Copper is an indispensable trace metal element and is mainly absorbed in the stomach and small intestine and excreted into the bile. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel approach for renal anemia management. Many intestinal genes, including <i>divalent metal transporter 1</i>, <i>duodenal cytochrome B</i>, and copper transporter ATPase7A<i>,</i> related to iron absorption are transactivated by HlF-α, during iron deficiency. We first report 4 cases of patients with renal anemia who showed excess in serum copper level during roxadustat or daprodustat treatment, which were decreased to the normal level after discontinuing HIF-PHIs and changing the drug to darbepoetin alfa, suggesting that HIF-PHI is associated with serum copper excess. HIF-PHI modulates iron metabolism, such as iron absorption, sequestration, and mobilization, and may increase serum copper levels by increasing copper absorption and/or redistribution of copper in tissues. Therefore, it is urgent to examine the correlation between HIF-PHI use and serum copper levels because copper excess might be involved in several acute or chronic adverse events.

Despite the reports on glomerulonephritis associated with COVID-19 mRNA vaccines, no study has reported about the dense deposit disease (DDD). Here, we present a case of hilar lymphadenopathy after the COVID-19 mRNA vaccination, following which the patient developed tubulointerstitial nephritis (TIN) and DDD. A 74-year-old man received his second dose of mRNA vaccine, and on the next day, he developed fever, urticaria, and dyspnea. On further examination, he had pleural effusion and right hilar lymphadenopathies, which were improved with conservative therapy. After 48 days of the second vaccination, he developed renal dysfunction and new-onset hematuria. Light microscopy findings by renal biopsy revealed apparent mesangial cell proliferation, increased mesangial matrix in the glomeruli, and diffuse inflammatory cell infiltration in the interstitium. Immunofluorescence analysis revealed 1 + positive results for IgG and IgM, negative results for IgA, and 2 + positive results for C3 with a garland pattern on the capillary walls. Electron microscopy revealed that severe cell proliferation in the capillary rumen, and continuous, thickened, and highly dark-stained spotty dense deposits in the glomerular basement membrane; and noncontinuous spotty dense deposits in the tubular basement membrane. Based on the decrease in C3 and pathological findings, TIN accompanied with DDD was diagnosed. The mRNA vaccine might have contributed to the development of lymphadenopathies, TIN, and DDD in this case. Moreover, TIN and DDD might be associated with the activated alternative pathway induced by the mRNA vaccine.

Dysregulation in total body copper causes severe complications and excess copper can be toxic. Divalent metal transporter 1, duodenal cytochrome B, and copper transporter ATPase7A are included in the many intestinal genes transactivated by HlF-α. On July X, 2022 an 80-year-old female patient on peritoneal dialysis was prescribed roxadustat 100 mg, because darbepoetin was unable to increase hemoglobin level effectively. On the same day, icodextrin 1 L was initiated to mitigate edema. Laboratory data showed hemoglobin 9.1 g/dL, transferrin saturation 77%, copper 123 μg/dL, and iron 170 μg/dL before changing to roxadustat. The patient visited us 6 days after the change because of the appetite loss. Transferrin saturation and serum copper and iron levels increased to 90%, 170 and 203 μg/dL, respectively, which were decreased or normalized after discontinuing roxadustat and icodextrin, suggesting that even short-term roxadustat administration can influence copper levels as well as iron levels. Excess copper and iron levels during roxadustat treatment do not immediately equate with toxicity, but indicate a physiological compensation or transient imbalance of metabolism especially in patients treated with ferric citrate. Further investigation for the hypoxia-inducible factor-prolyl hydroxylase inhibitors effects on iron and copper metabolisms is needed. Determining the short-term effect of roxadustat on serum copper and iron in only this case is impossible. Therefore, further accumulation of similar cases is necessary to clarify the short-term effects of roxadustat on serum copper and iron.