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CHRONIC KIDNEY DISEASE:CHRONIC KIDNEY DISEASE:Causes and ManifestationsCauses and Manifestations

Vimar A. Luz, MD, FPCP, DPSNVimar A. Luz, MD, FPCP, DPSN

DEFINITIONSDEFINITIONS

Chronic renal disease (CRD)Chronic renal disease (CRD) is a pathophysiologic is a pathophysiologic process (last more than 3 months) with multiple etiologies, process (last more than 3 months) with multiple etiologies, resulting in the inexorable attrition of nephron number and resulting in the inexorable attrition of nephron number and function, and frequently leading to end-stage renal disease function, and frequently leading to end-stage renal disease (ESRD). (ESRD).

ESRDESRD represents a clinical state or condition in which there represents a clinical state or condition in which there has been an has been an irreversible irreversible loss of endogenous renal function, loss of endogenous renal function, of a degree sufficient to render the patient permanently of a degree sufficient to render the patient permanently dependent upon renal replacement therapy (dialysis or dependent upon renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia. transplantation) in order to avoid life-threatening uremia.

DEFINITIONSDEFINITIONS

AzotemiaAzotemia- - refers to the retention of nitrogenous waste refers to the retention of nitrogenous waste products as renal insufficiency developsproducts as renal insufficiency develops

UremiaUremia-- is the clinical and laboratory syndrome, is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of reflecting dysfunction of all organ systems as a result of untreated or undertreated acute or chronic renal failure. untreated or undertreated acute or chronic renal failure.

Definition Of Chronic Kidney Disease (CKD)Definition Of Chronic Kidney Disease (CKD)

GFR <60 mL/min/1.73mGFR <60 mL/min/1.73m22 for for 3 months, 3 months,

and/orand/or

Kidney damage for Kidney damage for 3 months3 months

Identifying kidney damageIdentifying kidney damage

ProteinuriaProteinuria

Urine sediment abnormalitiesUrine sediment abnormalities

Imaging testsImaging tests

Abnormalities in blood or urine compositionAbnormalities in blood or urine composition

BiopsyBiopsy

NKF. Am J Kidney Dis 2004; 43(5 Suppl 1):S65

ESTIMATION OF GFRESTIMATION OF GFR

Cockcroft-Gault formulaCockcroft-Gault formula

MENMEN Ccr=(140-age) (weight in kg)Ccr=(140-age) (weight in kg) or or 1.23 (140-age)(wt)1.23 (140-age)(wt)

72 x Pcr (mg/dl)72 x Pcr (mg/dl) Pcr (umol/L) Pcr (umol/L)

WOMENWOMEN Ccr= (140-age) (wt)Ccr= (140-age) (wt) or or 1.04 (140-age)(wt)1.04 (140-age)(wt)

85 x Pcr(mg/dl)85 x Pcr(mg/dl) Pcr (umol/L) Pcr (umol/L)

*overestimates Ccr in obese pts and those on low protein diet*overestimates Ccr in obese pts and those on low protein diet

Determine chronicity of the diseaseDetermine chronicity of the disease– HistoryHistory

– Renal biopsy- predominance of glomerulosclerosis or interstitial Renal biopsy- predominance of glomerulosclerosis or interstitial fibrosisfibrosis

– Renal ultrasound to measure kidney sizeRenal ultrasound to measure kidney sizeSmall kidneys (<9cm)Small kidneys (<9cm)

Chronic disease with normal size kidneysChronic disease with normal size kidneys– Diabetic nephropathyDiabetic nephropathy– HIV-assd nephropathyHIV-assd nephropathy– Infiltrative diseases ( myeloma kidney)Infiltrative diseases ( myeloma kidney)

Prevalence Of CKDPrevalence Of CKDIn US Population (Age In US Population (Age >> 20 Years) 20 Years)

StageStage DescriptionDescription GFR (mL/min/1.73mGFR (mL/min/1.73m22)) Number of PeopleNumber of People% of Relevant % of Relevant

PopulationPopulation

11Kidney damage with normal Kidney damage with normal

or or GFR GFR 9090 5,900,0005,900,000 3.33.3

22Kidney damage with mild Kidney damage with mild

GFRGFR 60-8960-89 5,300,0005,300,000 3.03.0

33 Moderate Moderate GFR GFR 30-5930-59 7,600,0007,600,000 4.34.3

44 Severe Severe GFR GFR 15-2915-29 400,000400,000 0.20.2

55 Kidney failureKidney failure < 15< 15(or dialysis)(or dialysis) 300,000300,000 0.10.1

19,500,00019,500,000 10.9%10.9%

NKF-K/DOQI. NKF-K/DOQI. Am J Kidney DisAm J Kidney Dis. 2001;37(suppl 1):S1-S238.. 2001;37(suppl 1):S1-S238.

NNHeS 2003-2004 Renal Report NNHeS 2003-2004 Renal Report Prevalence of CKD in Filipino adults using Prevalence of CKD in Filipino adults using

predicted GFR from MDRD equationpredicted GFR from MDRD equation

Stages of GFR Stages of GFR

11 > =90 > =90 72.8%72.8%

22 60-89 60-89 24.6%24.6%

33 30-59 30-59 2.2%2.2%

44 15-29 15-29 0.2%0.2%

55 <15<15 0.2%0.2%

The prevalence of CKD Stage 3 - 5 is 2.6% Approximately 1,212,306 adult Filipinos

National Statistics OfficeNational Statistics Office

Kidney disease

is now # 10

cause of mortality

in the Philippines

CKDdeath

Stages in Progression of Chronic Kidney Stages in Progression of Chronic Kidney Disease and Therapeutic StrategiesDisease and Therapeutic Strategies

Complications

Screening Screening for CKDfor CKD

risk risk factors:factors:diabetesdiabetes

hypertensihypertensionon

age >60age >60family family historyhistory

US ethnic US ethnic minoritiesminorities

CKD riskCKD riskreduction;reduction;

Screening forScreening forCKDCKD

DiagnosisDiagnosis& treatment;& treatment;

Treat Treat co-morbidco-morbidconditions;conditions;

Slow Slow progressionprogression

EstimateEstimateprogression;progression;

TreatTreatcomplications;complications;

Prepare forPrepare forreplacementreplacement

ReplacementReplacementby dialysisby dialysis

& transplant& transplant

NormalIncreased

riskKidneyfailure

Damage GFR

6 Mechanisms of Renal Disease Progression


Persistent glomerular injury leading to HTN then single nephron GFR



Protein leak increasing Angiotension II




Downstream cytokine bath





Neutrophils then macrophages, T lymphocytes leading to interstitial nephritis






Tubular epithelium responds by detaching from their basement membrane forming new interstitial fibroblasts






Tubular epithelium responds by detaching from their basement membrane forming new interstitial fibroblasts

Surviving fibroblasts lay down collagenous matrix disrupting adjacent tubules and surrounding vessels leaving an acellular scar

RISK FACTORS FOR CRDRISK FACTORS FOR CRD

family hx of heritable renal disease, HPN, DM, autoimmune diseasefamily hx of heritable renal disease, HPN, DM, autoimmune diseaseolder ageolder agepast episode of acute renal failurepast episode of acute renal failurecurrent evidence of kidney damage even with normal or increased current evidence of kidney damage even with normal or increased GFRGFR– proteinuriaproteinuria– abnormal urinary sedimentabnormal urinary sediment– urinary tract structural abnormalities ( VUR)urinary tract structural abnormalities ( VUR)

Normal annual mean decline in GFR- begins at age 20 to 30 years= Normal annual mean decline in GFR- begins at age 20 to 30 years= 1ml/min per 1.73m21ml/min per 1.73m2

- mean GFR at age 70 is 70ml/min- mean GFR at age 70 is 70ml/min

CAUSES OF CKDCAUSES OF CKD

COMMONCOMMON– Diabetic nephropathyDiabetic nephropathy– GlomerulonephritisGlomerulonephritis– Interstitial nephritis (including pyelopnephritis)Interstitial nephritis (including pyelopnephritis)– Hypertension/vascularHypertension/vascular– Hereditary/congenital diseaseHereditary/congenital disease– NeoplasmsNeoplasms


LESS COMMONLESS COMMON– MetabolicMetabolic

CystinosisCystinosis

OxalosisOxalosis

NephrocalcinosisNephrocalcinosis

CystinuriaCystinuria

hyperuricemiahyperuricemia

– VascularVascularIschemic renal diseaseIschemic renal disease

SclerodermaScleroderma

Hemolytic uremic syndromeHemolytic uremic syndrome

Postpartum renal failurePostpartum renal failure

– DysproteinemiasDysproteinemiasAmyloidAmyloid

MyelomaMyeloma

CryoglobulinemiaCryoglobulinemia

Light chain deposition diseaseLight chain deposition disease


LESS COMMONLESS COMMON– HereditaryHereditary

Alport syndromeAlport syndrome

Fabry diseaseFabry disease

Tuberous sclerosisTuberous sclerosis

Sickle cell diseaseSickle cell disease

– VasculitisVasculitisWegener’s granulomatosisWegener’s granulomatosis

Microscopic polyangitisMicroscopic polyangitis

Polyarteritis nodosaPolyarteritis nodosa

lupuslupus

– MalignancyMalignancyRenal cell carcinomaRenal cell carcinoma

lymphomalymphoma

– StructuralStructuralCystic kidney disease other than adult-onset cysticCystic kidney disease other than adult-onset cystic

Congenital and acquired abn of the urinary tract e.g spina bifida,spinal cord Congenital and acquired abn of the urinary tract e.g spina bifida,spinal cord injuryinjury

Stage 1 and 2- usually asymptomaticStage 1 and 2- usually asymptomatic

Stage 3 and 4-Stage 3 and 4-AnemiaAnemiaLoss of energyLoss of energyAnorexiaAnorexiaMalnutritionMalnutritionAbn in Ca and Ph metabolismAbn in Ca and Ph metabolismAbn in Na, water, K acid-base homeostasisAbn in Na, water, K acid-base homeostasis

Stage 5-Stage 5-Severe disturbances in activities of daily living, sense of Severe disturbances in activities of daily living, sense of well being, nutrition,water and electrolyte well being, nutrition,water and electrolyte homeostasis-----UREMIAhomeostasis-----UREMIA

MANIFESTATIONS MANIFESTATIONS

NeurologicNeurologic– CentralCentral

Daytime drowsiness and a tendency to sleep, which Daytime drowsiness and a tendency to sleep, which progresses to increasing obtundation and, eventually, progresses to increasing obtundation and, eventually, comacomaDecreased attentiveness and performance of cognitive tasksDecreased attentiveness and performance of cognitive tasksImprecise memoryImprecise memorySlurred speechSlurred speechAsterixis and myoclonusAsterixis and myoclonusSeizuresSeizures Disorientation and confusionDisorientation and confusion

– PeripheralPeripheralSensorimotor peripheral neuropathy, often with burning Sensorimotor peripheral neuropathy, often with burning dysesthesiadysesthesiaSingultus (hiccup)Singultus (hiccup)Restless leg syndromeRestless leg syndromeIncreased muscle fatigability and muscle crampsIncreased muscle fatigability and muscle cramps

MANIFESTATIONS MANIFESTATIONS

CardiovascularCardiovascular

Accelerated atherosclerosisAccelerated atherosclerosis

CardiomyopathyCardiomyopathy

PericarditisPericarditis

PulmonaryPulmonary

Atypical pulmonary edemaAtypical pulmonary edema

PneumonitisPneumonitis

Fibrinous pleuritisFibrinous pleuritis

GastrointestinalGastrointestinal

Anorexia progressing to nausea and vomitingAnorexia progressing to nausea and vomiting

Stomatitis and gingivitisStomatitis and gingivitis

ParotitisParotitis

Peptic ulcer diathesisPeptic ulcer diathesis

Gastritis and duodenitisGastritis and duodenitis

EnterocolitisEnterocolitis

PancreatitisPancreatitis

AscitesAscites

DermatologicDermatologic

PruritusPruritus

Dystrophic calcificationDystrophic calcification

Changes in skin pigmentationChanges in skin pigmentation

HematologicHematologicAnemiaAnemiaAltered neutrophilic chemotaxisAltered neutrophilic chemotaxisDepressed lymphocyte functionDepressed lymphocyte functionBleeding diathesis with platelet dysfunctionBleeding diathesis with platelet dysfunction

EndocrinologicEndocrinologicSecondary hyperparathyrodismSecondary hyperparathyrodismCarbohydrate intolerance due to insulin resistanceCarbohydrate intolerance due to insulin resistanceType IV hyperlipidemiaType IV hyperlipidemiaAltered peripheral thyroxine metabolismAltered peripheral thyroxine metabolismTesticular atrophyTesticular atrophyOvarian dysfunction with amenorrhea, dysmenorrhea, dysfunctional Ovarian dysfunction with amenorrhea, dysmenorrhea, dysfunctional uterine bleeding, cystic ovarian diseaseuterine bleeding, cystic ovarian disease

OphthalmicOphthalmicConjunctival or cornel calcificationsConjunctival or cornel calcifications

PHYSICAL EXAMINATIONPHYSICAL EXAMINATION

Abdominal masses (PKD)Abdominal masses (PKD)

Diminished pulses (atherosclerotic peripheral vascular Diminished pulses (atherosclerotic peripheral vascular diseases)diseases)

Abnormal bruit ( renovascular disease)Abnormal bruit ( renovascular disease)

PallorPallor

Excoriations (uremic pruritus)Excoriations (uremic pruritus)

Muscle wastingMuscle wasting

Uremic breathUremic breath

hypertensionhypertension

LABORATORY FINDINGSLABORATORY FINDINGS

Elevated BUN, creatinineElevated BUN, creatinine

AnemiaAnemia

HyperphosphatemiaHyperphosphatemia

ProteinuriaProteinuria

HypoalbuminemiaHypoalbuminemia

HypercholesterolemiaHypercholesterolemia

hyperuricemiahyperuricemia

HyperkalemiaHyperkalemia

HyponatremiaHyponatremia

Metabolic acidosisMetabolic acidosis

FLUIDS, ELECTROLYTES AND ACID-BASE FLUIDS, ELECTROLYTES AND ACID-BASE DISORDERSDISORDERS

ECF VOLUME EXPANSIONECF VOLUME EXPANSION

HYPONATREMIAHYPONATREMIA

HYPERKALEMIAHYPERKALEMIA

METABOLIC ACIDOSISMETABOLIC ACIDOSIS

LIFE THREATHENING EMERGENCIES IN CKDLIFE THREATHENING EMERGENCIES IN CKD

Fluid overload/Pulmonary EdemaFluid overload/Pulmonary Edema

HyperkalemiaHyperkalemia

Pericardial Effusion with tamponadePericardial Effusion with tamponade

Metabolic acidosisMetabolic acidosis

FEATURES OF HYPERKALEMIAFEATURES OF HYPERKALEMIA

Muscle weaknessMuscle weakness

lower extremities and ascends, respiratory lower extremities and ascends, respiratory muscles and those supplied by cranial nerves are muscles and those supplied by cranial nerves are sparedspared

abnormal cardiac conduction which can lead to fatal abnormal cardiac conduction which can lead to fatal arrhythmiaarrhythmia

PERICARDIAL EFFUSION WITH TAMPONADEPERICARDIAL EFFUSION WITH TAMPONADE

Subacute tamponadeSubacute tamponade

less dramatic; chest discomfort or easy fatigueless dramatic; chest discomfort or easy fatigue

hypotension with narrow pulse pressurehypotension with narrow pulse pressure

elevated jugular venous pressureelevated jugular venous pressure

Acute tamponadeAcute tamponade

sudden onsetsudden onset

associated with chest pain and dyspneaassociated with chest pain and dyspnea

markedly elevated CVPmarkedly elevated CVP

hypotension commonhypotension common

heart sounds mutedheart sounds muted

pulsus paradoxuspulsus paradoxus

Manifestations of Metabolic acidosisManifestations of Metabolic acidosis

Involve the respiratory, cardiovascular, neurologic and Involve the respiratory, cardiovascular, neurologic and skeletal systemsskeletal systems

Kussmaul’s respirationKussmaul’s respiration

increased susceptibility to cardiac arrhythmia increased susceptibility to cardiac arrhythmia (hyperkalemia)(hyperkalemia)

decreased level of consciousness due to a 2’ decrease decreased level of consciousness due to a 2’ decrease in intracerebral pH in intracerebral pH

PhosphorusPhosphorus– A major component of bone, along with A major component of bone, along with

calciumcalcium– One of the first substances to be deranged in One of the first substances to be deranged in

CKDCKDTriggers a sequence of events that may ultimately Triggers a sequence of events that may ultimately lead to renal bone disease lead to renal bone disease

Phosphate BindersPhosphate Binders

Further limits the Further limits the absorption of phosphate absorption of phosphate by binding it in the gutby binding it in the gutAdministered with mealsAdministered with mealsConventional bindersConventional binders– Aluminum hydroxideAluminum hydroxide– Calcium saltsCalcium salts

Recent developmentsRecent developments– Sevelamer hydrochlorideSevelamer hydrochloride– Lanthanum carbonateLanthanum carbonate

CARDIOVASCULAR DISEASECARDIOVASCULAR DISEASE

Leading cause of morbidity and mortality in pts with CRD Leading cause of morbidity and mortality in pts with CRD at all stagesat all stages

30-45% of pts reaching ESRD already have advanced 30-45% of pts reaching ESRD already have advanced cardiovascular complicationscardiovascular complications

Hypertension is the most common complication of CRD Hypertension is the most common complication of CRD and ESRDand ESRD

Volume overload is the major cause of HPN in uremiaVolume overload is the major cause of HPN in uremia

Anemia-normochromic, normocyticAnemia-normochromic, normocytic

Declining renal function –beginning at Declining renal function –beginning at stage 3stage 3– reduced erythropoietin productionreduced erythropoietin production– decreased red blood cell half-lifedecreased red blood cell half-life– tendency toward gastrointestinal bleeding. tendency toward gastrointestinal bleeding.

ABNORMAL HEMOSTASISABNORMAL HEMOSTASIS

Associated with prolongation of bleeding timeAssociated with prolongation of bleeding time

Decreased activity of platelet factor IIIDecreased activity of platelet factor III

Abnormal platelet aggregation and adhesivenessAbnormal platelet aggregation and adhesiveness

Impaired prothrombin consumptionImpaired prothrombin consumption

Manifestations: increased tendency to abnormal bleeding and Manifestations: increased tendency to abnormal bleeding and bruising, occult GI bleedingbruising, occult GI bleeding

Greater susceptibility to thromboembolic complications esp Greater susceptibility to thromboembolic complications esp nephrotic ptsnephrotic pts

NEUROMUSCULAR ABNORMALITIESNEUROMUSCULAR ABNORMALITIES

Central, peripheral and autonomic neuropathyCentral, peripheral and autonomic neuropathy

Abnormalities in muscle composition and functionAbnormalities in muscle composition and function

Due to retained nitrogenous metabolites and middle molecules and Due to retained nitrogenous metabolites and middle molecules and PTHPTH

Become clinically evident at stage 3Become clinically evident at stage 3

Mild manifestations- disturbances in memory,sleep and Mild manifestations- disturbances in memory,sleep and concentrationconcentration

Hiccups,cramps, fasciculations, twitching, asterixis, chorea seen in Hiccups,cramps, fasciculations, twitching, asterixis, chorea seen in uremiauremia

Seizure and comaSeizure and coma

GASTROINTESTINAL AND NUTRITIONAL GASTROINTESTINAL AND NUTRITIONAL ABNORMALITIESABNORMALITIES

Uremic fetor-breakdown of urea in salivaUremic fetor-breakdown of urea in saliva

Gastritis, peptic disease, mucosal ulcerationGastritis, peptic disease, mucosal ulceration

Increased incidence of diverticulitis, pancreatitisIncreased incidence of diverticulitis, pancreatitis

Anorexia, hiccups, nausea, vomitingAnorexia, hiccups, nausea, vomiting

Protein-calorie malnutrition as a consequence of low protein and Protein-calorie malnutrition as a consequence of low protein and caloric intakecaloric intake

ENDOCRINE AND METABOLIC DISTURBANCESENDOCRINE AND METABOLIC DISTURBANCES

Impaired glucose metabolism- slowing of the rate of blood glucose Impaired glucose metabolism- slowing of the rate of blood glucose level after a glucose loadlevel after a glucose load

FBS usually normal or slightly elevatedFBS usually normal or slightly elevated

Plasma level of insulin slightly elevatedPlasma level of insulin slightly elevated

Impaired response to insulin and glucose utilizationImpaired response to insulin and glucose utilization

Drug dosing needed, some drugs cant be used, metformin Drug dosing needed, some drugs cant be used, metformin contraindicated when GFR is about 25-50%contraindicated when GFR is about 25-50%

Low estrogen levelLow estrogen level

Impotence, oligospermia, germinal cell dysplasia commonImpotence, oligospermia, germinal cell dysplasia common

DERMATOLOGIC ABNORMALITIESDERMATOLOGIC ABNORMALITIES

Pallor, defective hemostasis (ecchymoses, hematomas)Pallor, defective hemostasis (ecchymoses, hematomas)

Pruritus, excoriationsPruritus, excoriations

Deposition of pigmented metabolites or urochromes (uremic frost)Deposition of pigmented metabolites or urochromes (uremic frost)

Thank you and good dayThank you and good day

GFR differentiationGFR differentiation

Stage 0 >90 (+) risk factors for CKDStage 0 >90 (+) risk factors for CKDStage 1 Stage 1 90 (+) evidence of kidney 90 (+) evidence of kidney

damage (proteinuria, abnormal urine damage (proteinuria, abnormal urine sediment and imaging studies)sediment and imaging studies)

Stage 2 60 to 89Stage 2 60 to 89Stage 3 30 to 59Stage 3 30 to 59Stage 4 15 to 29Stage 4 15 to 29Stage 5 < 15Stage 5 < 15