Management of Acute Renal Failure

Martin Turman, MD, PhD

Acute Renal Failure

Definition: Sudden deterioration in the ability of the kidneys to maintain fluid, solute or electrolyte homeostasis

Common in PICU patients (10-20%) Greater than 50% mortality ARF in PICU patients has an independent

and significant impact on mortality

ARF: Causes and mortality

Primary renal disease: 33%– Hemolytic uremic syndrome: 88%– Obstructive uropathy– Renal vein/artery thrombosis– Primary glomerulonephritis (RPGN)

Overall mortality: 6% Most primary renal diseases develop RF

gradually and do not need emergent dialysis

Extrarenal causes of ARF: 67% of total

Post-op heart or other heart

failure 32%

Sepsis 17%

Cancer related14%

Liver transplant or

failure16%

Trauma6%

Other15%

Overall mortality: 62%!!

In third world: V/D/D-induced ATN most common cause of ARF

Data pooled from Ped. Nephrol. 7:703, 8:334, 6:470, and 7:434

ARF: Risk factors for mortality Multi-organ failure Bacterial Sepsis Fungal sepsis Hypotension/vasopressors Ventilatory support Initiation of dialysis late in hospital course Oliguria/anuria: with oliguric ARF, mortality is > 50%

compared to < 20% with non-oliguric ARF

Best cure is to prevent

Have a high index of suspicion for reversible factors - volume depletion, decreasing cardiac function, sepsis, urinary tract obstruction

Be sure patient is well-hydrated when exposing patient to nephrotoxic drugs

Anticipate problems

Avoid worsening the ARF– Adjust medicines for renal insufficiency– Avoid nephrotoxins if possible– Avoid intravascular volume depletion

(especially in third-spacing or edematous patients)

Case #1

ET is a 3 year old who presented with abdominal pain and vomiting for 3 days. He underwent surgery for intussuception.

Post-operatively he had oliguria. BUN and creatinine were 80 and 2.5. Sodium was 145.

Two 5 cc/kg fluid boluses had minimal effect on urine output. He had anasarca with severe periorbital and pedal edema.

How do you proceed from here? General approach to ARF – what is the 1st

question to ask in the DDx? Is it pre-renal, renal or post-renal? What labs help you decide this? BUN:Cr ratio and fractional excretion of sodium

(FE-Na) What labs do you need to calculate the FE-Na? urine lytes + urine creatinine near same time as

serum lytes to calculate

Prerenal azotemia

Decreased effective circulatory volume– Hypovolemia

» GI losses (V/D, ileostomy, NG drainage)» Hemorrhage (trauma, GI bleeding)» Cutaneous losses (burns)» Renal losses (diabetes insipidus or mellitus)

– Loss of fluids from intravascular space» Third spacing» Septic (capillary leak) or anaphylactic shock» Hypoalbuminemia (Neph syndrome, protein-losing enteropathy)

Prerenal azotemia

Decreased local blood flow to kidney– Renal artery stenosis or RVT– Drug-induced renal vasoconstriction

» cyclosporin, tacrolimus

– Hepatorenal syndrome Diminished cardiac output

– Congestive Heart Failure– Arrythmias, tamponade, etc.– Cardiovascular surgery

Postrenal Failure

Kidney stone (usually UVJ) Ureteropelvic junction (UPJ) or UVJ

obstruction Bladder: "prune belly"; neurogenic bladder;

fungus ball Urethra: posterior urethral valve; foreign

body Iatrogenic: obstructed Foley; narcotics

Intrinsic Acute Renal Failure

Acute tubular necrosis– Prolonged prerenal azotemia of any cause

Nephrotoxin-induced (aminoglycosides; amphotericin)

Primary glomerular diseases– Hemolytic uremic syndrome– All other forms of glomerulonephritis (RPGN)

Intra-renal obstruction: rhabdomyolysis, tumor lysis syndrome

Evaluation of ARF - 1

In history, seek clues regarding secondary causes - symptoms of CHF, liver disease, sepsis, systemic vasculitis, prodromal bloody diarrhea; birth asphyxia

Check for symptoms of primary renal disease - UTI sx, gross hematuria, flank pain, Hx of strept infection, drug exposure (esp. CSA, aminoglycosides and amphotericin for renal toxins or narcotics for bladder dysfunction)

Evaluation of ARF - 2

During exam, look for secondary causes– Causes of decreased effective circulatory

volume - CHF, ascites, edema, sepsis– Signs of systemic illness - (vasculitis, SLE,

HSP): rash, arthritis, purpura – Signs of RVT and obstructive uropathy:

enlarged kidneys or bladder - CHECK FOLEY; Give Narcan

Evaluation for ARF - 3 Lytes, BUN, Cr; CBC with platelets (HUS) UA: hematuria, myoglobinuria, proteinuria,

RBC casts, eosinophils Urine indices Renal US (with Doppler flow to rule out

renal vein thrombosis) RPGN evaluation: anti-DNase B, C3, ANA,

Anti-GBM, ANCA, renal biopsy

Urinary indices in ARF

500

U-osm

350

PR

ATN

40

U/P Cr

20

PR

ATN

40

U-Na

20PR

ATN

FE-Na

1%

PR

ATN

2%FE-Na = (U/PNa ÷ U/PCreatinine ) *100

Adopted from J. Crit. Illness 4:32

Use of FE-Na

FE-Na < 1: Decreased effective blood volume; ATN 2o to myo- or hemo-globinuria or contrast dye; sepsis sometimes, CSA, acute glomerulonephritis, hepatorenal syndrome

FE-Na > 2: ATN, chronic GN, diuretics, salt-wasting nephropathy

Unpredictable: Obstructive or reflux nephropathy, normal people

Back to Case #1 (intussuception)

ET had no proteinuria and small hematuria on urinalysis. A FE-Na was 0.1%. A serum albumin was 2.2.

Thus, he had pre-renal azotemia because of loss of intravascular fluid secondary to hypoalbuminemia and third spacing.

After receiving 25% albumin and further fluid resuscitation his UOP and Creatinine normalized.

Clinical Case #2 S.E. is a 10 year-old with acute lymphocytic

leukemia receiving chemotherapy Has fever, neutropenia and thrombocytopenia UOP is 1.2 cc/kg/hour On clinical exam she has very moist mucus

membranes BUN and creatinine are 110 and 0.7. Albumin is

3.5

Assessment of case #2

Is she in renal failure?– Creatinine is normal, so NO!

Why is BUN so high?

Use of plasma BUN: Cr ratio

In pre-renal BUN:Cr > 20 usually However, BUN may be increased

disproportionately with blood products, excess amino acids in TPN, GI or other bleed; increased catabolism (treatment with steroids, fever).

Clinical Case #3

CE is a 15 yo male who presented with URI symptoms, then headache, vomiting, abdominal pain, knee pain, edema, and a purpuric rash on his legs. He had not voided for 24 hours.

What is diagnosis?– HSP

Physical exam and labs

BP was 152/94. He had anasarca. Heart and lung exams were normal.

A urinalysis revealed hematuria and proteinuria. BUN and Creatinine were 76 and 8.0. Albumin was 3.1

He has aggressive HSP nephritis

Fluid management in ARF

This kid weighs 70 kg. What percent “maintenance” should you run his IV at?– NO FLUIDS - Hep-lock it!! He’s fluid

overloaded and hypertensive – he doesn’t need any fluid

How were the maintenance calculations derived? – What goes into the formula?– Insensibles + UOP = maintenance

Fluid management in ARF If this kid had an albumin of 1.0 and mucus

membranes were very dry, what fluids would you give him?– Bolus of NS like any other dehydrated kid – but

cautiously Now you have the kid euvolemic by exam but still

has no UOP. He’s NPO though, so what fluid rate should you run now?– Insensibles + UOP = maintenance (i.e. about ¼ to 1/3

of a normal kid’s maintenance or 400 cc/M2)

Management of ARF - Volume status

Water balance – "Maintenance" is IRRELEVANT in ARF!!!

– If euvolemic, give insensibles + losses + UOP

– If volume overloaded, they don't need anything (except the minimum for meds and glucose)

» concentrate all meds; limit oral intake

– Need frequent weights and BP, accurate I/O

– Insensibles = 30 cc/100 kcal or 400cc/M2/day

– If has any UOP, Lasix + zaroxolyn may help with fluid overload

Hypertension Could be from volume overload or from

intrinsic renal disease If has volume overload, need to directly

vasodilate (calcium channel blockers, clonidine, nicardipine drip, nitropruside, etc.)

If intrinsic renal disease, ACE may work also Goal is to prevent stroke, congestive heart

failure

Back to Case #3 (nephritis)

K+ 6.5, Bicarb 14 Calcium 5.8, Phosphorus 9.3 Hematocrit 30.3%, Platelets 280K

Hyperkalemia With ARF, K+ will increase and will be worsened by

infection, hemolysis, acidosis DON'T IGNORE A HIGH K+ just because the

specimen is hemolyzed especially in a patient who could easily be hyperkalemic

How can you tell if it is “real”?– check EKG for peaked T waves, widened QRS

It’s real. What’s the first thing to do?– Emergently stabilize membranes with calcium to prevent

arrhythmia

Hyperkalemia What’s next?

– Shift K+ intracellularly with:» insulin (+ glucose to prevent hypoglycemia)» bicarbonate infusion» albuterol (SQ/aerosol)

– Check IV fluids to ensure no intake What happens to ionized calcium level as you correct the

acidosis?– Increases albumin binding so ionized calcium decreases

What’s the third step?– Remove from body with Lasix, Kayexalate, dialysis

Hypocalcemia and hyperphosphatemia

Ca+2 x PO4 > 60-70 is risk for metastatic calcification, including in the cardiac conduction system

Often are reciprocal: as PO4 Ca+ Sx of hypocalcemia: irritability, tetany, sz If hypoalbuminemic:

– check ionized Ca or– correct (0.8 increase of Ca for each 1.0 of albumin below

4)

Hypocalcemia and hyperphosphatemia

Reduce PO4 with calcium acetate if can swallow pills, calcium carbonate if needs liquid

Diet restriction Avoid exogenous PO4: Fleet's, carafate,

TPN

Acidosis

Correct if bicarbonate is < 15 Acidosis makes the kids feel terrible BUT...

– watch sodium and fluid overload– watch lowering ionized calcium levels (by

increasing binding of calcium to albumin)

Anemia and uremic bleeding

Anemia results from lack of renal erythropoietin production + increased loss

Underlying disorder may also cause hemolysis (DIC, HUS, SLE) or decreased RBC production (sepsis, leukemia)

Uremic PLT's do not function well, so have increased bleeding: treat with cryo-precipitate and DDAVP (causes transient improvement in PLT function; estrogen

Indications for renal replacement therapy

Volume overload – Pulmonary edema, CHF, refractory HTN– NOT for peripheral edema, esp. with cap. leak

Hyperkalemia Hyperphosphatemia/Hyperuricemia in TLS Uremic side-effects: mentation, sz,

pericarditis, pleuritis Need to maximize nutrition

Modes of renal replacement therapy

CVVH, CVVD, CVVDHF - gentle, but slower than hemodialysis; need large lines and heparin

Peritoneal dialysis - also gentle and don't need heparinization but slow and catheter may leak or not work

Hemodialysis - very fast, but need big lines and systemic heparinization; causes hemodynamic instability and uremic dysequilibrium symptoms

Unproven or controversial treatments

Diuretics could decrease tubular obstruction by helping to "flush out" casts– BUT, may worsen electrolyte problems– May cause ototoxicity

126 post-op heart adult patients given Lasix drip– Creatinine -fold higher! (Lassnigg, JASN 11:97,2000)

Still consider if patient is volume overloaded or has hyperkalemia

Unproven or controversial treatments

"Renal dose" dopamine could increase renal perfusion, esp. with concurrent norepinephrine– Works in animal models, BUT:– May depress respiratory drive – May trigger arrythmias – Induces a state of “hypopituitarism”– It’s an added expense– No conclusive clinical studies demonstrating benefit

Effect of low-dose Dopamine on ARF

Source Type of Study Severity Efficacy

Lindner Established ARF Mod-severe Yes

Graziani Established ARF Mod-severe Yes

Lumlertgul Established ARF Severe No

Lumlergul Established ARF Moderate Yes

Duke Established ARF Mild No

Weisberg Prophylaxis IVC Chronic No

Adopted from Alkhunaizi & Schrier, Am J Kidney Dis 28:315

Are there any new treatments?

MANY in vitro and animal studies of ARF demonstrate improvement with various factors– Glycine, thyroxine, anti-intercellular adhesion

molecule-1 (ICAM-1), platelet-activating factor (PAF) antagonist, various growth factors, etc.

New potential therapies

Growth factors– Insulin-like growth factor (IGF-1), epidermal growth

factor, hepatocyte growth factor» May help in recovery from ARF by improving

regeneration, by protecting cells from injury or facilitating their recovery

» IGF-1 trial - failed to decrease need for dialysis» GH for critically ill patients WORSENED outcome

New potential therapies

Calcium channel blockers– Most studies demonstrate benefit post transplant

– One small study demonstrates improved GFR after malaria-induced ARF

– Conflicting results with contrast-induced ARF

– Large meta-analysis showed no prospective placebo-controlled studies have shown benefit – only poorly designed studies did.

CVVH to remove cytokines, etc. for patients with systemic inflammatory response syndrome

New potential therapies

Endothelin antagonists for ATN– Remarkably effective in animal models– Humans with radiocontrast nephrotoxicity:

» Multicenter trial» ET antagonist given 30 min before contrast» Agent EXACERBATED renal insufficiency

New potential therapies

Atrial natriuretic peptide (ANP)– ANP dilates afferent & constricts efferent

» Leads to increased GFR

– Inhibits vasoconstrictors (endothelin, etc.)– Improves outcome in animals with ATN

New potential therapies

Anaritide trials– 504 patients with oliguric and non-oliguric

ARF (NEJM 336:828, 1997)» Improved dialysis-free survival in oliguric

patients (27% vs. 8%)» Worsened outcome for non-oliguric ARF

(59% vs. 48%)

– 222 patients (AJKD 36:767, 2000) with oliguric ARF – NO benefit (21% vs. 15%)

"The great tragedy of Science - the slaying of a beautiful hypothesis by an ugly fact."

T.H. Huxley (1825-1895) Collected Essays

The End

Any questions???