Chronic Kidney Disease Presentation

1. Chronic Kidney Disease
HIMANI
GROUP-18
18 FEB 2023

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. What is CKD?
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
Variant
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. TREATMENT
• High blood pressure medications. People with kidney disease can have worsening high blood
• pressure. Your doctor might recommend medications to lower your blood pressure —
• commonly
• angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers — and to
• preserve kidney function.
High blood pressure medications can initially decrease kidney function and change electrolyte
• levels, so you might need frequent blood tests to monitor your condition. Your doctor may also
• recommend
• a water pill (diuretic) and a low-salt diet.
• Medications to relieve swelling. People with chronic kidney disease often retain fluids. This can
• lead
• to swelling in the legs as well .as high blood pressure. Medications called diuretics can help
• maintain
• the balance of fluids in your body.
• Medications to treat anemia. Supplements of the hormone erythropoietin , sometimes with
• added iron,
• help produce more red blood cells. This might relieve fatigue and weakness associated with
• anemia.
• Medications to lower cholesterol levels. Your doctor might recommend medications called
• statins to
• lower your cholesterol. People with chronic kidney disease often have high levels of bad
• cholesterol,
• which can increase the risk of heart disease

20. Treatment for end-stage kidney disease
If your kidneys can't keep up with waste and fluid clearance on their own and you develop complete or near-comple
• Dialysis. Dialysis artificially removes waste products and extra fluid from your blood when your kidneys can n
• longer do this. In hemodialysis, a machine filters waste and excess fluids from your blood.
In peritoneal dialysis, a thin tube inserted into your abdomen fills your abdominal cavity with a dialysis
• solution
• that absorbs waste and excess fluids. After a time, the dialysis solution drains from your body, carrying the w
• with it.
• Kidney transplant. A kidney transplant involves surgically placing a healthy kidney from a donor into your
• body. Transplanted kidneys can come from deceased or living donors.
• Medications to protect your bones. Calcium and vitamin D supplements can help prevent weak bones and lo
• your risk of fracture. You might also take medication known as a phosphate binder to lower the amount of
• phosphate in your blood and protect your blood vessels from damage by calcium deposits (calcification).
• A lower protein diet to minimize waste products in your blood. As your body processes protein from
• foods,
• it creates waste products that your kidneys must filter from your blood. To reduce the amount of work your kidn
• must do, your doctor might recommend eating less protein. A registered dietitian can suggest ways to lower yo
• protein intake while still eating a healthy diet

21. 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.