Chronic Kidney Disease is defined as a slow loss of renal function over time that decreases the ability to remove waste from the body. It affects about 26 million Americans and is increasing due to diabetes and hypertension. Several genes have been associated with chronic kidney disease risk, including UMOD and MMP20. Variants in these genes slightly modify disease risk, usually by less than 20%, with the greatest effects seen after age 50 and in the presence of other risk factors like hypertension and diabetes. Genetic testing can slightly refine disease risk estimates, but lifestyle factors like controlling blood pressure and diabetes have a much greater impact on prevention and risk reduction.

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
SNP Ancestral
Allele
Varian
t Allele
Odds
Ratio
p-value Significance
rs4293393 T C 0.76
(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.
rs13333226 G A 0.87 3.6x10-11 Presence of G allele is associated
with better renal function.
rs12917707 G T 0.80 2x10-12 Presence of T is associated with
20% decreased risk of CKD.

14. MMP20 Gene
SNP Ancestral
Allele
Variant
Allele
Odds
Ratio
p-value Significance
rs1711437 G A P-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.