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Tough Renal Cases in the Hospital

Sharon Anderson, M.D.Div. of Nephrology and HypertensionOregon Health & Science University

Portland VA Medical CenterOctober 2012

UCSF 2012

Take Home Messages

• ALWAYS– Stop ACEI/ARBs, NSAIDs, PPI– Initiate basic workup; consider renal ultrasound or postvoid residual

– Maximize BP (patient’s normal range) and consider intravenous fluids (but not too much)

– Scrutinize all drug doses• SOMETIMES

– Stop diuretics, statin• NEVER

– Order 24‐hour urine for anything, or prot/Cr ratio

Epidemiology and Etiology

• 1% at time of admission• 5% of all hospital admissions; 30% of ICU admissions

• Complicates 25% of inpatient stays

Incidence of Organ Failure in the ICUMurugan R, et al. Nat Rev Nephrol 7:209, 2011

Rates of AKI, by Age [Medicare]

www.usrds.org

Year

Outcomes of AKI in Hospitalized PatientsLiangos O, et al. CJASN 1:43, 2006

• Review of discharge data from 29,039,599 U.S. hospitalizations, 2001

• 558,032 cases of AKI (19.2 per 1000)

• Risk factors: older age, male gender, black race; presence of CKD, CHF, COPD, sepsis, cardiac surgery

LOS by Acute Single Organ Dysfunction

0 2 4 6 8

Median LOS (days)

CardiacNeuro

HepaticHeme

RespAKI

Serum Cr does not increase until half of kidney function is lost!

Caveats to eGFR

• An estimate based on population data ‐‐ not the patient’s actual GFR

• Not reliable when used in patients: – With GFR > 60 ml/ min/1.73 m2

– With rapidly changing creatinine levels (e.g., acute kidney injury in the ICU)

– With extremes in muscle mass, e.g. cachexia, paraplegia, ESLD

– Under age 18No urine = no GFR, no matterwhat Cr or eGFR is reported

Causes of AKI

Hilton, R. BMJ 2006;333:786-790

Acute kidney injury

Initial Evaluation

• Careful H+P (drugs)• Urinary studies

– UA with micro– FENa (or FEurea)– Urine eosinophils

Hortus sanitatis(Mainz: Jacob Meydenbach, 23 June 1491)

Case 1: Severe Burns‐1

• 68 year old woman suffered second and third degree burns. No prior medical history, on on meds. Normally her BP runs 140/80 mmHg.

• She is volume resuscitated. The next day, BP is 110/60, HR 120, JVP not visible, lungs clear.

• Na 138, K 3.8, BUN 35; Cr 1.1 • UA: SG 1.025, bland sediment, UNa 10 mEq/L, UCr 45 mg/dl

Case 1: Severe Burns‐2

• On day 5, she has diffuse edema, JVP = 11 cm. BP is 130/75, HR 85, UO 280 ml/24 hrs.

• Na 134, K 5.9, BUN 68; Cr 5.6 • UA: SG 1.010, occ RBCs, pigmented muddy brown casts, UNa 45 mEq/L, UCr 45 mg/dl

Diagnostic Utility of Urine MicroscopyPerazella MA, et al. CJASN 3:1615, 2008

• Cross‐sectional study of 267 consecutive patients seen by consult service over one year

• Developed a scoring system (1‐3), based on presence or absence of renal tubular epithelial cells and granular casts

• In patients with high pretest probability of ATN, score > 2 → high PPV, low NPV for diagnosis of ATN

Diagnostic Utility of Urine MicroscopyPerazella MA, et al. CJASN 3:1615, 2008

• “Can we get a urine spin?”

Muddy brown granular casts

FENa vs. FEurea on DiureticsCarvounis CP, et al. Kidney Int 62:2223, 2002

• Compared FENa and FEurea in 102 patients with AKI, and effect of diuretics

• Conclusion: Low FEurea(< 35%) was more sensitive and specific than FENa, especially in the presence of diuretics

FENa vs. FEurea on DiureticsPepin MN, et al. AJKD 50:566, 2007

• In patients not on diuretics, FENa is better than FEurea at diagnosing prerenal AKI

• In patients on diuretics, because of low specificity, FEurea is not very helpful

Sensitivity Specificity

No diuretics FENa 78% 75%

FEurea 48% 75%

Diuretics FENa 58% 81%

FEurea 79% 33%

Ultrasound in Acute Kidney InjuryLicurse A, et al. Arch Intern Med 170:1900, 2010

• Cross‐sectional study of 997 patients admitted to one hospital, Jan. 2005‐May 2009, who had AKI and had renal ultrasound

• Multivariate logistical regression model to create risk strata for hydronephrosis ± intervention


• 7 factors associated with hydronephrosis:– History of hydronephrosis– Recurrent UTIs– Diagnosis c/w obstruction– Nonblack race– Absence of: nephrotoxin exposure, CHF, prerenal AKI

Case 1: Severe Burns

• Day 1: Prerenal– Euvolemic to dry on exam– BUN 35 mg/dl; Cr 1.1 mg/dl (ratio > 20:1)– UA: SG 1.025, bland sediment, UNa 10 mEq/L, UCr45 mg/dl; FENa = 0.14%

• Day 5: ATN– Evidence of volume overload– BUN 68, Cr 4.6; ratio < 20:1– UA: SG 1.010, + muddy browns, FENa = 3.36%

Initial Evaluation

• Often useful: Renal ultrasound or postvoid residual

• Often useful: CPK; bladder pressure• Not useful:

– 24‐hour urine (for anything)– Urine protein/Cr ratio (inaccurate in absence of steady state, consistent creatinine excretion)

Non-Oliguric vs. Oliguric vs. Anuric

• Urine output is helpful– Oliguria: more common with obstruction, prerenal azotemia

– Nonoliguric: intrarenal causes – nephrotoxic ATN, acute GN, AIN

• Degree of oliguria helps with prognosis– Higher mortality with oliguric AKI– Lower likelihood of renal function recovery with oliguria

– Severe (or recurrent) AKI = risk factor for CKD

1.5 2.0

7.0

4.5

3.23.6 3.9

June Oct

Recurrent AKI→ CKD

SCr(mg/dl)

AKI Increases Risk of CKDLo LJ, et al. Kidney Int 76:893, 2009

• Analysis of 556,090 Kaiser pts over 8 yrs, with baseline eGFR > 45 ml/min/1.73m2

• Dialysis‐requiring AKI was independently associated with a 28x risk of developing Stage 4‐5 CKD and 2x risk of death

Adj hazard ratio 28.1 [21.1-37.6]

+ AKI

- AKI

Case 2: “The Flu”

• 78 year old male with HTN, GERD, DJD.• Meds: Losartan, metoprolol, omeprazole, naprosyn. Usual BP = 150/80; baseline Cr 1.1

• Now c/o “the flu” with nausea, diarrhea x 4 days

• Exam: BP 120/74, HR 65, no JVD or edema• Labs: Na 136, K 4.5, BUN 36, Cr 2.2; UA consistent with ATN

Pre‐Renal Causes

• Normotensive ischemic nephropathy• Cardiorenal syndromes• Intra‐abdominal hypertension• “Septic ATN”

Prerenal Causes

• It is not always necessary to find documented overt hypotension or volume depletion

• In the presence of drugs which impair the kidney’s ability to autoregulate, even modest insults can result in AKI

Normotensive Ischemic AKIAbuelo JG. NEJM 357:797-805, 2007

Normal Perfusion Pressure Decreased Perfusion Pressure

Decreased perfusion pressure in presence of NSAIDs

↑ vasodilatoryprostaglandins

↑ Ang II

↓ vasodilatoryprostaglandins

↑ Ang II

Normal GFR Normal GFR Maintained

Low GFR

HHHHHHHHHh

Hh

Afferent Arterioles in the Aging Human GlomerulusHill GS, et al. Kidney Int 63:1027, 2003

Normal Hypertrophic

Dilated AA with large hyaline deposit

Normal Perfusion Pressure Decreased Perfusion Pressure

Decreased perfusion pressure in presence of NSAIDs Decreased perfusion pressure in presence of ACEI


↑ Ang II


↓ Ang II ↓ vasodilatoryprostaglandins

↑ Ang II

Normal GFR Normal GFR Maintained

Low GFR Low GFR

Case 2: “The Flu”

• Normotensive ischemic nephropathy• BP 120/65 is << his baseline; likely has intrarenal small vessel vascular disease

NSAIDs: Cannot dilateafferent arteriole

ARBs: Cannot constrictefferent arteriole

Cardiorenal Syndrome(s)

Ronco C. JACC 52:1527, 2008

Cardiorenal SyndromesRonco C, et al. JACC 52:1527, 2008

• CRS Type 1: acute cardiac decompensa on → AKI• CRS Type 2: chronic heart failure → CKD• CRS Type 3: “acute renocardiac syndrome”

– AKI → acute heart problems• CRS Type 4: “chronic renocardiac syndrome”

– CKD → chronic heart problems• CRS Type 5: systemic condi on → both cardiac and renal dysfunction

Case 3 – Abdominal Pain

• 74 year old woman admitted with CAP • PMH = Type 2 DM, HTN, CKD, depression• BUN 20, Cr 1.6 (baseline); WBC 11,000, CXR = RML infiltrate

• Started on O2, ceftriaxone, enoxaparin; continued on insulin, lisinopril, carvedilol, sertraline

• Day 4: c/o vague abdominal and flank pain. Exam = mild tenderness left flank

• BUN 32, Cr 3.2; UA: trace blood and protein, 1‐2 WBCs, 5‐10 RBCs.

Abdominal Compartment Syndrome (Intra‐abdominal Hypertension)• Definitions

– IAH: Sustained IAP > 12 mmHg– ACS: Sustained IAP > 20 mmHg with new organ dysfunction

• Kidneys are at risk with even relatively low levels of IAH

• Originally described in post‐surgical patients; now recognized in many other settings

Mohmand H, et al. JASN 22:615, 2011

Abdominal Compartment Syndrome (Intra‐abdominal Hypertension)• Predisposing conditions/risk factors

– Trauma, major burns, abdominal surgery– ↓ abdominal wall compliance: mechanical ven la on, obesity, ↑ head of bed

– ↑ abdominal contents: ileus, ascites– ↑ capillary permeability: acidosis, sepsis, large volume resuscitation, polytransfusion, pancreatitis, coagulopathy

Mohmand H, et al. JASN 22:615, 2011

What do IAP Measurements Mean?

Pressure (mmHg) Interpretation0 Normal1-10 Common in most ICU patients> 12 Intra-abdominal hypertension15-20 Dangerous IAH - consider non-

invasive interventions>20-25 Impending ACS - strongly

consider decompression

Retroperitoneal Hematoma due to EnoxaparinErnits M, et al. Am Surg 71:430, 2005

• At least 2 dozen case reports• Many are spontaneous (no anatomic cause)• May lead to ACS, AKI, and death• Risk factors may include higher doses, presence of AKI or CKD, older age, concomitant meds affecting hemostasis

• Appropriate dosing, early recognition, reversal of anticoagulation, treatment of ACS are essential

Case 3 – Abdominal Pain

• Diagnostic test: Abdominal CT• Diagnosis: Retroperitoneal hematoma associated with enoxaparin

“Septic ATN”Schrier RW, et al. NEJM 351:159, 2004

Case 4 – New AKI

• 62 year old male seen for routine evaluation• PMH = HTN, GERD, hypothyroidism• Meds = atenolol, enalapril, omeprazole, levothyroxine, ASA

• Exam = OK except 1+ edema• Labs: CBC normal; BUN 38, Cr 3.2 (baseline 1.0)• UA: SG 1.015, 1+ prot, tr blood, 3‐5 RBCs, 15‐20 WBCs, no bacteria, no eosinophils

The Scourge of AIN

• AIN is ALWAYS in the differential!• Acute interstitial nephritis has been reported with dozens (hundreds?) of drugs

• 2011: PPIs are a leading cause of AIN

Praga M. Kidney Int 77:956, 2010

Myths about Drug-Induced AINMichel D, et al. JASN 9:506, 1998

• Myth: Occurs only after 7‐10 days of exposure

• Truth:– Can occur after months to years of exposure (especially NSAIDs)

– Can occur within 48 hours upon re‐exposure to a previously tolerated drug

Myths about Drug-Induced AINMichel D, et al. JASN 9:506,1998

• Myth: Eosinophiluria is a hallmark• Truth:

– 70% specific, but only 40% sensitive– Can also be seen in:

• Bladder cancer• UTI• RPGN• Atheroemboli• Prostatitis

Case 4 – New AKI

• Dx: AIN due to omeprazole• Rx: Stop PPIs. If AKI does not resolve promptly, consider steroids (data ±however)

AIN: Beta-Lactams vs. NSAIDSGonzalez E, et al. Kidney Int 73:940, 2008

Beta‐Lactam Antibiotics NSAIDs

Duration of exposure 2 weeks 5 months

Fever/rash/eosinophilia 80% 20%

Eosinophiluria 80% 15%

> 3 gms proteinuria < 1% 83%

Rate of recovery Fast Slow

Development of CKD Rare Common

Benefit of steroids Probably Probably not

Statin Rhabdomyolysis by AgeOshima Y. Int Med 50:845, 2011

Rhabdomyolysis

• Statins: any statin; dose‐related; ↑ risk with many other drugs (e.g., fibrates, calcineurin inhibitors)

• Plasma sta n drug levels can ↑ in sepsis• Think about rhabdo in post‐operative AKI

– Typical: prolonged surgery in obese patient– Less frequently, can occur even in minimally invasive surgery

Cholesterol Emboli

• Rare complication of aortic manipulation, but can be spontaneous

• Acute or subacute decline in function 1‐2 weeks after the procedure

• Anticoagulation may precipitate it• Purple toes, livido reticularis may be present• Labs: Eosinophilia and low C3, C4• Renal prognosis is very poor; not reversible, no specific treatment

Hyperphosphatemic AKI after Bowel PrepMarkowitz GS, et al. JASN 16:3389, 2005

• 31 cases of nephrocalcinosis on biopsy• 21 (68%) had recent bowel prep with oral sodium phosphate or equivalent “acute phosphate nephropathy”

• Mean baseline Cr 1.0 mg/dl; presented one month after colonoscopy with mean Cr 3.9 mg/dl

• 4 (13%) required permanent dialysis

Special Considerations: AKI in the Elderly

• In older patients:– AKI is more frequent– AKI is a risk factor for CV events, including mortality

– CV risk factors risk of AKI– AKI is a risk factor for subsequent CKD

Increased Susceptibility of Older Subjects to AKIAdapted from Anderson S, et al. JASN 22:28, 2011

HYPOALBUMINEMIA

Risk Factors: Peri‐Operative AKI

Preoperative Factors Intraoperative Factors Postoperative Factors

Pre‐existing AKI or CKDDiabetesCardiac dysfunctionOlder ageSepsisVolume depletionHepatic dysfunctionCrush injuryNephrotoxinsVascular diseaseDrugs (ACEI/ARBs, NSAIDs)

Hypovolemia (bleeding, insensible losses)Renal ischemiaInflammation↑ intra‐abdominal pressureAnesthesia: vasodilation, ↓ cardiac outputNephrotoxinsEmbolismImmobilization (rhabdo)

Hypovolemia (bleeding, insensible losses)Renal ischemiaInflammation↑ intra‐abdominal pressureAnesthesia: vasodilation, ↓ cardiac outputNephrotoxinsUrinary tract obstructionAcute lung injuryMechanical ventilation

Adapted from Chronopoulos A. Nat Rev Nephrol 6:141, 2010

• Areas for future research– Heterogeneity of AKI in older patients– Mechanisms– Role of biomarkers– Management issues, with special attention to HRQOL

Anderson S, et al. JASN 22:28, 2011

Diuretics May be OK!

• Stopping diuretics when AKI is diagnosed is not always the right thing to do

• Diuretics are beneficial – and should NOT be withheld – in:– Cardiorenal syndrome

If I Had a Nickel . . .

• Classic scenario:– Patient comes in with decompensated CHF– Diuresis is initiated– Creatinine increases; diuretics are stopped– Patient is discharged on either (1) no diuretics; or (2) the same dose he/she came in on, with plan to “titrate diuretics in followup clinic visit”

– Patient is readmitted with decompensated CHF

Diuretics May be OK!

• Stopping diuretics when AKI is diagnosed is not always the right thing to do

• Diuretics are beneficial – and should NOT be withheld – in:– Cardiorenal syndrome– Recovery from AKI

Avoid Volume Overload Post AKIGrams ME, et al. CJASN 6:966, 2011

• Post‐hoc analysis of the Fluid and Catheter Treatment Trial (FACTT), a multicenter RCT (n = 1000) testing conservative vs. liberal fluid management in patient with acute lung injury

• Examined association of post‐AKI fluid balance and diuretic use with 60‐day mortality in those patients who developed AKI

• Results: Positive fluid balance post AKI was strongly associated with mortality; diuretic use correlated with 60‐day survival

Fluid Balance and Survival Post AKIGrams ME, et al. CJASN 6:966, 2011

*

*

* p < 0.001

Case 5: Management of CHF

• 84 year old woman with ischemic cardiomyopathy, baseline EF 35%, admitted with decompensated CHF

• No response to i.v. bolus furosemide 80 mg; transient response to 120 mg i.v.

• Next step?– Bolus 120 mg 3x/daily– Bolus 120 mg 3x/daily; metolazone before 1st dose– Start lasix continuous infusion– Switch to bumetanide

Diuretics: Bolus vs. Infusion?Felker GM, et al. NEJM 364:797, 2011

• Prospective, multicenter RCT of furosemide in 308 patients with acute decompensated heart failure

• Evaluated bolus vs. constant infusion; high vs. low dose

• Co‐primary endpoints: patients’ global assessment of symptoms, and change in SCr


• Prospective, multicenter RCT of furosemide in 308 patients with acute decompensated heart failure

• Evaluated bolus vs. constant infusion; high vs. low dose

• Co‐primary endpoints: patients’ global assessment of symptoms, and change in SCr

• Results: No significant difference in 1⁰ outcomes; high dose had some benefits in 2⁰ outcomes (greater diuresis)


p = 0.89 p = 0.001


• Major limitations:– Did not reflect clinical practice: we usually try furosemide infusion only after bolus has failed

– Fixed doses for the first 48 hours, regardless of response

– Does not answer the question of whether, when, and how to transition from bolus to infusion therapy

A Comment on Diuretic Infusion Rates

• Always give a large bolus before starting the infusion, and every time dose is increased

• One method:– Start at furosemide 5 mg/hr (after bolus)– Titrate up by 5‐mg increments every 3 h (with bolus before each dose increase)

– If no response at 30‐40 mg/hr, probably futile to continue

Case 5: Management of CHF

• Plan: Bolus with 80 mg, then start lasix drip at 5 mg/hr

• Rebolus and ↑ rate by 5 mg/hr at 3‐hr increments until diuresis is consistent

Opinion!

Dialysis When Indicated – No Rules

• Numerous studies have tried to determine whether dialysis should be early or late; intermittent vs. continuous; high dose or low dose

• No study has shown a consistent benefit (mortality, recovery of renal function) with any specific regimen

• Best: Dialysis for specific indications, as needed

Dialysis Method – No Rules

• Numerous studies have tried to determine whether dialysis should intermittent (conventional HD) vs. continuous (CRRT)

• No study has shown a consistent benefit (mortality, recovery of renal function) with any specific regimen

• Best: Dialysis method tailored for the patient situation

Department of Veterans AffairsCOOPERATIVE STUDIES PROGRAM

Intensity of Renal Support for Acute Kidney Injuryin the Critically Ill

VA/NIH Acute Renal Failure Trial Network. NEJM 359:7, 2008

Overview of Study DesignVA/NIH Trial. NEJM 359:7, 2008

Management StrategyIntensive Less-Intensive

Hemodynamically Stable PatientsIHD* 6x/week 3x/week

Hemodynamically Unstable PatientsCVVHDF 35 mL/kg/hr 20 mL/kg/hr

SLED* 6x/week 3x/week* Target Kt/V: 1.2-1.4 per treatment

n = 1124

Results: 60-Day All Cause MortalityVA/NIH Trial. NEJM 359:7, 2008

ATN Trial SummaryVA/NIH Trial. NEJM 359:7, 2008

• Intensive renal support did not– ↓mortality– ↑ recovery of kidney func on– Alter the rate of non‐renal organ failure

• Intensive management strategy was associated with:– More hypotension, hypophosphatemia, hypokalemia

Case 6: Prophylaxis for Contrast Nephropathy

• A 56 year old male with CKD3 (eGFR 35) presents with severe chest pain and NSTEMI. ETT is consistent with reversible ischemia, and cardiology recommends coronary angiography.

• What is his risk of developing contrast injury?• What is the best prophylactic regimen?

Saline Saline + NACBicarbonate Bicarbonate + NAC

Prediction of CIN in Cardiac CathMehran R, et al. JACC 44:1393, 2004

Prophylaxis for Contrast Nephropathy

• Despite numerous trials (and even more meta‐analyses), there is no convincing evidence that N‐acetylcysteine provides benefit beyond that of hydration alone

• There is no convincing evidence that sodium bicarbonate provides benefit beyond that of sodium chloride alone

• Best practice: Sodium chloride

Systematic Review: Sodium BicarbonateZoungas S, et al. Ann Intern Med 151:631, 2009

Favors Bicarbonate

Favors Saline

PublishedStudies

UnpublishedStudies

The ACT TrialACT Investigators. Circ 124:1250, 2011

2,308 Patients undergoing an angiographic procedure with at least one of the following risk factors:

Age > 70 yearsChronic Kidney Disease

Diabetes MellitusHeart Failure or LVEF <0.45

Shock

ConcealedRandomization

Acetylcysteine 1200mg Orally Twice Daily for 2 Doses Before and 2 Doses After Procedure

Matching Placebo

Primary Endpoint: Contrast-induced nephropathy (CIN)(↑ serum creatinine ≥ 25% above baseline 48h-96h after angiography)

Secondary Endpoints: Total mortality, CV mortality, need for dialysis, 2x ↑ SCr, side effects

The ACT Trial: ResultsACT Investigators. Circ 124:1250, 2011

• No difference in the primary end point: 12.7% in both groups (RR 1.00; 95% CI, 0.81–1.25)

• No difference in the secondary end point: 3.9% for N‐acetylcysteine and 3.8% for placebo (↑SCr >0.5 mg/dL)

• No difference in the 30‐day clinical end points: all‐cause mortality, CV mortality, need for dialysis

• No benefit in any subgroup (age, diabetes, gender, baseline SCr level, type of contrast)

Circulation 124:1250, 2011

Give Fluids!

“Renalism”: Underuse of Coronary AngioChertow GM, et al. JASN 15:2462, 2004

• Cooperative Cardiovascular Project: Analysis of patients with discharge diagnosis of acute MI (n = 85,743)

• Selected elderly patients (age 65‐89) for analysis; n = 57,284

• Classified by presence/absence of CKD (Cr 1.5‐5.0 mg/dl)

• Similar proportions had appropriate indications for angio by standard, published criteria


One-Year Mortality

26.4

52.6

010203040506070

No CKD CKD

Perc

ent o

f Pat

ient

s

Coronary Angio

46.8

25.2

0102030405060

No CKD CKD

Perc

ent o

f Pat

ient

s

p < 0.0001p < 0.0001


One-Year Mortality by Intervention Status [CKD Patients]

0102030405060

No angio CABG PTCA Both

Perc

ent o

f Pat

ient

s

*

* p < 0.01

Take Home Messages

• ALWAYS– Stop ACEI/ARBs, NSAIDs, PPI– Initiate basic workup; consider renal ultrasound or postvoid residual

– Maximize BP (patient’s normal range) and consider intravenous fluids (early, not late)

– Scrutinize drug doses

Nitrates+Hydralazine in CHFCohn JN, et al. NEJM 314:1547, 1986

Risk reduction withISDN-hydral = 36%

Take Home Messages

• SOMETIMES– Stop diuretics – but not if in CHF, or recovering from AKI

• NEVER– Order 24‐hour urine for anything, or prot/Cr ratio

Consider calling nephrology sooner rather than later . . .

Early vs. Late (or No) Referral in AKIMeier P, et al. CJASN 6:2215, 2011

• Retrospective study of hospital‐acquired AKI in non‐critically ill patients

• Over 5 years, 4296 patients (4.12% of admits) had 4727 episodes of hospital‐acquired AKI

• Stratified by timing of nephrology referral: early (within 5 days), late (> 5 days), or none

• RRT was needed in 31% of late, vs. 24% of early referrals (p = 0.02)


None Late Early No AKI Nephrology Referral

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