age of 65 is rare in Indian population. Due to lack of awareness about vasculitis in India, one quarter of patients receive antitubercular treatment before initiating proper treatment.[3] The ANCA-associated vasculitis is rare and accounts for 0.001% of hospital admissions in India.[3]

In a study done on elderly population (above the age of 75) with vasculitis, 151 patients were included from United Kingdom, the Czech Republic, and Sweden,[4] to study the outcome of ANCA-associated vasculitis. It was reported that advancing age with elevated creatinine and low Birmingham Vasculitis Activity Score had high mortality. The subjects who were treated with immunosuppressant and the patient who had yet not developed advanced renal failure had better prognosis at 2 years.


  Dr Manish Malik (Department of Nephrology, SGRH) Top


Rapidly progressive glomerulonephritis is the most dreaded complication of AAV.[5] MPO ANCA vasculitis patients have more renal impairment but better outcomes than anti-PR3 ANCA vasculitis. Immunosuppressive therapy is pivotal to improve survival of patients with active systemic AAV, including older adults.[4] Combination treatment with steroids and cyclophosphamide (dose adjusted for age and eGFR) is the first-line induction therapy.[6] Rituximab induction with cyclophosphamide is a good steroid-sparing induction regimen.[7] For patients with life-threatening and organ-threatening disease, plasma exchange has shown benefits.[8]


  Dr Lalit Duggal (Department of Rheumatology, SGRH) Top


I suggested low-dose rituximab for this patient in view of the clinical findings, renal involvement, anaemia, age factor and kidney biopsy findings for management of systemic vasculitis. In a meta-analysis of 143 participants, it was reported that remission was more likely in patients who had received I/V cyclophosphamide than oral cyclophosphamide. The study also showed that the former had fewer side effects. However, in this patient, in view of age and due to worsening renal failure, we gave rituximab instead of cyclophosphamide after 15 days for second dose (since the latter would need dose modification).

In RITUXIVAS,[7] rituximab was compared with cyclophosphamide / azathioprine for ANCA-associated vasculitis and was found to be noninferior to cyclophosphamide. Rituximab is the preferred drug for severe ANCA-associated vasculitis as per the 2021 ACR guidelines.


  Dr. Atul Kakar Top


In a study of 151 patients,[4] 45 patients (30.6) needed dialysis at the time of diagnosis; however, 26.7% were free of dialysis on follow-up. Hence, although we know that renal failure at the time of diagnosis for ANCA-associated vasculitis has poor prognosis, but these data showed that about one quarter of the patient would improve. We also know that prognosis of an untreated ANCA-associated vasculitis is poor and is associated with 90% mortality at 2 years, mostly due to respiratory failure.

All these points were discussed at bed side with the attendant and treated the patient with second dose of rituximab after 2 weeks interval. The patient is currently requiring renal replacement therapy while maintaining her serum creatinine in the range of 2.5–3 mg/dL.


  Final Diagnosis Top


MPO-positive vasculitis requiring renal replacement therapy in elderly patient.

Key message

Anti-MPO vasculitis with systemic involvement should be treated aggressively keeping in mind the high mortality. Choice of the immunomodulators should be based on clinical and biochemical profile of the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75:1583-94.  Back to cited text no. 1
    
2.
Langford CA. Vasculitis in the geriatric population. Clin Geriatr Med 2005;21:631-47.  Back to cited text no. 2
    
3.
Rajappa M. Assessment of activity and damage in ANCA associated vasculitis in India. Arthritis Res Ther 2002;4:88.  Back to cited text no. 3
    
4.
Weiner M, Goh SM, Mohammad AJ, Hruskova Z, Tanna A, Bruchfeld A, et al. Outcome and treatment of elderly patients with ANCA-associated vasculitis. Clin J Am Soc Nephrol 2015;10:1128-35.  Back to cited text no. 4
    
5.
Jennette JC, Nachman PH. ANCA glomerulonephritis and vasculitis. Clin J Am Soc Nephrol 2017;12:1680-91.  Back to cited text no. 5
    
6.
de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 2009;150:670-80.  Back to cited text no. 6
    
7.
Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.  Back to cited text no. 7
    
8.
Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007;18:2180-8.  Back to cited text no. 8
    


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Clinic Pathologi...
Dr Atul Gogia
Dr Jyoti Kotwal ...
Dr Sonia Badwal
Dr Tanvi Batra
Dr. Atul Kakar
Dr Manish Malik ...
Dr Lalit Duggal ...
Dr. Atul Kakar
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