A 48-year-old man with end stage kidney failure, on maintenance dialysis since 2011, was referred in February 2020 with a 6-month history of general malaise and progressive evolvement of painless icterus and necrotizing skin ulcers.
The patient’s medical history included diabetes mellitus (DM) type I with end stage kidney failure, ischemic cardiomyopathy (obstructive lesions of left anterior descending coronary artery resolved by stent placement in 2018) and signs of predominantly diastolic heart failure (ultrasound of the heart prior to the occurrence of the symptoms referred to herein showed a 49% ejection fraction, mild mitral and aortic regurgitation, moderate pulmonary hypertension with 47 mmHg). His official therapy consisted of lacidipin, furosemide, acetylsalicylic acid, calcium carbonate, bisoprolol, sevelamer, pantoprazole, and was substantially unchanged in the last year.
In December 2018, the patient underwent stem cell transplantation in Ukraine. The stem cell clinic NBS/ICH/Kiev/London promised-as cited from the brochure, with many grammatical errors »…it is expected strengthening of the regenerative abilities of the body, improving of all functions of organs and tissues and repairing of pathologically damaged tissues, rejuvenate body…« The patient explained he mostly hoped for restitution of his kidney function. Although the patient could not provide an exact operative report, he explained that the product was supposed to be stem cells of embryonal origin and was injected in a single infusion in his peripheral vein. The stem cell clinic claimed in their informative material that examination (including determination of normal heart, lungs, kidney and liver function, as well as ruling out infection) would be performed. However, the patient could not recall any preadmission testing.
At the current referral, jaundice (bilurubin 142/116 μmol/l, increased alkaline phosphatase, slightly elevated alanine aminotransferase) and necrotizing skin changes predominated in the clinical picture (Figure 1A and 1B). He described his skin wounds as aching and itching. The first skin lesions appeared 6 months after stem cell treatment, starting as bullae, which then burst, and a scab formed underneath. The wounds spread all over the body, the most severely affected being the skin on the arms and legs. A deep punch skin biopsy disclosed segmental medial basophilic calcification with focal atrophy of smooth muscle in media, intimal fibroplasia of small and/or medium sized arteries and arterioles in subcutaneous adipose tissue consistent with calciphylaxis. Additional staining with von Kossa highlighted subtle calcium deposits also in the interstitium of the dermis and elastic fibers. Inflammation was relatively scant as well as extravasation of erythrocytes. There were no changes suggestive for graft versus host disease (Figure 1C and 1D).
However, the patohistological diagnosis of calciphylaxis was not consistently supported by clinical findings, as there was no severe deterioration of phosphate/calcium metabolism on admission, parathyroid hormone was within limits and, according to the angiologist's clinical assessment and ultrasound Doppler measurements of perfusion pressure in the lower extremity arteries, macrovascular peripheral arterial disease was not likely.
The first laboratory signs of icterus were present in September 2019. Investigations of icterus included transabdominal and endoscopic ultrasound, which showed hepatosplenomegaly without signs of extrahepatic cholestasis. The most likely infectious, metabolic and autoimmune causes, as well as biliary obstruction (see Supplementary Table) were ruled out. Since the patient also experienced severe deterioration of heart function in the same time frame (heart ultrasound revealed a severe reduction of the left ventricular ejection fraction to 30%, segmental contraction disorders, right-sided heart failure, and moderate mitral regurgitation), the differential diagnosis included liver congestion due to heart failure of unknown etiology (acute coronary syndrome was ruled out). This was not however supported by the liver histology (Figure 2 A and B), which revealed subacute hepatitis with portal inflammation of mixed type (mainly neutrophilic and eosinophilic granulocytes) without convincing signs of chronic liver congestion. We concluded that the hepatic impairment was probably the result of combined liver defect: chronic congestive hepatopathy (dilated sinusoids and ultrasound dilated hepatic veins) and toxic injury of idiosyncratic type, which manifested as cholestatic hepatitis, revealed by liver biopsy. A reasonable trigger for this reaction was, however, unclear and difficult to identify.
In accordance with assumed calciphylaxis, treatment with sodium thiosulphate, intensified dialysis and hyperbaric oxygen were initiated. The inflammatory parameters decreased, the patient was cardiopulmonary compensated, with better but not normal laboratory results (bilirubin 45/45 μmol/l) and with slight improvement in skin condition. He insisted on dismission and continued with regular dialysis thrice weekly at our outpatient service. Four days after dismission he was found dead in his apartment. An autopsy was not performed.