Clinical Manifestations of Glomerular Disease (Brozna) 1 and 2 Flashcards
Kidney filters how much blood/ urine?
20% Cardiac Output Filters 1700 liters/day
1,000 mL urine/day
What part of the kidney is most susceptible to ischemic injury?
Since the arcuate arteries do not anastomose, the central portion of the renal lobe is most susceptible to ischemic injury
The two capillary beds
unique feature of renal circulation : two capillary beds arranged in series.
1. Afferent arteriole –> glomerulus (filtration of fluid and solutes).
- via the efferent arteriole–> the peritubular capillary network (fluid and solutes reabsorbed by the tubules are returned to the circulation.)
What is the final common pathway to end-stage renal failure?
Chronic hypoxia is the final common pathway to end-stage renal failure. Ischemia of the kidney is induced by the loss of peritubular capillaries in the tubulointerstitium in the late stage of renal disease
Glomerular filter consists of
fenestrated endothelium, basement membrane, and foot processes of epithelial cells. Note the filtration slits and diaphragm situated between the foot processes.
Note also that the basement membrane consists of a central lamina densa, sandwiched between two looser layers, the lamina rara interna and lamina rara externa
Assessment of renal function includes what?
Urine analysis
- Color, volume, cells, casts, pH, osmolality, protein, urea, creatinine, glucose
Blood examination
- Serum creatinine (used to estimate GFR, not specific)
- Blood urea (increased in many renal diseases with various glomerular, tubular or interstitial damage, not specific)
Glomerular function tests
- Glomerular filtration rate (GFR) is proportional to serum creatinine
Tubular function test
- Urine concentration test (requires water deprivation for 14 hours–> Specific gravity greater than 1.02 (normal)
- Vasopressin test
Urine sediment: dysmorphic RBC suggests what?
White blood cell cast are most typical for what?
dysmorphic RBC suggests glomerular disease (it squishes through the fenestration)
White blood cell cast are most typical for acute pyelonephritis
acute kidney injury
Increase in serum creatinine by ≥ 0.3mg/dLwithin 48 hours; or
Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days; or
Urine volume less than 0.5mL/kg/hfor six hours
Estimation of glomerular filtration rate through the calculation of creatinine clearance is mandatory
In most healthy people, the normal GFR is 90 mL/min/1.73 𝐦^𝟐 or higher.
A result of 60–89 mL/min/1.73 𝐦^𝟐 without kidney damage may be normal in some people (such as the elderly, infants).
A result of 60–89 mL/min/1.73 𝐦^(𝟐 )for three months or more, along with kidney damage (such as persistent protein in the urine), means the person has early kidney disease.
When GFR is less than 60 ml/min/1.73 m2 for 3 months or more, chronic kidney disease is present.
GFR must decline to approx half the normal level before the serum creatinine concentrtion rises above the upper limit of normal.
Chronic Kidney Disease
- Kidney damage > 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by either:
- pathological abnormalities; or
- Markers of kidney damage, including abnormalities in teh composition of the blood or urine, or abnormalities in imaging tests - GFR 3 months, with or without kidney damage
5 stages of chronic renal failure
- GFR 90+. Normal kidney function but urine findings or structural abnormalities or genetic trait point to kidney disease
- GFR 60-89. Mildly reduced kidney function, and other findings (as for stage 1) point to kidney disease
3a. GFR 45-59 Moderately reduced kidney function
3b. GFR 30-44 - GFR 15-29. Severely reduced kidney function
- GFR less than 15 or on dialysis.
Clinical Manifestations of Renal Diseases
hematuria proteinuria edema hypertension oliguria anuria increased serum creatinine increased serum BUN mass
Uroscopy
is the histologic medical practice of visually examining a patient’s urine for pus, blood or other symptoms of disease. It dates back to ancient Egypt Babylon and India
13th century description of symptoms of chronic nephritis
The signs of hardness in the kidneys are that the quantity of the urine is diminished, that there is heaviness of the kidneys, and of the spine with some pain: and the belly begins to swell up after a time and dropsy is produced the second day…
foamy urine is associated with
proteinuria
Bright Disease
= Glomerulonephritis
In 19th century Bright Disease became known as a chronic but incurable disorder… along with tuberculosis and cancer as diagnoses that could extinguish all hope and interest in life
Bright Disease was the FEARED disease of the 1800s
What the microscope and labs of late 1800s said about Bright disease
Acute form of Bright disease that made urine bloody as well as albuminuric, caused flank pain and was associated with blood engorged swollen kidneys –> Acute glomerulonephritis
Bright disease dominated by extreme albuminuria and stubborn dropsy, large pale kidneys –> Nephrotic syndrome
Bright disease arising from narrowing and hardening of the kidneys’ arterial network –> Vascular kidney diseases
4 groups of kidney pathology
Can divide kidney diseases into those that affect the basic morphologic components: Blood vessels Tubules Interstitium Glomeruli
Early manifestations of disease affecting each of these components tend to be distinct and some components seem to be more vulnerable to specific forms of renal injury
For example:
Most glomerular diseases are immunologically mediated.
Pathogenesis of Glomerular Injury
- Most forms of human glomerulonephritis result from immunologic mechanisms
- Most precipitating factors initiate similar immune responses that result in glomerulonephritis via shared common pathways
- Most human glomerular diseases are characterized by glomerular immunoglobulin deposition +/- complement
- Immune deposits form either actively (AbAg) or passively as exogenous antigens become trapped in glomerulus due to glomerular filtration
Two forms of antibody-associated injury have been established:
Injury byantibodies reacting in situ within the glomerulus,either binding to insoluble fixed (intrinsic) glomerular antigens or extrinsic molecules planted within the glomerulus.
Injury resulting from deposition of circulating antigen-antibody complexes in the glomerulus.
*** the major cause of glomerulonephritis resulting from formation of antigen-antibody complexes is in situ immune complex formation, and not deposition of circulating complexes.
Pathogenesis of Glomerular Injury
Cellular immunity can lead to the production of cytokines
Cause the glomerular basement membrane to lose its negative charge
Damage podocytes causing the process fusion
Mesangial cell proliferation and matrix formation
Podocytes, mesangial cells, endothelial cells interact with each other
Growth factors Cytokines Vasoactive agents Chemokines Complement receptors
Podocyte injury frequently results in mesangial cell proliferation, whereas mesangial cell injury leads to foot process fusion and proteinuria
Four Types of Immune Reactions
Type I immune reaction (anaphylactic)
Hypersensitivity reaction mediated by IgE which occurs relatively rapidly following exposure to previously encountered antigen
Type II immune reaction (antibody mediated)
Caused by antibodies which react with self-antigens
Type III immune reaction ( immune complex mediated)
Involve the deposition of preformed immune complex which result in complement activation
Type IV immune reaction (delayed hypersensitivity cell-mediated)
Mediated predominantly by T cells
In situ Formation of Immune Complexes in the Glomerulus
Intrinsic antigens in the glomerulus
Antibody to glomerular basement membrane –> Goodpasture disease
Antibody to phospholipase A2 receptor –> Membranous nephropathy
Extrinsic antigens trapped (planted) in the glomerulus
Cationic molecules
Nuclear proteins
Infectious agent antigens
Deposition of Circulating Immune Complexes
Glomerular injury can be caused by the trapping of circulating immune complex
Immune complex antigens may be of endogenous origin
DNA, tumor antigens
Immune complex antigen may be of exogenous origin Microbial antigens (streptococcal proteins) Viral antigens (hepatitis virus)
Immune Complex Localization
Several factors affect glomerular localization of antigen, antibody or complexes:
Molecular charge and size
Cationic molecules tend to cross glomerular basement membrane and deposit in sub-epithelial location
Anionic molecules are excluded from the basement membrane and localized in sub-endothelial locations
Neutral charge antigens or complexes tend to accumulate in the mesangium
Antibody mediated immune injury
Immune complex formation leads to complement activation and activation of leukocyte mediated injury pathways
Primary Renal Disease
Pathologic changes in the kidney in the absence of associated systemic disease
Only kidneys are affected
Secondary Renal Disease
Systemic disease causes the renal disease Diabetes mellitus Systemic lupus erythematosus Hypertension Amyloidosis
Terms used to Describe
Histologic Lesions in Glomeruli
Focal- Involving less than 50% of glomeruli
Diffuse- involving > 50% of glomeruli
Segmental- involving part of a glomerular tuft
Global- involving all of a glomerular tuft
Acute renal failure
Oliguria or anuria (reduced or no urine flow)
Recent onset of progressive azotemia
Overwhelming majority due to “Acute Kidney Injury” (acute tubular necrosis) but some cases may be the result of vascular or extensive glomerular injury. interstitial, or vascular injury or acute tubular injury.
Chronic renal failure
Prolonged symptoms and signs of uremia
End result of all progressive chronic parenchymal renal diseases
Also termed “End Stage Renal Disease” (ESRD)”
Glomerular immunopathology often develops from
intra-glomerular complement activation via the classical (immune complex-related) or alternative (immune complex independent) complement pathway
Immune complexes can form in different compartments of the glomerulus, which determines the resulting histopathological lesion, as different glomerular cell types are primarily activated in each compartment
Can divide kidney diseases into those that affect the basic morphologic components:
Blood vessels
Tubules
Interstitium
Glomeruli
Clinical Presentation of Vascular Kidney Diseases
Benign nephrosclerosis
Slight drop in GFR and mild proteinuria
Malignant nephrosclerosis
Rapidly increasing blood pressure, increased intracranial pressure with headaches, papilledema and retinal hemorrhages
Thrombotic microangiopathies
Microangiopathic hemolytic anemia (DIC)
Hemolytic uremic syndrome (HUS)
Thrombotic thrombocytopenic purpura (TTP)
Clinical Presentations of Tubular and Interstitial Kidney Diseases
Acute interstitial nephritis (uncommon)
Sudden onset and rapid decline in renal function
Immunologic hypersensitivity reaction (drug or infectious agent)
Chronic interstitial nephritis
Protracted onset and slow decline in renal function (progressive scarring)
Toxins, drugs, infections, obstruction, immunologic and ischemia
Acute tubular injury/necrosis (ATN)
Sudden onset and rapid decline in renal function
Ischemia and direct toxic injury to the tubules
Clinical Presentations of Glomerular Kidney Diseases
Asymptomatic hematuria and / or proteinuria
Macroscopic hematuria
Nephritic syndrome (Glomerulonephritis)
Nephrotic syndrome
Rapidly progressive glomerulonephritis
Chronic glomerulonephritis (chronic kidney disease)
Asymptomatic hematuria/proteinuria
Proteinuria 150 mg to 3 g per day
Hematuria >2 red blood cells per high-power field in spun urine
MOST hematuria is Not glomerular in origin
Macroscopic hematuria
Brown/red painless hematuria
Asymptomatic hematuria + proteinuria between attacks of hematuria
MOST hematuria is Not glomerular in origin
Nephritic syndrome clinical presentations
Oliguria Hematuria with red cell casts Proteinuria usually less than 3 g/day edema hypertension abrupt onset and usually self-limiting
Nephrotic syndrome clinical presentations
Proteinuria >3.5 g per day (adult); >40mg/hr per m2 (child) Hypoalbuminemia less than 3.5 g/dl Edema Hypercholesterolemia Lipiduria
Rapidly progressive glomerulonephritis
Renal failure over days to weeks Proteinuria usually less than 3 g/day Hematuria with red cell casts may have features of vasculitis blood pressure often normal
Chronic glomerulonephritis (chronic kidney disease)
Hypertension
** Renal impairment (GFR impairment (GFR less than 60 ml/min for 3 months)
Proteinuria usually less than 3 g/day
Shrunken smooth kidneys
Histopathologic Classification of Glomerulonephritis– Heptinstall’s Pathology of the Kidney. These are histological patterns, not diagnoses
No abnormality by light microscopy
Thick capillary walls without hypercellularity or mesangial expansion
Thick walls with mesangial expansion but no hypercellularity
Focal segmental glomerulosclerosis without hypercellularity
Mesangial or endocapillary hypercellularity
Extracapillary hypercellularity
Membranoproliferative, lobular or nodular pattern
Advanced diffuse global glomerular sclerosis
No abnormality by light microscopy
Glomerular disease with no light microscopic changes
(e.g., minimal change glomerulopathy, thin basement membrane nephropathy)
Mild or early glomerular disease (biopsy sampling)
(e.g., lupus nephritis, IgA nephropathy, membranous glomerulopathy, amyloidosis, etc.)
Focal segmental glomerulosclerosis
Focal segmental glomerular sclerosis is clinicopathologic term used to describe steroid resistant nephrotic syndrome in children and adolescents
TO Determine the cause of a patient’s kidney disease
need…
integration of data from light microscopy, immunofluorescence microscopy, electron microscopy, serology, and other laboratory and
clinical observations
Microscopic hematuria with proteinuria
Much greater risk of significant glomerular injury and renal biopsy is indicated
**Isolated non-nephrotic proteinuria
Functional proteinuria:
Orthostatic (postural) proteinuria (children and young adults),
Transient proteinuria (fever, exercise common in young individuals)
Acute illnesses
Dehydration
May be an early sign of a serious glomerular or tubular lesion
**Normal urinary sediment, no hematuria, normal GFR, no hypertension, no diabetes
Microscopic hematuria
(common in children and adults)
Urologic origin 80% (bladder, ureters, prostate) if no proteinuria
Strenuous exercise or unexplained with no urologic findings
Differential of glomerular hematuria without proteinuria, renal insufficiency or red blood cell casts
Thin basement membrane nephropathy (benign familial hematuria)
Alport syndrome (familial)
IgA nephropathy
Confirm Microscopic Hematuria
Microscopic hematuria is usually defined as >3-5 RBC/hpf
Cannot use urine dipstick alone (false positives- myoglobin, bilirubin)
Prevalence of microscopic hematuria in schoolchildren ~2-4% on one urinalysis 0.4% after 4 UA in 1 year
> 70% of children with isolated microscopic hematuria on a single UA will not have persistent hematuria after further testing
Urine sediment:
Red blood cells with normal morphology
Extraglomerular origin
Hypercalciuria
Urethra injury
Cystitis
Urine sediment:
Dysmorphic red blood cells
Glomerular origin
IgA nephropathy
Alport syndrome
Thin glomerular basement membrane disease
Thin Basement Membrane Nephropathy
(Benign Familial Hematuria)
Diffuse thinning of glomerular basement membrane
Normal light microscopy and immunofluorescence
Persistent microscopic hematuria (also episodic macroscopic hematuria)
Affects 1% of general population (autosomal dominant)
Most present with only hematuria (mild proteinuria may be present)
Normal renal function and excellent prognosis (risk of progression
Alport Syndrome
(Hereditary Nephritis)
Inherited disorders of basement membranes (mutations of type IV collagen alpha chain proteins) Major clinical features Hematuria Progressive nephritis with proteinuria Declining renal function Sensorineural deafness Ocular abnormalities
Clinical course is gender dependent
Affected males have severe disease
Affected females have mild disease
Fine structural feature of the kidney that occurs in most patients with AS is the variable thickening, thinning, and splitting/lamellation of the GBM
No pathognomonic lesions by light microscopy
Glomerular basement membrane fails to stain by immunofluorescence for α3, α4, α5 *** Type IV collagen chains
IgA nephropathy
IgA nephropathy also can also present with macroscopic hematuria
(Berger disease) is characterized by IgA deposits in the mesangial regions and is the most common type of glomerulonephritis worldwide
Episodic gross hematuria occurring within 1 day of acute respiratory infection (50% of children)
Major clinical presentations are episodic macroscopic hematuria with persistent microscopic hematuria
40 to 50% present with one or recurrent episodes of visible hematuria following upper respiratory infection
Most have only a few episodes of visible hematuria and episodes usually recur for only a few years.
30 to 40% have microscopic hematuria and mild proteinuria
Gross hematuria will eventually occur in 20 to 25 percent of these patients
Disease of uncertain duration
5-10% present with either nephritic syndrome or acute rapidly progressive glomerulonephritis
Episodic Painless Macroscopic Hematuria Caused by Glomerular Disease
Observed primarily in children and young adults and less commonly past age of 40
Most cases are caused by IgA nephropathy
IgA Vasculitis
Henoch-Schönlein purpura(HSP) is a small-vessel vasculitis affecting the skin, joints, gut, and kidneys that predominantly affects children
Most children have mild illness that resolves spontaneously
Tissue deposition of IgA
Skin rash (palpable purpura)
RARE Intestinal bleeding or intussusception
Nephritis associated with HSP is characterized by mesangial IgA deposition and is indistinguishable from IgA nephropathy
IgA Nephropathy Pathogenesis Theory
IgA glomerular deposits are predominantly polymeric IgA
Levels of plasma polymeric IgA are increased
Aberrant glycosylation of IgA
Direct deposit of glycosylated IgA or deposit of immune complex of IgA and IgG anti IgA
Alternate pathway of complement activation with C3 deposits usually in the absence of C1q and C4
**The regular recurrence of IgA nephropathy and Henoch-Scholein purpora nephritis after renal transplantation strongly implies an abnormality in the host IgA immune system
Nephritic syndrome
Hematuria with red cell casts Proteinuria usually less than 3 g/day Edema Hypertension Oliguria (low urine output) Azotemia Abrupt onset and frequently self-limiting
Histological features of kidney diseases
Acute proliferative glomerulonephritis
- poststreptococcal glomerulonephritis - postinfectious glomerulonephritis
Focal proliferative glomerulonephritis
- lupus nephritis - IgA nephropathy
Diffuse proliferative glomerulonephritis
- lupus nephritis - Goodpasture’s nephritis - vasculitis induced glomerulonephritis - membranoproliferative glomerulonephritis - crescentic glomerulonephritis
Acute Proliferative Glomerulonephritis(Post-streptococcal Glomerulonephritis)
Beta hemolytic group A streptococcus specific nephritogenic strains are capable of inducing acute post-streptococcal glomerulonephritis
Streptococcal pyogenic exotoxin B (SPE B) probably major antigen involved in the pathogenesis of most cases of APSGN.
Follows upper-respiratory tract infections, such as pharyngitis or tonsillitis and skin infections (impetigo)
Most commonly affects children and young adults
Variable clinical presentation from asymptomatic microscopic hematuria to the full-blown acute nephritic syndrome that may progress
Onset of clinical symptoms is typically abrupt 1- 3 weeks after upper respiratory group A streptococcal infection; (3-6 weeks after skin infection, impetigo)
Classic presentation is acute nephritic syndrome Hematuria (100%); Gross hematuria (30%) Edema Hypertension Proteinuria
Variable decline in glomerular filtration (rise in serum creatinine)
Acute proliferative glomerulonephritis(post-streptococcal) : Children vs Adults
Children tend to clear in 6 –8 weeks – renal biopsy not generally indicated
95% recover completely with conservative therapy (water and salt restriction); no long term sequellae
Acute Proliferative Glomerulonephritis(Poststreptococcal Glomerulonephritis)
Pathologic Features
All glomeruli are affected (Diffuse)
-Patients who are asymptomatic or have mild disease may have biopsies that show little glomerular involvement, whereas patients with diffuse endocapillary proliferative glomerulonephritis are more likely to have full-blown acute nephritic syndrome
Acute proliferative glomerulonephritis
- Proliferation of mesangial and endothelial cells
- Interstitial infiltrates of lymphocytes, monocytes and neutrophils
Glomerular immune deposits (immune complexes)
- Complement (C3) - 100%
- Immunoglobulin G or M -~60-70%
Residual renal injury is common in older adults
(Focal glomerular sclerosis and mesangial expansion)
Poststreptococcal glomerulonephritis (PSGN) is usually diagnosed based upon the presence of:
Acute nephritic symptoms Virtually all patients present with microscopic hematuria Gross hematuria (30%) Edema Hypertension Proteinuria AND Recent group A beta hemolytic streptococcal infection
Renal biopsy is not performed in most patients to confirm the diagnosis of PSGN, since the resolution of PSGN typically begins within one week of presentation.
Acute proliferative glomerulonephritis(Post-infectious, Non-streptococcal)
Staphylococcus-associated glomerulonephritis is as common as post-streptococcal glomerulonephritis in adults
Most of the other causes of bacterial infection-associated glomerulonephritis, including that due toStaphylococcusinfection occur when the patient is still infected.
Immune complex mediated disease (thought to be preformed complexes)
Often IgA antibody to staphylococcal antigen
Hepatitis virus B and C and HIV can be associated with postinfectious acute proliferative glomerulonephritis
Parasites (malaria, toxoplasmosis) can be associated with postinfectious acute proliferative glomerulonephritis
Membranoproliferative Glomerulonephritis synonym: Mesangiocapillary Glomerulonephritis
Includes pathologically distinct forms of glomerulonephritis:
Immune complex mediated disease (Type 1 MPGN) **
Subendothelial dense deposits and splitting of GBM
Complement mediated disease (Dense Deposit Disease) **
Dense intramembranous deposits, formally type II MPGN
Accounts for 10% of nephrotic syndrome in children and
young adults (Type 1 more frequent than dense deposit disease)
Clinical findings of membranoproliferative glomerulonephritis
range from microscopic hematuria with or without mild proteinuria to nephrotic syndrome and severe glomerulonephritis with hypertension and reduced GFR. (Combined nephritic/nephrotic pattern)
Type 1 MPGN
Most have either subendothelial and/or mesangial immune complex deposits (antigens are unknown)
Thought to be infectious agent antigens trapped in glomeruli
~ 1/3 will have circulating immune complexes
Thickened GBM with double contour (tram-tracking)
Most present as adolescents or young adults
Approximately two thirds of the patients develop hypocomplementemia with predominant depletion in C3 levels
Approximately 50% progress to chronic renal failure within 10 years
Dense Deposit Disease
Often has light microscopic features that resemble MPGN type I, dense deposit disease is also called type II MPGN.
Less common than type 1 MPGN
Most are persistent C3 activation (70% of patients)
Histological aspects of membranoproliferative glomerulonephritis
Thickening of capillary walls, usually global and diffuse.
There is also hypercellularity. Much of this hypercellularity is mesangial proliferation, and some of the capillary wall thickening is caused by mesangial interposition into the subendothelial zone of the capillary loops.
Nephritic Syndrome Children/Adolescents
IgA glomerulopathy
Post-streptococcal glomerulonephritis
Hemolytic uremic syndrome (Thrombotic microangiopathy)
Henoch-Schonlein purpura (IgA nephropathy)
Membranoproliferative glomerulonephritis (nephritic / nephrotic presentations)
Nephritic Syndrome Adults
IgA nephropathy
Goodpasture syndrome
Post-streptococcal glomerulonephritis
Diffuse proliferative glomerulonephritis (eg Lupus)
Rapidly progressive crescentic glomerulonephritis
Membranoproliferative glomerulonephritis (nephritic / nephrotic presentations)
Key concepts of nephritic syndrome
Acute postinfectious glomerulonephritis
prototypic example of nephritic syndrome
Rapidly progressive glomerulonephritis-
nephritic syndrome and rapid loss of renal function
3 things that change the GFR calculation
Age, female, african american
