Acute Kidney Injury and Chronic Kidney Disease: Classifications and Interventions for Children and Adults

Transcription

1 Acute Kidney Injury and Chronic Kidney Disease: Classifications and Interventions for Children and Adults Teresa V. Lewis, PharmD, BCPS Assistant Professor of Pharmacy Practice University of Oklahoma College of Pharmacy Adjunct Assistant Professor of Pediatrics University of Oklahoma College of Medicine 1 Disclosures Teresa V. Lewis, Pharm.D., BCPS Nothing to disclose

2 Objectives 1. When given specific patient details, identify those with increased Identify which adult or pediatric patients are at risk for development of acute kidney injury (AKI) and recommend appropriate preventive interventions. 2. Design an evidence-based plan to manage AKI for a given patient. 3. Compare and contrast the RIFLE, prifle, and Kidney Disease Improving Global Outcomes (KDIGO) classification systems for AKI. 4. List risk factors for development of chronic kidney disease (CKD). 5. Compare and contrast the Kidney Disease Outcomes Quality Initiative (KDOQI) staging of CKD with the Kidney Disease Improving Global Outcomes (KDIGO) CKD staging criteria. 6. Design an evidence-based plan to prevent progression of CKD for a given patient. 3 Kidney Development and Maturation Nephrogenesis Begins around 9 weeks of gestation Complete by 36 weeks of gestation Immature renal function at birth Lower renal blood flow Immature glomeruli Immature renal tubule function Kidney function will be similar to adult values by age 2 years 4

3 Presentation Outline Diagnostic Workup Acute Kidney Injury Drug Induced Nephrotoxicity Chronic Kidney Disease 5 DIAGNOSTIC WORK-UP

4 Blood Urea Nitrogen (BUN) Normal: 8-20 mg/dl Amino-acids metabolized to ammonia and converted in liver to urea Urea is filtered and reabsorbed in proximal tubule (dependent on water reabsorption) Normal BUN:Serum creatinine (Scr) ratio is 10-15:1 Elevated BUN:Scr ratio suggests true or effective volume depletion 7 Serum Creatinine (Scr) Freely filtered Actively secreted Scr lags behind glomerular filtration rate (GFR) by 1-2 days due to: 1. Slow accumulation 2. Increased tubular secretion 3. Increased extra-renal clearance 8

5 Glomerular Filtration Rate (GFR) Amount of blood that passes through the glomeruli each minute Best indicator of kidney function Expressed as ml/minute/1.73 m 2 9 Normal GFR Values By Age GFR (ml/min/1.73 m 2 )

6 Urinalysis Component Normal Value ph Comments ph suggest presence of bacteria ph may be due to renal tubular dysfunction Glucosuria when blood glucose > 180 mg/dl Glucose 0 Fanconi syndrome: glucosuria with normal serum glucose Ketones 0 Present in diabetic ketoacidosis, fasting, or starvation 11 Urinalysis Component Normal Value Nitrite Negative Comments Present due to conversion from urinary nitrate by bacteria in the urine Indication of urinary tract infection Negative value does not rule out infection in children Leukocyte esterase Negative Released by lysed granulocytes in urine Normal: up to 3 per high-power field Possible urinary tract infection or inflammation: > 3 per high-power field Heme Negative Hemoglobin or myoglobin due to hematuria, hemolysis, or rhabdomyolysis 12

7 Urinalysis Component Protein (Albumin) Specific gravity Normal Value < 30 mg/day to Comments microalbuminuria: mg/day macroalbuminuria: >300 mg/day Most useful to evaluate sodium disorders or volume status 13 Urine Dipstick Interpretations Result Protein amount Negative Less than 10 mg/dl Trace mg/dl mg/dl mg/dl mg/dl 4+ Greater than 1000 mg/dl 14

8 Urine Sodium (U Na ) Measures the ability of the kidney to concentrate urine When volume depleted, the kidney will retain sodium so U Na will be low (5-10 meq/l) When kidney cannot concentrate urine, U Na will be elevated > 30 meq/l 15 Fractional excretion of sodium (Fe Na ) Measures the ability of the kidney to concentrate urine Reflects acute changes Fe Na % = [(Urine Na + x Scr)/(Serum Na + x Ucr)]x100 Fe Na ~1% = normal kidney function Fe Na < 1% = volume depletion Fe Na > 2% = renal damage or drug interaction Fe Na >4% suggests post-renal azotemia Fe Na may not be not reliable following recent diuretic therapy 16

9 Urine Osmolality Measures the ability of the kidney to concentrate urine Represents the number of osmotically active particles in the urine Normal range mosm/kg Depends on hydration status > 500 mosm/kg = highly concentrated urine 17 Acute Kidney Injury

10 Kidneys Are Vulnerable To Injury Due To: Large vascular surface area High energy requirements of tubular cells (e.g. loop of Henle) High renal blood flow requirements: ~20-25% of resting cardiac output Intrarenal drug metabolism can lead to toxicity if metabolism results in a nephrotoxic metabolite or prolonged exposure Proximal tubule uptake of toxins 19 Epidemiology AKI is common in hospitalized patients (incidence: 13-18%) Main causes of AKI in hospitalized patients Pre-renal azotemia Intrinsic azotemia (a.k.a renal azotemia) due to acute tubular necrosis (ATN) is associated with a high incidence of AKI in critical care patients Drug-induced nephrotoxicity 20

11 Morbidity ~90% will recover and live independently, but half will have subclinical effects Some will have chronic kidney disease (CKD) or require longterm dialysis AKI is associated with an increased risk for developing CKD 21 Mortality AKI is an independent risk factor for mortality Mortality: ~15-80% depending on the cause, severity of AKI and clinical setting 10% mortality with uncomplicated AKI > 50% mortality rate in patients with AKI and multi-organ failure Up to 80% mortality rate in patients who require renal replacement therapy 22

12 General Recommendations 1. Assess risk for AKI 2. Prevent AKI 3. Detect AKI 4. Identify cause of AKI 5. General management of AKI 23 AKI Risk Factors Neonates have higher rates of AKI (especially premature babies) Age older than 65 years History of AKI Chronic kidney disease (CKD) Hypovolemia (true or effective volume depletion) Obstruction of urine flow (e.g. BPH, kidney stones, anatomical abnormalities such as posterior urethral valves, etc) Exposure to nephrotoxic medications Use of iodinated contrast within the past week Presence of Comorbidities 24

13 Comorbidities (Other Disease States) Diabetes Heart failure Hypertension or hypotension Liver disease Malignancy Organ failure Sepsis 25 Question: Which of the following increases a patient s risk for developing AKI? A. AKI 12 years ago B. Premature neonate C. Congestive heart failure D. Dehydration 26

14 General Recommendations 1. Assess risk for AKI 2. Prevent AKI 3. Detect AKI 4. Identify cause of AKI 5. General management of AKI 27 PREVENT AKI Identify patients at risk for AKI and correct factors when possible Use a tracking system to permit early recognition of patients who are at risk for AKI Increase frequency of monitoring 28

15 Risk Minimization Strategies Assess baseline renal function (Clcr, GFR, historical S Cr ) Adjust doses for renal function (use Cockcroft-Gault for adults, Schwartz or Bedside Schwartz for children) Discontinue or avoid concomitant nephrotoxins Use alternative agents where possible Limit dose and duration of nephrotoxic medications Take appropriate measures prior to nephrotoxic procedures Supportive measures 29 General Recommendations 1. Assess risk for AKI 2. Prevent AKI 3. Detect AKI 4. Identify cause of AKI 5. General management of AKI 30

16 Detect AKI Standardized definition for diagnosis and classification AKI classification and staging helps predict patient outcomes Detection is mostly based on monitoring serum creatinine + urine output The different staging systems are generally similar with some differences in Scr and urine output criteria 31 AKI Classification Systems 1. RIFLE 2. prifle 3. KDIGO 32

17 RIFLE Risk Injury Failure Glomerular Filtration Rate (GFR) Criteria Scr x 1.5 Or GFR decreased > 25% from baseline Scr x 2 Or GFR decreased > 50% from baseline Scr x 3 Or GFR decreased > 75% Or Acute on chronic kidney injury: Scr > 4 mg/dl & Scr acutely by 0.5 mg/dl or higher Urine Output (UO) Criteria < 0.5 ml/kg/hr > 6 h < 0.5 ml/kg/hr > 12 h < 0.3 ml/kg/hr for 24 h Or Anuria for 12 h 33 RIFLE Loss ESRD Criteria Persistent acute renal failure (ARF): complete loss of kidney function requiring dialysis > 4 weeks End Stage Renal Disease: complete loss of kidney function requiring dialysis > 3 months 34

18 Considerations With Urine Output As A Marker of AKI In Adults Weight and urine output is a non-linear relationship so overweight/obese patients may be misclassified as having AKI if using a weight based urine output criterion Urine output criterion will not be reliable if patients are receiving diuretic therapy 35 Pediatric RIFLE (prifle) Glomerular Filtration Rate (GFR) Criteria Urine Output (UO) Criteria Risk GFR decreased > 25% UO < 0.5 ml/kg/hr x 8 h Injury GFR decreased > 50% UO < 0.5 ml/kg/hr x 16 h Failure GFR decreased > 75% Or GFR < 35mL/min/1.73m 2 UO < 0.3 ml/kg/hr x 24 h Or Anuria x 12 h 36

19 prifle Criteria Loss Persistent ARF: complete loss of kidney function requiring dialysis > 4 weeks ESKD End Stage Kidney Disease: complete loss of kidney function requiring dialysis > 3 months 37 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline For AKI Increase in Scr by > 0.3 mg/dl within 48 hours; Or Increase in Scr to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; Or Urine volume < 0.5 ml/kg/h for 6 hours 38

20 Limitations With KDIGO AKI Criteria Time frame for development of AKI No stipulation as to when this time frame may occur Example: a patient may be hospitalized for several weeks and develop AKI during week 4 of their hospitalization Exclusion of urine output for assessing AKI in children Pediatric healthcare professionals rely heavily on urine output to assess fluid balance The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) has stated that further pediatric research is needed in order to identify the best metric for defining AKI in children 39 Limitations To Using Scr As a Biomarker For AKI May not have reliable record of baseline Scr Scr lags behind glomerular filtration rate (GFR) Affected by nutrition, renal tubule secretion, medications, etc Wide range of normal values Children: Small Scr changes can lead to large GFR differences. Example: 5 month-old, Ht: 60 cm Scr: 0.2 mg/dl, GFR 135 ml/min/1.73m 2 Scr: 0.4 mg/dl, GFR ~68 ml/min/1.73m 2 40

21 Recommendations For Using Scr Rather than using one isolated value for determining AKI look at the trends in renal function When baseline Scr is not available Consider population based normative values for the patient s baseline Scr The lowest Scr during hospitalization may usually be considered as equal to or higher than the patient s true baseline value 41 Question: Apply the KDIGO criteria to these Scr trends and identify the patient(s) who has AKI during hospital day 14 Patient Baseline Day 1 Day 2 Day 7 Day 10 Day 14 Scr Scr Scr Scr Scr Scr 87 yr-old female yr-old male yr-old male yr-old female

22 General Recommendations 1. Assess risk for AKI 2. Prevent AKI 3. Detect AKI 4. Identify cause of AKI 5. General management of AKI 43 AKI Classification By Pathophysiologic Mechanism 1. Pre-renal azotemia 2. Intrinsic azotemia 3. Post-renal azotemia By Type of Injury Hemodynamically mediated Glomerulonephritis Tubular epithelial damage Interstitial nephritis Obstructive nephropathy Others 44

23 Mechanisms of Renal Injury Hemodynamically mediated Prerenal azotemia Glomerulonephritis Intrinsic azotemia Tubular epithelial damage Intrinsic azotemia Interstitial nephritis Intrinsic azotemia Obstructive nephropathy Post renal azotemia Drug induced rhabdomyolysis Variable, but likely intrinsic or post renal 45 General Recommendations 1. Assess risk for AKI 2. Prevent AKI 3. Detect AKI 4. Identify cause of AKI 5. General management of AKI 46

24 General Management of AKI (Prevention Is Best) 1. Avoid hypovolemia. Administer IV hydration if appropriate to optimize hemodynamic status 2. Correct fluid and electrolyte imbalances 3. Avoid routine use of loop diuretics. Use loop diuretics only for treating fluid overload or edema for: Patients awaiting renal replacement therapy Or For patients in whom renal function is recovering and they do not require renal replacement therapy 47 General Management of AKI (Prevention Is Best) 4. Identify and minimize the number of nephrotoxic medications 5. Use medications that do not harm the kidneys or use agents that have less nephrotoxicity. (e.g. liposomal amphotericin B instead of conventional amphotericin B) 6. Estimate the patient s renal function and adjust medications accordingly 7. Therapeutic drug concentration monitoring when available (e.g. aminoglycoside, vancomycin, etc) 48

25 Drug Induced Nephrotoxicity 49 Renal Assessment Based on Type of AKI Lab Test Normal Prerenal Intrinsic Post renal BUN 8-20 mg/dl S Cr mg/dl BUN:S Cr < 20:1 >20 ~ 15 ~ 15 U Na variable < 20 > 40 >40 Fe Na (%) 0.5% <1% >1-2% variable U Osm normal U Osm :S Osm - >1.5 <1.3 <1.5 U Cr :S Cr - >40:1 <20:1 <20:1 UA Normal Normal Casts, cellular debris, Cellular debris, blood crystals or normal

26 Mechanisms of Drug-Induced Renal Injury Hemodynamically-mediated (Pre-renal) Tubular Epithelial Damage (Intrinsic) Interstitial Nephritis (Intrinsic) Obstructive Nephropathy (Post-renal) Rhabdomyolysis 51 Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) 52

27 Mechanism of Renal Injury Due to NSAIDs Afferent arteriole Cyclooxygenase X mediated synthesis of vasodilatory prostaglandins (prostacyclin and prostaglandin E 2 ) Efferent arteriole Prostaglandin production leading to afferent arteriole vasoconstriction and GFR 53 Risks and Prevention Risks Concomitant administration with angiotensin-converting enzyme inhibitors (ACEI) angiotensin II receptor blockers (ARB) Atherosclerotic CV disease Diuretic therapy Polypharmacy Prevention and Management Use alternative analgesics Optimize volume status 54

28 ACEI/ARB 55 Mechanism of Renal Injury Due to ACEI/ARB Synthesis and activity of angiotensin II resulting in dilation of the efferent arteriole Afferent arteriole Efferent arteriole X Efferent arteriole vasodilation hydrostatic pressure lead to decreased proteinuria (benefit) but also cause renal ischemia and GFR 56

29 Presentation Up to 30% in S cr during first 3 weeks may be expected with these agents Reversible upon discontinuation If rise in Scr persists for more than 4 months at the lowest dose then may need to discontinue 57 Risks and Prevention Risks Concomitant administration with NSAIDs Bilateral renal artery stenosis or severe atherosclerotic disease Chronic kidney disease Prevention and Management Initiate ACEI/ARB at low doses Consider alternative antihypertensive agents Closely monitor renal function and serum potassium on initiation Optimize volume status 58

30 Question: Which of the following can cause AKI by interfering with renal perfusion? A. Ketorolac B. Losartan C. Ramipril D. All of the above 59 Mechanisms of Drug-Induced Renal Injury Hemodynamically-mediated (Pre-renal) Tubular Epithelial Damage (Intrinsic) Interstitial Nephritis (Intrinsic) Obstructive Nephropathy (Post-renal) Rhabdomyolysis 60

31 Acute Tubular Necrosis (ATN) Most common type of drug induced nephrotoxicity Common cause of AKI in hospitalized patients Mechanism of injury ischemic or toxic injury causing tubule cells to die and slough off into the tubule lumen forming obstructive casts that prevent glomerular filtration. 61 Labs and Renal Assessment Oliguria - UO leads to fluid retention and management of fluid balance becomes a challenge Loss of urine concentrating ability ( BUN:S cr, U Osm, U Na, Fe Na > 1%) UA has dirty brown casts (dead tubular cells) 62

32 Vasopressin Antidiuretic hormone analog Administer in conjunction with fluids in patients who have vasomotor shock Vasopressin increases blood pressure and enhances diuresis 63 Diuretics Diuretics do not improve morbidity or mortality associated with AKI Should Not be used as a preventive measure for AKI Adverse Effects: High doses of loop diuretics can cause irreversible ototoxicity (tinnitus, hearing loss). Increased risk with concomitant ototoxins, furosemide infusion rates > 4 mg/min (240 mg/h), or renal impairment 64

33 Diuretic Role Diuretics should be reserved for patients who have volume overload And still produce urine High-dose loop diuretics for oliguria of less than 48 hours duration that has not responded to adequate hydration Monitoring parameters: fluid status, blood pressure, heart rate, sodium, potassium, magnesium, calcium, renal function 65 Other Therapies Dopamine Data show lack of efficacy Some data suggests deleterious effects with its use Renal replacement therapy may be needed 66

34 Aminoglycosides 67 Presentation Gradual in S cr and in ClCr after 5 10 days of therapy Can be nonoliguric renal failure Electrolyte abnormalities can occur but are rare (e.g. Mg, K, Ca, Phos) Usually reversible because the proximal tubules can regenerate. (Up to 3 weeks for Scr to return to baseline) 68

35 Mechanism of Renal Injury Due To Aminoglycosides Aminoglycosides are cations which readily binds to anion phospholipids within proximal tubular epithelial cell membranes They undergo intracellular transport and concentration in lysosomes ultimately result in cellular dysfunction and release of lysosomal enzymes This results in cellular damage to proximal tubular epithelial cells This damage leads to obstruction of the tubular lumen and back-leakage of the glomerular filtrate across the damaged tubular epithelium Risks Large cumulative dose Prolonged duration of therapy At least 5-7 days of therapy in patients with normal hemodynamic status Increased risk for progression of injury to renal cortex Frequency of dosing Repeated courses of aminoglycoside therapy because of aminoglycoside sequestration in the renal cortex Relative affinity of an aminoglycoside for proximal tubule cell plasma membrane Troughs > 2 mg/l Mg, K deficiencies prior to therapy 70

36 Prevention and Treatment Maintain adequate urine production (1 ml/kg/h) Monitor S cr every 1-2 days during therapy Use alternative antibiotics Use of extended interval dosing (i.e. once daily dosing of aminoglycosides) Limit dose and duration Appropriate pharmacokinetic drug monitoring 71 Radiographic Contrast Media 72

37 Contrast-Induced Nephropathy (CIN) Presentation Usually reversible and nonoliguric Definition: Scr > 0.5mg/dL at 2-7 days after IV contrast Can see of mg/dl S Cr with peak 1-5 days after exposure Recovery in days after exposure 73 Mechanism of Injury Mechanism not well understood but may be due to: Direct tubular toxicity Renal ischemia Initial transient osmotic diuresis followed by tubular proteinuria and enzymuria Proteinuria directly damages cells Systemic hypotension occurs secondary to osmotic diuresis Renal ischemia occurs secondary to vasoconstriction and diuresis 74

38 Risks Iodinated contrast dye High osmolar ionic mosm/kgh 2 O (e.g. diatrizoate, iothalamate) Low osmolar ionic ~600 mosm/kgh 2 O (e.g. ioxaglate) Low osmolar nonionic mosm/kgh 2 O (e.g. iohexol, iopamidol, ioversol) Iso-osmolar mosm/kgh 2 O (e.g. iodixanol, iotrolan) High osmolar > Low osmolar nonionic agents > iso-osmol agents Large doses of contrast Pre-existing renal disease (especially diabetic nephropathy) 75 General Prevention Strategies Alternative imaging for high risk patients Avoid high osmolar agents Give the smallest possible dose Use iso or low osmolality agents Hold or discontinue nephrotoxic medications (NSAID, ACEI, diuretics) hours before contrast in high risk patients Hold metformin if egfr is < 45 ml/min. Do not restart for at least 48 hours 76

39 Hydration NS hydration 1 ml/kg/h (up to 150ml/h) 6 12 hours preprocedure, intra-procedure, and 6 12 hours post-procedure OR Isotonic sodium bicarbonate added to IV fluid to maintain urinary ph > 6.5 as an alternative to NS Begin 1 hour prior to procedure - 3 ml/kg/h Continue 6 hours post procedure - 1 ml/kg/h No compelling evidence for routine use of N acetylcysteine 1200 mg BID for adults on the day before and day of procedure appears to have slightly better outcomes compared to 600mg BID 77 Amphotericin B 78

40 Clinical Presentation K, Mg, Na wasting Inability to concentrate urine Distal renal tubular acidosis 79 Mechanism of Injury Direct tubular epithelial cell toxicity Tubular permeability and necrosis Arterial vasoconstriction and ischemia Ultimately this results in tubular cell damage Cell energy and oxygen requirements leading to medullary tubular epithelial cell necrosis and renal failure 80

41 Risks High daily doses (cumulative doses of conventional amphotericin B > 2-3 g) Concomitant use of diuretics or nephrotoxins Rapid infusions 81 Prevention and Treatment Consider alternative antifungals Limit cumulative amphotericin B dose Use liposomal formulation (AmBisome, Abelcet, Amphotec ) Adults: 1000 ml NS load 500 ml NS IV over 30 min before and after infusion Children: ml/kg NS Maintain adequate urine production to 1 ml/kg/h 82

42 Foscarnet 83 Mechanism of Renal Injury Due To Foscarnet Ionization of foscarnet with ionized calcium results in precipitation of foscarnet-calcium complex into glomeruli and renal tubules This results in crystalline glomerulonephritis, tubular necrosis and obstruction. 84

43 Prevention and Treatment Consider alternative antiviral agent if feasible Maintain adequate hydration with vigorous IV pre-hydration Maintain adequate urine production to 1 ml/kg/h 85 Methotrexate 86

44 Mechanism of Renal Injury Due to Methotrexate Methotrexate is poorly soluble at an acidic ph Acidic urine leads to precipitation of methotrexate and its metabolites in the renal tubules High-dose IV methotrexate can precipitate in the renal tubules and can cause direct tubular injury 87 Risk Volume depletion increases risk for nephrotoxicity Sustained elevation in plasma methotrexate concentration Prolonged exposure even at low doses can increase the risk for toxicity over time Coadministration of drugs that compete with methotrexate secretion by the renal tubules can lead increase the risk for toxicity Probenecid NSAIDs 88

45 Prevention and Treatment Maintain adequate hydration (~ L/m 2 /24 h of fluid administered 12 hours before methotrexate infusion and continue for hours) Alkalinize urine to ph > 7 prior to, during, and after administration of high dose methotrexate Leucovorin rescue to protect healthy cells from toxic effects of methotrexate Glucarbidase may prevent systemic toxicity 89 Mechanisms of Drug-Induced Renal Injury Hemodynamically-mediated (Pre-renal) Tubular Epithelial Damage (Intrinsic) Interstitial Nephritis (Intrinsic) Obstructive Nephropathy (Post-renal) Rhabdomyolysis 90

46 Medications Associated with Acute Interstitial Nephritis (AIN) Analgesics Aspirin NSAIDs: ibuprofen, ketoprofen, naproxen Anticonvulsants: carbamazepine, phenytoin, valproate sodium Antimicrobials Beta lactams: penicillin, ampicillin, methicillin, cephalosporins Rifampin Sulfonamides Anti-neoplastic agents: adriamycin, carboplatin, gemcitabine Diuretics: furosemide, chlorthalidone, hydrochlorothiazide Other: allopurinol, cimetidine, omeprazole, contrast dye, ACEIs 91 Clinical Presentation Renal Manifestations Elevated blood urea nitrogen and Scr +/- Oliguria Sterile pyuria with leukocyte casts Microscopic hematuria Eosinophiluria Non-nephrotic range proteinuria Nonspecific Symptoms Fever, rash, and eosinophilia May present with generalized hypersensitivity reactions Malaise Anorexia Weight loss Nausea and vomiting 92

47 Corticosteroids Consider use if no clinical improvement or presence of interstitial fibrosis on renal biopsy Prednisone or Prednisolone 1-2mg/kg/day (max: mg/day) for 1-2 weeks Slow taper when renal function approaches baseline Total duration of therapy: ~ 2-3 months Methylprednisolone IV mg/kg/day for severe interstitial fibrosis 93 Mechanisms of Renal Injury Hemodynamically Mediated Drug Induced Nephrotoxicity (Prerenal) Drug Induced Tubular Epithelial Damage (Intrinsic) Drug Induced Acute Interstitial Nephritis (Intrinsic) See AKI notes Drug Induced Obstructive Nephropathy (Post-renal) Drug Induced Rhabdomyolysis 94

48 Types of obstructive nephropathy: Intratubular Precipitation of tissue degradation products, drugs or metabolites inside the tubules Agents Acyclovir Foscarnet Methotrexate 95 Types of obstructive nephropathy: Extrarenal Obstruction in the lower urinary tract (ureters, bladder) Agents Anticholinergic medications (antihistamines, tricyclic antidepressants, anti-emetics) Cyclophosphamide Ifosfamide 96

49 Types of obstructive nephropathy: Nephrolithiasis Abnormal crystal precipitation in the renal collecting system Presents with crystalluria, dysuria, urinary frequency, back pain, flank pain, but a normal GFR. Agents Triamterene (Dyrenium, Maxzide, Dyazide ) Indinavir (Crixivan ) 97 Mechanisms of Renal Injury Hemodynamically Mediated Drug Induced Nephrotoxicity (Prerenal) Drug Induced Tubular Epithelial Damage (Intrinsic) Drug Induced Acute Interstitial Nephritis (Intrinsic) See AKI notes Drug Induced Obstructive Nephropathy (Post-renal) Drug Induced Rhabdomyolysis 98

50 General Information Most common with HMG-CoA reductase inhibitors Can also occur with narcotics, heavy alcohol use, amphetamines, cocaine, CNS depressants Presents as obstructive AKI or ATN HMG-CoA reductase inhibitors Specific Mechanism of Injury - Myoglobin precipitates in the kidney causing direct toxicity and obstruction 99 Clinical Findings and Renal Assessment History/Physical Exam Muscle pain, weakness Labs and Renal Assessment creatine kinase (CK), electrolyte disturbances, lactate dehydrogenase (LDH), lactic acidosis Oliguria UA = Tea-colored urine due to myoglobinuria, cellular debris 100

51 Risks & Prevention Risks Concomitant use of fibrates, niacin or CYP3A4 inhibitors Heavy exercise Prevention : avoid medications that increase risk of rhabdomyolysis 101 Treatment Vigorous hydration ml NS per hour Goal urine output ml/h while myoglobinuria persist Monitor for volume overload Alkalinization of urine (minimizes precipitation) once hydration is established Change to sodium bicarbonate 75 meq in 1000 ml in 0.45% NS Monitor ph Supportive care Correct electrolyte imbalances 102

52 CHRONIC KIDNEY DISEASE (CKD) Age-Adjusted Prevalence of Chronic Kidney Disease Among Adults in the United States Women Men Caucasians Mexican Americans African Americans Percentage 104

53 Prevalence of End Stage Kidney Disease (ESRD) By Ethnicity Compared to Caucasians African Americans: 3.7 times greater prevalence Hispanics: 1.5 times greater prevalence Asian/Pacific Islanders: 1.5 times greater prevalence Native Americans: 1.4 times greater prevalence Number of Kidney Related Deaths in Oklahoma Per 100,000 Total Population % of all Oklahoma deaths US Rank: 21 st highest rate 14.2% of all Oklahoma deaths US Rank: 21 st highest rate 14.2% of all Oklahoma deaths US Rank: 24 th highest rate

54 Causes of Chronic Kidney Disease and End Stage Renal Disease 1. Diabetic nephropathy (main cause of CKD and ESRD in the United States) 2. Hypertension (2 nd leading cause) 3. Glomerular disease (3 rd leading cause) 4. Cystic diseases 5. Tubulointerstitial diseases 107 Susceptibility Factors for CKD Risk Older age Family history of kidney disease Low socioeconomic status African American, Hispanic, Native American, Asian/Pacific Islander Reduced kidney mass Low birth weight Useful for identifying individuals at high risk for CKD 108

55 Initiation Factors For CKD Risk Diabetes Hypertension Infections Kidney stones Exposure to nephrotoxic medications Conditions that directly result in kidney damage Modifiable by pharmacologic therapy 109 Risk Factors for Progression of CKD Diabetic patients with poor glycemic control Uncontrolled hypertension Worsening proteinuria Smoking Factors associated with worsening damage or rapid decline in kidney function 110

56 CKD DEFINITION AND CLASSIFICATION CKD Definition Presence of kidney damage > 3 months Or GFR < 60 ml/min/1.73m 2 with or without other markers of kidney damage > than 3 months 112

57 Stage KDOQI CKD Stages Description Glomerular Filtration Rate (GFR) ml/min/1.73 m 2 1 Kidney damage with normal or GFR > 90 2 Kidney damage with mild in GFR Moderate in GFR Severe in GFR Kidney failure < 15 (or dialysis) 113 Green=low risk Yellow=moderate risk Orange=high risk Red=very high risk 114

58 Slow Progression of CKD ACEI or ARB for diabetic patients with CKD and urine albumin excretion mg/24 h ACEI or ARB for diabetic or non-diabetic patients with CKD and urine albumin excretion > 300 mg/24 h Consider dose increases if albuminuria is still present or blood pressure is not controlled 115 Dual ACEI and ARB Therapy Rationale for dual therapy Incomplete elimination of angiotensin II by ACEI ARB offer additional reduction in angiotensin II activity Despite greater reductions in proteinuria, dual therapy is not recommended due to higher rates of renal dysfunction and hyperkalemia 116

59 Questions? 117