Chronic Kidney Disease

1. Chronic Kidney Disease Ulysses Rosas May 8th, 2012

2. Outline • Define Chronic Kidney Disease. • Briefly discuss it’s pathophysiology, epidemiology, and risk factors. • Discuss the role of genetics in Chronic Kidney Disease. • Look at relationship between the UMOD gene and MMP20 gene with chronic kidney disease. • Assess how these genes affect the risk and diagnosis of Chronic Kidney Disease. • What knowledge would a physician and patient want to know to understand how their genotype affects their risk for developing chronic kidney disease.

3. Que es Eso? Chronic Kidney Disease is defined as a slow lose of renal function over time. This leads to a decreased ability to remove waste products from the body and perform homeostatic functions.

4. Clinical Definition • GFR of less than 60 ml/minute per 1.73m2 per body surface area (normal is 125ml/min) . • GFR Calculator: http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm • Presence of kidney damage, regardless of the cause, for three or more months

6. Epidemiology • CKD affects about 26 million people in the US • Approximately 19 million adults are in the early stages of the disease • On the rise do to increasing prevalence of diabetes and hypertension • Total cost of ESRD in US was approximately $40 billion in 2008

7. Pathophysiology • Repeated injury to kidney

8. Symptoms • Hematuria • Flank pain • Edema • Hypertension • Signs of uremia • Lethargy and fatigue • Loss of appetite • If asymptomatic may have elevated serum creatinine concentration or an abnormal urinalysis

9. Risk Factors • Age of more than 60 years • Hypertension and Diabetes • Responsible for 2/3 of cases • Cardiovascular disease • Family history of the disease. • Race and ethnicity • Highest incidence is for African Americans • Hispanics have higher incidence rates of ESRD than non-Hispanics.

10. Convergence of Genetic Factors • Genes for heart and vascular disease • Genes that maintain ionic balance • Genes for glomerulonephritis • Genes for diabetes • Genes that may be involved in inherited renal diseases

11. Genetics of CKD • Markers of kidney function found to be 27-33% heritable. • Serum creatinine, GFR, albumin, proteinuria, BUN • Many genes associated with chronic kidney disease: • APOL1 in African Americans • UMOD • SHROOM3 • GATM-SPATA5L1 • MMP20 • MPPED2, DDX1, CDK12, CASP9, and INO80 • LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2, and SLC7A9N

12. Genes Looked At • UMOD gene • Encodes urodoulin protein. • Function unknown but thought to be involved immunologically. • UMOD is transcribed exclusively in renal tubular cells of the thick ascending limb of the loop of Henle. • MMP20 • Encodes a member of the matrix metalloproteinase family, which are involved in the breakdown of extracellular matrix in normal physiological processes. • MMP20 degrades amelogenin, found mostly in tooth enamel. • MMP20 recently implicated to be associated with kidney disease aging.

13. UMOD Gene

14. MMP20 Gene

15. Risk Translated • Average population risk for chronic kidney disease is 3.4% • In people with rs4293393-T, serum creatinine increases faster with age (especially over the age of 50), and with comorbid conditions such as hypertension and diabetes. • In people with rs13333226-G, is associated with a slightly lower risk of hypertension and a 7.7% reduction per allele for risk of CV events. • In people with rs12917707-T, we see a 20% decreased risk of CKD • In people with rs1711437-A, their creatinine clearance is approximately that of someone who is 4–5 years younger.

16. What Should Patients and Doctors Know • In general CKD is characterized by a gradual loss of the kidney’s filtration capacity. • Markers Don’t tell everything • Genetic variants found so far only account for 1.4% of variance seen in eGFR, and at most the relative risk for CKD is modified by 20% per loci.

17. What Should Patients and Doctors Know • Genetic Risk does not translate into clinical risk • Complex interaction with environmental factors • Would need to calculate a likelihood ratio in conjunction with a probability of disease prevalence to gain a better estimate of clinical risk.

18. What Should Patients and Doctors Know • Prevention • Keep diabetes and blood pressure controlled • If at risk perform screening tests • Reduce exposure to nephrotoxic drugs • Eat right and exercise • Know your family history • If you have a positive family history ask doctor to perform common screening tests for kidney function.

19. Sources • Wheeler et al 2009. Sequential Use of Transcriptional Profiling, Expression Quantitative Trait Mapping, and Gene Association ImplicatesMMP20 in Human Kidney Aging. • Padmanabhan S et al. (2010) . “Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.”PLoS Genet. 6(10):e1001177. • Gudbjartsson DF et al. (2010) . “Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.” PLoS Genet. 6(7):e1001039. • Köttgen A et al. (2009) . “Multiple loci associated with indices of renal function and chronic kidney disease.” Nat. Genet. 41(6):712-7.