1. Chronic Kidney Disease Ulysses Rosas May 8 th, 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 1.73m 2 per body surface area (normal is 125ml/min). – GFR Calculator: http://www.kidney.org/professionals/kdoqi/gfr_calculator. cfm 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 SNPAncestral Allele Varian t Allele Odds Ratio p-valueSignificance rs4293393TC0.76 (also reported as 1.25) p-=.001 (also reported as 4.1x10 -10 ) Associated with autosomal dominant forms of kidney disease, medullary cystic kidney disease type 2, and familial juvenile hyperuricemic nephropathy. C allele protective. rs13333226GA0.873.6x10 -11 Presence of G allele is associated with better renal function. rs12917707GT0.802x10 -12 Presence of T is associated with 20% decreased risk of CKD.

14. MMP20 Gene SNPAncestral Allele Variant Allele Odds Ratio p-valueSignificance rs1711437GAP-value =3.6x10 -5 Associated with kidney ageing. Only explains 1-2% of variance in GFR.

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.