CHRONIC KIDNEY DISEASE

Gülçin Kantarcı, MDYeditepe University Department of Internal MedicineDivision of Nephrology

REFERENCE &SUGGESTED READING •Current Medical Diagnosis and Treatment,

Maxine A. Papadakis, Stephen J. McPhee, Eds. Michael W. Rabow, Associate Ed. http://accessmedicine.com Chapter 22. Kidney Disease

•http://www.uptodate.com .(Definition and staging of chronic kidney disease in adults, Screening for chronic kidney disease, Epidemiology of chronic kidney disease)

AIMS & OBJECTIVESState • the definition,• pathophysiology, •clinical findings and •prevention methods of chronic kidney

disease.

Chronic kidney 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-Stage Renal Disease(ESRD)Advanced CKD requiring renal replacement therapy (RRT) in order to maintain life.

Major Causes of Chronic Kidney Disease Cause Examples Chronic tubulointerstitial nephropathies

Glomerulopathies (primary) Focal glomerulosclerosis Idiopathic crescentic glomerulonephritis IgA nephropathyMembranoproliferative glomerulonephritisMembranous nephropathy

Glomerulopathies associated with systemic disease DM,AmyloidosisHemolytic-uremic syndromePostinfectious glomerulonephritisSLEWegener's granulomatosis

Hereditary nephropathies Hereditary nephritis (Alport's syndrome)Medullary cystic diseaseNail-patella syndromePolycystic kidney disease

Hypertension Malignant glomerulosclerosisNephroangiosclerosis

Obstructive uropathy Benign prostatic hyperplasiaPosterior urethral valvesRetroperitoneal fibrosisUreteral obstruction (congenital, calculi, malignancies)Vesicoureteral reflux

Renal macrovascular disease Renal artery stenosis

CKD Incidence CKD Prevalence

Prevalence is estimated to be 8—16% worldwide

Pathophysiology of CKD

Loss of nephron mass

Structural and functional hypertrophy of the remaining nephrons

Restoration of

GFR

Kidney damage, as defined by structural abnormalities or functional abnormalities other than decreased GFR

Glomerular HyperperfusionHyperfiltrationHypertension

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).

GLOMERULAR ULTRAFILTRATION

Oncotic Pressure

HydraulicPressure

Hydraulic Pressure

Glomerular capillaries

Bowman’s capsule

• Rate of glomerular plasma flow• Total surface area+

Decreased GFR is expected when

• Glomerular hydraulic pressure is

• Tubule hydraulic pressure is • Plasma colloid pressure • Renal (glomerular) blood flow • Permeability is • Filtration surface area

Loss of 50% of the total nephron mass

hyperfiltration withoutserious adverse consequences

Loss of > 50% of the total nephron mass

Over time: proteinuriaFocal and segmental glomerulosclerosis

CompensatoryAdaptive responses

Maladaptive responses

Mechanisms of progressive renal scarring

•Glomerulosclerosis

•Tubulointerstital scarring

•Vascular sclerosis

GLOMERULOSCLEROSIS

ß in renal functional mass

Glomerular HyperperfusionHyperfiltrationHypertension

• Endothelial &epithelial injury• Transudation of macromoleculesinto mesangium

Progressive mesangial expansion

GLOMERULOSCLEROSIS

Tubulointerstitial Scarring

Injured tubular cells

Inflammatory mediatorsChemokinesCytokines

Growth factors

Inflammatory cells

Synthesis ECM

TUBULOINTERSTITIAL FIBROSIS

Vascular Sclerosis•Afferent arteriolar hyalinosis

Glomerular sclerosis

•Postglomerular arterial hyalinosisInterstitial ischemia and fibrosisDamage to peritubular capillaries

Factors Affecting The Progression of CKD

Non modifiable susceptibility factors• Age• Gender• Genetics• Race

Initiation factors• Glomerulonephritis• TIN• Hypertension• Diabetes• Dyslipidemia

Modifiable risk factors• ?

Modulating factors of progressive renal scarring

•Genetic/Racial/ gender-related•Systemic and intraglomerular hypertension•The degree of proteinuria• Intrarenal deposition of Ca, P, urate•Hyperlipidemia (LDL)•Use of NSAIDs(Pg inhibitors)•High protein diet•Persistent metabolic acidosis•Extent of tubulointerstitial disease

Screening for chronic kidney diseasepatients 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 factors for 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

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

Assessment of renal functionGFR = [UCr x V]/SCr60 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

Estimation equations • Cockcroft-Gault • MDRD • CKD-EPI

• Cockcroft-Gault equation

(140 - age) x lean body weight [kg]• CCr (mL/min) = ——————————————— Cr [mg/dL] x 72For woman X0.85

Finding CommentPrior in serum Cr CKDSmall kidneys in U/S CKDNormal/ kidneys AKI

Exceptions:PCKDDiabetic NephropathyMultiple Myeloma

Anemia/Hyperhosphatemia/ Hypocalcemia

CKD

Oliguria/ daily in Cr/BUN AKI

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

Classification:

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

Clinical Abnormalities in CKD

•Fluid & electrolyte disturbances•Acid-Base disorders•Cardiovascular complications•Hematologic complications•Neurologic complications•Bone ,phosphate & calcium abnormalities•Endocrine disorders

Fluid & Electrolyte Disturbances in CKD

▫Early findings: poliuria- nocturia▫Expansion of ECF▫Hyponatremia

Dilutional Impaired Na conservation

▫Hyperkalemia only when GFR<10ml/min Oliguria /anuria develops Potassium sparing diuretics used ACEI and Beta blockers Acidosis

• Peritubular increase in hydraulic pressure• Atrial natriuretic peptides• Osmotic diuresis• Salt wasting forms of CRF

• Urine osmolality is decreased• Isosthenuria when GFR <25ml/min

PolyuriaNocturia

Fex of Na

INCREASED

Fex of Water

INCREASED

Fractional excretion of solutes per nephron

Solute diuresis (obligatory water loss)

HYDROGEN AND BICARBONATE TRANSPORT

Ph =7.35-7.45(H+ concentration)

Daily acid production:1mmol H/kg bw

Acids consume buffersHCO3

HCO3 is regenerated in the kidneyReabsorbed from the ultrafiltrate

maintaining plasma HCO3 concentrations

H+ excreted in the urine combines with NH3 NH4 +

No change in arterial pH/ plasma HCO3 until GFR < 30% of normal

Metabolic acidosis in CKD is due to:• Decreased nephron mass• Leading to limited NH4 production and HCO3 regeneration

METABOLIC ACIDOSIS IN CKD

Plasma HCO3 (24mEq/L) Decreased (14-18 mEq/L)

pH and stable HCO3 levels maintained at the expense of buffering by bone (CaPO4-CaHCO3)

Cardiovascular complications in CKD

•Hypertension▫Salt and water retension▫Hyperrenninemia

•Pericarditis•Accelerated atherosclerosis

▫Coronary artery disease▫Cerebrovascular disease▫Peripheral vascular disease

•Pulmonary edema

13 March 2014

Hematologic complications in CKD

•Normochromic normocytic anemia▫ biosynthesis of erythropoetin▫Bone-marrow depressive effect of uremic

toxins▫ Hemolysis▫ GI loss of blood

•Abnormal hemostasis▫ bleeding time▫Abnormal platelet aggregation

&adhesiveness▫ activity of platelet factor 3

•Enhanced susceptibility to infection

INCIDANCE OF ANEMIA IN CKD• CrCl >50ml/dk %25

• CrCl 35-49ml/dk %44

• CrCl 25-34ml/dk %51

• CrCl < 25ml/dk %87

BFU-E CFU-E

Pronormoblast, eritroblast

Stem cell

Matur cells

EPO

GM-CSF,IL3,IGF-1

ERITROPOESISCD 34 Eritron

Apoptosis

EPO

Neurologic complications

Uremic encephalopathy• Inability to concentrate, drowsiness• Insomnia, behavioral changes•Neuromuscular irritability

▫Hiccups, cramps, fasciculations▫Asterixis, chorea, stupor, seizures

Peripheral neuropathyRestless Legs

Bone phosphate & calcium abnormalities in CKD

• biosynthesis of 1,25-dihidroksikolekalsiferol

•Hypocalcemia•Hyperphosphatemia•Hyperparathyroidism•Acidosis

• RenalOsteodystrophy• Osteomalacia

TUBULAR PHOSPHATE TRANSPORT• Under physiologic conditions 80-90% is

reabsorbed• Parathyroid hormone augments

phosphate excretion

Dietary P Transient inPlasma P

Transient inPlasma Ca

(CaPO4 deposition in bone)

PTH secretion P excretion P balancerestored

In CKD PTH is persistently elevated

X

Alterations in Vitamin D metabolism

Vit Dsynthesized in the skin

25(OH)kolekalsiferolin the liver

1,25(OH2)kolekalsiferolin the kidney

Synthesis of active Vit D is reduced in CKD

Contributes to hypocalcemia and hyperparathroidism

X

Endocrine disorders in CKD

•Secondary hyperparathyroidism•Glucose intolerance•Disturbances of insulin metabolism

▫Hyperinsulinemia▫Peripheral insulin resitance

•Pituitary, throid & adrenal are normal•Libido and fertility

GFR 35-50% of normal symptom-freeBUN and Cr. levels

Normalrenal functions

maintained*endocrine*excretory*regulatory

GFR 20-35% of normal azotemia still asymptomatic

GFR < 20% of normal overt renal failure

UREMIC SYNDROME

ESRDUremic Syndrome•Renal excretory failure

▫Uremia▫Hyperkalemia

•Renal endocrine failure▫Anemia▫Renal osteodystrophy

•Renal metabolic failure & acidosis

UREMIC ‘TOXINS’

Products of protein and amino acid metabolism:

▫Urea (80% of total (excreted nitrogen)▫Guanidino compounds

Guanidine Creatinine Creatin

▫Urates and Hippurates▫End - products of nucleic acid metabolism▫End - products of aliphatic amine metabolism▫End – products of aromatic amino acid

metabolism▫Other nitrogenous substances

UREMIC TOXINS

•Advanced glycation end-products•Parathyroid hormone• Inhibitors of somatomedin and insulin

action•β–melanocyte–stimulating hormone•Glucagon•Luteinizing hormone•Prolactin

•Uremic toxins cause:

▫Anorexia▫Malaise▫Pigmentation▫Vomiting▫Pruritus▫Headache▫Platelet dysfunction (Guanidinosuccinic acid)

Pigmentation: a diffuse brown pigmentation is typical of longstanding renal failure; it may be caused by retention of β–melanocyte–stimulating hormone.

Nodular prurigo: extensive nodular prurigo associated with severe pruritus (note the scratch marks) in a man with advanced renal failure shortly before the initiation of renal replacement therapy.

Objectives in the Management of CKD

•To Calculate the functional reserve•To Correct the reversible factors that may

lower the functional reserve•Treat underlying disease where possible•To stop or slow down the progression•To prevent and treat the uremic

complications Increase quality of life and life expectation

Management of CKD•Dietary management

▫Protein restriction (0.6g-0.8 g/kg/day)▫Salt restriction (3-4g/day)▫Potassium restriction▫Phosphorus restriction▫Magnesium restriction

•Management of hypertension•Management of anemia (erythropoetin)•Management of renal bone disease•Avoiding nephrotoxic medication,

hypovolemia•Preperation for renal replacement

therapy

Management of hyperphosphatemia

•Phosphorus restriction in the diet•Oral P binding agents

▫CaCO2▫Ca acetate▫AlOH▫Sucralfate▫Iron containing agents▫Lantanium▫Sevelamer HCL

Management of Hypertension•Salt restriction•ACE inhibitors

▫Especially in diabetic nephropathy, in all CKD patients except: renal artery stenosis

▫Monitor for possible in serum Cr and K•Diuretics•Calcium channel blockers•Beta blockers•Alpha blockers•Central acting agents

Management of Anemia•Erythropoetin administration (sc/iv)•Replacement when necessary of

▫Iron▫Folic acid▫B12

•Blood transfusion

Management of Renal Bone Disease•Normalization of serum Ca and P

▫Oral P binding agents▫Prefer Ca containing ones▫Except when serum Ca x P > 55

(extraskeletal calcifications)•Follow up serum PTH levels

▫Start calcitriol/1aOH D when PTH > 2-3xN

Vascular Calcification in a ESRD patient

Smooth tissue calcification

Avoiding Nephrotoxic Medication

•Nonsteroidal antiinflammatory drugs

•Vancomycin

•Aminoglycosides

Preparation for Renal Replacement Therapy•Patient education for RRT options

• Inform about Transplantation

•Vascular access if HD anticipated

•PD catheter replacement if CAPD planned

END STAGE RENAL FAILURE

HEMODIALYSIS

TRANSPLANTATIONPERITONEAL DIALYSIS

Hollow fiber dialyzer

‘Acute’ on ‘Chronic’ concept•Acute Impairment of renal function due to an additional problem over underlying CKD:▫Acute hypovolemia▫Nefrotoxic drug use▫Infection▫Obstruction▫Heart Failure▫Accelerated hypertension