07 Mato Acute Renal Failure

Acute Renal Failure

Anthony R Mato, MD

Basic Facts

• Renal failure over the course of hours to days.

• The result will be failure to excrete nitrogenous waste and electrolyte imbalance.

• Hard to define: in 26 studies, no two used the same definition!!!

Classic laboratory definition

• Cr increase of .5 mg / dl.

• Increase in more than 50% over baseline Cr.

• Decreased in calculated Cr Clearance by more than 50%.

• Any decrease in renal function that requires dialysis.

Basic Differential Diagnosis

• Pre-Renal: Decreased renal perfusion without cellular injury. – 70% of community

acquired cases.

– 40% of hospital acquired cases.

– 1 cause of Intra-Renal failure.

• Intra-Renal: – ATN: Ischemic, toxic insult

to the renal tubule. Tubular

– AIN: Inflammation and edema.

– GN:Injury to the filtering mechanism.

• Post-Renal: obstruction the urinary outflow tract.  

Prerenal Failure•Often rapidly reversible if we can identify this early.

•The elderly at high risk because of their predisposition to hypovolemia and renal atherosclerotic disease.

•This is by definition rapidly reversible upon the restoration of renal blood flow and glomerular perfusion pressure.

•THE KIDNEYS ARE NORMAL.

•This will accompany any disease that involves hypovolemia, low cardiac output, systemic dilation, or selective intrarenal vasoconstriction.

Differential Diagnosis

• Hypovolemia– GI loss: Nausea, vomiting, diarrhea– Renal loss: diuresis, hypo adrenalism, osmotic

diuresis (DM) – Sequestration: pancreatitis, peritonitis,trauma,

low albumin.– Hemorrhage, burns, dehydration.

Differential Diagnosis

• Renal vasoconstriction: hyper Ca, norepi, epi, cyclosporine, tacrolimus, ampho B.

• Systemic vasodilation: sepsis, medications, anesthesia, anaphylaxis.

• Cirrhosis with ascites• Hepato-renal syndrome• Impairment of autoregulation: NSAIDs, ACE,

ARBs. • Hyperviscosity syndromes: MM, WM, PCV

Differential Diagnosis

• Low CO– Myocardial diseases– Valvular heart disease– Pericardial disease– Tamponande– Pulmonart HTN

PE– Pos pressure mechanical ventillation

Reduced arterial stretch and activated baro-receptors

Neuro-humoral responses activated to maintain blood volume and pressure

•Sympathetic nervous system

•AT II system

•AVP system

They will act together to maintain flow to the heart and the brain at the expense of other non-essential vascular beds.

Renal afferent vaso-dilation is triggered via : PGE2 (afferent), Local myogenic reflex, ATII(efferent)

We have maximum dilation at SBP of 80 mm Hg. PHYSIOLOGY OF

HYPOVOLEMIA

Intrinsic Renal Disease

• Anatomic organization seems to work best. ARF DOES NOT EQUAL ATN.

• 30% of cases of intrinsic renal failure will not show any evidence of ATN on UA. – Glomerulus – Vessels– Interstitum– Tubules

THE DIFFERENTIAL DIAGNOSIS

Differential Diagnosis

Tubules : ATN • Ischemic Injuries to the renal tubule:

– Takes 1-2 weeks to recover from after perfusion has been normalized.

– In the extreme form this can lead to bilateral renal cortical necrosis

• Three phases: – Initiation phase– Tubuloglomerular feedback: afferent arteriole constriction

triggered by an increase in the salt delivery sensed by the macula densa.

– Recovery phase: tubular epithelial cell repair and regeneration. This may be associated with a marked diuretic phase.

ATN: Ischemic

• Hypovolemia

• Low cardiac output

• Renal vasoconstriction

• Systemic dilation

• Hemorrhage

ATN : Toxic

• Exogenous– Radiocontrast

– CSP

– TAC

– Amino glycosides

– Chemotherapy

– Ethylene glycol

– Tylenol

• Endogenous– Myoglobin

– Hemoglobin

– Uric acid

– Oxylate

– Light chains

ATN : Toxic facts• ATN : Exacerbated in the elderly, CRI, hypovolemia, and exposure to

multiple toxins. • Intrarenal vaso-constriction: radiocontrast, cyclosporin, tacrolimus.

Initially they will look prerenal.• Contrast – toxicity is worst in patients with CRI, DM, MM, CHF,

hypovolemia. This is dose related.• Direct toxicity to epithelial cells: frequent offenders are : acyclovir,

foscarnet, aminoglycosides (30% of patients with therapeutic levels will have ARF), Ampho B (causes vasoconstriction as well as direct toxicity).

• Cisplatin (mitochondrial injury). • Myoglobin and hemoglobin will both increase epithelial cell oxidative

stress. They also inhibit NO vasoconstriciton. • Light chains : can form intratubular casts and are directly toxic. UA

crystal deposition.

Allergic : AIN

Allergic reaction in the tubules. IT IS PARAMOUNT TO IDENTIFY THE OFFENDING AGENT AND REMOVE IT. There may be some role for steroids in the case of AIN.

AIN : Allergic • Beta lactams / Cephalosporins• Sulfinamides• TMP• NSAIDs• Diuretics• Captopril• Autoimmune diseases• Infiltrative diseases• Infections: Legionella / Hanta virus

Others

• Infection: Pyelonephritis, CMV, Candida

• Infiltration: lymphoma, leukemia, sarcoid

• Intratubular deposition and obstruction

Post Renal Causes

If we can identify this early, this can be readily reversible. This accounts for fewer than 5% of cases of ARF.

Differential Diagnosis

• BPH #1 • Prostatitis• Prostate / Cervical cancer• Retroperitoneal fibrosis /

disorders• Extraluminal malignancy• Neurogenic bladder /

anticholinergic drug use: functional obstruction

• Bilateral renal calculi • Myeloma light chains

• Papillary necrosis• Urethritis with spasm• Inadvertent surgical ligature• Intraluminal Thrombosis• Intraluminal (collecting

system) crystal disease• Uric acid• Calcium oxylate• Acyclovir• Sulfonamide• MTX

Ricky’s Story 50 year old man presents to the ED

with a 1 day history of RUQ pain, N/V. He also reports fever and chills and decreased urine output. PMH is a sore throat a week ago, tx w/ an antibiotic. He is on ibuprofen only. T = 102, HR 123, BP 80/60. In general, he is an ill-appearing. Abd: + tenderness RUQ; no peritoneal signs; remainder of exam is WNL.

Ricky’s Story

Labs:• WBC 20 w/ • 16% bands• Hgb 14• Plts 300• Na 140• K 4.1• Cl 111• HCO3 22• BUN 35• Cr 1.6 (baseline is 0.7) 

Any additional questions?

H and P : Prerenal

• Thirst, orthostatic dizziness, hypovolemia on exam, tachycarida, decreased JVP, poor skin turgor, dry mucous membranes, reduced axillary sweating.

• Start of new medications: NSAIDs, ACE, ARBs. Stigmata of chronic liver disease. Advanced CHF. Signs of sepsis.

H and P: Intrinsic Renal

• Recent history or hypovolemia / septic shock. Careful review of clinical data, pharmacy, nursing, and radiology records for evidence of toxin exposure. History of myeloma. Recent rhabdo.

• Flank pain (worry for arterial occlusion) : SC nodules, livedo reticularia, hollenhorst plaques, digital ischemia with palpable pulses. Fevers, arthralgias, pruritis erythemetous rash: AIN.

H and P : Post renal

• Presence of suprapubic and flank pain. Pain radiating to the groin. History of nocturia, frequency, hesitancy.

• History of anticholinergic medication use.  

What is your differential?

What additional workup do you want to diagnose

the etiology of his ARF / abdominal pain?

Urinalysis

• Dip: pH, SG, glucose, protein, nitrite, leuk esterase, bili, heme.

• Micro: RBCs, WBCs, casts, crystals, bacteria.

• Normal: 0-2 RBCs, 0-4 WBC, occasional hyaline cast.

Urinalysis: Prerenal / Post-renal

• Sediment is acellular and may contain hyaline casts

• This is protein that is normally part of the urine (Tamm-Horsfall Protein).

• Post renal : Sediment is classically acellular and “bland”.

• May also see pyuria and hematuria. No casts.

Renal : ATN • Muddy brown casts

– (contain tubular-epithelial cells).

• They are usually associated with microscopic hematuria and mild tubular proteinuria (< 1 g / d) from impaired re-absorption.

• CASTS ARE ABSENT IN 30% OF THE CASES OF ATN.

Renal : GN

• Red blood cell casts are the classic finding.

• Dysmorphic RBCs.• These indicate

glomerular injury. • These are rarely seen in

acute ATN. • May also see proteinuria:

> 1 g / day.

Renal : AIN

• White cell / granular casts.

• KEEP IN MIND THAT BROAD GRANULAR CASTS REFELCT CHRONIC RENAL DISEASE (fibrosis).

• Eosinophiluria (> 5%) is a classic finding (Hansel’s Stain) – especially in antibiotic associated AIN.

Common UA Patterns

• Rhabdo: dip is pos for heme, neg for RBCs

• MM: dip is neg for protein, + for light chains on UPEP

• EG: look for calcium oxylate crystals, elevated AG, elevated osm gap.

• TLS: uric acid crystals (can also be a normal variant of concentrated urine)

URINE BLING

Results

• Tbili : 2.0• Alk: 269• ALT : 44• AST : 44• UA : SG 1.02, trace ketones• Micro : No cells, No casts, No crystals• Urine Na: 10• Urine Cr: 80

Renal Failure Indices• Fractional excretion of Na: this will relate the clearance of Na

to that of Cr. • In the case of prerenal disease Na is actively reabsorbed to

restore intravascular volume. • This is not the case in renal injury (absorptive mechanisms are

broken). In either case Cr is NOT reabsorbed. So we have the makings of a comparative ratio. The cut off is 1%.

U Na / P Na __________ x 100% = .14% (Prerenal)

U Cr / P Cr

Keep in mind…• Keep in mind that when pre renal patients are receiving

diuretics or have bicarbonaturia all bets are off. • Also salt wasting states such as CRI and adrenal

insufficiency will also alter results. • In 15% if patients with ATN FeNa can be < 1 % :

reflecting patchy injury with partially preserved function. • In GN, acute urinary post renal obstruction, and vascular

diseases the FeNa will often be < 1%.• Urine sodium, specific gravity, urine osm, BUN : Cr ratio

are less sensitive and of limited value in differentiating this differential.

Additional Labs• Peak Cr:

– In prerenal disease : may fluctuate with hemodynamics. Rise will be rapid. This is true for contrast (5 days to peak and 7 to normal)

– Atheroembolization (later peak and return to baseline), and ischemia (later peak and return to baseline).

– Rise will be delayed in toxin exposure. • Rhabdo: elevated K, Phos, hypocalcemia with elevations in CK and UA.• TLS: elevated UA, K, Phos, low Ca, elevated Cr and elevated LDH

(intracellular enzyme).• Elevated anion gap + elevated osm gap : suggests ethylene glycol /

methanol exposure. • Anemia may suggest hemolysis, MM, or TTP.• Eosinophillia may suggest AIN, atheroembolic disease, PAN.

Back to Ricky

• An abdominal CT with contrast shows acute cholecystitis. He is given an intravenous dose of ampicillin and gentamycin, along with normal saline.

• The next morning you note LE edema and bibasilar crackles. His blood pressure has improved to 110/70 and fever has resolved. His overnight urine output was 150cc.

• Na 137, K 6.7, Cl 100, H2CO3 15, BUN 37, Cr 2.7

Why is he hyperkalemic?What is the management?

Does need dialysis?

Hyperkalemia

• Plasma Potassium > 5.0

• Pseudohyperkalemia– Prolonged tourniquet use– Hemolysis– Leukostasis / Thrombocytosis

Physiology

• A large meal has enough potassium to kill us. How will the body handle this load initially.

• Buffering system will stimulate liver / muscle N-K ATPase– Insulin

– Epinephrine

– Aldosterone

The Kidney to the Rescue

• Kidney handles it in a unique way.

• It virtually reabsorbs 100% of the K in the proximal tubule (70%) and the loop of henle (30%).– Solvent Drag– Single Effect / Paracellular

pathway

• We reabsorb almost all of the K before we reach the distal segments.

The Principal Cell• BL membrane we have a Na/ K

ATPase • On the apical side we have

amilloride Na channels and other channels that allow the movement for K.

• Tight junctions - the potential across the apical membrane is – 30. The BM is at - 70mv.

• The common denominator: intracellular K will raise electrochemical gradient for K inside of the cell will cause an increase in K secretion into the urine.

The Key Players

1. K concentration

2. Aldosterone

3. Flow

4. Distal Na

5. ADH

6. Acid base status of the blood

Differential Diagnosis

• Increased intake : rare except in iatrogenesis• Cellular release

– TLS, Rhabdomyolysis, exercise, trauma

– Metabolic acidosis

– Insulin deficiency

– Hyperkalemic periodic paralysis

– Digoxin toxicity, beta blockers

– Adrenal insufficiency

– Succinylcholine

Differential Diagnosis

• Impaired excretion– Renal failure– Primary hypoaldosteronism– Secondary hypoakdosteronism

• ACE, NSAIDs, Heparin, Type 4 RTA

– Aldo resistance • K sparing diuretics, bactrim, pentamidine, sickle cell disease,

multiple myeloma.

– Gordon’s syndrome (enhanced Cl reabsorption, less K secretion, HTN)

– Ureter Diversion to Jejunum.

Symptoms / Signs

• Flaccid paralysis• Arrhythmia

– Peaked T waves– PR / QRS prolongation– AV conduction delay– Loss of P waves– Sine wave– V fib

Treatment : Keep the Physiology in mind.

• EKG changes necessitate treatment:– Calcium gluconate: stabilized myocardium– Insulin / Glucose: intracellular shift – Bicarbonate: intracellular shift– Beta 2 agonists: intracellular shift– Diuretics: IV Lasix – Kayexylate: exchanges K for Na– Dialysis

Dialysis Needs

• A : acidosis• E : electrolytes• I : intoxication (methanol, ethylene glycol,

isopropanol, theophylline, lithium, salicylates)

• O : volume overload • U : uremia (pericarditis, seizures,

encephalopathy)

Why did his renal failure worsen?

Additional Labs

• U OSM 300

• Muddy brown casts

• U Na 80

• U Cr 40 Calculate FeNa?

What is highest on your differential?

How does this alter your treatment plan?

Treatment• Prevention is the key.

– Appropriate volume resuscitation.– Renal dosing of potentially toxic meds– To estimate GFR : Cockcroft-Gault Formula: takes weight and age

into account. (ONLY IN STABLE CREATININE) MULTIPLY BY .85 IN WOMEN.

– When appropriate follow serum drug levels for dosage adjustment. – Use of NSAIDS, ACR, ARBs, diuretics should be used sparingly

in patients who are hypovolemic or have renovascular disease. – Allopurinol / IVFs use in patients high risk for TLS.– Ethanol for EG toxicity / NAC for tylenol toxicity.– Alkalinization of urine : to prevent MTX toxicity.

Prerenal disease

• IVFs: keep in mind where the loss is coming from and administer fluids accordingly.

• Inotropes, preload / after-load reduction, anti-arrythmics, mechanical aids in CHF.

• Large volume paracentesis: to decrease intra-abdominal pressure and increase venous return from the kidneys.

Post Renal Treatment

• Foley catheter

• Nephrostomy tube

• Stenting

• 5% will develop a salt wasting diuresis.

Intrinsic Renal Disease• Intrinsic renal disease: NO SPECFIC REVERSING

THERAPIES FOR ISCHEMIC AND NEPHROTOXIC DISEASE. SUPPORTIVE CARE.

• Follow electrolytes. Avoid further insult.• GN: may respond to steroids, alkylating agents,

plasmapheresis.• AIN: glucocorticoids may be of use. • Malignant HTN: control of blood pressure. • Scleroderma: HTN and ARF may responsive to ACE.

Case 2 : Fred 85 year old man with a PMHx

significant for osteoarthritis is admitted to the hospital for confusion. Physical exam reveals a thin, disoriented man: T = 98, HR = 80, BP = 120/80, wt = 75 kg, and a suprapubic mass. He takes no medication except for naproxen.

• Labs: Na 131, K 4.8, Cl 98, HCO3 15• BUN 65, Cr 7.3 (baseline on

computer: 1.3)What is the FeNa?

What is the baseline Cr clearance?

Cockcroft-Gault:

(140-age) x wt/(Cr x 72)

What is your differential?

The Intervention

The next morning the creatinine is 2.5 and his mental status has cleared.

Geraldine

45 yr old female with a PMH for HTN presents with “HEADACHE, ”low back pain, and left should pain. You decide to order labs and discover discover a Cr 2.0 (baseline 1.0), Calcium 10.0, and mild pan-cytopenia (Hb 10.0, Pts 144). FeNa is 2.0. UA dip is bland (no protein, no leuks, no nitrites)

What additional tests would you like?

Multiple Myeloma

Multiple Myeloma The minimal criteria for the diagnosis of multiple

myeloma include a bone marrow usually containing more than 10 percent plasma cells (or presence of a plasmacytoma) plus at least one of the following:

• A monoclonal protein (M-protein) in the serum (usually >3 g/dL)

• An M-protein in the urine • Lytic bone lesions.

Additionally, at least some of the following: Anemia, hypercalcemia, azotemia, hypoalbuminemia, bone demineralization (THE MINOR CRITERIA)

Sam’s Case

30 year old man with diabetes, hypertension and chronic renal insufficiency (baseline creatinine of 2.5) presents to VA clinic for routine follow-up. His medications are captopril, HCTZ and insulin. Physical exam is unremarkable.

Na= 138, K=5.8, Cl=110, HCO3=20, BUN=30, Cr=2.4,Glu=129

What is your differential for elevated Potassium?

What is your plan management plan?

Acid / Base : Basics

The normal renal response to acidemia is to reabsorb all of the filtered bicarbonate and to increase hydrogen excretion primarily by enhancing the excretion of ammonium ions in the urine. Each hydrogen that is secreted results in the regeneration of a bicarbonate ion in the plasma.

Proximal Tubule• Reabsorption of filtered bicarbonate

predominantly occurs in the proximal tubules primarily by Na-H exchange.

• Approximately 85 to 90 percent of the filtered load is reabsorbed proximally.

• By comparison, 10 percent is reabsorbed in the distal nephron primarily via hydrogen secretion by a proton pump (H-ATPase).

• Under normal conditions, virtually no bicarbonate is present in the final urine.

Distal Tubule• We need to deal with acid load from protein

catabolism.• There must be sufficient buffering compounds

available to bind hydrogen ions. • The principal buffers in the urine are ammonia

(excreted and measured as ammonium) and phosphate (referred to and measured as titratable acidity).

• Failure to excrete sufficient ammonium net retention of H+ and metabolic acidosis.

• Impaired hydrogen ion secretion is the primary defect in distal RTA while impaired ammoniagenesis is the primary defect in type 4 RTA and renal failure.

Renal Tubular Acidosis

• Renal tubular acidosis (RTA) is a disorder of renal acidification out of proportion to the reduction in GFR.

• RTA is characterized by hyperchloremic metabolic acidosis with a normal serum anion gap [Na+– (Cl–+ HCO3

–)].

• There are multiple forms of RTA, depending on which aspects of renal acid handling have been affected.

Type I (DISTAL)• Distal nephron does not lower urine pH normally:

– The collecting ducts permit back-diffusion of H+ from lumen to blood with inadequate transport of H+.

– Causes a reduction in ammonium excretion. – [Urinary] and K conservation can be impaired.– Chronic acidosis lowers tubule reabsorption of calcium

hypercalciuria and mild 2nd hyperparathyroidism. – Hypercalciuria, alkaline urine, and urine citrate cause calcium

phosphate stones.– Growth retardation is common and improves with correction of

the acidosis by alkali. – Since the kidney does not conserve potassium or

concentrate the urine normally, polyuria and hypokalemia occur. Sometimes fatal.

Diagnosis and Treatment

• Normal AG acidosis• Urine pH > 5.5• Nephrocalcinosis• Oral ammonium load

will worsen acidosis.• Urine anion gap is

positive (vs. GI): • Na + K – Cl

• Treat with bicarbonate.

Type II RTA (Proximal)• Bicarb resorption in prox tubule is impaired.• Distal tubule resorption is overwhelmed at first.• Equilibrium is established at bicarb of 16.• Urine pH is normal / high. • Ammonium challenge does not affect urine

acidification. • Expect bicarbonaturia. FE Bicarb.• Bicarbonate must be given in LARGE doses.

Alkali therapy can worsen hypokalemia.

Type IV RTA • Distal secretion of K and H+ is abnormal producing a non

AG acidosis with hyperchloremia.• Hypo aldosteronism: DM, ACE, NSAIDs, TMP, adrenal

disease (high Renin level). • Tubular inflammation (low Renin state) with interstitial

inflammation (SSD), K sparing diuretics (aldactone, amilloride).

• HYPERKALEMIA IS THE PRIMARY PROBLEM. K MAY INHIB IT AMMONIA EXCRETION.

• Do not have bicarbonaturia (vs. Type II). • Urine is APPROPRIATELY acidic (pH < 5.5)

Treatment

• Lower potassium

• Remove drugs that lower aldosterone production.

• High dose mineralocorticoids (beware of CHF).

• Liberal Na intake.

• Exchange resins.

Comparison of Normal Anion-Gap Acidosis

Finding Type 1 RTA Type 2 RTA Type 4 RTA GI Bicarbonate Loss

Normal anion-gap acidosis Yes Yes Yes Yes

Minimum urine pH >5.5 <5.5 <5.5 5 to 6

% Filtered bicarbonate excreted <10 >15 <10 <10

Serum potassium Low Low High Low

Fanconi syndrome No Yes No No

Stones/nephrocalcinosis Yes No No No

Daily acid excretion Low Normal Low High

Urine anion gap Positive Positive Positive Negative

Daily bicarbonate replacement needs <4 mmol/kg >4 mmol/kg <4 mmol/kg Variable