Calciphylaxis in a Patient With Lupus Nephritis and Acute Kidney Injury: A Rare Case Report and Literature Review

Abstract

Calciphylaxis is a rare and severe disease characterized by calcification, fibrosis, and thrombosis of small blood vessels. Although it primarily affects patients with end-stage renal disease (ESRD) on dialysis, limited cases have been reported of calciphylaxis in patients with acute kidney injury (AKI) and lupus. This case report describes the occurrence of calciphylaxis in a 35-year-old female recently diagnosed with lupus nephritis class IV and AKI requiring dialysis.

Introduction

Calciphylaxis is a rare condition caused by calcification, fibrosis, and thrombosis of small blood vessels. ¹ The most common form of calciphylaxis is uremic calciphylaxis, which is most commonly seen in patients with chronic kidney disease (CKD). ² However, calciphylaxis can also occur in patients with normal renal function or less advanced forms of CKD, known as nonuremic calciphylaxis, albeit at a lower incidence. ² The disease usually presents as painful lesions involving the adipose tissue and primarily occurs on the thighs and abdomen. In patients with CKD, calciphylaxis may be associated with several risk factors, including elevated calcium, phosphorus, obesity, hypoalbuminemia, female gender, warfarin use, and protein C or S deficiencies. ³ Nonuremic calciphylaxis, however, is associated with malignancy, autoimmune disease, alcoholic liver disease, and the use of glucocorticoids. ⁴

We describe a case of calciphylaxis in a 35-year-old female recently diagnosed with class IV lupus nephritis-associated acute kidney injury (AKI) with 2-month duration of kidney replacement therapy.

Case History

A 35-year-old female with a recent diagnosis of kidney-biopsy-proven class IV lupus nephritis, heart failure with a preserved ejection fraction of 40% to 55%, and hyperthyroidism presented with new-onset skin lesions on her bilateral thighs a month ago, which progressively enlarged and associated with pain and pruritus. She reported unintentional weight loss over the last few months. There was no history of trauma. A skin biopsy failed to reveal a diagnosis.

A diagnosis of systemic lupus erythematosus (SLE) and concomitant class IV lupus nephritis along with acute tubular injury, diagnosed via a kidney-biopsy as an etiology for AKI, was made 4 months prior, when she was admitted for heart failure exacerbation and was found to manifest clinical signs and symptoms of SLE along with hypocomplementemia and an elevated anti-nuclear antibody titer. Her kidney function worsened that necessitated kidney replacement therapy for 2 months. Her AKI eventually resolved, and she was able to come off dialysis, with complete kidney function recovery in the subsequent 2 months.

During the current admission, 2 stellate-shaped purpuric patches and plaques on the left upper and posterior thigh and hip, and on the right thigh were observed. These patches were painful, firm, and indurated, with focal overlying necrosis. Serology workup revealed a decreased level of phosphorus, ionized calcium, albumin, and total protein levels, and an elevated parathyroid hormone (PTH) level. Our suspicion for Protein C and S deficiency was low, and these were checked later when lesions were healing; both were found to be within normal limits (Table 1). The computed tomography (CT) scan revealed scattered foci of calcifications in the vascular distribution along the branch vessels of the lower extremity arterial system as well as buttocks and anterior subcutaneous pelvic soft tissue. A right lateral thigh subcutaneous skin biopsy was suggestive of calciphylaxis. Treatment with intravenous sodium thiosulfate 25 g thrice weekly was started.

Table 1.

Laboratory Tests Results.

Laboratory tests	Result	Normal range
Phosphorus	1.4 mg/dL	3-4.3 mg/dL
Ionized calcium	2.2 mg/dL	4.4-5.2 mg/dL
Albumin	3.2 g/dL	3.5-5.2 g/dL
Total protein	5.4 g/dL	6.0-8.3 g/dL
PTH	171.0 pg/mL	15-65 pg/mL
Protein S Ag, Total	60%	60%-150%
Protein S Ag, Free	68%	61%-136%
Protein C Ag, Total	77%	60%-150%

Abbreviations: PTH: parathyroid hormone; Ag, Antigen; dL, deciliter; g, gram; mg, milligram; mL, milliliter; pg, picogram.

In subsequent follow-up appointments, significant improvement in the patient’s skin lesions was observed, along with a notable reduction in reported pain. After 8 months of treatment, sodium thiosulfate administration was discontinued.

Discussion

Calciphylaxis is rare, with incidence rate of 1% to 4% in patients with renal failure and an estimated 1-year survival rate between 20% and 50%; incidence appears to increase over time.^2,5 Typically afflicted are elderly white females with the median age of involvement ranging from 50 to 70 years.^2,6,7 Affliction of young adults and children is infrequent and is usually associated with severe kidney damage leading to kidney failure.^8,9

Calciphylaxis occurs due to an imbalance of pro- and anti-calcification mechanisms in the body. A number of theories have been proposed regarding the pathogenesis of this condition, including differentiation of vascular smooth muscle cells into osteoblast-like phenotypes and the proliferation of chondrocytes that deposit hydroxyapatite crystals throughout the body. Adipocytes may also calcify and promote vascular smooth muscle cell calcification when exposed to high circulating levels of phosphorus. Vitamin K deficiency can lead to less activation of matrix Gla protein, which inhibits tissue calcification. Low levels of calcification inhibitors, such as osteoprotegerin and fetuin-A, and high levels of promoters of calcification, such as bone morphogenic protein-4 and osteopontin, are also thought to be involved in the pathogenesis.^10,11

In patients with calciphylaxis, there is usually painful skin lesions, such as livedo reticularis, reticulate purpura, and violaceous plaques. These lesions may progress into blisters and ulcers, as well as causing additional infections. Early recognition and initiation of treatment are crucial. Skin biopsy is needed for definitive diagnosis. ¹²

There are several risk factors associated with calciphylaxis (Table 2). Kidney injury is a substantial risk factor, with most cases occurring in those on hemodialysis, while there are also reports in post kidney transplantation. ¹ Other risk factors include dysregulated calcium and phosphate balance including hyperphosphatemia, hypercalcemia, hyper- and hypo-parathyroidism. Diabetes mellitus, obesity, autoimmune, and hypercoagulable conditions are also associated with an elevated risk of calciphylaxis. Medications, including warfarin, calcium supplements, calcium-phosphate binders, active vitamin D, glucocorticoids, iron, and trauma associated with subcutaneous heparin and insulin, are also associated with an increased risk of calciphylaxis.^2,11

Table 2.

Risk Factors Associated With Uremic and Nonuremic Calciphylaxis.^3,4

Uremic calciphylaxis	Nonuremic calciphylaxis
Female gender Obesity Glucocorticoids Diabetes mellitus Alcoholic liver disease Protein C or S deficiencies Elevated calcium Elevated phosphorus Hypoalbuminemia Warfarin	Female gender Obesity Glucocorticoids Diabetes mellitus Alcoholic liver disease Protein C or S deficiencies Malignancy Autoimmune disease

Limited cases have been reported on calciphylaxis in patients with AKI due to decompensated alcoholic cirrhosis or severe clinical conditions such as necrotizing fasciitis who undergo dialysis, ranging from 29 to 65 years.^13-17 However, there are no documented reports of patients with lupus nephritis with significant kidney damage who had calciphylaxis.

It is important to highlight that while the initial skin biopsy suggested calciphylaxis, it did not conclusively confirm the diagnosis. It is not uncommon for biopsies to provide inconclusive results when assessing this condition.^10,18

While some clinicians may choose to repeat the skin biopsy, we decided to start empirical treatment based on our patient’s medical history and the findings from the CT scan instead of repeating the biopsy, which was a painful procedure for the patient. ¹⁹

Thus, when a patient displays clinical signs and symptoms of calciphylaxis with an inconclusive skin biopsy, it is recommended to perform further workup by performing CT scans and considering empiric treatment with sodium thiosulfate in cases with a high suspicious of calciphylaxis.

Conclusion

We described the occurrence of calciphylaxis in a young female with proliferative lupus nephritis-related AKI that briefly necessitated hemodialysis. The diagnosis of calciphylaxis, a rare and highly fatal disease, must be suspected at an early stage to avoid the delay in care that can lead to a poor outcome. Early identification and abrogation of risk factors and timely treatment are crucial. Due to the complexity of this disease, a multidisciplinary team approach is recommended for optimal management.