In the name of GodIn the name of God

Chronic Renal Chronic Renal FailureFailure

By: By:

Dr. Shahram AlaDr. Shahram Ala

(PharmD, BCPS)(PharmD, BCPS)

KidneyKidney

Each kidney has about 1 million Each kidney has about 1 million nephronsnephrons Receives 25% 0f GFR (1200 ml/min, > Receives 25% 0f GFR (1200 ml/min, >

1700 lit/d)1700 lit/d) 1-1.5 lit urine (waste products & excess 1-1.5 lit urine (waste products & excess

water)water) Reabsorption of sodium, glucose, waterReabsorption of sodium, glucose, water Secretion of urea, Cr, K+, H+, Secretion of urea, Cr, K+, H+,

phosphate phosphate

Other functions of Other functions of kidneyskidneys

Renin secretionRenin secretion

Erythropoietin secretionErythropoietin secretion

Activation of vit D3 (Calcitriol)Activation of vit D3 (Calcitriol)

Renal FailureRenal Failureup to 75% of function can be lost before up to 75% of function can be lost before

it is noticeableit is noticeable

ARF:ARF: Rapid Rapid onset, usually onset, usually reversible, rapid reversible, rapid reduction in reduction in urine volumeurine volume

CRF:CRF: Slow Slow onset, onset, progressive, is progressive, is not reversiblenot reversible

Treatment Modalities Treatment Modalities

HemodialysisHemodialysis Peritoneal DialysisPeritoneal Dialysis Renal TransplantRenal Transplant

In 1950s, Life expectancy of ESRD In 1950s, Life expectancy of ESRD patients was just a few days to weekspatients was just a few days to weeks

Classification Classification

Worldwide ESRDWorldwide ESRD

CRF & ESRDCRF & ESRD

CRF and ESRD are significant CRF and ESRD are significant causes of morbidity & mortalitycauses of morbidity & mortality

Analgesic NephropathyAnalgesic Nephropathy Tubulointerstitial renal diseaseTubulointerstitial renal disease (Papillary necrosis and (Papillary necrosis and

interstitial nephritis) due to ingestion of a mixture of 2 interstitial nephritis) due to ingestion of a mixture of 2 analgesics usually with codeine or caffeineanalgesics usually with codeine or caffeine

More prevalent in More prevalent in femalesfemales (5-7.1 times) with peak (5-7.1 times) with peak incidence between 4incidence between 4thth and 5 and 5thth decade decade

Salt-wasting nephropathy, ↓urine concentrating & Salt-wasting nephropathy, ↓urine concentrating & acidifying capacityacidifying capacity

Symptoms:Symptoms: flank pain, pyuria, hematuria, urethral flank pain, pyuria, hematuria, urethral obstructionobstruction

Mechanism:Mechanism: oxidative metabolite of oxidative metabolite of acetaminophen beside reduced acetaminophen beside reduced glutathione capacity (due to ASA)glutathione capacity (due to ASA)

Management:Management: abstinence from abstinence from NSAIDs & combination analgesics, NSAIDs & combination analgesics, high fluid intake (if possible), high fluid intake (if possible), management of ESRD is similar to management of ESRD is similar to other causesother causes

Analgesic Nephropathy Analgesic Nephropathy (cont.)(cont.)

Medication UseMedication Use Both HD & PD patients receive a median Both HD & PD patients receive a median

of 8 different drugs including:of 8 different drugs including: Antihypertensives (CCBs, ACEIs)Antihypertensives (CCBs, ACEIs) Antidiabetic agentsAntidiabetic agents ErythropoietinErythropoietin Phosphate-binding agentsPhosphate-binding agents MultivitaminsMultivitamins Vit D supplementsVit D supplements ASA ASA AnalgesicsAnalgesics GI agentsGI agents WarfarinWarfarin

Nonadherence & drug-related problemsNonadherence & drug-related problems

General feature in CRFGeneral feature in CRF Most patients are symptom free until Most patients are symptom free until

renal function is <25% normalrenal function is <25% normal

At renal function <10% normal, uremic At renal function <10% normal, uremic symptoms occurssymptoms occurs

At renal function<5%, dialysis or At renal function<5%, dialysis or transplant is requiredtransplant is required

Intact nephron hypothesisIntact nephron hypothesis

PathogenesisPathogenesis

Glomerular capillary hypertensionGlomerular capillary hypertension

Microalbuminuria or proteinuria Microalbuminuria or proteinuria

Increased renal plasma flow Increased renal plasma flow (with high Pr (with high Pr Intake)Intake)

Dyslipoproteinemia (esp. TG-rich apo-B-Dyslipoproteinemia (esp. TG-rich apo-B-lipoproteins)lipoproteins)

Clinical assessmentClinical assessment

Evaluation of renal functionEvaluation of renal function BUN, SrCrBUN, SrCr Clcr= (140-Age)BW/72*SrCr (*%85 for Females)Clcr= (140-Age)BW/72*SrCr (*%85 for Females) Clcr based on urine collection and measurement of Clcr based on urine collection and measurement of

UCrUCr Due to TS of creatinine in renal dysfunction, Clcr Due to TS of creatinine in renal dysfunction, Clcr

overestimates the GFRoverestimates the GFR

Proteinuria (Alb, Alb/Cr Ratio)Proteinuria (Alb, Alb/Cr Ratio) Microalbuminuria: 30-300 mg/24hMicroalbuminuria: 30-300 mg/24h Overt proteinuria: >300 mg/24hOvert proteinuria: >300 mg/24h

Dipstick test (Reagent strips) Dipstick test (Reagent strips) Alb/Cr : 30-300 µg/mg (Microalbuminuria)Alb/Cr : 30-300 µg/mg (Microalbuminuria)

PreventionPrevention

AntihypertensivesAntihypertensives

Dietary Protein RestrictionDietary Protein Restriction

Treatment of DyslipoproteinemiaTreatment of Dyslipoproteinemia

Intensive Glu Control (in Diabetic Intensive Glu Control (in Diabetic patients)patients)

HTN is both a cause and a result of RFHTN is both a cause and a result of RF

HTN causes glumerolar hyperperfusion HTN causes glumerolar hyperperfusion leading to progressive renal damageleading to progressive renal damage

Goal of BP: Goal of BP: 130/85 (in patients with some degree of renal 130/85 (in patients with some degree of renal

failure) failure) 125/75 (in patients with proteinuria >1gr)125/75 (in patients with proteinuria >1gr)

HTN & CRFHTN & CRF

Prevention:Prevention:Which Antihypertensives?Which Antihypertensives?

ACEIs ACEIs (Enalapril, Captopril, Lisinopril) (Enalapril, Captopril, Lisinopril) Ag II play a central role in glomerular capillary Ag II play a central role in glomerular capillary

pressure pressure ARAsARAs (Losartan, Irbesartan, Valsartan, Candesartan, (Losartan, Irbesartan, Valsartan, Candesartan,

Eprosartan, Telmisartan)Eprosartan, Telmisartan)

CCBsCCBs (Diltiazem, Verapamil are superior to (Diltiazem, Verapamil are superior to Nifedipine)Nifedipine) Effects on renal hemodynamic, Effects on renal hemodynamic,

cytoprotective & antiproliferative propertiescytoprotective & antiproliferative properties ACEIs+CCBsACEIs+CCBs

Prevention:Prevention: Dietary Protein Restriction Dietary Protein Restriction

There is an association between There is an association between “Protein“Protein ingestion”ingestion” & &“GFR”“GFR” and and “Renal Plasma Flow”“Renal Plasma Flow”

For GFR>25 or in Diabetics → 0.6-0.8 g/kg/dayFor GFR>25 or in Diabetics → 0.6-0.8 g/kg/day

GFR<25 or in Diabetics with RF → 0.3-0.6 GFR<25 or in Diabetics with RF → 0.3-0.6 g/kg/dayg/kg/day

Protein restriction may delay development of ESRD, Protein restriction may delay development of ESRD, but no definitive conclusions could be madebut no definitive conclusions could be made

Prevention:Prevention:Treatment of Treatment of

DyslipoproteinemiaDyslipoproteinemia ↑↑TG (Up to 70% of patients), ↓HDL, ↔ Total-CTG (Up to 70% of patients), ↓HDL, ↔ Total-C

Progression of renal diseaseProgression of renal disease Cardiovascular morbidity & mortalityCardiovascular morbidity & mortality

Treatment:Treatment: Based on individual lipid profile, generally Based on individual lipid profile, generally

NCEP guidelines are used NCEP guidelines are used

Gemfibrozil (Clofibrate accumulates in CRF)Gemfibrozil (Clofibrate accumulates in CRF) StatinesStatines

ESRDESRD Uremic Toxins:Uremic Toxins:

urea, guanidine, purine & pyridine urea, guanidine, purine & pyridine derivatives, aliphatic & aromatic amines, derivatives, aliphatic & aromatic amines, PTHPTH

Secondary Complications:Secondary Complications: Mild Renal Dysfunction:Mild Renal Dysfunction: fluid overload, HTNfluid overload, HTN Mod to Severe Renal Dysfunction:Mod to Severe Renal Dysfunction: ↑ ↑ K, ↑ P, ↓Ca, Metabolic acidosis, K, ↑ P, ↓Ca, Metabolic acidosis, AnemiaAnemia

Metabolic Effects of Metabolic Effects of UremiaUremia

Fluid/Electrolytes/Acid-Base:Fluid/Electrolytes/Acid-Base: Fluid retention, ↑K, ↑Mg, ↑P, ↓Ca, Metabolic acidosisFluid retention, ↑K, ↑Mg, ↑P, ↓Ca, Metabolic acidosis

Hematologic:Hematologic: Anemia, Hemostatic abnorm., Immune suppresionAnemia, Hemostatic abnorm., Immune suppresion

CVS:CVS: HTN, CHF, Pericarditis, Atherosclerosis, Arrhytmia, HTN, CHF, Pericarditis, Atherosclerosis, Arrhytmia, ↓ ↓ exercise tolerance exercise tolerance

Endocrine:Endocrine: Hyperpara, Altered thyroid function, Hypophyseal-Hyperpara, Altered thyroid function, Hypophyseal-

gonadal dysfunc, Erythropoietin deficiencygonadal dysfunc, Erythropoietin deficiency

Metabolic Effects of Uremia Metabolic Effects of Uremia (Cont.)(Cont.) GI:GI:

Anorexia, Nausea, Vomiting, Delayed gastric emptying, Ulcers, GI Anorexia, Nausea, Vomiting, Delayed gastric emptying, Ulcers, GI bleedingbleeding

Musculoskeletal:Musculoskeletal: Renal bone disease, Amyloidosis, Extraskeletal calcificationRenal bone disease, Amyloidosis, Extraskeletal calcification

Neurologic:Neurologic: Lethargy, Tremor, Asterixix, Cramp, Motor weakness, Peripheral Lethargy, Tremor, Asterixix, Cramp, Motor weakness, Peripheral

neuropathyneuropathy

Skin:Skin: Altered pigmentation, PruritusAltered pigmentation, Pruritus

Psychologic:Psychologic: Depression, Anxiety, Psychosis Depression, Anxiety, Psychosis

TreatmentTreatment

Dialysis (HD, PD)Dialysis (HD, PD) TransplantTransplant

PharmacotherapyPharmacotherapy

To Slow the rate of progressionTo Slow the rate of progression

To manage secondary complicationsTo manage secondary complications

ConclusionConclusion