Chronic Active Antibody-Mediated Rejection Following COVID-19 Infection in a Kidney Transplant Recipient: A Case Report

Kidney transplant recipients who develop coronavirus disease 2019 (COVID-19) are at increased risk of life-threatening illness, which often requires reducing immunosuppression despite the potential risk of causing an allograft rejection. Herein, we describe the clinical presentation and course of a kidney transplant recipient who acquired COVID-19 and was hospitalized with severe symptoms and hypoxemia. Upon admission, the patient was found to have elevated de novo donor-specific antibodies (DSA) yielding a positive cytotoxicity crossmatch and concurrent elevated plasma donor-derived cell-free DNA (dd-cfDNA) level, indicating a possible ongoing rejection despite improvement in his serum creatinine. Because of persistent positive COVID-19 tests and stable serum creatinine, a kidney allograft biopsy was initially deferred and his dd-cfDNA and DSA were monitored closely postdischarge. Three months later, because of persistent elevated dd-cfDNA and positive DSA, a kidney allograft biopsy was performed, which showed chronic active antibody-mediated rejection. Accordingly, the patient was treated with intravenous immunoglobulin and his maintenance immunosuppressive regimen was increased.     

Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease

PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.

Abbreviations

6MWD

6‐min walking distance

ACEI

ACE inhibitor

ARB

angiotensin receptor blocker

BPS

British Pharmacological Society

CCB

calcium channel blocker

CKD

chronic kidney disease

C_max

maximum plasma/serum concentration

CTEPH

chronic thromboembolic pulmonary hypertension

CVD

cardiovascular disease

CYP2C19

cytochrome P450, family 2, subfamily C, polypeptide 19

CYP2C9

cytochrome P450, family 2, subfamily C, polypeptide 9

CYP2D6

cytochrome P450, family 2, subfamily D, polypeptide 6

CYP3A

cytochrome P450, family 3, subfamily A

CYP3A4

cytochrome P450, family 3, subfamily A, polypeptide 4

CYP450

cytochrome P450 enzyme family

DN

diabetic nephropathy

ED

erectile dysfunction

eGFR

estimated GFR

ERA

endothelin receptor antagonist

ET

endothelin

ET‐1

endothelin‐1

FGR

fetal growth restriction

GSK3B

glycogen synthase kinase 3 β

HbA1c

glycated Hb

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

IC₅₀

half maximal inhibitory concentration

IUPHAR

International Union of Basic and Clinical Pharmacology

MI

myocardial infarction

mitoK_ATP

mitochondrial ATP‐sensitive potassium channels

NAION

nonarteritic anterior ischaemic optic neuropathy

Na⁺/K⁺‐ATPase

sodium–potassium pump

NOS1

neuronal NOS

NOS2

inducible NOS

NOS3

endothelial NOS

PAH

pulmonary arterial hypertension

PDE5I

PDE type 5 inhibitor

PH

pulmonary hypertension

PPHN

persistent pulmonary hypertension of the newborn

RCT

randomised controlled trial

RHTN

treatment‐resistant hypertension

RP

Raynaud''s phenomenon

sGC

soluble GC

SGLT2

sodium–glucose cotransporter 2

T_max

time taken to reach the maximum plasma concentration

T2DM

type 2 diabetes mellitus

UACR

urinary albumin/creatinine ratio

V/Q

ventilation/perfusion

     

Bilirubin and its oxidation products damage brain white matter

Brain injury after intracerebral hemorrhage (ICH) occurs in cortex and white matter and may be mediated by blood breakdown products, including hemoglobin and heme. Effects of blood breakdown products, bilirubin and bilirubin oxidation products, have not been widely investigated in adult brain. Here, we first determined the effect of bilirubin and its oxidation products on the structure and function of white matter in vitro using brain slices. Subsequently, we determined whether these compounds have an effect on the structure and function of white matter in vivo. In all, 0.5 mmol/L bilirubin treatment significantly damaged both the function and the structure of myelinated axons but not the unmyelinated axons in brain slices. Toxicity of bilirubin in vitro was prevented by dimethyl sulfoxide. Bilirubin oxidation products (BOXes) may be responsible for the toxicity of bilirubin. In in vivo experiments, unmyelinated axons were found more susceptible to damage from bilirubin injection. These results suggest that unmyelinated axons may have a major role in white-matter damage in vivo. Since bilirubin and BOXes appear in a delayed manner after ICH, preventing their toxic effects may be worth investigating therapeutically. Dimethyl sulfoxide or its structurally related derivatives may have a potential therapeutic value at antagonizing axonal damage after hemorrhagic stroke.     

Molecular alterations in the hippocampus after experimental subarachnoid hemorrhage

Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro-Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation.