Early onset calciphylaxis following acute kidney injury secondary to anti-glomerular basement membrane antibody disease

Abstract

Calciphylaxis is commonly associated with end-stage renal disease (ESRD) and renal transplant. We present a rare case of early onset calciphylaxis in a patient presenting with acute kidney injury (AKI) secondary to anti-glomerular basement membrane (anti-GBM) antibody disease. A 65-year-old obese Caucasian woman with type 2 diabetes mellitus and hypertension presented with a 1-month history of painless gross haematuria and worsening lower extremity oedema. Laboratory results indicated AKI and nephrotic-range proteinuria. Anti-glomerular antibodies were elevated. Renal biopsy revealed focal crescentic glomerulonephritis with linear capillary immunoglobulin G staining consistent with anti-GBM antibody disease. She was treated with haemodialysis, plasmapheresis, steroids, bumetanide and cyclophosphamide. Two months later, she developed necrotic lesions on bilateral thighs. Wound biopsy was consistent with calciphylaxis. This case highlights that calciphylaxis, usually seen in patients with chronic kidney disease or ESRD, can manifest in patients with AKI as well.

Background

Calciphylaxis is a rare, life-threatening disorder characterised by ischaemia and necrosis of skin due to calcification of arterioles and capillaries in the dermis and subcutaneous adipose tissue.¹ It portends an extremely poor prognosis with survival of less than 1 year.² Commonly associated conditions include end-stage renal disease (ESRD) and renal transplant.³ Rarely, it can occur in patient with early chronic kidney disease (CKD), acute kidney injury (AKI) or even normal renal function.⁴ When it develops in patients without ESRD, it is termed as non-uremic calciphylaxis (NUC).⁵ In patients with ESRD, the interval from initiation of dialysis to appearance of calciphylaxis averages 30 months in the USA.⁶ There is no approved treatment for calciphylaxis.³ Risk factors include hypercalcaemia, hyperphosphataemia, hyperparathyroidism, obesity, female gender, thrombophilia, hypoalbuminaemia, diabetes, certain medications including warfarin, systemic glucocorticoids, calcium-based binders and vitamin D analogues, inflammatory and autoimmune conditions, and recurrent skin trauma.^{5 7} Physical examination findings of a classic painful black lesion covered by an eschar helps with diagnosis⁸ and biopsy is not indicated in patients with ESRD. In non-uremic patients, biopsy helps diagnose calciphylaxis and is characterised by dermo-hypodermal and pannicular arteriolar calcification, subintimal fibrosis and thrombotic occlusion.^{9 10} Treatment revolves around eliminating risk factors, wound care and pain control.⁵ Bisphosphonates, sodium thiosulfate or hyperbaric oxygen are commonly used to treat calciphylaxis but there is no effective treatment to date.^{3 11 12} It is rare to see early onset calciphylaxis after AKI. To the best of our knowledge, this is the first case of early onset calciphylaxis in a patient with recently diagnosed anti-glomerular basement membrane (anti-GBM) antibody disease.

Case presentation

A 65-year-old obese Caucasian woman with a history of well-controlled type 2 diabetes, hypertension, cerebrovascular accident, chronic obstructive pulmonary disease, hypothyroidism presented with 1-month history of painless gross haematuria associated with generalised fatigue, decreased urine output, reduced oral intake and worsening lower extremity oedema bilaterally. She denied flank or abdominal pain, dysuria, urgency or changing frequency of urination, fever, weight loss, arthralgias, cough, haemoptysis, dyspnoea, rash, recent trauma, chest pain, bleeding elsewhere or non-steroidal anti-inflammatory drugs use. She denied any prior episodes of haematuria. No recent antecedent illness was reported. She was a former smoker with a 17 pack-year smoking history. Family history was unremarkable. Home medication list included levothyroxine, insulin aspart, albuterol inhaler and clopidogrel. Vital signs were stable on presentation. Notable physical examination included 1+lower extremity pitting oedema bilaterally. No petechiae or rash were seen. The patient was treated as below and sent home. Two months later, she presented with approximately 2 cm painful large eschar on the right medial thigh with fibrinous debris at the base and fibrinous liquefaction without fluctuance or surrounding erythema. Multiple stage II/III ulcers on bilateral buttocks, left lateral and left medial thigh and sacrum were noted.

Investigations

• White cell count 17 700/μL (normal 3400–10 800), haemoglobin 66 g/L (111–159), platelets 225 ×10⁹/L (150–450), 0 eosinophils.

• Albumin 2.1 g/dL (2.9–4.4), calcium 7.2 mg/dL (8.7–10.2), ionised calcium 1.04 mmol/L (1.14–1.33), phosphorous 10.4 mg/dL (2.4–4.7), Parathyroid hormone 999 pg/mL (12–88), serum creatinine 6.62 mg/dL (baseline creatinine 0.75 mg/dL, normal range 0.51–1.0), 25-hydroxy vitamin D 28.6 ng/mL (30–100), haemoglobin A1c 6.0% (4.8–5.6).

• Partial thromboplastin time 37 s (25–38), prothrombin time 11.5 s (9.4–12.9), international normalised ratio 1.1 (0.83–1.14), creatine phosphokinase 59 IU/L (30–225).

• Urinalysis: 3+protein, 3+blood, numerous red cells (RCs), positive urine eosinophils. Urine microscopy—many RCs, no dysmorphic RCs or RC casts.

• 24-hour urine protein: 4.6 g.

• Viral hepatitis panel, HIV, c-ANCA (anti-neutrophil cytoplasmic antibodies), p-ANCA, atypical ANCA, anti-proteinase 3, anti-myeloperoxidase, anti-double-stranded DNA serologies were negative. C3, C4 complements were normal. Serum protein electrophoresis/urine protein electrophoresis with immunofixation, cryoglobulins were negative.

• Anti-nuclear antibodies were elevated 1:320 (speckled pattern) (<1:160).

• Anti-glomerular antibodies were elevated 69 (normal 0–20).

• Renal ultrasound was unremarkable.

• Renal biopsy revealed focal crescentic glomerulonephritis with linear immunoglobulin G (IgG) staining consistent with anti-GBM antibody disease. Acute tubular epithelial injury and severe arterionephrosclerosis were seen.

• CT abdomen and pelvis was unremarkable without any urologic abnormality.

• Ultrasound of wounds reported no fluid collection, infection or abscess.

• Skin biopsy of the right thigh wound revealed marked calcification of small-sized and intermediate-sized arteries, arterioles and capillaries consistent with calciphylaxis. There were no vasculitic changes (see figure 1A, B).

Figure 1.

(A) Ulcerated epidermis (thick arrow) and subcutaneous tissue with marked calcification of small-sized and intermediate-sized arteries (arrowhead). Acute and chronic inflammatory cells are present in epidermis, dermis and subcutaneous tissue (thin arrows) (H&E, magnification ×10). (B) Calcified capillary-sized vessels are in subcutaneous tissue (H&E, magnification ×100).

Treatment

The patient was started on dialysis 3 days a week, underwent 10 cycles of plasmapheresis, was treated with intravenous methylprednisone and later oral prednisone, bumetanide, cyclophosphamide and sevelamer. Two months later, the patient presented with right medial thigh eschar, along with stage II/III ulcers on bilateral buttocks, left medial and left lateral thigh and sacrum. The patient underwent skin biopsy that was consistent with calciphylaxis as described above. Her pain was adequately managed, wound ostomy was following. Sulfadiazine cream and daikin’s wet to dry dressings were applied over wounds. She underwent sharp excisional debridement of left lateral thigh wound, left medial thigh wound and right medial thigh wound.

Outcome and follow-up

Once calciphylaxis was confirmed, the plan was to continue haemodialysis along with sodium thiosulfate three times a week with appropriate wound care and pain management. We also planned to eliminate other risk factors like secondary hyperparathyroidism and steroid use in this case. However, the patient decided to go home with hospice on comfort care and declined all interventions. Unfortunately, she passed away within 4 months of initial presentation.

Discussion

To the best of our knowledge, this is the first case of early onset calciphylaxis in a patient with recently diagnosed anti-GBM antibody disease. It is unclear if there exists a direct relationship between the two. Anti-GBM antibodies are autoantibodies against type IV collagen, which is composed of 6 α chains, named α1–α6, that assemble in order to form heterotrimers.¹³ Anti-GBM autoantibodies against different target antigens are associated with disease severity.¹⁴ In calciphylaxis, microvascular calcification occurs via an active process involving upregulation of bone morphogenetic protein 2 (BMP-2), runt-related transcription factor 2 (RUNX-2) and osteopontin. These factors are affected by proinflammatory cytokines, such as tumour necrosis factor and interleukin 6. Thus, even if the antigen-antibody reaction did not directly contribute to the patient’s presentation, calcification of the blood vessel wall might have been accelerated as a result of systemic inflammation. Also, it would have been beneficial to examine whether IgG deposits were present around the blood vessels of the skin biopsy tissue similar to that found in GBM; however, immunofluorescence was not done in our case.

Calciphylaxis is a rare disease characterised by non-healing skin ulcers secondary to arterial calcification and thrombosis. It is typically diagnosed in patients with ESRD.³ When it develops in patients without ESRD, it is termed as NUC.⁵ The latter portends an extremely dismal prognosis, is rarer, with survival of less than 1 year from presentation.² Death by sepsis is the usual outcome in majority of cases.⁵ Calciphylaxis carries a 1-year mortality rate of 40%–50% and prognosis is even poorer once ulceration develops, with cause-specific mortality exceeding 80%.¹⁵ Pathophysiology of NUC remains elusive.⁷ Diagnosis of NUC requires skin biopsy and is characterised by dermo-hypodermal and pannicular arteriolar calcification, subintimal fibrosis and thrombotic occlusion.^{9 10} Therapeutic options are limited to pain control, wound care, control of infections and risk factors, and surgical debridement.⁵ Recently, other therapeutic interventions used in the treatment of uremic calciphylaxis are being studied including sodium thiosulfate, hyperbaric oxygen, lanthanum carbonate, statins, bisphosphonates, cinacalcet and sevelamer.^{5 16} Calciphylaxis has a predilection for the lower extremities and areas rich in adipose tissue.¹⁷

Our patient did have traditional risk factors for NUC including obesity, female gender, acutely elevated phosphorous and PTH levels (from secondary hyperparathyroidism), steroids use, high calcium-phosphate product, hypoalbuminaemia, autoimmune disease and diabetes.^{5 7} Chemotherapy medications including cyclophosphamide is an additional risk factor which was used in our case for the treatment of anti-GBM antibody disease.⁵

In this case, presence of skin lesions raised the suspicion for overlapping ANCA vasculitis; however, ANCA serologies were negative. Calciphylaxis may be confused with pressure ulcers especially in bed-ridden and debilitated patients. Clinical suspicion confirmed with biopsy can help differentiate between the two. The average time to onset of calciphylaxis in patients with ESRD in the USA is 30 months,⁶ whereas the development of calciphylaxis following AKI was very rapid in our case. Therefore, reasonable suspicion for calciphylaxis should exist as it can develop relatively rapidly as well. This case highlights that calciphylaxis, usually seen in patients with CKD or ESRD, can manifest in patients with AKI as well.

Learning points.

• Calciphylaxis results in an extremely poor prognosis with likely imminent death within 1 year from initial presentation.

• Although typically seen in patients with end-stage renal disease (ESRD), chronic kidney disease and renal transplant, calciphylaxis rarely can occur following an acute kidney injury (AKI).

• Multiple risk factors for non-uremic calciphylaxis include obesity, female gender, hyperparathyroidism, elevated calcium-phosphorous product, hypoalbuminaemia, autoimmune diseases, diabetes, warfarin, steroids and chemotherapy medications.

• Calciphylaxis can be confused with pressure ulcers especially in debilitated patients. Biopsy in such situation can help differentiate between the two.

• Although the average time of onset of calciphylaxis in patients with ESRD in the USA is 30 months, it can develop relatively rapidly following AKI as in our case.