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209 Cards in this Set

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What is clearance?
The volume of plasma rendered free of a substance in one minute.

Clearance = amount of substance in urine per minute/concentration of substance in plasma

OR

C = U * Volume of urine / P in ml/minute
Ccr is unchanged because you double the plasma concentration and double the amount filtered so the clearance remains the same
#5
#5

Increased pressure will result in stretch and resulting constriction of the afferent arteriole + increased sodium detected by the distal tubule will cause signalling for renin release and constriction of the afferent arteriole.
Tubular function calculations:
OR

clearance/GFR
Spironolactone
#3
#4
#4
#2
#1
Beta-hydroxybutarate
What is the normal excretion of creatinine per day?
50 mg per Kg of weight
overestimates GFR
Types of glomerular injury:
Segmental Glomerularsclerosis:
What does "focal" mean?
That less than 50% of the glomeruli on light microscopy are involved
Diffuse glomerular process:
Membranous GN:
Membranoproliferative GN:
Glomerular Crescents:
Mesangial Expansion:
Linear Pattern IF:
Granular Pattern IF:
Membranoproliferative GN
FSGC
3 functions of the mesangium:
Phagocytic, contractile and proliferation (ECM)
What two proteins are in the podocyte slit diaphragm?
Nephrin and Podocin
What is the basement membrane made out of?
Type IV Collagen
Where are the different collagen types located?
I = Bone
II = Cartilage
IV = Kidney and Lungs and Eyes
III = Everywhere else
Glomerulonephritis:
Nephrotic Vs Nephritic GN:
Normal protein secretion by the glomerulus:
Mechanisms of proteinuria:
Proximal Tubule Dysfunction:
Overload Proteinuria:
Clinical Syndromes of Kidney disease:
Patterns of Glomerular Injury:
Immune VS nonimmune injury:
What type of kidney disease has a linear IF pattern:
Goodpasture's Disease

Everything else is a granular pattern.
The vasculitides have a "pauci-immune pattern" (looks pale and diffuse)
What type of kidney disease has a linear IF pattern:
Goodpasture's Disease

Everything else is a granular pattern.
The vasculitides have a "pauci-immune pattern" (looks pale and diffuse)
What type of kidney disease has a linear IF pattern:
Goodpasture's Disease

Everything else is a granular pattern.
The vasculitides have a "pauci-immune pattern" (looks pale and diffuse)
What type of kidney disease has a linear IF pattern:
Goodpasture's Disease

Everything else is a granular pattern.
The vasculitides have a "pauci-immune pattern" (looks pale and diffuse)
What type of kidney disease has a linear IF pattern:
Goodpasture's Disease

Everything else is a granular pattern.
The vasculitides have a "pauci-immune pattern" (looks pale and diffuse)
What type of kidney disease has a linear IF pattern:
Goodpasture's Disease

Everything else is a granular pattern.
The vasculitides have a "pauci-immune pattern" (looks pale and diffuse)
Immune mediated injury:
Immune complex mediated:
Cytotoxic Antibodies:
Electrical charge and location of deposition:
Definition of Azotemia:
Azotemia: refers to an elevation of blood urea nitrogen and creatinine levels and is largely related to a decreased GFR.

Prerenal azotemia: encountered when there is hypoperfusion of the kidneys, which decreases GFR in the absence of parenchymal damage.

Postrenal Azotemia: results when urine flow is obstructed below the level of the kidney.
Definition of uremia:
When azotemia progresses to clinical manifestations and systemic biochemical abnormalities, it is termed uremia. Uremia is characterized not only by failure of renal excretory function but also by a host of metabolic and endocrine alterations incident to renal damage.

*uremic gastroenteritis, peripheral neuropathy and uremic fibrinous pericarditis*
Acute nephritic syndrome:
A glomerular syndrome dominated by the acute onset of usually grossly visible hematuria, mild to moderate proteinuria, azotemia, edema and hypertension; it is the classic presentation of acute post-renal streptococcal glomerulonephritis.
Nephrotic Syndrome:
A glomerular syndrome characterized by heavy proteinuria (over 3.5 gm/per day), hypoalbuminemia, severe edema, hyperlipidemia and lipiduria
Rapidly progressive glomerulonephritis:
Results in loss of renal function in a few days or weeks and is manifested by microscopic hematuria, dysmorphic red blood cells and red blood cells casts in the urine sediment and mild to moderate proteinuria.
Nephritis caused by circulating immune complexes:
Type III hypersensitivity reaction
Antigen-antibody complexes are trapped in the glomeruli, where they produce injury in large part through the activation of complement and the recruitment of leukocytes. Glomerular lesions usually consist of leukocyte infiltration into glomeruli and variable proliferation of endothelial, mesangial and parietal epithelial cells. “Clumps” of deposits can be seen in the subendothelium, subepithelium or mesangium. A granular pattern is seen with IF.
If the complexes are from a short lived process, the glomeruli may recover. If the process is chronic, repeated cycles of immune complex formation, deposition and injury may occur, leading to chronic GN.
Nephritis caused by In Situ immune complexes:
The best characterized disease in this group is the anti-GBM antibody GN. Deposition of antibodies toward the GBM produces a linear pattern on IF. The basement membrane antigen responsible is a component of the a3 chain of collagen type IV. Sometimes these antibodies also cross-react with the basement membranes of lung alveoli, leading to Goodpasture’s syndrome. Histology may show crescents and severe glomerular damage.
Antibodies may also react with “planted” antigens such as DNA, bacterial proteins and aggregations of IgG. Most of these will have a granular pattern on IF. The location of the antigens determine the reaction; complexes deposited in the endothelium or subendothelium elicit an inflammatory response in the glomeruli with infiltration of leukocytes. Complexes deposited in the epithelium or subepithelium are largely non-inflammatory and elicit lesions similar to those of Heymann nephritis or membranous nephropathy.
Mediators of immune injury:
A major pathway of antibody initiated injury is complement-leukocyte-mediated. Activation of complement leads to generation of chemotactic C5 and the recruitment of neutrophils and monocytes. Neutrophils produce proteases, which cause GBM degradation; free radicals, which cause cell damage; and arachidonic acid metabolites, which reduce GFR.
Another model includes activation of the C5-C9 lytic component without neutrophil activation. This causes epithelial cell detachment and stimulates mesangial and epithelial cells to secrete various mediators of cell injury. The membrane attack complex also upregulates TGF-b receptors on podocytes, which leads to synthesis of ECM and thickening of the GBM.
Antibodies directed to glomerular cell antigens may also be directly cytotoxic to glomerular cells. Other mediators of glomerular damage include monocytes and macrophages, platelets (prostaglandins and growth factors) and fibrin related products (leukocyte infiltration and cell proliferation).
Other mechanisms of glomerular injury:
Podocyte injury – Injury is reflected by morphological changes in the podocytes, which include effacement of the foot processes, vacuolization and retraction and detachment of cells from the GBM and functionally by proteinuria. Loss of slit diaphragms is key in the development of proteinuria. Abnormalities of the slit diaphragm may also result from mutations in its components, such and nephrin and podocin. Such mutations are the cause of rare hereditary forms of the nephrotic syndrome.
Nephron loss – Once renal disease destroys enough functioning nephrons to reduce the GFR to 30-50% of normal, proteinuria develops and kidneys develop widespread glomerulosclerosis. This is because the remaining glomeruli undergo hypertrophy to maintain renal function, but this leads to maladaptive changes that lead to endothelial and epithelial cell injury, increased permeability to proteins and accumulation of proteins and lipids in the mesangial matrix. This is followed by capillary collapse and obliteration, hyaline entrapment, increased deposition of mesangial matrix, and ultimately by segmental or global sclerosis of glomeruli.
What are the three most frequent causes of nephrotic syndrome in adults?
Diabetes, amyloidosis and SLE.
The nephrotic syndrome:
Any damage to the glomeruli allows protein to escape from the plasma into the glomerular filtrate. This results in proteinuria and hypoalbuminemia. The generalized edema of nephrotic syndrome is a consequence of the drop in plasma oncotic pressure due to loss of albumin and primary salt and water retention by the kidney (due to drop in vascular volume and resultant increase in aldosterone secretion). Hyperlipidemia may result from low albumin triggering the liver to produce more lipoproteins. Increased lipidemia results in lipiduria.
Minimal change disease:
The most frequent cause of nephrotic syndrome in children ages 1 – 7.
Characterized by glomeruli that have a normal appearance by light microscopy but show effacement of podocyte foot processes when viewed with electron microscopy. Proximal tubules laden with protein droplets and lipids may also be seen. The pathogenesis is unclear, but is thought to be a result of a T-cell derived factor that damages podocytes.
Clinical course: No hypertension or loss of renal function is seen, just proteinuria. Usually just the smaller proteins such as albumin are detected in the urine. Children with this disease do well with a short course of corticosteroid therapy, but adults respond more slowly and are more prone to relapse.
Focal and segmental glomerulosclerosis:
FSGS is a lesion characterized by sclerosis affecting some but not all glomeruli (focal) and involving only segments of each affected glomerulus. This histologic picture is often associated with the nephrotic syndrome, with a higher incidence of hematuria and hypertension than minimal change disease. The proteinuria is non-selective and response to corticoid therapy is poor. At least 50% of FSGS patients will progress to renal failure in ten years. In general, adults fare less well than children.
The pathogenesis is unclear, but injury to the podocytes is thought to be the initiating event. As with MCD, permeability-increasing factors produced by lymphocytes have been proposed as a cause.
The affected glomeruli show increased mesangial matrix, obliterated capillary lumens and deposition of hyaline masses and lipid droplets. On EM podocytes show effacement of the foot processes.
Membranous Nephropathy (membranous glomerulonephritis):
This slowly progressive disease is most common between 30 and 50 years of age and is characterized by the presence of subepithelial immunoglobulin-containing deposits along the GBM. Well developed cases show diffuse thickening of the capillary wall. It is idiopathic in about 85% of cases, but may also be caused by infections, malignant tumors, SLE or other autoimmune conditions, exposure to inorganic salts (gold, mercury) and drugs (NSAIDs, captopril, penicillamine).
MGN is a chronic immune complex nephritis; either from circulating antigen-antibody complexes or antibodies toward endogenous or planted antigens. The pathogenesis of the disease involves complement formation of the C5-C9 attack complex on podocytes. Complement also activates mesangial cells and podocytes, inducing them to produce proteases and oxidants that damage capillary walls, with consequent alterations in filtration.
Onset in idiopathic cases is characterized by the insidious development of the nephrotic syndrome with non-selective proteinuria and non-responsiveness to corticoid therapy. Only about 40% suffer progressive disease terminating in renal failure within 2-20 years. 10-30% have a more benign course with partial or complete remission of proteinuria.
Membranoproliferative glomerulonephritis:
Manifested histologically by alterations in the GBM and mesangium and by proliferation of glomerular cells. Some patients present only with hematuria or proteinuria in the non-nephrotic range; others have a combined nephrotic-nephritic picture. Two major types of MPGN (I and II) are distinguished on the basis of distinct ultrastructural, IF and pathological findings. Type I is far more common.
Most cases of type I seem to be caused by circulating immune complexes, but the inciting antigen is unknown. The pathogenesis of type II, also known as dense deposit disease, is less clear. The abnormality seems to be excessive complement activation – not necessarily caused by antibodies. Some patients have an autoantibody against C3 convertase that leads to uncontrolled cleavage of C3 and activation of the alternative complement pathway. Mutations in the gene for factor H leading to deficiency in factor H may also lead to uncontrolled complement activation. Autoantibodies to factor H or mutations in C3 that prevent factor H inhibition may also occur. Hypocomplementemia may occur in these patients due to complement consumption.
On light microscopy, both types appear similar with large glomeruli with a lobular appearance, proliferation of mesangial and endothelial cells and well as infiltrating leukocytes. The GBM is thickened.
On EM, Type I is characterized by subendothelial deposits. Type II is characterized by dense ribbon like deposits in the lamina densa portion of the GBM.
The prognosis of MPGN is poor. No patients will go into remission. Dense deposit disease has a worse prognosis, and it tends to recur in renal transplant recipients. Like many other GN’s, type I may occur in association with other known disorders such as SLE, hepB and C, chronic liver disease and bacterial infections.
The nephritic syndrome:
A clinical complex, usually of acute onset, characterized by hematuria with dysmorphic RBC’s and RBC casts in the urine, some degree of oliguria and azotemia and hypertension. There may be some proteinuria and edema, but not as severe as in the nephrotic syndrome. The lesions that cause the nephritic syndrome have in common proliferation of the cells within the glomeruli, accompanied by a leukocytic infiltrate. This inflammatory reaction injures the capillary walls, permitting escape of RBC’s in the urine and inducing hemodynamic changes that lead to reduction in GFR. The reduce GFR leads to oliguria, fluid retention and azotemia. Hypertension is the result of fluid retention and some renin release from the ischemic kidneys.
Acute nephritis may be produced by systemic disorders such as SLE, or it may be the result of primary glomerular disease such as acute post-infectious GN.
Acute post-infectious (Post-streptococcal) GN:
Typically caused by glomerular deposition of immune complexes resulting in diffuse proliferation and swelling of resident glomerular cells and infiltration of leukocytes, especially neutrophils. The inciting antigen may be exogenous or endogenous. The classic case of post-streptococcal GN develops in a child 1 to 4 weeks after the individual recovers from a group A strep infection. Only certain strains of B-hemolytic strep are capable of evoking glomerular disease. In most cases the infection is localized to the pharynx or the skin.
Typical features of immune complex disease, such as hypocomplementemia and granular deposits of IgG and complement on the GMB are seen. On light microscopy, the characteristic change in PIGN is a fairly uniformly increased cellularity of the glomerular tufts that affects nearly all the glomeruli. The increased cellularity is caused both by proliferation and swelling of endothelial and mesangial cells and by neutrophilic and monocytic infiltrate. In a few cases there may also be “crescents” that develop in response to severe inflammation – this is an ominous sign. EM shows subepithelial “humps” nestled against the GBM. These deposits are usually cleared over a period of two months.
Onset tends to be abrupt, heralded by malaise, a slight fever, nausea and the nephritic syndrome. In usual cases, oliguria, azotemia and hypertension are mild to moderate. The urine appears smoky brown rather than bright red. Serum complement levels will be low and ASO antibody titers are elevated in post-strep cases. Recovery occurs in most children, but some will develop rapidly progressive GN due to severe injury with crescents or chronic renal disease due to scarring. Adults have a higher rate of progressing to end stage renal disease than children.
IgA nephropathy (Berger disease):
Usually effects children and young adults and begins with an episode of gross hematuria that occurs within 1 or 2 days of a nonspecific upper respiratory tract infection. Typically, the hematuria lasts several days and then subsides, only to recur every few months. It is often associated with loin pain. IgA nephropathy is one of the most common causes of recurrent hematuria and is the most common cause of glomerular disease revealed by biopsies worldwide.
The pathogenic hallmark is the deposition of IgA in the mesangium. Henoch-Schonlein purpura is also characterized by IgA deposition, but in the vessels of the skin producing a rash, the GI tract producing abdominal pain and in the joints and kidneys. The pathogenesis of IgA nephropathy is an abnormality of IgA production and clearance. IgA is increased in the serum by 50% due to increase production in the marrow. Genetics may play a role. Increased IgA synthesis in response to respiratory or GI exposure to environmental antigens may lead to deposition of IgA and IgA-containing immune complexes in the mesangium, where they activate the alternative complement pathway and initial glomerular injury. This disease occurs more frequently in individuals with celiac disease and liver disease.
Histologically, the glomeruli may show mesangial widening and segmental inflammation or crescentic GN. IF shows deposition of IgA in the mesangial regions.
Many individuals maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 25-50% of cases during a period of 20 years.
Hereditary nephritis:
Refers to a group of hereditary glomerular diseases caused by mutations in GBM proteins. The best studied entity is Alport syndrome, in which nephritis is accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts and corneal dystrophy.
The GBM is composed of type IV collagen which is made up of complexes of alpha chains. This type of collagen also is found in the eye. Mutations of any of the alpha chains results in defective collagen assembly and the disease manifestations of Alport syndrome.
Glomeruli appear normal till late in the course, when secondary sclerosis may occur. With progression, there is increasing glomerulosclerosis, vascular sclerosis, tubular atrophy and interstitial fibrosis. On EM, the basement membrane appears thin and attenuated early in the course. Late in the course, the GBM develops irregular foci of thickening or attenuation with pronounced splitting and lamination of the lamina densa, yielding a “basket weave” appearance.
Inheritance is X-linked, with males more affected than females. Affected individuals present between ages 5 to 20 years and overt renal failure occurs between 20 and 50 years of age.
Rapidly progressive (crescentic) glomerulonephritis:
Characterized by rapid and progressive loss of renal function with features of the nephritic syndrome, often with severe oliguria and death from renal failure within weeks to months. Regardless of the cause, the histologic picture is characterized by the presence of crescents produced by proliferation of the parietal cells of Bowman’s capsule in response to injury and by infiltration of monocytes and macrophages.
Type I is anti-GBM antibody mediated, with or without lung involvement and has a 12% frequency.
Type II is immune complex mediated and has a 44% frequency.
Type III is pauci-immune or ANCA associated and has a 44% frequency.

The prognosis is roughly related to the number of crescents; those with crescents in less than 80% of the glomeruli have a better prognosis than those with a higher number.
Anti-glomerular basement membrane antibody (Type I) crescentic GN:
Characterized by linear deposits of IgG and, in many cases, C3 on the GBM. In some of these individuals the anti-GBM antibodies also bind to the pulmonary alveolar capillary basement membranes to produce Goodpasture’s syndrome. Anti-GBM antibodies are present in the serum and are helpful in diagnosis. Affected individuals benefit from plasmapheresis, which removes pathogenic antibodies from the circulation.
Grossly, the kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces. Glomeruli show segmental necrosis and GBM breaks, with proliferation of the parietal epithelial cells in response to the exudation of plasma proteins including fibrin into the Bowman’s space. These distinctive lesions of proliferation are called crescents due to their shape as they fill Bowman’s space. Crescents are formed both by proliferation of parietal cells and migration of monocytes/macrophages into the Bowman’s space. The uninvolved portion of the glomerulus shows no proliferation.
IF is characteristic with a strong linear staining pattern. EM may show ruptures in the GBM. Crescents eventually obliterate Bowman’s space and compress the glomeruli. Fibrin strands are prominent between the cellular layers in the crescents.
Immune complex-mediated (type II) crescentic GN:
Can be a complication of any of the immune complex nephritides, including post-streptococcal GN, SLE, IgA nephropathy and Henoch-Schonlein purpura. IF studies show a granular pattern and EM demonstrates discrete deposits. Affected individuals usually cannot be helped by plamsapheresis.
Pauci-immune (type III) crescentic GN:
Defined by the lack of anti-GBM antibodies or significant immune complex deposition. Most of these individuals have ANCA antibodies in the serum. In some cases, type III CrGN is a component of microscopic polyangiitis or Wegener granulomatosis. In many cases, however, pauci-immune CrGN is limited to the kidney and is thus called idiopathic.
IF studies are negative for immunoglobulin and complement and there are no detectable deposits by EM.
Chronic Glomerulonephritis:
An important cause of end stage renal disease presenting as chronic renal failure. By the time chronic GN is discovered, the glomerular changes are so advanced that it is difficult to discern the nature of the original lesion. Although chronic GN may develop at any age, it is usually first noticed in young and middle aged adults.
Grossly, the kidneys are symmetrically contracted and the surfaces are red-brown and diffusely granular. Microscopically, advanced scarring of the glomeruli is seen, sometimes to the point of complete sclerosis. There is also marked interstitial fibrosis, associated with atrophy of tubules in the cortex and loss of portions of the peritubular capillary network. The arteries are thick walled with narrowed lumens, secondary to hypertension. Lymphocytic infiltrates are present in the interstitial tissue.
Most often, chronic GN develops insidiously and is discovered late in its course. Very frequently, renal disease is first detected with the discovery of proteinuria, hypertension or azotemia on routine medical examination. Some individuals may have transient episodes of either nephrotic or nephritic syndromes. As the glomeruli are lost, protein loss decreases. Hypertension is very common and its effects may dominate the clinical picture.
Without treatment, the prognosis is poor; relentless progression to uremia and death is the rule. Rate of progression is extremely variable. Dialysis and kidney transplant alter this course and allow long-term survival.
Clinical features of subepithelial injury:
Clinical features of subendothelial or mesangial injury:
Features of subendothelial injury:
Mechanisms of Glomerular Damage:
Typical "oval body fat cast":
Common denominator of all nephrotic syndromes:
Visceral epithelial cells (podocytes)
EM of minimal change disease:
Cytokines wipe out all the negative charges on the GBM. Note effacement of the foot processes.
What is a common cause of minimal change disease in adults?
NSAID's
What is the most common cause of nephrotic syndrome in african americans?
FSGS (focal segmental glomerulosclerosis)
Differentiation between idiopathic and secondary FSGS:
The idiopathic (on left) has diffuse effacement of podocytes (no foot processes seen)
The secondary (on right) shows some podocyte foot processes still left.
Glomerulomegaly on light microscopy:
Seeing large glomeruli means that the type of FSGS is secondary; due to attempts at compensation from a chronic process.
Secondary causes of FSGS:
Obesity and secondary FSGS:
Focal Global GS:
Progression of secondary FSGS produces these type of lesions.
Clinical differentiation of idiopathic and secondary FSGS:
How do ACE inhibitors lower blood pressure through the kidney?
By blocking renin production, the efferent arterioles vasodilate, allowing more blood flow through the glomeruli and reducing pressure.
Histology of membranous GN:
Subepithelial deposits of membranous GN (IgG mediated):
Appearance of membranous GN on silver stain and IF:
Note the characteristic "spiking" pattern on silver stain.
IF pattern is granular.
If an elderly man presents with membranous GN, what disease do you need to rule out?
Cancer
Other consequences of protienuria:
Hallmarks of acute nephritic syndrome:
Histology of acute diffuse proliferative nephritis:
EM of acute diffuse proliferative nephritis:
Note deposits in the subepithelium due to lack of ability to filter particles out. Large particles will get stuck in the endothelium.
Membranoproliferative GN types I and II
Which complement factors will be low in GN?
Either C4 and C3 in the classical pathway

OR

Just C3 in the alternative pathway
Histology of membranoproliferative disease:
Note the arrow pointing toward the "tram track" thickened membrane
EM of membranoproliferative disease:
Note the subendothelial deposits
What disease often causes MPGN most?
Hep C
EM of MPGN Type II:
Also called "dense deposit disease"
*Uses the alternative complement pathway*
Rapidly progressive GN:
Classification of crescentic GN by IF:
Formation of Crescents:
Noncollagenous portion of the alpha3 chain of collagen type IV.
Linear pattern
Asymptomatic Hematuria/Proteinuria
Frequently seen after a respiratory or GI illness. Can be from toxic antibodies form that attack the mesangial cells.

1. Mesangial nephropathy (IgA nephropathy)
2. Glomerular basement membrane abnormalities (Alports syndrome; thin basement membrane nephropathy)
Histology of mesangial cell proliferation:
EM of granular deposits in the mesangium:
Alport's Syndrome:
Morphology of glomerular lesions in Alport's syndrome:
EM of Alport's sydrome "basket weave" pattern:
Chronic nephritic syndrome:
Histology of focal global sclerosis:
Clinical presentations of glomerular diseases:
Tubulointerstitial nephritis:
Refers to a group of inflammatory diseases of the kidneys that primarily involve the interstitium and tubules. The glomeruli may be spared or affected only late in the course.

1. Acute pyelonephritis
2. Chronic pyelonephritis and Reflux nephropathy
3. Drug induced interstitial nephritis
Acute pyelonephritis Pathogenesis:
The principle causative agents are enteric gram negative rods. E. coli is the most common but it may also be caused by Proteus, Klebsiella, Enterobacter and Pseudomonas species. Bacteria can reach the kidneys via hematogenous spread (less common; from septicemia or infective endocarditis) or via ascending infection from the lower urinary tract.
The first step is adhesion of the bacteria to the mucosal surfaces, followed by colonization of the distal urethra. Expansive growth of bacterial colonies moving against the flow of urine leads to bladder infection; this may also occur during catheterization and cystoscopy. In the absence of instrumentation, UTI most commonly affect females due to a short urethra, close proximity to the rectum and trauma during intercourse.
Outflow obstruction or bladder dysfunction contribute to infection susceptibility. In the presence of stasis, bacteria in the bladder can multiply undisturbed, without being flushed out or destroyed by the bladder wall. From the bladder, the bacteria ascend to infect the ureters, renal pelvis and parenchyma.
An important predisposing factor in the pathogenesis of an ascending infection is incompetence of the vesicoureteral orifice; normally the valve is one-way and prevents retrograde urine flow. This condition, termed vesicoureteral reflux, is present in 20-40% of young children with UTI. It is usually a congenital defect. VUR can also be acquired in individuals with a flaccid bladder resulting from spinal cord injury and with neurogenic bladder dysfunction secondary to diabetes.
Acute pyelonephritis histology:
One or both kidneys may be involved. Characteristically, discrete, yellowish, raised abscesses are apparent on the renal surface. The characteristic histological feature is suppurative necrosis or abscess formation within the renal parenchyma – these abscesses may rupture into the tubular spaces leading to white cell casts found in the urine. Typically, the glomeruli are not involved.
When obstruction is prominent, pus may be unable to drain and fills the renal pelvis, calyces and ureter, producing pyonephrosis. A second and infrequent form of pyelonephritis is papillary necrosis. This is common among diabetics. It is also seen with the chronic interstitial nephritis associated with analgesic abuse. This lesion consists of a combination of ischemic and suppurative necrosis of the renal papilla. Grossly, the papilla appear gray-white to yellow. Microscopically, the papillary tips show coagulative necrosis with a surrounding neutrophilic infiltrate.
Acute pyelonephritis clinical course:
Often associated with predisposing conditions such as urinary obstruction, instrumentation of the urinary tract, vesicoureteral reflux, pregnancy, age and sex (becomes more common in males later in life due to prostatic hyperplasia), preexisting renal lesions, diabetes mellitus and immunosuppression or immunodeficiency.
The onset is usually sudden with pain at the costovertebral angle and systemic evidence of infection, such as chills, fever and malaise. Urinary findings include pyuria and bacteriuria. There are usually indications of bladder and urethral irritation (dysuria, frequency and urgency). Even without antibiotic treatment the disease tends to be self-limiting. The symptomatic phase usually lasts about one week. The disease is usually unilateral and individuals thus do not develop renal failure because they still have one functioning kidney.
In cases with predisposing influences, the disease may become recurrent or chronic, particularly when it is bilateral. The development of papillary necrosis is associated with a much poorer prognosis. These persons have evidence of overwhelming sepsis and often, renal failure.
The diagnosis of acute pyelonephritis is established by finding leukocytes by urinalysis and bacteria by urine culture.
Chronic pyelonephritis and Reflux nephropathy pathogenesis:
Chronic pyelonephritis is an entity in which predominantly interstitial inflammation and scarring of the renal parenchyma is associated with grossly visible scarring and deformity of the pelvicaliceal system. Chronic pyelonephritis is an important cause of chronic renal failure. It can be divided into two forms; chronic obstructive pyelonephritis and chronic reflux-associated pyelonephritis.
Chronic obstructive pyelonephritis; obstruction predisposes the kidney to infection. The disease can be bilateral, as with congenital abnormalities of the urethra, resulting in fatal renal insufficiency unless the anomaly is corrected – or unilateral, such as occurs with calculi and unilateral obstructive lesions of the ureter.
Chronic reflux-associated pyelonephritis (reflux nephropathy); This is the more common form of chronic pyelonephritic scarring and results from superimposition of a UTI on congenital vesicoureteral reflux and intrarenal reflux. Reflux may be unilateral or bilateral; thus the renal damage either may cause scarring and atrophy of one kidney or may involve both and lead to chronic renal insufficiency.
Chronic pyelonephritis and Reflux nephropathy morphology and clinical course:
One or both kidneys may be involved, but even when involvement is bilateral, the kidneys are not equally damaged and are therefore not equally contracted. This uneven scarring is useful in differentiating chronic pyelonephritis from the more symmetrically contracted kidneys associated with vascular sclerosis and chronic GN. The hallmark of chronic pyelonephritis is scarring involving the pelvis or calyces, or both, leading to papillary blunting and marked calyceal deformities.
The microscopic changes are largely non-specific; the parenchyma shows the following features:
Uneven interstitial fibrosis with infiltration of lymphocytes, plasma cells and neutrophils, dilation or contraction of tubules; often neutrophils are seen in the tubules, chronic inflammatory infiltration and fibrosis involving the calyceal mucosa and wall, vascular changes similar to those of arteriolosclerosis caused by hypertension and either normal glomeruli or some glomerulosclerosis.
Clinical course: Often the disease is heralded by the onset of hypertension. US can be used to determine the size and shape of the kidneys. Pyelograms are characteristic; they show the affected kidney to be asymmetrically contracted, with some degree of blunting and deformity of the calyceal system. The presence or absence of significant bacteriuria is not helpful diagnostically. If the disease is bilateral and progressive, tubular dysfunction occurs with loss of concentrating ability, manifested by polyuria and nocturia. Some persons with chronic pyelonephritis or reflux nephropathy ultimately develop glomerular lesions of global sclerosis and secondary FSGS. These are associated with proteinuria and eventually contribute to progressive chronic renal failure.
Acute drug induced interstitial nephritis:
This is an adverse reaction to methicillin, ampicillin, rifampin, thiazides, NSAID’s and numerous other drugs. Features of the disease suggest an immune mechanism. Evidence of hypersensitivity includes a latent period, eosinophilia and rash and recurrence of hypersensitivity after reexposure to the same or a cross reactive drug. Serum IgE levels are increased in some persons, suggesting type I hypersensitivity. The mononuclear or granulomatous infiltrate, together with positive skin tests to drugs suggest a T cell mediated (type IV) hypersensitivity reaction. The most likely pathogenesis is that the drugs act as haptens that covalently bind to other proteins after secretion from the tubules and become immunogenic. The resultant tubulointerstitial injury is then caused by IgE and cell mediated immune reactions to tubular cells or their basement membranes.
Histologically, the abnormalities seen in drug-induced nephritis are in the interstitium, which shows pronounced edema and infiltration by mononuclear cells, macrophages, eosinophils and neutrophils. The glomeruli are normal except in cases caused by NSAID’s when the hypersensitivity reaction also leads to effacement of the podocyte foot processes and the nephrotic syndrome develops.
The disease begins an average of 15 days after exposure and is characterized by fever, eosinophilia, rash and renal abnormalities. Renal findings include hematuria, minimal or no proteinuria and leukocyturia. A rise in serum creatinine or acute renal failure with oliguria develops in 50% of cases. Recovery follows the removal of the drug, but may take several months for renal function to return to normal.
Analgesic nephropathy:
Individuals who consume large amounts of analgesics may develop chronic interstitial nephritis, often associated with renal papillary necrosis. Aspirin and acetaminophen are the major culprits. Pre-existing renal disease seems to be a necessary precursor to analgesic-induced renal failure.
Papillary necrosis is the initial event, and the interstitial nephritis in the overlying renal parenchyma is a secondary phenomenon. Acetaminophen injures cells by both covalent binding and oxidative damage. The ability of aspirin to inhibit prostaglandin synthesis suggests that this drug my induce its effect by inhibiting the vasodilatory effects of prostaglandin and predisposing the papilla to ischemia.
The necrotic papilla appear yellow-brown, as a result of the accumulation of breakdown products of phenacetin (from acetaminophen) and other lipofuscin like pigments. The papilla may shrivel and be sloughed off. Microscopically, the papilla show coagulative necrosis associated with loss of cellular detail but preservation of tubular outlines. Foci of calcification may occur in the necrotic areas.
Clinical features of analgesic nephropathy include chronic renal failure, hypertension and anemia. The anemia results in part from damage to red cells by phenacetin metabolites. Cessation of analgesic intake may stabilize or improve renal function. A complication of analgesic abuse is the increased incidence of transitional cell carcinoma of the renal pelvis or bladder in persons who survive the renal failure.
At what rate of urine production in 24 hours is a patient considered to have renal failure?
Less than 400 mL per day
What is the most common cause of acute renal failure?
Acute tubular necrosis
Acute tubular necrosis pathogenesis:
ATN is a reversible lesion that arises in a variety of clinical settings. Most of these, ranging from severe trauma to acute pancreatitis to septicemia, have in common a period of inadequate blood flow to the peripheral organs, often in the setting of marked hypotension and shock. The pattern of ATN associated with shock is called ischemic ATN. A second pattern, called nephrotoxic ATN, is caused by a variety of poisons, including heavy metals, organic solvents and a multitude of drugs such as gentamicin and other antibiotics, and radiographic contrast agents.
The decisive events in both ischemic and nephrotoxic ATN are believed to be tubular injury and persistent and severe disturbances in blood flow resulting in diminished oxygen and substrate delivery to tubular cells. Tubular epithelial cells are sensitive to anoxia and toxins. Alteration of integrins that anchor tubular cells to the underlying basement membrane results in shedding of tubular cells into the urine. Further damage to the tubules and the resultant debris can block urine flow and eventually increase intratubular pressure, decreasing GFR. Fluid from the damaged tubules may leak into the interstitium, resulting in increased interstitial pressure and collapse of the tubules. Ischemic tubular cells also express chemokines, cytokines and adhesion molecules such as P-selectin that recruit leukocytes that can participate in tissue injury.
Ischemic renal injury is also characterized by severe hemodynamic alterations that cause reduced GFR. Intrarenal vasoconstriction can cause both reduced glomerular plasma flow and reduced oxygen delivery to the tubules in the outer medulla. Vasoconstriction is mediated by increased release of endothelin and decreased production of nitric oxide and prostaglandins.
Acute tubular necrosis histology:
Ischemic ATN is characterized by necrosis of short segments of the tubules; most often in the straight portions of the proximal tubule and the ascending thick limbs. There is often a variety of tubular injuries including attenuation of proximal tubular brush borders, blebbing and sloughing of brush borders, vacuolization of cells and detachment of tubular cells into the urine. Casts containing hemoglobin are often found in the distal tubules and collecting ducts. When ATN is caused by a crush injury, casts contain myoglobin. The interstitium shows mild edema with an inflammatory infiltrate.
The histologic picture of toxic ATN is basically similar, but necrosis is most prominent in the proximal tubule and the tubular basement membranes are generally spared. If the patient survives for a week, epithelial regeneration comes in the form of a low cuboidal covering and mitotic activity in the remaining tubular epithelial cells. Except where the basement membrane is destroyed, regeneration is total and complete.
Acute tubular necrosis clinical course:
The initiation phase, lasting about 36 hours, is usually dominated by the inciting event in the form of ischemic ATN. The only indication of renal involvement is a slight decline in urine output with a rise in serum creatinine. At this point, oliguria can be explained on the basis of a decrease in blood flow to the kidneys.
The maintenance phase begins anywhere from the second to sixth day. Urine output falls markedly, usually to between 50-400 mL per day. Complete anuria is rare. The clinical picture is dominated by the signs and symptoms of uremia and fluid overload. In the absence of careful supportive treatment or dialysis, patients may die during this phase.
The recovery phase is ushered in by a steady increase in urine output. Because tubular function is still deranged, serious electrolyte imbalances may occur during this phase. There is also an increased vulnerability to infections. 25% of deaths occur during this phase. Subtle functional impairment of the kidneys may last for months; patients who do not die from the underlying precipitating problem have a 90-95% chance of recovering from ATN.
What is the minimum amount of urine production required to get rid of waste?
What is the minimum and maximum concentrating ability of the kidney?
50 mOsm/day minimun
1200 mOsm/day maximum
What is a limitation that must be taken into consideration when calculating GFR?
Creatinine levels must be at a steady state; the same over a period of days.
*You cannot use the formula to calculate a new GFR if the creatinine suddenly changes!!
Azotemia differential diagnosis:
Manifestations of acute renal failure:
Causes of ARF:
Pathogenesis of prerenal azotemia:
Lab values in prerenal azotemia:
The BUN to creatinine ratio increases because BUN is reabsorbed along with sodium in the proximal tubule; when kidneys don't get enough blood, way more sodium and therefore way more BUN is reabsorbed.
Treatment of prerenal ARF:
Sepsis caused ARF:
Presentation of acute tubular necrosis:
Causes of acute tubular necrosis:
Patterns of tubular injury:
ATN and ATP depletion:
Pathophysiology of ATN:
Aminoglycoside caused ATN:
Causes of intratubular obstructions:
Heme caused ATN:
Contrast caused ATN:
How do you differentiate between kidney failure from inadequate blood flow from that of tubule dysfunction?
Fractional Excretion of Na.
Low in blood flow problem
High in tubule problem
Histology of ATN:
Diffuse Cortical Necrosis:
Causes of Interstitial necrosis:
Acute vs. Chronic TIN:
Histology of acute vs. chronic interstitial nephritis:
Acute on the left
Chronic on the right
Physiologic defects in TIN:
Drug induced acute interstitial nephritis:
Mechanism of renal derangement with use of NSAID's:
Causes of chronic interstitial nephritis:
What two renal diseases can give the kidney a "bumpy lumpy" appearance?
Chronic pyelonephritis and analgesic nephropathy
If a patient presents with new onset gout, hypertension and chronic kidney disease, which metal toxicity is responsible?
Chronic lead toxicity
Differentiation between prerenal and renal disease:
Urinalysis findings in different renal pathology:
Indications for dialysis:
All of the above
Acute tubular necrosis
Acute interstitial nephritis
Stages of chronic kidney disease:
75%
Compensation of remaining nephrons
Outline of the progression to end stage renal disease:
Normal calcium homeostasis:
Calcium homeostasis in CKD:
High turnover variant:
Low turnover variant:
Vascular calcification as a result of CKD:
High serum levels of calcium-phosphate precipitate out and calcify vessels.
This process can happen to the coronary vessels, which is one reason people with CKD have a higher risk of coronary events.
Metabolic acidosis in CKD:
Once enough nephrons have been lost, the ability of the proximal tubules to make enough ammonia to carry out excess H+ is lost.
Normocytic, normochromic
Abnormalities of potassium levels in CKD:
Uremia in CKD:
How does CKD cause abnormal growth in children?
GH produced by the pituitary acts on the liver to produce IGF-1. Inactive IGF-1 is bound to proteins and active IGF-1 is free in the serum.
In patients with CKD, there are higher levels of binding proteins so there is less IGF-1 and less growth.
Post kidney transplant complications:
Recommendations for preventions of diabetes related kidney damage:
In order of importance!!
Drugs that work on the afferent and efferent arterioles in the glomeruli:
The effect on creatinine level of a CCB vs. a ACE or ARB
A CCB leads to more glomerular damage over time due to constant higher pressures.
An ACEI or ARB will lower the pressure in the glomeruli, leading to a decrease in GFR and an increase in creatinine, BUT...this preserves more nephrons over time leading to a better outcome.
Main points from the EBM Diabetes lecture:
Microvascular complications of DM:
Renal lesions in DM patients:
AGE receptors and their effects:
Renal AGE receptors:
Causes of hyperfiltration:
Glomerular circulation in diabetics:
The efferent arterior is the first vessel to be hyalinized in DM; the reason why it vasoconstricts.
Which is more important to control in type II diabetics to prevent complications; blood sugar or blood pressure?
Blood pressure
Three systemic diseases that commonly involve the kidney:
Symptoms of Lupus:
Signs and Labs for Lupus:
LE cell phenomenon - RBC's phagocytosed by WBC's
Lupus nephritis classification:
Presentation of lupus nephritis:
Presentation of lupus nephritis part 2:
Note subendothelial deposits
Lupus Nephritis class V:
Note the thickened capillary walls
Treatments for lupus nephritis:
Acute renal failure in myeloma:
Dehydration combined with blockage of tubules from light chains and calcium leads to ARF
Associated with multiple myeloma
Associated with secondary amyloidosis
Treatment of renal amyloidosis:
What effects does sickle cell anemia have on the kidney?
Renal papillary necrosis and glomerulosclerosis
What treatments are there to prevent sickle cell anemia kidney damage?
Control sickling events
Blood pressure control
ACEI for patients with proteinuria