ACUTE RENAL FAILURE

Dr. D. Feinfeld

 

Objectives

 

 

-Learn about major causes of acute renal shut-down and how to distinguish pre-renal, intrinsic, and obstructive mechanisms of its development.

            -Use different plasma and urinary parameters and calculate fractional excretion of sodium to assist in diagnosing the causes of acute renal failure.

            -Learn about pathophysiologic mechanisms of different phases of acute renal failure, hazards accompanying each phase, and therapeutic strategies relevant for each phase.

 

 

ACUTE RENAL FAILURE:

 

            Any process that decreases renal function (measured by glomerular filtration rate) over a period of hours to days.

 

Acute renal failure almost always evolves in the hospital, in sick patients.  The clinician will note a rise in the BUN and creatinine over a period of days.  Oliguria (Urine output less than 400 ml/day) may accompany the rapid fall in renal function.

 

POINTS:

 

      1.  Acute Renal Failure is not a disease but is the final common pathway of different processes.

 

      2.  The acute onset of renal failure ensures that neither the kidneys nor the body will have time to adapt to the loss of renal function.

 

      3.  Acute Renal Failure, like Gaul, is divided into three parts:

 

Initial Approach to Acute Renal Failure

 

            Always ask:

 

                        Is it Pre-Renal (Decreased renal perfusion)?

 

                               Post-Renal (Obstruction to urine flow)?

 

                               Parenchymal Renal Disease

 

Note that these three processes are not mutually exclusive, and any two of them or all three of them may be present at the same time.  Therefore, it is important, even if it seems obvious why the renal function is falling, to look for evidence of all three.

 

Pre-Renal Failure is best treated by improving renal perfusion.  Post-Renal Failure is best treated by relieving the obstruction.  If these processes are not looked for, they cannot be treated appropriately.

 

Pre-Renal Failure

 

Pathogenesis:  Any process that sharply decreases renal perfusion

 

            Hypotension

            Volume depletion (fluid loss, bleeding, etc.)

            Congestive heart failure

            Third-spacing of plasma volume (trauma, hypoalbuminemia)

            Hepatic failure (causes pre-renal vasoconstriction)

            Renal vascular occlusion (without infarction)

            Prostaglandin inhibiting drugs

 

Reflex response to renal hypoperfusion:

 

            1.  Decreased GFR

                        Þ azotemia

            2.  Increased ADH (response to ¯ effective plasma volume)

                        Þ water retention

            3.  Na+ retention as follows:

 

            Increased renal renin release

                                    ¯

            Angiotensin I production

                                    ¯

            Angiotensin II production (there is ACE in the kidney)

                  Local effect                                    Systemic effect

                        ¯                                                          ¯

            Efferent arteriole construction    ­ aldosterone

                        ¯                                                          ¯         

               ­ Filtration fraction                            ­ distal Na+ absorption

                        ¯

       ­ proximal Na+ absorption

 

Hence, the kidneys are primed to retain Na+ maximally.


 



PRE-RENAL AZOTEMIA

 

1)         ENHANCED FRACTIONAL TUBULAR NA REABSORPTION

 

2)         ENHANCED FRACTIONAL H20 REABSORPTION

 

3)         ENHANCED FRACTIONAL UREA REABSORPTION

 

 

ENHANCED Na REABSORPTION IN PRE-RENAL AZOTEMIA

 

                                    A)        STARLING FORCES

 

                                    B)        ANGIOTENSIN II

 

                                    C)        ALDOSTERONE

 

                                    D)        ADRENERGIC NERVOUS SYSTEM

 

 

URINARY Na IN PRE-RENAL AZOTEMIA

 

U Na:  < 10 mEq/L      (NML = 50-100)

 

FRACTIONAL EXCRETION OF SODIUM: FE Na: < 0.5%          (NML = > 1%)

 

            Na EXCRETION = UNa x V

 

            Na FILTERED  =  GFR x PNa

 

                                    SODIUM EXCRETED                                    UNa x V

            FE Na  =  ---------------------------------------  x 100%   =  -----------------------  x  1

                                    SODIUM FILTERED                                  U/PCr x V x PNa

 

                                    UNa/PNa

                        100 x  ---------------   (make sure the U and P values are in the same units)

                                    UCr/PCr

 

 

ENHANCED FRACTIONAL H20 REABSORPTION

 

 

A)        ENHANCED Na REABSORPTION

 

B)        INCREASED VASOPRESSIN

 

URINE OSMOLALITY IS HIGH:  >  600 mOsm/Kg

 

URINE / PLASMA OSMALALITY RATIO:  >  2

 

URINE / PLASMA CREATININE RATIO:   >  40

 

 

BUN/ CREATININE RATIO IN PRE-PRENAL AZOTEMIA

 

 

A)        ENHANCED H20 REABSORPTION WITH AN INCREASE IN UREA CONCENTRATION IN THE COLLECTING DUCT.

 

B)        INCREASED VASOPRESSIN

 

RISE IN BUN WILL EXCEED THAT OF PLASMA CREATININE:

 

 

                                                            BUN

                                    PLASMA -------------------  >  20

                                                      CREATININE

 

POST-RENAL AZOTEMIA:

 

      OBSTRUCTION OF THE URINARY TRACT DISTAL TO THE KIDNEY, WITH SUBSEQUENT DECREASE IN GLOMERULAR FILTRATION RATE.

 

 

 

 

Post-Renal Failure

 

There are three stages following total urinary tract obstruction:

 

         Early:  There is reflex adaptation which tends to maintain GFR despite rising tubular hydrostatic pressure.  There is afferent arteriolar dilitation, with enhanced glomerular perfusion and capillary pressure.  This phase lasts only 12 – 24 hours.

 

         Late:  After 12 –24 hours, the afferent vasodilatation ceases.  Instead, there is a progressive fall in renal perfusion.  Glomerular blood flow and capillary pressure decrease, and GFR drops.  The elevated tubular hydrostatic pressures fall, with the cessation of urine formation.  This phase continues until the obstruction is relieved.   However, if prolonged, the ischemia leads to progressive permanent nephron loss.

 

         Recovery:  (after relief of the urinary obstruction):   With release of the pressure, the pre-renal vessels relax, perfusion is restored, and glomerular filtration increases in the nephrons which survive.  Tubular pressure returns to normal.  However, the dilatation of the calyces and collecting system may remain permanently.

 


 

 



 


Tubular Function in Post-Renal Failure

 

         Acute (during the first 12-24 hours; rarely seen):  The high tubular hydrostatic pressure enhances tubular absorption of Na+ and H20

 

         Chronic (after 24 hours of obstruction):  Tubular reabsorption is decreased due to the noxious effect of high pressure and ischemia.  This may not become evident until the obstruction is relieved.

 

                 Immediately, there is a post-obstructive diuresis, which is profound and often lasts for weeks.  It is due to the osmotic diuresis from the retained urea and other osmotically active particles and is maintained by the prolonged tubular dysfunction.

 

                 Chronically, even after the diuresis has subsided, the tubules continues to have decreased ability to reabsorb Na+ and secrete K+ and H+.  The patient may have salt wasting, hyperkalemia, and acidosis.  Concentrating ability may not return for months, causing a form of nephrogenic diabetes insipidus.

 

 

POST-RENAL AZOTEMIA

 

1)   COMPLETE:            ANURIA

 

2)   INCOMPLETE:

 

            ACUTE PHASE:         ENHANCED Na AND H20 REABSORPTION:

 

                                                            OLIGURIA

 

                                                            UNa < 10 mEq/L

 

                                                            U/P OSM >2

 

            SUBACUTE AND CHRONIC PHASES: TUBULAR Na AND H20 WASTING

 

                                                            POLYURIA

 

                                                            UNa > 20 mEq/L

 

                                                            U/P OSM = 1.0

 

Parenchymal Renal Disease Causing Acute Renal Failure

 

            Common:                     Acute Tubular Necrosis

                                                Acute Interstitial Nephritis

                                                Acute Glomerulonephritis

            Less Common: Vasculitis

                                                Pre-Eclampsia

                                                Hemolytic-Uremic Syndrome (mostly children)

 

Acute Tubular Necrosis

By far the most common intrinsic renal disease causing ARF (>90%)

 

Pathology:  Patchy necrosis of tubular segments.  N.B.:  There is tubular dysfunction out of proportion to the histological injury.  The tubular injury is reversible, and renal function usually returns if the patient survives the uremia and the underlying disease.

 

Three processes may lead to ATN:

            1.  Acute toxic injury to tubular cells

                     Metals (Hg, As, Bi, Cr, Pt)

                     Solvents (CCl4, glycols, tetrachloroethylene)

                     Drugs (aminoglycosides, cisplatin, amphotericin, radiocontrast agents,

                        Pentamidine)

            2.  Pigment deposition in tubular cells

                     Myoglobinuria

                     Hemoglobinuria (usually 20 to transfusion reaction)

            3.  Ischemia

                     Any process that causes pre-renal failure may progress to causing ischemic

                        ATN.

 

How does a tubular injury cause decreased glomerular filtration?

            Four theories:

                     Intratubular Obstruction

                     Back-leak of filtration across damaged epithelium

                     Decreased renal blood flow

                     Decreased filtration properties of glomerulus

 

            None of these in itself is an adequate explanation.

   Solution:  All of these processes probably play some role and interact with each other  to shut down GFR.

 

Recent theories suggest that in all forms of ATN there is ischemic injury to the medullary thick ascending limb of the loop of Henle, regardless of where the initiating lesion takes place.  Such injury is due to hemdynamic changes in the renal microcirculation and the already low pO2 in the segment.

 

 

 

 


 

 


FEATURES OF EVOLVING ISCHEMIC INJURY

EVOLVING ISCHEMIC INJURY

 

1)  FURTHER FALL IN GFR

 

2)  LOSS OF CONCENTRATING ABILITY STARTS EARLY:       U OSM FALLS

                                                                                                            U/P OSM:  2.0-1.2

      URINE OUTPUT MAY INCREASE ABOVE 400 ML/24 HRS.  HOWEVER, IF THE FALL IN GFR IS SEVERE OLIGURIA WILL PERSIST.

 

3)  FRACTIONAL Na REABSORPTION STARTS FALLING:        U Na: 10-12 mEq/L

                                                                                                            FE Na: 0.5-1%

 

4) UREA REABSORPTION STARTS DECREASING.  SINCE CHANGES IN PLASMA BUN LAG BEHIND CHANGES IN UREA EXCRETION PLASMA BUN AND PLASMA BUN/CR MAY REMAIN ELEVATED.

 

5)  URINALYSIS:       PROTEINURA 0.5-2 GM/DAY

                                    MICROHEMATURIA; DEGENERATING RENAL TUBULAR CELLS

                                    CASTS:  GRANULAR CASTS, MUDDY BROWN CASTS.

 

 

FEATURES OF ACUTE TUBULAR NECROSIS

 

ACUTE TUBULAR NECROSIS

 

1)  Na WASTING:      U Na > 20

                                    FE Na > 1% (OFTEN > 3%)

 

2)  LOSS OF CONCENTRATING ABILITY:            U OSM FALLS

                                                                                    U/P OSM 1.0-1.2

                                                                                    U/P CR < 40

 

3)  UREA WASTING:  PLASMA BUN/CREATININE < 20

      A RATIO GREATER THAN 10 WILL OCCUR IF ATN WAS PRECEDED BY

      PROLONGED HYPOPERFUSION OR THERE IS INCREASED UREA

      PRODUCTION (HYPERCATABOLIC STATE).

 

4). URINE OUTPUT WILL DEPEND ON THE SEVERITY AND ETIOLOGY OF THE ATN.  IF THE INSULT IS SEVERE OLIGURIA WILL BE PRESENT, FE Na > 1%.  IF THE INSULT IS LESS SEVERE POLYURIA (400 –2000 ML/DAY) MAY BE SEEN.  FE Na WILL BE LOWER THAN IN OLIGURIC ATN: = < 1%.  IN SOME SETTINGS (AMINOGLYCOSIDE NEPHROTOXICITY) POLYURIA IS COMMON.

 

1)      URINALYSIS:  SAME AS IN EVOLVING ISCHEMIC INJURY.

 

 

 

 

 

 

 

ACUTE GLOMERULONEPHRITIS

 

SEDIMENT:                RBC, LIPID, OVAL FAT BODIES

                                    CASTS:  RBC, PIGMENTED

 

PROTEINURIA:          2 – 4 +

 

FE Na:                         < 1%

 

CLINICAL CLUES:    HYPERTENSION

                                    NEPHROTIC SYNDROME

                                    SIGNS OF SYSTEMIC DISEASE

 

 

Acute Interstitial Nephritis

 

Definition:  An acute inflammation of the kidney where the primary lesion in the interstitial space between nephron structures.  The principal effects are decreased GFR and involvement of the tubules.

 

Causes:

            1.  Originally described in sepsis

                        Streptococci

                        Diphtheria

                        Brucella

                        Legionella

                        Salmonella

                        Leptospira

                        Rocky Mountain spotted fever

                        Measles

                        Infectious mononucleosis

                        Toxoplasmosis

            2.  Now, most often seen as a drug reaction, usually allergic b-lactam antibiotics

                        Penicillin, ampicillin, methicillin

                        Other penicillins

                        Cephalosporins

                Sulfonamides (including trimethoprim/sultamethoxazole)

                Rifampin

                Non-steroidal anti-inflammatory drugs (often accompanied by nephrotic

syndrome)

                Diuretics (thiazides, furosemide)

                Any other allergen (allopurinol, H2 blockers, etc.)

            3.  Idiopathic AIN (Unknown allergen)

                May be seen accompanying uveitis

 

Clinical picture of AIN

 

Background:  severe infection or exposure to allergen

Progressive azotemia, sometimes accompanied by loin pain or allergic manifestations.

Urinalysis:  1-2+ proteinuria, hematuria, pyuria

            Sediment may have eosinophils if cause is drug reaction

Hyperkalemia or metabolic acidosis common

FENa usually > 3 % due to tubular involvement

 

Course:  If recognized and treated early, AIN usually reverses.  Often a biopsy diagnosis.

            Sepsis-related AIN responds to treatment of infection

            Allergic AIN responds to withdrawal of allergen

                        Short course of cortocosteroids may be of benefit.

 

 

PATHOPHYSIOLOGICAL CONSEQUENCES OF ACUTE RENAL FAILURE

 

 

1.  LOW GFR MANIFESTED BY HIGH PLASMA CREATININE AND BUN, LEADS TO RETENTION OF TOXINS WHICH CAUSE UREMIA.

 

2. IMPAIRED SODIUM HANDLING.  SODIUM EXCRETION IS FIXED AND DEPENDENT ON URINE VOLUME.  RELATED CLINICAL PROBLEMS ARE:

            A)  SODIUM DEFICIT (VOLUME CONTRACTION)

            B)  SODIUM EXCESS (VOLUME EXPANSION)

 

3. IMPAIRED ABILITY TO CONCENTRATE AND DILUTE THE URINE.  RELATED CLINICAL PROBLEMS ARE:  HYPER AND HYPONATREMIA.  URINE VOLUME MAY RANGE FROM 3-5 L/DAY TO LESS THAN 400 ML/DAY.  COMPLETE ANURIA IS RARE EXCEPT IN BILATERAL CORTICAL NECROSIS.  POLYURIC ACUTE RENAL FAILURE IS USUALLY INDICATIVE OF A MILD TO MODERATELY SEVERE INSULT WHILE MARKED OLIGURIA IS SEEN IF TUBULAR INJURY IS SEVERE AND GFR IS VERY LOW.

 

4. IMPAIRED POTASSIUM HANDLING.  POTASSIUM EXCRETION IS FIXED AND DEPENDENT ON URINE VOLUME.  RELATED CLINICAL PROBLEMS ARE:  HYPO AND HYPERKALEMIA.

 

5.  IMPAIRED ACID EXCRETION.  URINE pH IS TYPICALLY LOW 5.5 TO 5.0 THIS REFLECTS A NORMAL ABILITY OF THE COLLECTING DUCT TO REABSORB THE VERY SMALL AMOUNTS OF HCO3- THAT ARE FILTERED AND REACH THE DISTAL TUBULE AND THE ABILITY OF THE COLLECTING DUCT TO MAINTAIN A STEEP LUMEN TO BLOOD H+ GRADIENT.  TITRATIABLE ACIDITY AND AMMONIUM EXCRETION ARE DEPRESSED.