Cholemic Nephropathy as Cause of Acute and Chronic Kidney Disease. Update on an Under-Diagnosed Disease

Cholemic nephropathy (CN) is a recognized cause of acute kidney injury (AKI) in patients with severe hyperbilirubinemia (sHyb) and jaundice. Pathophysiological mechanisms of CN are not completely understood, but it seems caused both by direct toxicity of cholephiles and bile casts formation in nephrons enhanced by prolonged exposure to sHyb, particularly in the presence of promoting factors, as highlighted by a literature reviewed and by personal experience. The aim of our update is to retrace CN in its pathophysiology, risk factors, diagnosis and treatment, underlining the role of sHyb, promoting factors, and CN-AKI diagnostic criteria in the different clinical settings associated with this often-concealed disease. Our purpose is to focus on clinical manifestation of CN, exploring the possible transition to CKD. Cholemic nephropathy is an overlooked clinical entity that enters differential diagnosis with other causes of AKI. Early diagnosis and treatment are essential because renal injury could be fully reversible as rapidly as bilirubin levels are reduced. In conclusion, our proposal is to introduce an alert for considering CN in diagnostic and prognostic scores that include bilirubin and/or creatinine with acute renal involvement, with the aim of early diagnosis and treatment of sHyb to reduce the burden on renal outcome.

Pharmacogenetic Associations Between Atazanavir/UGT1A1*28 and Efavirenz/rs3745274 (CYP2B6) Account for Specific Adverse Reactions in Chilean Patients Undergoing Antiretroviral Therapy

Background: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and atazanavir (ATV), a protease inhibitor, are drugs widely used in antiretroviral therapy (ART) for people living with HIV. These drugs have shown high interindividual variability in adverse drug reactions (ADRs). UGT1A1*28 and CYP2B6 c.516G>T have been proposed to be related with higher toxicity by ATV and EFV, respectively.Objective: To study the association between genetic polymorphisms and ADRs related to EFV or ATV in patients living with HIV treated at a public hospital in Chile.Methods: Epidemiologic, case–control, retrospective, observational study in 67 adult patients under EFV or ATV treatment was conducted, in the San Juan de Dios Hospital. Data were obtained from patients’ medical records. Genotype analyses were performed using rtPCR for rs887829 (indirect identification of UGT1A1*28 allele) and rs3745274 (CYP2B6 c.516G>T), with TaqMan® probes. The association analyses were performed with univariate logistic regression between genetic variants using three inheritance models (codominant, recessive, and dominant).Results: In ATV-treated patients, hyperbilirubinemia (total bilirubin >1.2 mg/dl) had the main incidence (61.11%), and moderate and severe hyperbilirubinemia (total bilirubin >1.9 mg/dl) were statistically associated with UGT1A1*28 in recessive and codominant inheritance models (OR = 16.33, p = 0.028 and OR = 10.82, p = 0.036, respectively). On the other hand, in EFV-treated patients adverse reactions associated with CNS toxicity reached 34.21%. In this respect, nightmares showed significant association with CYP2B6 c.516G>T, in codominant and recessive inheritance models (OR = 12.00, p = 0.031 and OR = 7.14, p = 0.042, respectively). Grouped CNS ADRs (nightmares, insomnia, anxiety, and suicide attempt) also showed a statistically significant association with CYP2B6 c.516G > T in the codominant and recessive models (OR = 30.00, p = 0.011 and OR = 14.99, p = 0.021, respectively).Conclusion: Our findings suggest that after treatment with ATV or EFV, UGT1A1*28 and CYP2B6 c.516G>T influence the appearance of moderate-to-severe hyperbilirubinemia and CNS toxicity, respectively. However, larger prospective studies will be necessary to validate these associations in our population. Without a doubt, improving adherence in patients living with HIV is a critical issue to the success of therapy. Hence, validating and applying international pharmacogenetic recommendations in Latin American countries would improve the precision of ART: a fundamental aspect to achieve the 95–95–95 treatment target proposed by UNAIDS.

Bilirubin adsorption for the treatment of severe hyperbilirubinemia after cardiac surgery: A retrospective cohort study

Objective: Severe hyperbilirubinemia after cardiac surgery increases in-hospital and 1-year mortality. Our present study aimed to analyze the safety and efficacy of bilirubin adsorption (BA) in patients with post-cardiac-surgery severe hyperbilirubinemia. Methods: We retrospectively included patients who underwent BA due to severe hyperbilirubinemia after cardiac surgery in our center between January 2015 and December 2018. The change of serum bilirubin, alanine aminotransferase, aspartate aminotransferase, and 30-day and 1-year mortality were assessed as endpoints. Univariate and multivariate analyses were employed to identify the risk factors of patient 30-day mortality. Result: A total of 25 patients with 44 BA treatments were included. One BA treatment reduced total bilirubin (TB) concentration from 431.65 ± 136.34 to 324.83 ± 129.44 µmol/L ( p < 0.001), with a reduction rate of 24.8%. No clinically relevant thrombosis of the extracorporeal circuit occurred during the BA treatment. The 30-day and 1-year mortality rates were 68% ( n = 18) and 84% ( n = 21), respectively. Multivariate analysis identified that TB level before BA treatment (odds ratio [OR] 1.010, 95% confidence interval [CI] 1.000–1.019; p = 0.043) was an independent risk factor of 30-day mortality. Conclusions: BA treatment should be considered as an effective and safe method for the reduction of serum bilirubin in patients with post-cardiac-surgery severe hyperbilirubinemia. Patients with higher TB level before BA treatment had a relatively increased risk of 30-day mortality. Further studies are needed to evaluate the timing of BA for severe hyperbilirubinemia after cardiac surgery.

Early Neurodevelopmental Outcome of Neonates with Gestation 35 Weeks or More with Serum Bilirubin in Exchange Range Without Encephalopathy: A Prospective Observational Study

ObjectiveTo describe early neurodevelopment outcomes of neonates with severe hyperbilirubinemia without acute bilirubin encephalopathy (ABE).MethodsNeonates born at gestation ≥35 weeks, admitted to NICU with total serum bilirubin (TSB) in exchange range with no features of ABE, were followed up until the age of 6 months. Infants were assessed for impaired hearing and neurodevelopment at 3 months and 6 months of age.ResultsA total of 59 neonates were enrolled in the study. At 3 months of age, 7.6 percent of neonates were found to have hypotonia and motor delay, whereas 42.3 percent had abnormal brainstem evoked response audiometery. At 6 months, 6.4 percent of neonates were found to have persistent neurodevelopmental impairment.ConclusionSevere hyperbilirubinemia is associated with impaired neurodevelopment and hearing even in infants without ABE. Peak TSB level strongly correlates with abnormal outcomes.

Jaundice

The jaundice chapter illustrates how to stabilize newborns with hyperbilirubinemia—a common condition—and avoid their developing severe hyperbilirubinemia. Prevention is accomplished by transcutaneous bilirubin testing, total serum bilirubintests, and the use of nomograms to evaluate risk for hyperbilirubinemia and direct appropriate care. Specific risk factors for jaundice and hyperbilirubinemia, treatment thresholds for phototherapy treatment or exchange transfusion, and a bilirubin-induced neurological dysfunction scoring tool for assessing severity in acute bilirubin encephalopathy cases are included. Related procedures, such as the direct antiglobulin test, volume expansion, and intravenous immunoglobulin administration are described. Focal skills, such as plotting and interpreting the nomograms, are applied in the case scenario.