Chronic Kidney Disease

Ulysses Rosas
May 8th, 2012

Outline
Define Chronic Kidney Disease.
Briefly discuss its 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.

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.

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_c
alculator.cfm

Presence of kidney damage, regardless of

the cause, for three or more months

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

Pathophysiology
Repeated injury to kidney

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

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.

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

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

Genes Looked At
UMOD gene
Encodes urodoulin protein.
Function unknown but thought to be involved
immunologically.
UMODis 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.

UMOD Gene
SNP

Ancest Varia Odds

ral
nt
Ratio
Allele
Allel
e

p-value

Significance

rs429339 T
3

0.76
(also
reporte
d 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.

rs133332 G
26

0.87

3.6x10-11

Presence of G allele is
associated with better
renal function.

MMP20 Gene
SNP

Ancestr Varia Odds

al
nt
Ratio
Allele
Allele

rs171143 G
7

pvalue

Significance

P-value Associated with kidney

=3.6x1 ageing. Only explains 10-5
2% of variance in GFR.

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 hypertensionand 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 45 years younger .

What Should Patients and

Doctors Know
In general CKD is characterized by a
gradual loss of the kidneys filtration
capacity.
Markers Dont 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.

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.

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.

Sources
Wheeler et al 2009.Sequential Use of Transcriptional
Profiling, Expression Quantitative Trait Mapping, and
Gene Association ImplicatesMMP20in 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.
Kttgen A et al. (2009). Multiple loci associated with
indices of renal function and chronic kidney
disease.Nat. Genet.41(6):712-7.