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Barry I Freedman,
Carl D Langefeld,
Jolyn Turner,
Marina Núñez,
Kevin P High,
Mitzie Spainhour,
Pamela J Hicks,
Donald W Bowden, Amber M Reeves-Daniel,
Mariana Murea,
Michael V Rocco,
Jasmin Divers
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ABSTRACT: Familial aggregation of non-diabetic end-stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in the high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2% of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared with one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated glomerular filtration rate (GFR; MDRD equation), and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.Kidney International advance online publication, 13 June 2012; doi:10.1038/ki.2012.217.
Kidney International 06/2012; · 6.61 Impact Factor
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ABSTRACT: To report the case of a kidney allograft recipient on a stable regimen of tacrolimus who exhibited increased tacrolimus concentrations within 24 hours of initiating ranolazine.
A 64-year-old kidney allograft recipient on a stable dose of tacrolimus (10 mg twice daily) was admitted for recent worsening of her chronic anginal pain. The patient was initiated on ranolazine 500 mg twice daily on hospital day 2. Tacrolimus concentrations rose from 7.0-10.1 ng/mL preadmission to 17.8 ng/mL within 24 hours of ranolazine initiation. Ranolazine therapy was continued due to the patient's beneficial response; therefore, the tacrolimus dose was eventually decreased by 70% to 3 mg twice daily to maintain steady-state trough concentrations between 6.6 and 7.9 ng/mL with ranolazine therapy. Ranolazine dechallenge on a subsequent admission produced subtherapeutic tacrolimus concentrations requiring dosage increases.
Ranolazine, an antianginal agent, is both a substrate and a weak inhibitor of CYP3A as well as a substrate and moderate inhibitor of the P-glycoprotein (P-GP) efflux transport system. Tacrolimus, an immunosuppressant, is also a substrate of CYP3A and P-GP. Through possible inhibition of both P-GP- and CYP3A-mediated first-pass metabolism and CYP3A systemic metabolism, ranolazine may have significantly increased serum concentrations of tacrolimus necessitating an eventual 70% decrease in the tacrolimus dose. Based on the Horn Drug Interaction Probability Scale, this interaction is possible.
We suggest that the eventual 70% decrease in tacrolimus dose after ranolazine initiation may indicate that ranolazine decreases the metabolism and clearance of tacrolimus, causing an elevation in tacrolimus concentrations and the potential for tacrolimus toxicity. Clinicians should be aware of this possible interaction when initiating ranolazine in patients on tacrolimus.
Annals of Pharmacotherapy 09/2010; 44(11):1844-9. · 2.13 Impact Factor
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ABSTRACT: C1q nephropathy is a rare kidney disease that can present with nephrotic syndrome and typically has the histologic phenotype of either minimal change disease or focal segmental glomerulosclerosis (FSGS). Disagreement exists about whether it is a distinct immune complex-mediated glomerulopathy or it resides in the spectrum of FSGS-minimal change disease. Two African American patients with C1q nephropathy histologically presenting as the collapsing variant of FSGS (collapsing C1q nephropathy) and rapid loss of kidney function were genotyped for polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9). Both cases were homozygous for the MYH9 E1 risk haplotype, the variant strongly associated with idiopathic FSGS, collapsing FSGS in human immunodeficiency virus-associated nephropathy, and focal global glomerulosclerosis (historically attributed to hypertensive nephrosclerosis). Collapsing C1q nephropathy with rapid progression to end-stage renal disease appears to reside in the MYH9-associated disease spectrum.
American Journal of Kidney Diseases 05/2010; 55(5):e21-4. · 5.43 Impact Factor
