Altered Renal Function

Overview of Kidney Diseases Classified by site or cause of disease Classified by site or cause of disease Organization by site: Organization by site: –Prerenal –Intrarenal (Renal) –Postrenal 2

Prerenal disease Results from inadequate blood flow to the kidney Results from inadequate blood flow to the kidney –Decreased intravascular volume –Lesions in the renal arteries –Hypotension 3

Renal diseases Result from direct damage to nephron Result from direct damage to nephron Glomerular disorders Glomerular disorders Tubulointerstitial disorders – disorders of the medullary tubules and interstitial cells Tubulointerstitial disorders – disorders of the medullary tubules and interstitial cells 4

Postrenal diseases Commonly due to urinary tract obstruction Commonly due to urinary tract obstruction –Kidney stones –Tumors of bladder, ureters or prostate gland 5

Obstructive Disorders Interference with urine flow at any point Interference with urine flow at any point Anatomic or functional Anatomic or functional Impedes flow proximal to blockage Impedes flow proximal to blockage Dilates urinary system Dilates urinary system Increases risk for infection Increases risk for infection Compromises renal function Compromises renal function Anatomic changes are called obstructive uropathy Anatomic changes are called obstructive uropathy 6

Causes of obstruction Congenital malformations Congenital malformations Stones Stones Abdominal tumor or inflammation and scarring Abdominal tumor or inflammation and scarring Tumor of urinary system or prostate Tumor of urinary system or prostate Severe pelvic organ prolapse in women Severe pelvic organ prolapse in women 7

Consequences depend on: Location of lesion Location of lesion Whether one or both upper urinary tracts are involved Whether one or both upper urinary tracts are involved Severity and completeness of blockage Severity and completeness of blockage Duration of blockage Duration of blockage Nature of the lesion Nature of the lesion 8

Obstruction causes dilation: Of ureters – hydroureter Of ureters – hydroureter Of renal pelvis and calyces –hydronephrosis Of renal pelvis and calyces –hydronephrosis Of both - ureterohydronephrosis Of both - ureterohydronephrosis 9

10 There was a large renal calculus (stone) that obstructed the calyces of the lower pole of this kidney, leading to a focal hydronephrosis (dilation of the collecting system).

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12 Here is a kidney with much more advanced hydronephrosis in which there is only a thin rim of remaining renal cortex

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Initial tubular damage decreases the ability to concentrate urine, causing an increase in urine volume, decrease concentration Initial tubular damage decreases the ability to concentrate urine, causing an increase in urine volume, decrease concentration Affected kidney cannot conserve water, sodium, or bicarb, or excrete potassium, or hydrogen ions. Affected kidney cannot conserve water, sodium, or bicarb, or excrete potassium, or hydrogen ions. Leads to metabolic acidosis and dehydration. Leads to metabolic acidosis and dehydration. 14

Recovery depends on Completeness of blockage and duration. 15

Body can partially compensate if one kidney is affected by compensatory hypertrophy of other kidney Body can partially compensate if one kidney is affected by compensatory hypertrophy of other kidney –No increase in number of nephrons –Increase in size of glomerulus and tubules –Ability decreases with age –Is reversible if other kidney recovers 16

Relief of obstruction of partial obstruction of both kidneys Usually mild Usually mild Restores fluid and electrolyte balance Restores fluid and electrolyte balance Occasionally, can result in output of 10L/day Occasionally, can result in output of 10L/day Can cause dehydration and electrolyte imbalance Can cause dehydration and electrolyte imbalance 17

Obstruction of bladder outlet or urethra affects upper and lower tracts. Partial obstruction can lead to over active bladder and urine retention Partial obstruction can lead to over active bladder and urine retention Can back up and cause hydroureter, hydronephrosis and impaired kidney function Can back up and cause hydroureter, hydronephrosis and impaired kidney function Urine can be a microbiological growth medium – infection of obstructed kidney can cause further damage and scarring Urine can be a microbiological growth medium – infection of obstructed kidney can cause further damage and scarring 18

Could lead to Hypertension Renin-angiotensin pathway in acute unilateral obstruction Renin-angiotensin pathway in acute unilateral obstruction –Increased renin  angiotensin I  angiotensin II  increased aldosterone  increased Na and water retention Due to water and sodium and urea retention in chronic bilateral partial obstruction Due to water and sodium and urea retention in chronic bilateral partial obstruction 19

Kidney stones or renal calculi Masses of crystals, protein or other substances Masses of crystals, protein or other substances Common cause of obstruction in adults Common cause of obstruction in adults 2-3 % of U.S. population 2-3 % of U.S. population Recurrence within 10 years is 50 % Recurrence within 10 years is 50 % 20

Influenced by age, gender, race, geographic location, season, fluid intake, diet and occupation. Influenced by age, gender, race, geographic location, season, fluid intake, diet and occupation. Seen in more men than women Seen in more men than women Less risk if physically active and drink adequate water Less risk if physically active and drink adequate water Other risk factors Other risk factors –Overweight, Caucasian, previous stones, infections 21

22 Type of Stone Frequency Calcium oxalate (or phosphate)75% - more in men Magnesium ammonium phosphate 12% (struvite, or "triple phosphate") - more in women Uric acid (Gout)6% Cystine 1% Other 6%

Increased renal excretion of these molecules Increased renal excretion of these molecules Decreased urine volume Decreased urine volume Change in pH of urine Change in pH of urine –Alkaline urine increases risk of calcium phosphate stones –Acid urine increases risk of uric acid stones 23

Size of stone determines likelihood it will be passed. < 0.5 cm 50 % chance < 0.5 cm 50 % chance 1 cm almost no chance ( unless ureter dilated by previous passage) 1 cm almost no chance ( unless ureter dilated by previous passage) Develop in renal tubules, calyces, ureter or bladder Develop in renal tubules, calyces, ureter or bladder 24

Clinical manifestations Pain (renal colic) – can determine location Pain (renal colic) – can determine location Nausea / vomiting Nausea / vomiting Chills, fever Chills, fever hematuria hematuria 25

Treatment Urinalysis and analysis of stones Urinalysis and analysis of stones Removal by surgery/ percutaneous lithotripsy Removal by surgery/ percutaneous lithotripsy Drugs to dissolve stones Drugs to dissolve stones 26

Prevention of future stones Treat underlying metabolic disorders Treat underlying metabolic disorders Water intake = urine output of 2 -3 L /day Water intake = urine output of 2 -3 L /day Reduction in dietary oxalates (chocolate, nuts, soybeans, rhubarb and spinach) and animal protein for uric acid stones Reduction in dietary oxalates (chocolate, nuts, soybeans, rhubarb and spinach) and animal protein for uric acid stones Increased dietary fiber Increased dietary fiber Do NOT decrease calcium intake – increases risk of stones Do NOT decrease calcium intake – increases risk of stones 27

Urinary Tract infections Bacteria most common cause Bacteria most common cause Can also be due to viruses, fungi or parasites Can also be due to viruses, fungi or parasites Classified by location in system or by complicating factors Classified by location in system or by complicating factors 28

Cystitis – inflammation of the bladder Cystitis – inflammation of the bladder –Urinary frequency –Dysuria – painful or difficult urination –Urgency –Lower abdominal, lower back or suprapubic pain May be uncomplicated in otherwise healthy individual May be uncomplicated in otherwise healthy individual 29

Incidence Young adult women – 0.2/month Young adult women – 0.2/month Lifetime risk in women 50% Lifetime risk in women 50% Young adult men prevalence < 1% Young adult men prevalence < 1% High risk groups: High risk groups: –Premature infants –Sexually active women –Women using a diaphragm or spermicide –Diabetics –HIV or immunosuppressive disorders –Obstruction of lower urinary tract 30

Most UTIs are caused by: gram negative bacteria of the intestinal tract Escherichia coli – 80% of all uncomplicated infections. Can form pili allowing bacterium to adhere to bladder epithelium Cranberry juice decreases bacterial adhesions by epicatechin Staphylococcus saprophyticus 10-20% Other entreobacter species (Klebsiella, Proteus) remaining 5% 31

Treatment Antibiotics Antibiotics Drink normal amounts of water, but avoid bladder irritants, such as caffeine Drink normal amounts of water, but avoid bladder irritants, such as caffeine 32

Nonbacterial cystitis Same symptoms but without infection Same symptoms but without infection Dysfunction of external sphincter, urethritis, or inflammation of glands near vagina Dysfunction of external sphincter, urethritis, or inflammation of glands near vagina – antibiotics, drugs to relax urethral sphincter, retraining of voiding habits Interstitial cystitis – may be due to an autoimmune reaction, mucus deficiency or abnormal mast cells. Interstitial cystitis – may be due to an autoimmune reaction, mucus deficiency or abnormal mast cells. 33

Tubulointerstitial disorders Acute pyelonephritis (pyelo – pelvis) Acute pyelonephritis (pyelo – pelvis) –Urinary obstruction and reflux of urine most common risk factors –One or both kidneys may be involved –Most common in women –Usually E. coli, Proteus or Pseudomonas –Usually By ascending microorganisms, but can be carried in blood. 34

Acute pyelonephritis Inflammation is usually focal, affecting pelvis, calyces, and medulla but glomeruli not usually involved. Inflammation is usually focal, affecting pelvis, calyces, and medulla but glomeruli not usually involved. Kidney is infiltrated with wbc’s – pyuria Kidney is infiltrated with wbc’s – pyuria Healing involves scarring and atrophy of affected tubules Healing involves scarring and atrophy of affected tubules 35

Acute pyelonephritis Clinical manifestations: Clinical manifestations: –Acute onset –Fever or chills –Flank or groin pain –Frequency and dysuria May be difficult to distinguish from cystitis – look for white cell casts May be difficult to distinguish from cystitis – look for white cell casts Treatment: Treatment: –Microorganism specific antibiotics 36

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Chronic Pyelonephritis Cause is more difficult to determine Cause is more difficult to determine More likely in patients with reflux or renal stones More likely in patients with reflux or renal stones Scarring can lead to impaired urine- concentrating ability, leading to chronic renal failure Scarring can lead to impaired urine- concentrating ability, leading to chronic renal failure May be due to drug toxicity from analgesics, such as phenacetin, aspirin, acetaminophen May be due to drug toxicity from analgesics, such as phenacetin, aspirin, acetaminophen Ischemia, radiation, immune-complex disease Ischemia, radiation, immune-complex disease 38

Chronic Pyelonephritis Manifestations are often minimal- Manifestations are often minimal- –Hypertension –Frequency and Dysuria –Flank pain Diagnosis Diagnosis –Urinalysis –Intravenous pyelography, ultrasound Treatment Treatment –Relieve obstruction –antibiotics 39

Normal glomerulus 40

Acute pyelonephritis 41 At high magnification, many neutrophils are seen in the tubules and interstitium in a case of acute pyelonephritis.

Ascending bacterial infection 42 This is an ascending bacterial infection leading to acute pyelonephritis.

Chronic pyelonephritis 43

Chronic pyelonephritis 44 The large collection of chronic inflammatory cells here is in a patient with a history of multiple recurrent urinary tract infections. This is chronic pyelonephritis.

Glomerular disorders Due to a change or dysfunction of the glomerular capillaries Due to a change or dysfunction of the glomerular capillaries –Changes in membrane permeability –Change in GFR –Protein or blood cells in the urine –Systemic changes – hypertension; edema; acid-base and electrolyte imbalances 45

Glomerulonephritis Caused by a number of factors, most commonly abnormal immune response Caused by a number of factors, most commonly abnormal immune response –Infection –Toxins –Vascular diseases –Systemic diseases (diabetes mellitus) Can be diffuse, focal or segmental Can be diffuse, focal or segmental Can be membranous, proliferative, sclerotic, or crecentic Can be membranous, proliferative, sclerotic, or crecentic Often divided into acute, rapidly progressive and chronic forms. Often divided into acute, rapidly progressive and chronic forms. 46

Acute Glomerulonephritis Often associated with streptococcal infection Often associated with streptococcal infection Abrupt onset 7-10 days after strept throat or skin infection (impetigo) Abrupt onset 7-10 days after strept throat or skin infection (impetigo) –Also staphylococcus or viruses Strept antigens deposit in glomerular basement membrane and attract neutrophils and macrophages, initiating phagocytosis and release of inflammatory mediators that damage cells on both side of the basement membrane. Strept antigens deposit in glomerular basement membrane and attract neutrophils and macrophages, initiating phagocytosis and release of inflammatory mediators that damage cells on both side of the basement membrane. 47

Poststreptococcal GN 48 Post-streptococcal glomerulonephritis is immunologically mediated, and the immune deposits are distributed in the capillary loops in a granular, bumpy pattern because of the focal nature of the deposition process.

Acute Glomerulonephritis Symptoms occur days after infection Symptoms occur days after infection –Hematuria –Proteinuria –Decreased GFR, oliguria –Hypertension –Edema around eyes, feet and ankles –Ascites or pleural effusion Biopsy – immune complexes and proliferation Biopsy – immune complexes and proliferation Most recover without significant loss of renal function or recurrence Most recover without significant loss of renal function or recurrence 49

Rapidly Progressive GN Develops over a period of days or weeks Develops over a period of days or weeks Primarily adults in 50’s and 60’s Primarily adults in 50’s and 60’s May be idiopathic or assoc. with a proliferative disease May be idiopathic or assoc. with a proliferative disease By the time of diagnosis patient has renal insufficiency By the time of diagnosis patient has renal insufficiency Proliferation of cells in Bowman’s space with crescent formation Proliferation of cells in Bowman’s space with crescent formation Progresses to renal failure in a few weeks or months Progresses to renal failure in a few weeks or months Hematuria is common, may see proteinuria, edema or hypertension Hematuria is common, may see proteinuria, edema or hypertension 50

RPGN 51 This immunofluorescence micrograph of a glomerulus demonstrates positivity with antibody to fibrinogen. With a rapidly progressive GN, the glomerular damage is so severe that fibrinogen leaks into Bowman's space, leading to proliferation of the epithelial cells and formation of a crescent.

Goodpasture Syndrome Antibody formation against pulmonary and glomerular capillary basement membranes Antibody formation against pulmonary and glomerular capillary basement membranes Activation of complement and neutrophils damage glomerular basement membrane Activation of complement and neutrophils damage glomerular basement membrane Men years of age Men years of age Pulmonary hemorrhage and renal failure Pulmonary hemorrhage and renal failure 52

Goodpasture Syndrome Treatment must begin early or prognosis is poor Treatment must begin early or prognosis is poor –Anticoagulants reduce fibrin content of crescents –Plasmapheresis with steroids and immunosuppression therapy –Dialysis or transplant if kidneys fail 53

Goodpasture’s syndrome 54 This immunofluorescence micrograph shows positivity with antibody to IgG has a smooth, diffuse, linear pattern that is characteristic for glomerular basement membrane antibody with Goodpasture's syndrome.

Chronic Glomerulonephritis Several diseases with a progressive course leading to chronic renal failure Several diseases with a progressive course leading to chronic renal failure Two patterns – deposition of antigen-antibody complexes, or antigens specific for GBM. Two patterns – deposition of antigen-antibody complexes, or antigens specific for GBM. Complement activation and phagocyte activity damage wall of capillary and cause proliferation of extracellular matrix, affecting GFR Complement activation and phagocyte activity damage wall of capillary and cause proliferation of extracellular matrix, affecting GFR 55

Chronic Glomerulonephritis At first see increased membrane permeability and lose cells (hematuria) or protein into urine (proteinuria) At first see increased membrane permeability and lose cells (hematuria) or protein into urine (proteinuria) Fibrin is deposited into Bowman’s space – crescent formation Fibrin is deposited into Bowman’s space – crescent formation Renal blood flow and GFR is reduced Renal blood flow and GFR is reduced 56

Chronic Glomerulonephritis Clinical manifestations: Clinical manifestations: –Hematuria – smoky brown-tinged urine as opposed to pink or red –Proteinuria > 3-5 g/day mostly albumin – ↓ GFR leads to fluid retention and hypertension After 10 – 20 years, renal insufficiency develops and progresses to renal failure After 10 – 20 years, renal insufficiency develops and progresses to renal failure 57

Chronic Glomerulonephritis Treatment: Treatment: –Treat underlying disease –Steroids do not change the course of the disease –Correct accompanying problems such as volume disorders, blood pressure –Ultimately dialysis or transplant 58

Nephrotic Syndrome Defined as excretion of 3.5 or more grams of protein / day Defined as excretion of 3.5 or more grams of protein / day Characteristic of glomerular injury Characteristic of glomerular injury Also see hypoalbuminemia, edema, hyperlipidemia Also see hypoalbuminemia, edema, hyperlipidemia Loss of immunoglobulins can increase susceptibility to infections Loss of immunoglobulins can increase susceptibility to infections 59

Nephrotic Syndrome Treatment: Treatment: –Diet – normal protein, low-fat, salt restricted –Diuretics –Immunosuppression –Protein supplements –Removal of glomerular membrane toxic factor 60

Renal Failure Acute renal failure – abrupt decrease in renal function Acute renal failure – abrupt decrease in renal function –Increase in BUN and creatinine –Usually oliguria (output < 30 ml/hour or 400 ml/day) –Most cases are reversible if diagnosed and treated early Prerenal most common cause – failure to restore blood volume or pressure and oxygen can lead to acute tubular necrosis or acute cortical necrosis Prerenal most common cause – failure to restore blood volume or pressure and oxygen can lead to acute tubular necrosis or acute cortical necrosis 61

Acute Renal Failure Intrarenal acute renal failure Intrarenal acute renal failure –Usually due to acute tubular necrosis Usually caused by ischemia most often after surgery ( %) Usually caused by ischemia most often after surgery ( %) Also sepsis, burns, obstetrical complications, antibiotics, radiocontrast media, other toxic substances Also sepsis, burns, obstetrical complications, antibiotics, radiocontrast media, other toxic substances –Whatever the cause, decreased GFR and oliguria 62

Acute Renal Failure Postrenal acute renal failure Postrenal acute renal failure –Usually due to urinary tract obstruction that affects both kidneys –Characterized by several hours of anuria with flank pain, followed by polyuria 63

Acute Renal Failure Clinical symptoms of ARF are divided into three stages: Clinical symptoms of ARF are divided into three stages: Stage1 Oliguria: ↓ urine vol about 25 % of normal to anuria can last 1-3 weeks ↑ BUN, plasma creatinine ↑ K + (hyperkalemia) and electrolyte imbalance fluid retention and edema congestive heart failure 64

Stage 2 Diuresis: 3-4 L/day of urine Tubules still damaged, but recovering Can lose too much Na + and K + May see extracellular volume depletion Stage 3 Recovery May take 3-12 months for plasma creatinine to return to normal About 30 % never regain normal kidney function. 65

Acute Renal Failure Treatment Treatment –Prevention if possible –Maintain individual’s life until renal function is recovered Correct fluid and electrolyte imbalances Correct fluid and electrolyte imbalances Treat infections Treat infections Maintain nutrition and cardiac function Maintain nutrition and cardiac function Remember drugs and/or medications are not excreted! Remember drugs and/or medications are not excreted! 66

Chronic Renal Failure Progressive and irreversible loss of nephrons Progressive and irreversible loss of nephrons Slow development (years) Slow development (years) Alterations in salt and water balance not apparent until renal function is less than 25% of normal. Alterations in salt and water balance not apparent until renal function is less than 25% of normal. Common causes: Common causes: –Chronic glomerulonephritis –Chronic pyelonephritis 67

Chronic Renal Failure Clinical manifestations are often described using the term uremia –symptoms due to accumulation of toxins in plasma. Clinical manifestations are often described using the term uremia –symptoms due to accumulation of toxins in plasma. –hypertension –Anorexia –Nausea –Vomiting –Diarrhea –Weight loss –Pruritis (itching) –Edema –Anemia –Neurologic changes 68

Chronic Renal Failure Diagnosis is by increased BUN and serum creatinine; imaging will show small kidneys, and can be confirmed by biopsy Diagnosis is by increased BUN and serum creatinine; imaging will show small kidneys, and can be confirmed by biopsy Management includes: Management includes: –Diet control – restrict proteins, potassium –Evaluate fluid and sodium levels –Treat with erythropoietin as needed. 69