FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2734314467> ?p ?o ?g. }

• W2734314467 endingPage "e185" @default.
• W2734314467 startingPage "e185" @default.
• W2734314467 abstract "Recent studies indicate that living kidney donors have higher rate of end-stage renal disease (ESRD) over their lifetime after donation compared with well-matched controls, with a much higher risk in African Americans (AA).1-3 Over the past decade, our understanding of the genetic underpinnings of chronic kidney disease (CKD) in the AA population has been enhanced by the discovery of common variants G1 and G2 in the apolipoprotein L1 gene (APOL1) that are associated both with higher rates of CKD and faster progression to ESRD.4 The G1 allele consists of missense variants in linkage disequilibrium, Ser342Gly and Ile384Met, and the G2 allele is a 2-amino acid deletion, delAsn388/Tyr389. 13% of the AA population carries 2 risk alleles (G1/G1, G1/G2, or G2/G2) and the inheritance of 2 risk alleles increases risk of hypertension-associated renal disease 7- to 10-fold and the risk of focal segmental glomerulosclerosis (FSGS) 10- to 17-fold. These risk alleles also appear to adversely affect renal allograft outcomes with deceased donor kidneys carrying 2 risk alleles having an approximately twofold increased risk of graft failure, whereas recipient genotype has no impact.5-7 We report a patient with FSGS and a strong family history of ESRD who received a kidney from a sibling. He developed abrupt and severe nephrotic syndrome with collapsing FSGS 10 years posttransplant unresponsive to plasmapheresis that rapidly progressed to ESRD. Although both recipient and donor carry 2 APOL 1 risk variants, the donor remains free of hypertension or proteinuria. The Recipient The recipient (III-2, Figure 1) is an AA male who at age 40 years developed FSGS unresponsive to steroids and progressing to ESRD within a year of diagnosis. In early 2005 at age 44 years, he underwent living donor transplant from his half-brother on his mother’s side. The patient was not sensitized and received daclizumab for induction, and maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone, which was discontinued early in the posttransplant period due to mood swings. Both the donor and recipient were cytomegalovirus IgG positive. Graft function was immediate and until late 2015, he maintained a creatinine in the range of 1.0 to 1.3 mg/dL. In his most recent routine follow-up approximately 1 year before developing nephrotic range proteinuria, his urine protein-to-creatinine ratio was 0.9 mg and serum creatinine was 1.3 mg/dL. He had no history of acute rejection episodes or microscopic hematuria after transplantation.FIGURE 1: Pedigree chart and chromatogram. A, Pedigree chart. III-3 is living donor to III-2. III-1, III-2, and IV-5 have been transplanted. III-2, III-3 and IV-5 are compound heterozygous for the ApoL1 G/G2 allele. Cause of ESRD in I-1 is not known. B, Chromatogram shows heterozygous G1 and G2 alleles.He presented to the transplant clinic in 2015 with a 2-week history of increasing lower extremity edema and decreasing urine output. Except for a self-limiting diarrheal illness approximately 3 months earlier, the review of systems was negative. On examination, he was hypertensive and with bilateral pitting edema. Laboratory testing at the time of his clinic visit revealed a serum creatinine of 2.8 mg/dL, serum albumin of 2.7 mg/dL, and a random urine protein-to-creatinine ratio of 12. Renal allograft biopsy showed several glomeruli with features of the collapsing variant of focal segmental glomerulosclerosis. C4d staining was negative (Figure 2). Further serum/plasma testing for human immunodeficiency virus, antinuclear antibody, perinuclear anti-neutrophil cytoplasmic antibodies and cytoplasmic antineutrophil cytoplasmic antibodies, hepatitis B and C antibodies, and parvovirus B19 and cytomegalovirus by polymerase chain reaction were negative.FIGURE 2: Transplant renal biopsy (III-2) showing collapsing FSGS. A, JMS stain, 400× (B) PAS stain, 400×, Collapsing FSGS with collapsed capillary tuft, protein droplets, podocyte hyperplasia. C, Electron micrograph: Transplant glomerulopathy with double layering of glomerular basement membrane (white arrow) and severe foot process effacement (black arrow).Genetic screening was performed with KidneySeq, a targeted renal multigene panel, to evaluate for genetic causes of kidney disease.8 Testing revealed that the patient is compound heterozygous for APOL1 risk alleles: G1 (c.1024A > G, p.Ser342Gly and c.1152T > G, p.Ile384Met) and G2 (c.1160_1165delATAATT). Patient was treated with 10 sessions of plasmapheresis, 1 dose of rituximab (375 mg/m2) and prednisone 20 mg daily with no clinical or laboratory response, and progressed to ESRD 8 weeks after the initial diagnosis. He is currently waitlisted for another kidney transplant. The Donor The donor (III-3, Figure 1) is his healthy half-brother, who was approved for kidney donation at age 43 years after a standard donor work-up. He had no history of hypertension or proteinuria, and normal renal imaging. His serum creatinine was 1.4 mg/dL, CKD-EPI GFR was 85.3 mL/min per 1.73 m2 and his adjusted measured creatinine clearance was 113 mL/min per 1.73 m2. His last known creatinine after nephrectomy was 1.8 mg/dL in late 2005. At the time of diagnosis of collapsing glomerulopathy in his brother (recipient), the donor serum creatinine was 1.7 mg/dL, CKD-EPI GFR was 52.2 mL/min per 1.73 m2, and blood pressure was 115/69 mm Hg. Urinalysis was negative for protein or blood, random urine protein-to-creatinine ratio was 0.1 mg. Focused genetic testing revealed that the donor is also a compound heterozygote for the APOL1 G1 and G2 risk alleles. Family History Although detailed family history was not originally available, it was subsequently learnt that the recipient’s son (IV-5, Figure 1), his half-sister (III-1) via his mother and his maternal grandfather had also progressed to ESRD. The recipient’s son presented at age 21 years with uremic symptoms, and carries the G1 and G2 risk alleles. The recipient’s half-sister presented at age 33 years with nephrotic syndrome and a renal biopsy demonstrated membranous nephropathy. DISCUSSION In 2005, we did not know the relationship between APOL1 variants and the increased incidence of CKD in AA. We only recently learned that both the donor (who is well) and the recipient (who has lost his allograft from recurrent FSGS), as well as one of the recipient’s children (who also underwent a kidney transplant) are compound heterozygous for the APOL1 variants. As most people with 2 risk variants remain well, albeit with a higher risk of CKD, it is likely that a second event, possibly another genetic risk variant or an environmental trigger, is required for onset and/or progression of kidney disease. Interestingly, a potential “second hit” in the recipient was the brief episode of diarrhea 3 months before the development of clinical symptoms of recurrent FSGS. We can only hypothesize this mechanism because the patient was not worked up for the diarrhea illness at the time he was symptomatic; therefore, it is not clear that the diarrhea was of infectious etiology, a mechanism proposed of the “second hit” associated to FSGS. Despite the presence of 2 risk variants and the reduction in eGFR that comes from donation, the donor has remained well, although he remains at higher risk for ESRD estimated at 1 in 104 over 15 years for African American men compared with 1 in 294 for white men.1 Due to the absence of proteinuria, hematuria, hypertension, or progressive decline in renal function (donor creatinine several months after nephrectomy was 1.8 and 1.7 mg/dL 10 years later), we did not biopsy the donor at the time of the diagnosis of recurrent disease in the recipient. Furthermore, we confirmed with genetic testing his predisposition to FSGS. The absence of a diagnostic biopsy of the donor is a limitation of our case because we do not have histologic confirmation that the donor is not affected by the disease. In principle, larger than expected decline in renal function or new onset proteinuria/hematuria should warrant thorough investigation by the transplant centers. There are 2 published cases of living donor transplants between siblings with APOL1 risk variants. In the first, of identical twin's compound heterozygous for the G1 and G2 alleles, the recipient developed FSGS progressing to ESRD at 5 and donor developing proteinuria 7 years postdonation.9 The second, of HLA identical siblings, reported that the recipient developed proteinuria from FSGS 5 years posttransplant, and the donor presented with hypertensive emergency, massive proteinuria, and advanced stage 5 CKD.10 Our case report is different: unlike the other 2 sibling pairs where both donor and recipient developed severe progressive CKD, in the case of our sibling pair, the donor remains well 10 years after transplantation. This likely relates to the fact that the other 2 pairs are genetically more alike with 1 set being monozygotic twins and the other sharing several alleles from both parents including the HLA loci, whereas our pair shares just 1 parent, supporting the notion that additional genetic loci or an environmental assault is necessary for the development of disease in the recipient or the donor with 2 APOL1 risk alleles. The emerging evidence that recipients of APOL1 risk bearing kidneys have a higher risk of graft failure imposes new challenges on the transplant community. Just recently, Julian et al11 studied the contribution of the APOL1 variants to a revised Kidney Donor Risk Index equation in a study with more than 600 deceased AA donors and demonstrated that replacing donor race with APOL1 genotype better defines risk associated with kidneys transplanted from these donors. The issue of the increased risk of ESRD in AA living donors with APOL1 risk variants is more complicated. We already acknowledge that AA donors have a substantially higher lifetime risk of ESRD compared with their white counterparts even without donation, with a twofold higher risk attributable to donation.1,2 If APOL1 genotyping will further refine this risk, then APOL 1 genotyping should be offered to all AA donors and be used to counsel rather than affirm or exclude donors, although this is controversial.12-16 In summary, we report the late and abrupt onset of collapsing FSGS with rapid progression to ESRD 10 years after the transplantation of a donor kidney with 2 APOL1 risk alleles. The donor sibling remains well despite the at-risk genotype. More research needs to be conducted on the impact of APOL1 and other risk variants on the development of CKD in both recipients and living donors." @default.
• W2734314467 created "2017-07-14" @default.
• W2734314467 creator A5000937519 @default.
• W2734314467 creator A5001930460 @default.
• W2734314467 creator A5003437910 @default.
• W2734314467 creator A5009177575 @default.
• W2734314467 creator A5090852510 @default.
• W2734314467 date "2017-08-01" @default.
• W2734314467 modified "2023-10-04" @default.
• W2734314467 title "Late Reoccurrence of Collapsing FSGS After Transplantation of a Living-Related Kidney Bearing APOL 1 Risk Variants Without Disease Evident in Donor Supports the Second Hit Hypothesis" @default.
• W2734314467 cites W1480717594 @default.
• W2734314467 cites W1531295370 @default.
• W2734314467 cites W1865072112 @default.
• W2734314467 cites W1988420740 @default.
• W2734314467 cites W2008905653 @default.
• W2734314467 cites W2074974042 @default.
• W2734314467 cites W2077388406 @default.
• W2734314467 cites W2101828966 @default.
• W2734314467 cites W2113634538 @default.
• W2734314467 cites W2145486738 @default.
• W2734314467 cites W2149588710 @default.
• W2734314467 cites W2423765581 @default.
• W2734314467 cites W2491645136 @default.
• W2734314467 cites W2507367425 @default.
• W2734314467 cites W2555433758 @default.
• W2734314467 cites W2562645789 @default.
• W2734314467 doi "https://doi.org/10.1097/txd.0000000000000697" @default.
• W2734314467 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5540623" @default.
• W2734314467 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28795137" @default.
• W2734314467 hasPublicationYear "2017" @default.
• W2734314467 type Work @default.
• W2734314467 sameAs 2734314467 @default.
• W2734314467 citedByCount "3" @default.
• W2734314467 countsByYear W27343144672018 @default.
• W2734314467 countsByYear W27343144672019 @default.
• W2734314467 crossrefType "journal-article" @default.
• W2734314467 hasAuthorship W2734314467A5000937519 @default.
• W2734314467 hasAuthorship W2734314467A5001930460 @default.
• W2734314467 hasAuthorship W2734314467A5003437910 @default.
• W2734314467 hasAuthorship W2734314467A5009177575 @default.
• W2734314467 hasAuthorship W2734314467A5090852510 @default.
• W2734314467 hasBestOaLocation W27343144671 @default.
• W2734314467 hasConcept C126322002 @default.
• W2734314467 hasConcept C142724271 @default.
• W2734314467 hasConcept C2778653478 @default.
• W2734314467 hasConcept C2779134260 @default.
• W2734314467 hasConcept C2780303639 @default.
• W2734314467 hasConcept C2911091166 @default.
• W2734314467 hasConcept C71924100 @default.
• W2734314467 hasConceptScore W2734314467C126322002 @default.
• W2734314467 hasConceptScore W2734314467C142724271 @default.
• W2734314467 hasConceptScore W2734314467C2778653478 @default.
• W2734314467 hasConceptScore W2734314467C2779134260 @default.
• W2734314467 hasConceptScore W2734314467C2780303639 @default.
• W2734314467 hasConceptScore W2734314467C2911091166 @default.
• W2734314467 hasConceptScore W2734314467C71924100 @default.
• W2734314467 hasIssue "8" @default.
• W2734314467 hasLocation W27343144671 @default.
• W2734314467 hasLocation W27343144672 @default.
• W2734314467 hasLocation W27343144673 @default.
• W2734314467 hasLocation W27343144674 @default.
• W2734314467 hasLocation W27343144675 @default.
• W2734314467 hasOpenAccess W2734314467 @default.
• W2734314467 hasPrimaryLocation W27343144671 @default.
• W2734314467 hasRelatedWork W2012225890 @default.
• W2734314467 hasRelatedWork W2057091235 @default.
• W2734314467 hasRelatedWork W2276919123 @default.
• W2734314467 hasRelatedWork W2412727020 @default.
• W2734314467 hasRelatedWork W2763360885 @default.
• W2734314467 hasRelatedWork W2981884515 @default.
• W2734314467 hasRelatedWork W3003571257 @default.
• W2734314467 hasRelatedWork W3048436868 @default.
• W2734314467 hasRelatedWork W4377262157 @default.
• W2734314467 hasRelatedWork W1556208436 @default.
• W2734314467 hasVolume "3" @default.
• W2734314467 isParatext "false" @default.
• W2734314467 isRetracted "false" @default.
• W2734314467 magId "2734314467" @default.
• W2734314467 workType "article" @default.