Thrombotic Microangiopathy in Renal Allograft Induced by Valproic Acid Treatment in Addition to Tacrolimus and Everolimus: A Case Report Free

Thrombotic microangiopathy (TMA) is defined by microvascular endothelial damage and thrombosis impairing kidney function. De novo TMA develops in 3–14% of kidney transplant recipients with approximately 40% classified as pathological TMA. This condition is characterized by biopsy-confirmed renal TMA without evidence of microangiopathic hemolytic anemia or thrombocytopenia [1]. Causes of TMA in renal transplant recipients include immunosuppressive drugs, ischemia/reperfusion injury, viral infections, and antibody-mediated rejection. Notably, calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, especially at higher concentrations, are associated with an increased TMA risk [2]. High doses of valproic acid may result in toxic levels, leading to systemic TMA [3, 4]. Although CNI, mTOR inhibitors, and valproic acid are associated with endothelial cell damage, there are no reports linking their combined use at standard doses to pathological TMA. However, we report a case of pathologic TMA in a renal allograft that may be induced by the combined use of tacrolimus (CNI), everolimus (mTOR inhibitor), and valproic acid at standard doses. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546925).

Four years ago, a 37-year-old woman presented proteinuria and microhematuria leading to a diagnosis of non-IgA mesangial proliferative glomerulonephritis based on renal biopsy findings. Following steroid therapy, proteinuria improved, but renal function declined progressively. An ABO-compatible living-related renal transplantation was performed with her father as the donor. As shown in Figure 1, the transplantation restored renal function to normal serum creatinine levels and resolved the proteinuria. The patient received an immunosuppressive regimen of tacrolimus, everolimus, and steroids, following induction therapy with basiliximab. Immunosuppressive drug dosages were adjusted to maintain optimal blood levels. Protocol biopsies conducted at 1 h, 3 weeks, and 1 year posttransplantation revealed donor-derived mesangial IgA deposition without glomerular abnormalities. No rejection or CNI toxicity was observed.

Eight months posttransplant, an abortive oral dose of rizatriptan and loxoprofen (non-steroidal anti-inflammatory drugs) was prescribed to manage migraine. Although migraine attacks occurred several times monthly, non-steroidal anti-inflammatory drugs were used only once or twice a month. Owing to persistent migraines, valproic acid at 400 mg/day was introduced 2.5 years after the transplant. Despite treatment, migraines persisted, leading to the prescription of galcanezumab, an anti-calcitonin gene-related peptide monoclonal antibody (CGRP mAb). At 3.5 years posttransplant, the dose of valproic acid was increased to 600 mg/day and later adjusted to 800 mg/day at 3 years and 10 months. As the valproic acid dosage for migraines (400–800 mg/day) is lower than that for epilepsy (400–1,200 mg/day) and its effective blood concentrations remain undefined, routine blood concentration monitoring is not required. In this instance, valproic acid blood levels were not measured. Nevertheless, the neurologist adjusted the dosage appropriately, ensuring no indications of liver damage, nausea, or other signs of toxicity.

Renal function declined gradually 3.5 years after the transplant with serum creatinine levels rising from 1.2 mg/dL to 1.4 mg/dL. Urinary protein, anemia, thrombocytopenia, hepatic dysfunction, and antihuman leukocyte antigen antibodies were absent. Blood pressure remained stable with no prior history or evidence of thrombophilic autoimmune disorders such as antiphospholipid antibody syndrome. A graft biopsy conducted 4 years posttransplant revealed light microscopy findings as shown in Figure 2. Severe thrombotic lesions were identified in two arterioles, characterized by fibrin thrombi, endothelial cell swelling and proliferation, foam cell infiltration, and smooth muscle cell degeneration and necrosis. Thrombus formation at the vascular pole of the glomerulus was associated with endothelial cell proliferation. Fibrin thrombi blocked the lumens of five afferent arterioles, resulting in ischemia in the glomeruli. Striped interstitial fibrosis and tubular atrophy affected 30% of the tissue. In the arterioles, degenerated smooth muscle cells were replaced with hyaline deposits. The Banff classification findings were recorded as follows: i0, t0, g0, v0, ptc0, ci2, ct2, cg0, cv0, ptcbm0, ah3, aah2. Capillary thrombi, mesangiolysis, and capillary double contours were absent in the glomeruli, and no evidence of focal segmental glomerulosclerosis was identified. Immunofluorescence microscopy results were negative. Endothelial cell assessment was not possible owing to the absence of glomeruli and blood vessels in electron microscopy sample. Antibody-mediated rejection was ruled out. The findings led to the diagnosis of TMA caused by CNI, mTOR inhibitors, and valproic acid.

Following the increase in the valproic acid dose, renal function deteriorated, prompting its discontinuation 1 month after the graft biopsy, while tacrolimus and everolimus were continued at their existing doses. Owing to worsening migraines, galcanezumab was replaced with another CGRP mAb, fremanezumab, leading to symptom improvement. After valproic acid withdrawal, renal function ceased to deteriorate and remained stable for 2 years.

Acute pathological TMA in renal allografts may be associated with the administration of standard doses of CNI, mTOR inhibitors, and valproic acid. This is the first case linking their concurrent use to pathological TMA in renal allografts. Both CNI and mTOR inhibitors are known to cause posttransplant TMA [4‒7], and their combined use poses a greater risk compared to using either drug alone [8]. Posttransplant TMA is most commonly observed within the first 6 months after transplantation, coinciding with higher target trough levels of CNI [2]. In this case, the blood levels of CNI and mTOR inhibitors remained within optimal ranges, with no evidence of TMA on renal biopsy up to 1 year posttransplantation. Therefore, CNI and mTOR inhibitors alone are unlikely to have caused acute TMA. Toxic levels of valproic acid have been associated with systemic TMA [3]. Blood concentration monitoring is generally unnecessary, as the therapeutic dose of valproic acid for migraines is lower than that for epilepsy and no optimal concentration has been defined. The maximum dose of 800 mg/day was suitable for migraine treatment, and no signs of nausea or liver damage linked to poisoning were observed, suggesting that the blood concentration of valproic acid likely remained below toxic levels.

Renal function deteriorated 3.5 years after the kidney transplant, following an increase in valproic acid dosage. A biopsy performed 4 years posttransplant revealed features of chronic CNI toxicity, including striped interstitial fibrosis and tubular atrophy and smooth muscle cell degeneration replaced by hyaline deposits. Additionally, the biopsy identified acute TMA features such as necrotic thrombotic microvascular lesions, degeneration and necrotic changes in smooth muscle cells, vascular endothelial cell enlargement, and foam cell infiltration. These pathological and clinical findings indicate that valproic acid contributed to acute and severe TMA by exacerbating chronic endothelial damage caused by CNI and mTOR inhibitors. Importantly, renal function stabilized after discontinuing valproic acid despite maintaining the same doses of tacrolimus and everolimus. This further supports that valproic acid induced acute TMA.

CGRP mAb has been approved by the Food and Drug Administration for migraine prophylaxis since 2018, with no reported adverse effects related to TMA or renal dysfunction [9]. Following the discontinuation of valproic acid, the patient’s renal function remained stable, despite the continued use of CGRP mAb. This indicates that CGRP mAb does not contribute to renal function decline.

Although TMA has diverse causes, its common pathogenic features include endothelial cell damage and thrombus formation in the microvessels. Drug-induced TMA typically arises from disruptions to multiple factors that maintain endothelial cell homeostasis. CNIs induce microvessel constriction, causing endothelial cell damage due to ischemia. Additionally, CNIs are believed to promote platelet aggregation and activate prothrombotic factors [10]. mTOR inhibitors reduce vascular endothelial growth factor (VEGF) expression in the kidneys and induce the death of endothelial progenitor cells [11, 12]. These anti-angiogenic effects are thought to play a role in the development of TMA. Valproic acid has been utilized as an anticonvulsant for over 50 years, with elevated blood levels reported to increase the risk of developing TMA [13]. As a histone deacetylase inhibitor, valproic acid impairs endothelial cell function and angiogenesis both in vitro and in vivo [14, 15]. In summary, CNI, mTOR inhibitors, and valproic acid impair endothelial cell function through distinct mechanisms, and their cumulative effects may lead to acute and severe TMA.

Acute and severe pathologic TMA occurred in a renal allograft due to the addition of valproic acid to CNI and mTOR inhibitors. Approximately 40% of posttransplant de novo TMA cases are pathologic TMA, diagnosable only through renal biopsy, and manifest as progressive renal failure or hypertension. When multiple medications that damage endothelial cells are administered even at proper dosages, drug-induced TMA can develop. This case highlights the importance of performing a renal biopsy when renal function declines.

We extend our gratitude to Editage (www.editage.com) for their assistance with English language editing.

Informed written consent was obtained from the patient for the publication of this case report and accompanying images. All studies adhered to the Declaration of Helsinki guidelines established by the World Medical Association. This article does not involve any studies conducted by the authors that included human participants. The Institutional Review Board of the Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital confirmed that ethical approval was not required for this case report and every effort was made to ensure the patient’s identity was protected.

The authors declare no conflicts of interest.

The authors confirm that no funding was received for this study.

Azusa Kobayashi and Asami Takeda made substantial contributions to the study’s concept, data analysis, and interpretation; drafted the manuscript’s initial version; approved the final version of the manuscript for publication; and accepted accountability for all aspects of the work. Shoji Saito, Hibiki Shinjo, Daiki Iguchi, Kenta Futamura, Manabu Okada, Takahisa Hiramitsu, Shunji Narumi, and Yoshihiko Watarai were involved in data acquisition, contributed to the manuscript revision, approved the final version for publication, and accepted accountability for all aspects of the work.

All data generated or analyzed in this study are included within this article. For any additional inquiries, the corresponding author may be contacted.