RENAL FAILURE

MP 2000

14TH MAY 2009

SUMMARY• Background to ARF• Pathophysiology• Classification into Pre-Renal, Renal and Post-

Renal ARF• Etiology ARF• Laboratory Studies• Chronic Renal Failure- Causes- Clinical manifestations- Specific Disorders (Anemia, Hypertension, Renal

osteodystrophy• Concluding Remarks

Background to Acute Renal Failure• Acute renal failure (ARF), is defined as an

abrupt or rapid decline in renal function.

• This condition is usually marked by a rise in serum creatinine concentration or azotemia (a rise in blood urea nitrogen [BUN] concentration).

• However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the only sign of a kidney injury may be decreased urine production.

• A rise in the creatinine level can result from medications (eg, cimetidine, trimethoprim) that inhibit the kidney’s tubular secretion.

• A rise in the BUN level can occur without renal injury, such as in GI or mucosal bleeding, steroid use, or protein loading

• So a careful inventory must be taken before

determining if a kidney injury is present.

Pathophysiology

• AFR may occur in 3 clinical patterns, including the following:

• (1) as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons

• (2) in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage

• (3) with obstruction to the passage of urine.

• Therefore, in general terms, ARF may be classified as:

- Pre-renal- Intrinsic, and - Post-renal• The classifications are useful in establishing a

differential diagnosis

• However many pathophysiologic features are shared among the different categories.

• Patients who develop ARF can be - oliguric or nonoliguric- Have a rapid or slow rise in creatinine levels- May have qualitative differences in urine

solute concentrations and cellular content. • The reason for this lack of a uniform clinical

presentation is a reflection of the variable nature of the injury.

• Classifying ARF as oliguric or nonoliguric based on daily urine excretion has prognostic value

• Oliguria: daily urine volume of less than 400 mL- - has a worse prognosis,

• Anuria daily urine output of less than 100 mL/d- if abrupt in onset, is suggestive of bilateral

obstruction or catastrophic injury to both kidneys.  

• Stratification of renal failure along these lines helps in decision-making (e.g. timing of dialysis) and can be an important criterion for patient response to therapy

A: Causes of Pre-renal ARF

A: Volume depletion:GI losses (vomiting, diarrhea)Cutaneous losses (burns, Stevens-

Johnson syndrome)Hemorrhage

B: Decreased cardiac output Heart failure

Pulmonary embolus

Acute myocardial infarction

Severe valvular disease

C: Systemic vasodilatation Sepsis

Anaphylaxis

Anesthetics

Drug overdose

D: VascularRenal artery obstruction (thrombosis,

emboli, dissection, vasculitis) Renal vein obstruction (thrombosis)Microangiopathy (e.g. in preeclampsia) Malignant hypertension Transplant rejection Atheroembolic disease

Anti–glomerular basement membrane (GBM) disease (Goodpasture syndrome)

Anti–neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-associated GN)

Immune complex Glomeluronephritis (lupus, postinfectious, primary membranoproliferative glomerulonephritis)

B: Causes of Intrinsic ARF (Glomerular)

IschemiaCytotoxicity caused by e.g.- Heme pigment (rhabdomyolysis,

intravascular hemolysis) - Crystals (tumor lysis syndrome)- Drugs (aminoglycosides, lithium,

amphotericin B, pentamidine, cisplatin, ifosfamide, radiocontrast agents)

B: Causes of Intrinsic ARF (Tubular)

Drugs (penicillins, cephalosporins, NSAIDs

Infections (pyelonephritis, viral nephritides)

Systemic disease (Sjogren syndrome, sarcoidosis)

B: Causes of Intrinsic ARF (Interstitial)

C: Postrenal causes of ARFUreteric obstruction (stone disease,

tumor, fibrosis, ligation during pelvic surgery)

Bladder neck obstruction (benign prostatic hypertrophy [BPH], cancer of the prostate [CA prostate], stone disease, hemorrhage/clot)

Urethral obstruction (strictures, tumor, phimosis)

Lab Studies in ARF Several laboratory tests are useful for - assessing the etiology of ARF- Can aid in proper management• These tests include: • - Urinalysis• - Serum Biochemical Tests (BUN, Serum

creatinine, Electrrolytes, Enzymes)• - CBC• - Urine Chemical Indices

Urine OutputChanges in urine output generally are

poorly correlated with changes in GFR.

Approximately 50-60% of all causes of ARF are nonoliguric

However, categories of anuria, oliguria, and nonoliguria may be useful in differential diagnosis of ARF.

Presence of Anuria ( <100 mL/d) suggests ARF due to:

- Urinary tract obstruction- Renal artery obstruction- Rapidly progressive glomerulonephritis- Bilateral diffuse renal cortical necrosisOliguria (100-400 mL/d) is suggsetive of ARF due

to: - Prerenal failure- Hepatorenal syndromeNonoliguria (>400 mL/d) accompanies- Acute interstitial nephritis- acute glomerulonephritis- partial obstructive nephropathy

Urinalysis:Microscopic examination of urine is essentialin establishing differential diagnosis• Normal urinary sediment without

hemoglobin, protein, cells, or casts generally consistent with prerenal and postrenal failure

• Granular casts - ATN, glomerulonephritis, interstitial nephritis

• RBC casts - Glomerulonephritis, malignant HTN

• WBC casts - Acute interstitial nephritis, pyelonephritis

• Eosinophiluria - Acute allergic interstitial nephritis

BUNThe urea concentration correlates poorly

with the GFR.

Because urea is highly permeable to renal tubules, urea clearance varies with urine flow rate.

Urea is filtered freely, but reabsorption along the tubule is a function of urine flow rate.

In prerenal conditions, low urine flow rates favor BUN reabsorption out of proportion to decreases in GFR

This results in a disproportionate rise of BUN relative to creatinine

In prerenal failure a serum BUN-creatinine ratio >20 may be seen

BUN concentration is dependent on nitrogen balance and renal function.

BUN concentration can rise significantly with no decrement in GFR by increases in urea production with steroids, trauma, or GI bleeding.

Basal BUN concentration can be depressed severely by malnutrition or advanced liver disease.

Serum creatinine Serum creatinine provides the most

accurate and consistent estimation of GFR.

Serum creatinine level varies by method of measurement

This becomes important when patients present with changes in creatinine measured in different labs.

Serum creatinine is a reflection of creatinine clearance

Serum creatinine is a reflection of creatinine clearance.

Serum creatinine is a function of its production and excretion rates.

Because Creatinine production is determined by muscle mass serum creatinine must always be interpreted with respect to patient's weight, age, and sex

Changes in serum creatinine reflect changes in GFR.

Stable changes in serum creatinine correlate with changes in GFR by the following relationships:• Creatinine 1.0 mg/dL - Normal GFR• Creatinine 2.0 mg/dL - 50% reduction in GFR• Creatinine 4.0 mg/dL - 70–85% reduction in

GFR• Creatinine 8.0 mg/dL - 90–95% reduction in

GFR

Complete blood count

Leukocytosis is common in ARF. Leukopenia and thrombocytopenia

suggest SLE associated ARF Anemia and rouleaux formation suggest

multiple myeloma.Eosinophilia suggests allergic interstitial

nephritis, polyarteritis nodosa, or atheroemboli

Coagulation disturbances indicate liver disease or hepatorenal syndrome.

Other Blood TestsCreatine phosphokinase (CPK) elevations

are seen in rhabdomyolysis and myocardial infarction.

Elevations in liver transaminases are seen in rapidly progressive liver failure and hepatorenal syndrome.

Hypocalcemia (moderate) is common in ARF.

Hyperkalemia is a common complication of ARF.

Urine chemical indices Differentiation of prerenal azotemia from ATN

takes on a special importance in early management of these patients

Aggressive fluid resuscitation is appropriate in prerenal ARF.

However, rapid fluid infusion in a patient with ATN who is unable to excrete the extra fluid could result in life-threatening volume overload.

Urine indices that suggest prerenal failureinclude the following:Urine specific gravity >1.018Urine osmolality (mOsm/kg H2O)

>500Urine sodium (mmol/L) <15-20Plasma BUN/creatinine ratio >20Urine/plasma creatinine ratio >40

Urine chemical indices in Prerenal failure

Urine indices that suggest ATN include the following:

Urine specific gravity <1.012Urine osmolality (mOsm/kg H2O) < 500Urine sodium (mEq/L) >40 Plasma BUN/creatinine ratio <10-15Urine/plasma creatinine ratio <20

Urine chemical indices in ATN

CHRONIC RENAL FAILURE

• Chronic renal failure (CRF) is defined as a permanent reduction in glomerular filtration rate (GFR) sufficient to produce detectable alterations in well-being and organ function.

• This usually occurs at GFR below 25 ml/min

• Any disorder that permanently destroys nephrons can result in chronic renal failure

Most Common Causes of CRF include:Diabetic nephropathy

Hypertensive nephrosclerosis

Glomerulonephritis

Interstitial nephritis

Polycystic kidney disease

Clinical Manifestations• Multiple symptoms and signs constitute the

uremic syndrome• Neurological Disorders: Fatigue, lethargy,

sleep disturbances, headache, seizures, encephalopathy, peripheral neuropathy including restless leg syndrome, paraesthesia, motor weakness, paralysis. 

• Hematologic Disorders: Anemia, bleeding tendency – due in part to platelet dysfunction. 

• Cardiovascular Disorders: Pericarditis, hypertension, congestive heart failure, coronary artery disease, myocardiopathy

• Pulmonary Disorders: Pleuritis, uremic lung. 

• Gastrointestinal Disorders: Anorexia, nausea, vomiting gastroenteritis, GI bleeding, peptic ulcer.

• Metabolic-Endocrine Disorders: Glucose intolerance, hyperllipidemia, hyperuricemia, malnutrition, sexual dysfunction and infertility

• Bone, Calcium, Phosphorus Disorders: Hyperphosphatemia, hypocalcemia, tetany, metastatic calcification, secondary hyperparathyroidism, 1,25-dihydroxy vitamin D deficiency, osteomalacia, osteitis fibrosa, osteoporosis, osteosclerosis.

 • Skin Disorders: Pruritus, pigmentation, easy

bruising, uremic frost.

• Psychological Disorders: Depression, anxiety, denial, psychosis.

• Fluid and Electrolyte Disorders: Hyponatremia, hyperkalemia, hypermagnesemia, metabolic acidosis, volume expansion or depletion.

. Anemia:

 Anemia is universal as GFR falls below 25 ml/min.; in certain disorders it may occur with mild renal insufficiency. Several factors contribute: 

• a. Erythropoiesis is markedly depressed, mainly due to reduced erythropoietin production; in addition, there may be reduced end-organ response to erythropoietin with reduced heme synthesis. 

• b. Red cell survival is shortened with a mild to moderate decrease in red cell life span, possible due to a “uremic” toxin.

• c. Blood loss is common in uremic patients, possibly secondary to abnormal coagulation due to decreased platelet function.

• d. Marrow space fibrosis occurs with osteitis fibrosa of secondary hyperparathyroidism resulting in decreased erythropoiesis.

• Hypertension occurs in 80% to 90% of patients with renal insufficiency. Several factors contribute:

• a. Expansion of extracellular fluid volume; this may arise because of reduced ability of the kidney to excrete ingested sodium.

• b. Increased activity of the renin-angiotensin system is common; many patients with advanced renal failure have renin levels that are not completely suppressed by the elevated blood pressure.

• c. Dysfunction of the autonomic nervous system occurs with insensitive baroreceptor sensitive and with increased sympathetic tone.

• d. Possible diminished presence of vasodilators: there may be decreased renal generation of prostaglandins or of factors in the kallikrein-kinin system.

. Hypertension:

PATHOGENESIS OF UREMIC SYNDROME

• Since the uremic syndrome resembles a systemic intoxication, the search for a putative uremic toxin has been the subject of intensive investigation

• As yet, however, no single compound has been found to produce the clinical picture of uremia.

• Therefore it is more likely that multiple factors contribute to the pathogenesis of this syndrome.

Retained Metabolic Products:• Many chemical compounds have been suspected to be

responsible for the uremic syndrome. • However, a distinct relationship between one or a combination

of these substances and the entire syndrome has not been established in man: This theory is supported by the following findings

• Marked symptomatic improvement occurs after decraesing protein in the diet. This suggests that metabolites of protein are retained in renal failure and exert toxic effects.

• 2. Effective dialysis results in marked symptomatic improvement even though protein continues to be ingested. This suggests that toxic metabolites are removed by dialysis.

• 3. Uremic plasma seriously interferes with a variety of normal cell functions. The same plasma after dialysis has no adverse effects.

Overproduction of Counter-regulatory Hormones

• In CRF there is overproduction of parathyroid hormone in response to hypocalcemia and

• Natriuretic hormone in response to volume overload

• These hormones have been suggested to contribute to many aspects of the uremic state.

Underproduction of Renal Hormones:

• Decreased erythropoietin production causes anemia.

• Decreased 1-hydroxylation of vitamin D3 contributes to bone disease.

• Clearly, these and other such deficiencies could play a role in the uremic state

Altered Calcium and Phosphorus Metabolism (Renal Osteodystrophy):

• As GFR decreases there is a slight retention of phosphorus.

• Phosphorus retention can lead to hypocalcemia, which stimulates PTH.

• The latter causes phosphaturia, with restoration of serum phosphorus and calcium toward normal.

• However, this occurs only at the expense of elevated serum PTH levels.

• This cycle repeats itself in progressive renal failure with PTH levels increasing progressively

• Ultimately, the renal tubule can no longer respond to higher levels of PTH with a further decrease in phosphorus reabsorption

• When this occurs, hyperphosphatemia develops, hypocalcemia may become prominent and PTH level can increase to very high levels.

• High PTH levels cause bone disease with severe osteitis fibrosa.

• Altered vitamin D metabolism occurs secondary to decreased renal mass or to phosphate retention, with decreased synthesis of 1,25 (OH)2 D3.

• This deficiency leads to: - Diminished intestinal absorption of calcium- impaired suppression of PTH secretion for

any increase in serum calcium level and altered collagen synthesis.

- With advanced renal failure, these events can lead to secondary hyperparathyroidism and osteomalacia.

• Normally, the kidney is site of:- fluid and electrolyte regulation - waste-product elimination.- acid-base homeostasis - hormone production and secretion- acid-base homeostasis• In the presence of renal failure, these functions are not

performed adequately and metabolic abnormalities OCCUR (anemia, acidemia, hyperkalemia, hyperparathyroidism, malnutrition, and hypertension)

• Uremia usually develops only after the creatinine clearance falls to less than 10 mL/min, although some patients may be symptomatic at higher clearance levels, especially if renal failure acutely develops

Concluding remarks I

Concluding remarks II

• Renal failure can be:• Acute or Chronic• The causes can be Pre-renal, Renal or Pos-

renal• ARF may progress to CRF• ARF can occur in the setting of CRF• The clinical manifestations are due to the

derangement of normal functions of the kidney