Chronic Kidney DiseaseUlysses RosasMay 8th, 2012

OutlineDefine 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 DefinitionGFR 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.cfmPresence of kidney damage, regardless of the cause, for three or more months

EpidemiologyCKD affects about 26 million people in the USApproximately 19 million adults are in the early stages of the disease On the rise do to increasing prevalence of diabetes and hypertensionTotal cost of ESRD in US was approximately $40 billion in 2008

PathophysiologyRepeated injury to kidney

SymptomsHematuriaFlank painEdemaHypertensionSigns of uremiaLethargy and fatigueLoss of appetiteIf asymptomatic may have elevated serum creatinine concentration or an abnormal urinalysis

Risk FactorsAge of more than 60 yearsHypertension and Diabetes Responsible for 2/3 of casesCardiovascular disease Family history of the disease. Race and ethnicityHighest incidence is for African AmericansHispanics have higher incidence rates of ESRD than non-Hispanics.

Convergence of Genetic FactorsGenes for heart and vascular diseaseGenes that maintain ionic balanceGenes for glomerulonephritisGenes for diabetesGenes that may be involved in inherited renal diseases

Genetics of CKDMarkers of kidney function found to be 27-33% heritable.Serum creatinine, GFR, albumin, proteinuria, BUNMany genes associated with chronic kidney disease:APOL1 in African Americans UMODSHROOM3GATM-SPATA5L1 MMP20MPPED2, DDX1, CDK12, CASP9, and INO80LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2, and SLC7A9N

Genes Looked AtUMOD geneEncodes 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.MMP20Encodes 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

SNPAncestral AlleleVariant AlleleOdds Ratiop-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. rs13333226GA0.873.6x10-11Presence of G allele is associated with better renal function.rs12917707GT0.802x10-12Presence of T is associated with 20% decreased risk of CKD.

MMP20 Gene

SNPAncestral AlleleVariant AlleleOdds Ratiop-valueSignificance

rs1711437 GAP-value =3.6x10-5Associated with kidney ageing. 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 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 KnowIn general CKD is characterized by a gradual loss of the kidneys filtration capacity.Markers Dont tell everythingGenetic 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 KnowGenetic Risk does not translate into clinical riskComplex interaction with environmental factorsWould 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 KnowPreventionKeep diabetes and blood pressure controlledIf at risk perform screening testsReduce exposure to nephrotoxic drugsEat right and exerciseKnow your family historyIf you have a positive family history ask doctor to perform common screening tests for kidney function.

SourcesWheeler 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.

Things that cause kidney disease: -Glomerulonephritis, a group of diseases that cause inflammation and damage to the kidney's filtering units. These disorders are the third most common type of kidney disease.-Inherited diseases, such as polycystic kidney disease, which causes large cysts to form in the kidneys and damage the surrounding tissue.-Malformations that occur as a baby develops in its mother's womb. For example, a narrowing may occur that prevents normal outflow of urine and causes urine to flow back up to the kidney. This causes infections and may damage the kidneys.-Lupus and other diseases that affect the body's immune system.-Obstructions caused by problems like kidney stones, tumors or an enlarged prostate gland in men.-Repeated urinary infections.

*The causes of acute or chronic kidney disease are traditionally classified by that portion of the renal anatomy most affected by the disorderThe two major causes of reduced renal perfusion are volume depletion and/or relative hypotension. This may result from true hypoperfusion due to bleeding, gastrointestinal, urinary, or cutaneous losses, or to effective volume depletion in heart failure, shock, or cirrhosisVarious vascular diseases can also lead to kidney disease.Direct etiologies from kidney: Tubular and interstitial disease, Glomerular disease, Obstructive uropathy

Acute tubular necrosis 45 percentPrerenal 21 percentAcute or chronic kidney disease 13 percent (mostly due to acute tubular necrosis and prerenal disease)Urinary tract obstruction 10 percent (most often older men with prostatic disease)Glomerulonephritis or vasculitis 4 percentAcute interstitial nephritis 2 percentAtheroemboli 1 percent

*_followed by American Indians and Alaska Natives, then Asian Americans and native Hawaiians and other Pacific Islanders, and finally Caucasians. *-APOL1: Autosomal recessive pattern of inheritance and confer a substantially higher risk of ESRD (10-fold higher risk of ESRD due to focal glomerulosclerosis and 7-fold higher risk of ESRD attributed to hypertension. APOL1 mutations are found exclusively among individuals of African descent and, although speculative, are believed to provide resistance to disease causing trypanosomes. The functional significance of these gene variants is unclear, but they may lead to diminished expression of APOL1 in podocytes and inappropriate expression in renal arterioles

Sources:APOL1: http://www.sciencemag.org.laneproxy.stanford.edu/content/329/5993/841.long

In aggregate, the 13 new renal function loci plus the three previously identified renal function loci account for 1.4% of the variation in eGFRcrea. Similar to what has been observed previously, we identified modest effects of the risk alleles on eGFR and CKD. Taken together, these renal function loci are associated with 1.4% of the variation in eGFRcrea

*Familial Juvenile hyperuricemic nephropathy type 1Familial juvenile hyperuricemic nephropathy type 2 (FJHN2) is characterized by hypoproliferative anemia with low hemoglobin concentrations found in mostaffectedchildren by age one year; hyperuricemia and gout found in most (not all) affected individuals; and slowly progressive chronic tubulo-interstitial kidney disease. Some affected children have polyuria (excessive urine production leading to frequent urination) and enuresismedullary cystic kidney disease type 2inherited diseases with similar renal morphology characterized by bilateral small corticomedullary cysts in kidneys of normal or reduced size and tubulointerstitial sclerosis leading to end-stage renal disease (ESRD)

*Rs4293393: http://jasn.asnjournals.org/content/21/2/337.full-observed lower urinary uromodulin concentrations per each copy of the C allele at rs4293393Rs12917707: http://www.nature.com/ng/journal/v41/n6/full/ng.377.htmlRs13333226: http://www.ncbi.nlm.nih.gov/pubmed/21082022?dopt=Abstract

*Source: http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000326901*