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The Genetics of Renal Disease

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The Genetics of Renal Disease RENALCONSULT The Genetics of Renal Disease I have heard about a gene that causes high TABLE 1 Q blood pressure. Did I Risk Associated With APOL1 Variations hear that right? Is testing for APOL1 gene Hypertension Hypertension- Sleeping this gene available now? allele variation risk related CKD risk sickness risk African-Americans have a higher risk for chronic kidney dis- Zero altered Average Average High ease (CKD), including end-stage renal disease (ESRD; defined as One altered H igher than H igher than Moderate kidney failure requiring dialysis average average or transplant), than any other ra- Two altered Highest risk Highest risk Low to absent cial or ethnic group in the United States.1 Previously, this has been attributed to poorly controlled hy- Foster et al reported that black APOL1 gene may have a higher pertension and diabetes, as well patients with two altered alleles risk for failure.6 as socioeconomic factors such as had a 31% higher risk for CKD and Genotyping for APOL1 (CPT limited access to health care. ESRD, compared with individu- code: 81479) is available in select Research now shows that auto- als with hypertension-induced laboratories at a cost of approxi- somal recessive genetic variations nephrosclerosis who had zero to mately $400.7 For a family that has a on chromosome 22q, the gene one altered alleles.4 Nondiabetic member affected by kidney failure that encodes apolipoprotein-1 black patients with CKD who have at a young age, knowing whether (APOL1; an HDL protein), pro- two altered alleles are at highest the APOL1 gene is carried in the mote hypertension. This subse- risk for focal segmental glomeru- family would allow early aggressive quently increases the risk for and losclerosis, HIV nephropathy, and hypertension management to help progression of CKD in black pa- CKD attributable to hyperten- prevent a lifetime of severe CKD. tients (who have up to 29x higher sion.2 The African-American Study risk than white patients without of Kidney Disease and Hyperten- In school, they always this genetic variation).2 sion found that black patients with emphasized the The APOL1 gene has two al- hypertension controlled by ACE Q abdominal exam to leles. Having at least one of them inhibitors had slower progression rule out Wilms tumors. Are provides resistance to Trypano- of CKD, regardless of allele varia- Wilms tumors still with us? soma brucei, the cause of “sleep- tion.5 Currently, there is no treat- Has treatment and evaluation ing sickness” transmitted by the ment for this genetic alteration.4 changed? tsetse fly, but increases risk for One could posit that black pa- Wilms tumor is a renal cancer CKD and ESRD (see Table 1).2,3 tients undergoing renal transplant found most commonly in chil- Black patients descending from would have a higher risk for renal dren younger than 9 and rep- the southern and western por- failure in the transplanted kidney resents approximately 7% of all tions of Africa are most likely to due to APOL1-related hyperten- malignancies in children.8,9 It can have two alleles, putting them at sion, compared to nonblack renal occur in one or both kidneys, with the highest risk for hypertension transplant recipients. Additional- earlier diagnosis noted with bilat- and associated CKD. ly, a donor kidney with an altered eral involvement. Risk is highest among non-Hispanic white per- Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is an NP in the Division of Nephrology at the University of Alabama at Bir- sons and African-Americans and mingham and is the communications chairperson for the National Kidney Foundation’s Council lowest among Asians.8 of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, who is a PA with Wilms tumor develops due to Metropolitan Nephrology in Alexandria, Virginia, and Clinton, Maryland; she is also past chair of the NKF-CAP. This month’s responses were authored by Susan E. Brown, MS, ARNP, ACNP-BC, a genetic mutation in the WT1 CCRN, who practices at Great River Nephrology in West Burlington, Iowa. gene located on the 11p13 chro- continued on page 33 >> 22 Clinician Reviews • NOVEMBER 2014 clinicianreviews.com RENALCONSULT >> continued from page 22 Referral to pediatric oncology is The National TABLE 2 12 imperative. Kidney Congenital Definitive diagnosis is made by Foundation Abnormalities histologic evaluation following bi- Council of Associated With opsy or surgical excision.13 Other Advanced Practitioners' Wilms Tumor possible diagnostic tests include (NKF-CAP) but are not limited to abdominal mission is to B eckwith-Weidemann ultrasound or CT; chest CT (to rule serve as an advisory resource for the syndrome out metastatic lung disease); uri- NKF, nurse practitioners, physician Bloom syndrome nalysis (to evaluate for hematuria assistants, clinical nurse specialists, and the community in advancing Denys-Drash syndrome and proteinuria); liver function the care, treatment, and education Fanconi syndrome studies (to evaluate for hepatic in- of patients with kidney disease and Frasier syndrome volvement); and laboratory stud- their families. CAP is an advocate Li-Fraumeni syndrome ies to measure coagulation, serum for professional development, calcium, blood urea nitrogen, cre- research, and health policies that Perlman syndrome impact the delivery of patient care S impson-Golabi-Behmel atinine, and complete blood count. and professional practice. For more syndrome Histologic examination for stag- information on NKF-CAP, visit Sotos syndrome ing (I-V) occurs following surgical www.kidney.org/CAP excision of the tumor. There are two WAGR syndrome staging systems available: the Na- gene variants associate with hypertension- Note: This list is not exhaustive. tional Wilms Tumor Study, based attributed nephropathy and the rate of kidney on postoperative tumor evaluation, function decline in African Americans. Kidney Int. 2013;83(1):114–120. mosome. Defects are also noted and the International Society of 6. Reeves-Daniel AM, DePalma JA, Bleyer AJ, et on the 11p15 chromosome and Pediatric Oncology, based on post- al. The APOL1 gene and allograft survival after the p53 tumor suppressor gene.10 chemotherapy evaluation.13 kidney transplantation. Am J Transplant. 2011;11(5):1025 -1030. Urbach et al recently identified a Treatment options include 7. Partners Healthcare Personalized Medicine. relationship between the LIN28 surgical excision (including com- Order APOL1 genotyping test for non-diabetic gene and Wilms tumor.11 Tumors plete nephrectomy of the affected nephropathy kidney disease. http://personal izedmedicine.partners.org/Laboratory-For- develop when embryonic renal kidney), chemotherapy based on Molecular-Medicine/Ordering/Kidney-Dis cells that should cease growing at tumor staging, and internal and/ ease/APOL1-Gene-Sequencing.aspx. Accessed the time of birth continue to grow or external radiation therapy.13 CR October 19, 2014. 8. Grovas A, Fremgen A, Rauck A, et al. The in the postnatal period. Wilms tu- Susan E. Brown, MS, ARNP, National Cancer Data Base report on patterns mor can be familial or sporadic. It ACNP-BC, CCRN of childhood cancers in the United States. can also be associated with vari- Great River Nephrology, Cancer. 1997;80(12):2321-2332. 9. Johns Hopkins Medicine. Wilm’s tumor. www. ous congenital anomalies mani- West Burlington, Iowa hopkinsmedicine.org/kimmel_cancer_center/ fested within various syndromes centers/pediatric_oncology/cancer_types/ (see Table 2), as well as isolated REFERENCES wilms_tumor.html. Accessed October 19, 1. United States Renal Data System. Annual data 2014. genitourinary abnormalities, es- report: atlas of chronic kidney disease and 10. Dome JS, Huff V. Wilms tumor overview. In: pecially in boys.10 end-stage renal disease in the United States Pagon RA, Adam MP, Ardinger HH, et al (eds). Most children present with a (2012). www.usrds.org/2012/view/v1_01. GeneReviews® [Internet]. Seattle, WA: Univer- aspx. Accessed October 19, 2014. sity of Washington, Seattle; 1993-2014. www. palpable, smooth, firm, generally 2. Kopp JB, Nelson GW, Sampath K, et al. APOL1 ncbi.nlm.nih.gov/books/NBK1294/. Accessed painless mass in the abdomen; genetic variants in focal segmental glomerulo- October 19, 2014. those who have bilateral renal in- sclerosis and HIV-associated nephropathy. 11. Urbach A, Yermalovich A, Zhang J, et al. Lin28 J Am Soc Nephrol. 2011;22(11):2129 -2137. sustains early renal progenitors and induces volvement usually present earlier 3. Parsa A, Kao L, Xie D, et al; AASK and CRIC Wilms tumor. Genes & Dev. 2014;28:971- than those with unilateral involve- Study Investigators. APOL1 risk variants, race 982. ment. Palpation of the abdomen and progression of chronic kidney disease. 12. Fernandez C, Geller JI, Ehrlich PF, et al. Renal N Engl J Med. 2013;369:2183-2196. tumors. In: Pizzo P, Poplack D (eds). Principles during examination, if vigorous, 4. Foster MC, Coresh J, Fornage M, et al. APOL1 and Practice of Pediatric Oncology. 6th ed, St can result in rupture of the renal variants associate with increased risk of CKD Louis, MO: Lippincott Williams & Wilkins. capsule and tumor spillage. Ad- among African Americans. J Am Soc Nephrol. 2011; 861. 2013;24(9):1484-1491. 13. Metzger ML, Dome JS. Current therapy for ditional symptoms include he- 5. Lipkowitz MS, Freedman BI, Langefeld CD, et Wilms’ tumor. Oncologist. 2005;10(10):815- maturia, fever, and hypertension. al; AASK Investigators. Apolipoprotein L1 826. clinicianreviews.com NOVEMBER 2014 • Clinician Reviews 33.
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