Chronic Kidney Disease

Ulysses Rosas
May 8th, 2012
 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.
 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_calculator.
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.
– 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.
 UMOD Gene

SNP Ancestral Varian Odds p-value Significance

Allele t Allele Ratio
rs4293393 T C 0.76 p-=.001 Associated with autosomal
(also (also dominant forms of kidney
reported reported as disease, medullary cystic kidney
as 1.25) 4.1x10-10) 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.
 MMP20 Gene

SNP Ancestral Variant Odds p-value Significance

Allele Allele Ratio
rs1711437 G A P-value Associated with kidney ageing.
=3.6x10-5 Only explains 1-2% 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 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.
 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.
 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 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.