Altered Renal Function

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

Prerenal disease Results from inadequate blood flow to the kidney Decreased intravascular volume Lesions in the renal arteries Hypotension Systemic disorders that decrease urine output Creatinine clearance? Plasma creatine? BUN?

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

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

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

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

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

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

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). The stasis from the obstruction and dilation led to infection. The infection with inflammation is characterized by the pale yellowish-tan areas next to the dilated calyces with hyperemic mucosal surfaces. The upper pole is normal and shows good corticomedullary demarcations.

Here is a kidney with much more advanced hydronephrosis in which there is only a thin rim of remaining renal cortex. Such a kidney is non-functional and a source for ongoing infection. If this process is unilateral, then the problem originates from the ureteral orifice up to the pelvis. In this case, a large "staghorn" calculus (so named because the prominent projections of the stone into the calyces resemble deer antlers) was present that filled up the pelvis and calyceal system. If this process were bilateral, then the problem would originate in the bladder trigone or urethra (or the prostate around the urethra) or some process (such as a large neoplasm) that could impinge on both ureters

Dilation leads to: Enlargement and fibrosis of distal nephron in 7 days Interference with distal and proximal nephron in 14 days Damage to glomeruli in 28 days, also see reduction in cortex and medulla

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

Recovery depends on Completeness of blockage and duration. Complete obstruction → damage to tubules within hours, and irreversible damage within 4 weeks. Partial recovery if removed within 56-69 days Partial obstruction can lead to permanent impairment of ability to concentrate urine, reabsorb bicarbonate, excrete ammonia, or regulate acid-base balance.

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

Relief of obstruction of partial obstruction of both kidneys or complete obstruction of one results in postobstructive diuresis. Usually mild Restores fluid and electrolyte balance Occasionally, can result in output of 10L/day Can cause dehydration and electrolyte imbalance

Obstruction of bladder outlet or urethra affects upper and lower tracts. Partial obstruction can lead to over active bladder and urine retention 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

Hypertension can result Renin-angiotensin pathway in acute unilateral obstruction Due to water and sodium and urea retention in chronic bilateral partial obstruction

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

Influenced by age, gender, race, geographic location, season, fluid intake, diet and occupation. Seen in more men than women Less risk if physically active and drink adequate water

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

Get increased concentrations of these molecules in the urine with: Increased renal excretion of these molecules Decreased urine volume Change in pH of urine Alkaline urine increases risk of calcium phosphate stones Acid urine increases risk of uric acid stones

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

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

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

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

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

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

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

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%

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

Nonbacterial cystitis Same symptoms but without infection Dysfunction of external sphincter, urethritis, or inflammation of glands near vagina Tx: 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.

Tubulointerstitial disorders 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 Us. E. coli, Proteus or Pseudomonas Proteus, Pseudomonas are urea splitters Us. By ascending microorganisms, but can be carried in blood.

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

Acute pyelonephritis 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 Treatment: Microorganism specific antibiotics

Chronic Pyelonephritis Cause is more difficult to determine More likely in patients with reflux or renal stones 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 Ischemia, radiation, immune-complex disease

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

Normal glomerulus

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

Ascending bacterial infection This is an ascending bacterial infection leading to acute pyelonephritis. Numerous PMN's are seen filling renal tubules across the center and right of this picture.

Chronic pyelonephritis Both lymphocytes and plasma cells are seen at high magnification in this case of chronic pyelonephritis. It is not uncommon to see lymphocytes accompany just about any chronic renal disease: glomerulonephritis, nephrosclerosis, pyelonephritis. However, the plasma cells are most characteristic for chronic pyelonephritis.

Chronic pyelonephritis 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 Changes in membrane permeability Change in GFR Protein or blood cells in the urine Systemic changes – hypertension; edema; acid-base and electrolyte imbalances

Glomerulonephritis 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 membranous, proliferative, sclerotic, or crecentic Often divided into acute, rapidly progressive and chronic forms.

Acute Glomerulonephritis Often associated with streptococcal infection 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.

Poststreptococcal GN 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.

Proliferative GN- poststretococcal This glomerulus is hypercellular and capillary loops are poorly defined. This is a type of proliferative glomerulonephritis known as post-streptococcal glomerulonephritis.

Acute Glomerulonephritis Symptoms occur 10-21 days after infection Hematuria Proteinuria Decreased GFR, oliguria Hypertension Edema around eyes, feet and ankles Ascites or pleural effusion Biopsy – immune complexes and proliferation Most recover without significant loss of renal function or recurrence

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

RPGN Here is another glomerulus with epithelial crescents squashing the glomerular tufts from all sides. RPGN may be idiopathic or may result from SLE, post-infectious GN (as in some cases of post-streptococcal GN), from various types of vasculitis, and from Goodpasture's syndrome.

RPGN Seen here within the glomeruli are crescents composed of proliferating epithelial cells. Crescentic glomerulonephritis is known as rapidly progressive glomerulonephritis (RPGN) because this disease is very progressive. There are several causes, and in this case is due to SLE. Note in the lower left glomerulus that the capillary loops are markedly thickened (the so-called "wire loop" lesion of lupus nephritis).

RPGN 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 Activation of complement and neutrophils damage glomerular basement membrane Men 20 - 30 years of age Pulmonary hemorrhage and renal failure

Goodpasture Syndrome 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

Goodpasture’s syndrome 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 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

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

Chronic Glomerulonephritis 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

Chronic Glomerulonephritis 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

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

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

Membranous glomerulonephritis Here is the light microscopic appearance of membranous glomerulonephritis in which the capillary loops are thickened and prominent, but the cellularity is not increased. Membranous GN is the most common cause for nephrotic syndrome in adults. Some cases of membranous GN can be linked to a chronic infectious disease such as hepatitis B, a carcinoma, or SLE, but many cases are idiopathic.

Nephritic Syndrome Alteration of filtration leads to loss of rbc’s Also decreased GFR Decreased urine output Azotemia (increased nitrogenous wastes in the blood) Renal tubules undergo disuse atrophy and scarring

Renal Failure 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

Acute tubular necrosis The tubular vacuolization and dilation here is a result of ethylene glycol poisoning. This is representative of acute tubular necrosis (ATN), which has many causes. ATN resulting from toxins usually has diffuse tubular involvement, whereas ATN resulting from ischemia (as in profound hypotension from cardiac failure) has patchy tubular involvement.

Acute Renal Failure Intrarenal acute renal failure Usually due to acute tubular necrosis Usually caused by ischemia most often after surgery (40 -50 %) Also sepsis, burns, obstetrical complications, antibiotics, radiocontrast media, other toxic substances Whatever the cause, get decreased GFR and oliguria

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

Acute Renal Failure 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

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.

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

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

Chronic Renal Failure 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

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

End stage kidney The microscopic appearance of the "end stage kidney" is similar regardless of cause, which is why a biopsy in a patient with chronic renal failure yields little useful information. The cortex is fibrotic, the glomeruli are sclerotic, there are scattered chronic inflammatory cell infiltrates, and the arteries are thickened. Tubules are often dilated and filled with pink casts and give an appearance of "thyroidization."

Atrophy There is a relatively normal kidney at the left with only a few scattered, shallow cortical scars and one fairly large pale tan-yellow scar in the upper pole. The left kidney is atrophic because of renal arterial occlusion. Such a situation can lead to hypertension (Goldblatt kidney).