CHRONIC K I DNEY D I SEASE

1. CHRONIC KIDNEY DISEASE Gülçin Kantarcı, MD Yeditepe University Department of InternalMedicine Division of Nephrology

2. REFERENCE &SUGGESTED READING • CurrentMedicalDiagnosisandTreatment, Maxine A. Papadakis, Stephen J. McPhee, Eds. Michael W. Rabow, Associate Ed. http://accessmedicine.comChapter22. KidneyDisease • http://www.uptodate.com .(Definition andstaging of chronickidneydisease in adults, Screeningforchronickidneydisease, Epidemiology of chronickidneydisease)

3. AIMS & OBJECTIVES State • the definition, • pathophysiology, • clinical findings and • prevention methods of chronic kidney disease.

4. Chronickidney disease (CKD) Chronic kidney disease is defined based on the presence of either kidney damage or decreased kidney function for three or more months, irrespective of cause. End-StageRenalDisease(ESRD) AdvancedCKDrequiringrenalreplacementtherapy (RRT) in ordertomaintain life.

5. MajorCauses of ChronicKidneyDisease

7. CKD Prevalence CKD Incidence Prevalence is estimated to be 8—16% worldwide

8. Pathophysiology of CKD Kidney damage, as defined by structural abnormalities or functional abnormalities other than decreased GFR Loss of nephron mass Structural and functional hypertrophy of the remaining nephrons Glomerular Hyperperfusion Hyperfiltration Hypertension Restoration of GFR

12. Chronic renal failure represents the end result of conditions that greatly reduce renal function by destroying renal nephrons and producing a marked decrease in the glomerular filtration rate (GFR).

13. GLOMERULAR ULTRAFILTRATION Glomerular capillaries Oncotic Pressure Hydraulic Pressure • Rate of glomerular plasma flow • Total surface area + • Decreased GFR is expectedwhen • Glomerularhydraulicpressure is  • Tubulehydraulicpressure is  • Plasmacolloidpressure  • Renal (glomerular) bloodflow  • Permeability is  • Filtrationsurfacearea  HydraulicPressure Bowman’s capsule

14. hyperfiltration without serious adverse consequences Loss of 50% of the total nephron mass Loss of > 50% of the total nephron mass Over time: proteinuria Focal and segmental glomerulosclerosis Compensatory Adaptive responses Maladaptive responses

15. Mechanisms of progressiverenalscarring • Glomerulosclerosis • Tubulointerstitalscarring • Vascularsclerosis

16. GLOMERULOSCLEROSIS Glomerular Hyperperfusion Hyperfiltration Hypertension • in renal functional mass • Endothelial & • epithelial injury • Transudation of • macromolecules • into mesangium Progressive mesangial expansion GLOMERULOSCLEROSIS

17. Tubulointerstitial Scarring Injuredtubular cells Inflammatorymediators Chemokines Cytokines Growthfactors Inflammatory cells   SynthesisECM TUBULOINTERSTITIAL FIBROSIS

18. VascularSclerosis • Afferentarteriolarhyalinosis • Glomerularsclerosis • Postglomerulararterialhyalinosis • Interstitialischemiaandfibrosis • Damagetoperitubularcapillaries

21. FactorsAffectingTheProgression of CKD • Nonmodifiablesusceptibilityfactors • Age • Gender • Genetics • Race • Initiationfactors • Glomerulonephritis • TIN • Hypertension • Diabetes • Dyslipidemia • Modifiable risk factors • ?

23. Modulatingfactors of progressiverenalscarring • Genetic/Racial/ gender-related • Systemicandintraglomerularhypertension • Thedegree of proteinuria • Intrarenaldeposition of Ca, P, urate • Hyperlipidemia (LDL) • Use of NSAIDs(Pginhibitors) • High protein diet • Persistentmetabolicacidosis • Extent of tubulointerstitialdisease

25. Screening for chronic kidney disease patients who are at risk for developing CKD should be screened with both • a urine test for proteinuria and • a blood test for creatinine to estimate glomerular filtration rate (GFR). • Risk factorsfor CKD • History of diabetes, cardiovascular disease, hypertension, hyperlipidemia, obesity, metabolic syndrome, smoking, human immunodeficiency virus (HIV) or hepatitis C virus infection, and malignancy • Family history of kidney disease • Treatment with potentially nephrotoxic drugs

26. DIAGNOSIS OF CKD • Careful history taking and physical examination • Assessment of renal function by estimation of the glomerular filtration rate (GFR) • Careful examination of the urine • Radiographic imaging of the kidneys • Serologic testing and tissue diagnosis with renal biopsy if noninvasive evaluation is not sufficient for diagnosis

27. Assessment of renalfunction GFR = [UCr x V]/SCr 60 kg woman: SCr = 1.2 mg/dL (106 micromol/L) UCr= 100 mg/dL (8800 micromol/L) V = 1.2 L/day • CrCl = [100 x 1.2]/1.2 = 100 L/day • This value has to be multiplied by 1000 to convert into mL and then divided by 1440 (the number of minutes in a day) to convert into units of mL/min. • CrCl = [100 x 1000]/1440 = 70 mL/min

28. Estimationequations • Cockcroft-Gault • MDRD • CKD-EPI • Cockcroft-Gault equation (140 - age) x lean body weight [kg] • CCr (mL/min) = ——————————————— Cr [mg/dL] x 72 Forwoman X0.85

30. KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification 2012

31. Classification: KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification 2012

32. ClinicalAbnormalities in CKD • Fluid & electrolytedisturbances • Acid-Base disorders • Cardiovascularcomplications • Hematologiccomplications • Neurologiccomplications • Bone ,phosphate & calcium abnormalities • Endocrinedisorders

33. Fluid & ElectrolyteDisturbances in CKD • Early findings: poliuria- nocturia • Expansionof ECF • Hyponatremia • Dilutional • ImpairedNaconservation • Hyperkalemiaonlywhen • GFR<10ml/min • Oliguria /anuriadevelops • Potassiumsparingdiureticsused • ACEI and Beta blockers • Acidosis

34. Peritubularincrease in hydraulicpressure • Atrialnatriureticpeptides • Osmoticdiuresis • Salt wastingforms of CRF Fex of Na INCREASED Fractional excretion of solutes per nephron   Solute diuresis (obligatory water loss) • Urineosmolality is decreased • Isosthenuriawhen GFR <25ml/min •  • Polyuria • Nocturia Fex of Water INCREASED

35. HYDROGEN AND BICARBONATE TRANSPORT Ph =7.35-7.45 (H+ concentration) Acidsconsumebuffers HCO3 Daily acidproduction: 1mmol H/kg bw HCO3 is regenerated in the kidney Reabsorbed from the ultrafiltrate  maintaining plasma HCO3 concentrations H+ excreted in the urine combines with NH3  NH4 +

36. METABOLIC ACIDOSIS IN CKD No change in arterialpH/ plasma HCO3 until GFR < 30% of normal Plasma HCO3 (24mEq/L)  Decreased (14-18 mEq/L) • Metabolicacidosis in CKD is dueto: • Decreasednephronmass • Leadingtolimited NH4 productionand HCO3 regeneration pHandstable HCO3 levelsmaintained at theexpense of bufferingby bone (CaPO4-CaHCO3)

37. Cardiovascularcomplications in CKD • Hypertension • Salt and water retension • Hyperrenninemia • Pericarditis • Accelerated atherosclerosis • Coronary artery disease • Cerebrovascular disease • Peripheral vascular disease • Pulmonary edema

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39. Hematologiccomplications in CKD • Normochromicnormocyticanemia •  biosynthesis of erythropoetin • Bone-marrowdepressiveeffect of uremictoxins • Hemolysis • GI loss of blood • Abnormalhemostasis •  bleeding time • Abnormalplateletaggregation &adhesiveness •  activity of plateletfactor 3 • Enhancedsusceptibilitytoinfection

40. INCIDANCE OF ANEMIA IN CKD • CrCl >50ml/dk %25 • CrCl 35-49ml/dk %44 • CrCl 25-34ml/dk %51 • CrCl < 25ml/dk %87

41. ERITROPOESIS CD 34 Eritron Apoptosis Pronormoblast, eritroblast Matur cells BFU-E CFU-E Stem cell EPO EPO GM-CSF,IL3,IGF-1

42. Neurologic complications Uremicencephalopathy • Inabilitytoconcentrate, drowsiness • Insomnia, behavioralchanges • Neuromuscularirritability • Hiccups, cramps, fasciculations • Asterixis, chorea, stupor, seizures Peripheralneuropathy RestlessLegs

43. Bone phosphate & calciumabnormalities in CKD •  biosynthesis of 1,25-dihidroksikolekalsiferol • Hypocalcemia • Hyperphosphatemia • Hyperparathyroidism • Acidosis • Renal • Osteodystrophy • Osteomalacia

44. TUBULAR PHOSPHATE TRANSPORT • Under physiologicconditions 80-90% is reabsorbed • Parathyroidhormoneaugmentsphosphateexcretion Transient  in Plasma P Transient  in Plasma Ca Dietary P  (CaPO4 deposition in bone) X PTH secretion  P excretion P balance restored InCKD PTH is persistentlyelevated

45. Alterations in Vitamin D metabolism 1,25(OH2) kolekalsiferol in thekidney Vit D synthesized in the skin 25(OH)kolekalsiferol in the liver X Synthesis of activeVit D is reduced in CKD Contributestohypocalcemiaandhyperparathroidism

46. Endocrinedisorders in CKD • Secondaryhyperparathyroidism • Glucoseintolerance • Disturbances of insulinmetabolism • Hyperinsulinemia • Peripheralinsulinresitance • Pituitary, throid & adrenal are normal • Libido andfertility

47. GFR  35-50% of normal  symptom-free BUN and Cr. levels Normal renal functions maintained *endocrine *excretory *regulatory GFR  20-35% of normal  azotemia still asymptomatic GFR  < 20% of normal  overt renal failure UREMIC SYNDROME

48. ESRDUremicSyndrome • Renalexcretoryfailure • Uremia • Hyperkalemia • Renalendocrinefailure • Anemia • Renalosteodystrophy • Renalmetabolicfailure & acidosis

49. UREMIC ‘TOXINS’ Productsof protein and amino acidmetabolism: • Urea (80% of total (excretednitrogen) • Guanidinocompounds • Guanidine • Creatinine • Creatin • UratesandHippurates • End - products of nucleicacidmetabolism • End - products of aliphatic amine metabolism • End – products of aromatic amino acidmetabolism • Othernitrogenoussubstances

50. UREMIC TOXINS • Advancedglycationend-products • Parathyroidhormone • Inhibitors of somatomedinandinsulinaction • β–melanocyte–stimulating hormone • Glucagon • Luteinizinghormone • Prolactin