Warren- Renal Pathophysiology Flashcards
What do the kidneys do?
Excrete waste products
regulate water and salt balance
regulate pH
endocrine fxn (renin, EPO)
Where are the kidneys located? How much do they weight? Where does the blood supply come from? What do they do?
Paired organs present in the retroperitoneum
Weigh approx. 150 gm each (~0.5% total body weight)
Blood supply by renal arteries, branching off of the aorta
Receive ~25% of the cardiac output–> allows them to do their main function!
Convert 1700 liters of blood into 1 liter of urine per day
What are the 4 components of the kidney?
glomeruli
tubules
interstitium
blood vessels
What is the glomerulus?
Anastomosing network of capillaries
Two layers of epithelium
- Parietal epithelium lines Bowman’s space
- Visceral epithelium is incorporated into the capillary wall (podocytes)
Fenestrated endothelial cells
Glomerular basement membrane (GBM)
Mesangial cells and matrix
What are the three division of the GBM?
Lamina rara interna, lamina densa, and lamina rara externa
LIGHT, dark, LIGHT
What type of collagen makes up the backbone of the GBM?
TYPE IV COLLAGEN monomers form backbone
What are the type IV collagen monomers made up of? Why are they important?
Six types of alpha chains exist (COL4A1-COL4A6)>
Three alpha chains make a triple helix to form a monomer>
Each monomer has a 7S domain at amino terminus, triple helical domain in the center, and a globular NONCOLLAGENOUS DOMAIN (NC1) at the carboxyl terminus
*Important because of their association with GLOMERULAR DISEASE (NC1 is ANTIGENIC SITE in anti-GBM nephritis)
What are other components of the GBM?
laminin, heparan sulfate, fibronectin
Overall it is NEGATIVELY CHARGED
What are the visceral epithelial cells? What do they do?
Also called podocytes
Interdigitate with lamina rara externa
Foot processes separated by filtration slits (nephrotic syndrome) of 20-30 nm
SYNTHESIZE MOST OF GBM components
What is the filtration slit diaphragm and what is it’s major role? What are 2 slit diaphragm proteins? How is this related to nephrotic syndrome?
Visceral epithelial cells maintain glomerular barrier function (exclusion of LARGE proteins and ALBUMIN) through the slit diaphragm
NEPHRIN and PODOCIN are 2 slit diaphragm proteins
MUTATIONS in genes encoding proteins involved in the slit diaphragm lead to NEPHROTIC SYNDROME
What are the mesangial cells?
Cells of mesenchymal origin
- Contractile, phagocytic, and proliferative–> fibrosis
- Secrete mediators of inflammation, lay down collagen
Matrix SUPPORTS the glomerular capillaries
What are the two basic things to remember about glomerular filtration?
Size: LARGE molecules are less permeable
Charge: NEGATIVE CHARGE, not as permeable
Near COMPLETE EXCLUSION of ALBUMIN in the urine normally
High PERMEABILITY TO WATER and small solutes
What does the proximal tubule do?
Proximal tubules reabsorb 2/3 of filtered Na and water, glucose, phosphate, potassium, amino acids, and proteins
Proximal tubules very sensitive to ISCHEMIA (Acute tubular necrosis d/t ischemic change in PT)
What is the JGA? What do the JG cells make? What does the macula densa make?
Located where AFFERENT arteriole enters glomerulus
JG cells make RENIN
Macula densa (cells in EARLY distal tubule) detects Cl- delivery
What is the interstitium?
Normally MINIMAL
Contains peritubular capillaries and fibroblast-like cells
EXPANSION in disease states (CKD–becomes expanded and fibrotic)
What percent of US residents have a kidney stone?
5%
How many americans have end stage renal disease? How many are on maintenance dialysis?
570,000 usually elderly
2/3 on dialysis
costs 42 BILLION
What are the general categories of renal disease?
Glomerular- immune mediated (ag-ab)
Tululointerstitial- TOXIC/ISCHEMIC and INFLAMMATORY reactions
Vascular
What is azotemia? What can cause azotemia?
biochemical abnormality that means increased BUN and creatinine!
- Pre-renal: LOW FLOW- hypoperfusion (hemorrhage, shock, dehydration, CHF)
- Renal disease
- Post-renal: obstruction of urine flow (stone, tumor)
What is uremia?
Azotemia AND clinical symptoms
Gastroenteritis anemia peripheral neuropathy* pruritis pericarditis*
What are the clinical presentations of NEPHRITIC syndrome?
Hematuria (VISIBLE pink urine!)
mild to mod proteinuria (UA)
HTN (more significant than in nephrotic; kidney can cause this, systemic can damage kidney)
What are the clinical presentations of nephrotic syndrome?
> 3.5gm/day proteinuria***
Hypoalbuminemia (don't have normal oncotic pressure in vessels)> tissue EDEMA (periorbital)
Liver gets revved up> makes apolipoproteins in excess> bind fat> HIPERLIPIDEMIA> LIPIDURIA(lipids in urine)
What is acute renal failure? What is the MCC?
Rapid onset azotemia (increase BUN/Cr)
Oliguria or anuria (no urine)
Due to glomerular, tubulointerstitial, or vascular disease
MCC is acute tubular necrosis
What is CKD?
GFR persistently <60 mL/min/1.73m2 for AT LEAST 3 months, persistent ALBUMINURIA
End result of ALL chronic renal disease
What are the clinical presentations of renal tubular defects?
Have to get up and go to the bathroom during the night:
Polyuria
Nocturia
Labs: Electrolyte imbalances (metabolic acidosis)
Inherited (RTA, cystinuria) or acquired (lead)
What is the clinical presentation of UTIs?
Pyuria and bacteriuria
Pyelonephritis (kidney) and/or cystitis (bladder)
What is the clinical presentation of Nephrolithiasis?
STONE formation
sudden flank pain>
RENAL COLIC
stone isn’t big enough to obstruct> sheds pieces of stone>
HEMATURIA (asymptomatic hematuria)
How do renal tumors present?
Often silent
Kidneys are in retroperitoneum. Can hide large mass w/out clinical visibility or pain.
What are the 4 stages of renal disease?
- Diminished Renal Reserve
- GFR is around 50% of normal (LOTS of reserve)
- Normal range BUN/Cr and asymptomatic (can’t usually pick up on labs) - Renal Insufficiency (CRI)
- GFR is 20 – 50% of normal
- Azotemia
- Anemia (decreased EPO fxn)
- Hypertension
* many elderly people> lose reserve as you age - Renal Failure (CRF) (WATER BALANCE ISSUES)
- GFR <5% of normal
- Terminal stage of uremia (need dialysis or kidney transplant)
What is a clearance test?
An approximation of GFR (the best overall measure of kidney function)
What is clearance equal to?
Clearance = UV/P
where:
U = urine concentration (mg/dl)
V = urine flow (ml/min) (urine collection for 24 hrs)
P = plasma concentration (mg/dl)
What analytes can be used to measure clearance?
Ideal analyte would be FREELY FILTERED in the kidney–>No tubular REABSORPTION or SECRETION
- Inulin - endogenous polysaccharide (Molecular weight ~5,000) IDEAL ANALYTE but requires continuous IV infusion
- Other exogenous markers
All require 24 hour urine collection
In general, “complex, expensive, and difficult to do in routine clinical practice”
What is another analyte that is used?
Creatinine
Endogenous, freely filtered, not reabsorbed
HOWEVER, ~10-20% secreted by proximal tubule
- Secretion varies between individuals
- Clearance estimate can EXCEED GFR by 10 - 40% ***
Serum levels related to body muscle mass and diet (meat in diet)
Can have extrarenal elimination of Cr by intestinal bacteria
*generally chosen as a clearance marker
Who will have higher creatinine?
eat a lot of MEAT and you’re BIG (lots of muscle mass) you’re going to have HIGHER creatinine
What is the OLD formula for estimated creatinine clearance?
Cockcroft-Gault
Cr Cl (ml/min) = (140 - age[yrs] x weight [kg])/ (72 x serum creatinine (mg/dl) x 0.85 if female)
Then requires height measurement and adjustment for body-surface area
What is the new equation that’s commonly used?
MDRD
Adjusts GFR for body SA
What are GFR estimates used for?
- Medicare ESRD program required documentation for eligibility of reimbursement based on GFR
- Used to assign patients on waiting lists for renal transplantation
- Used daily to determine drug dosages and effectiveness of therapy
- Define CKD as a persistent reduction in GFR < 60
- REcommend referral to nephrologist if GFR is less than 30
- GFR below 60 constitutes HIGH risk for CVD
What are clearance measurement still used?
- Unusual body habitus- Such as severe muscle wasting (amputees, wheel chair bound)
- Rapidly changing kidney function (acutely ill pt)
- Patients with GFR of 60 of greater–For instance, kidney donor eval, research protocols
What are common renal function tests?
- serum BUN
2. Serum creatinine
What produces BUN? What is it indicative of? What is a normal value? What affects BUN? What is it good for diagnosing?
Major END PRODUCT of protein nitrogen metabolism
LIVER produces urea from ammonia (which is produced by AA deamination)
Rough estimate of glomerular function
Normal is 10 - 20 mg/dl
Affected by kidney perfusion and body nitrogen balance (anabolism/catabolism)
Combined with serum creatinine, helps determine cause of azotemia
-Pre-renal, Renal, or Post-renal
What can cause a pre-renal increase in BUN?
- Increased synthesis of urea, increases BUN
Catabolism (burns, fever, stress) High protein diet GI bleed (protein leak in gut) Hemolysis (brk dwn RBC) Malignancy (tumors> necrosis> protein waste products)
- Decreased renal perfusion/low flow states
Hypotension/shock
CHF (congestive heart failure)
Dehydration
Renal vein thrombosis
Why is BUN sensitive to decreased renal perfusion?
The appropriate renal response in low flow states is to activate the RAS, which causes efferent arteriole constriction, and INCREASES Na and water reabsorption
Urea is PASSIVELY REABSORBED along with Na and water; when there is increased reabsorption in low perfusion states, the serum BUN increases out of proportion to any change in the GFR
*Reflection of the tubule reabsorbing more back into the blood stream
What causes renal increase in BUN?
Glomerular disease
ATN
interstitial disease
What causes post-renal increase in BUN?
Urinary tract obstruction
Benign prostatic hypertrophy (older men) Prostatic carcinoma Tumor of bladder or ureter Retroperitoneal mass Urinary calculi
What can cause a decrease in BUN?
- Decreased synthesis
- Low protein intake, androgen use, liver disease - Hemodilution
- Overhydration, psychogenic polydipsia, diabetes insipidus, pregnancy - Generally not diagnostically useful
What is creatinine? What does it do? What is creatinine in an individual? What is the normal range?
Waste product formed by the spontaneous dehydration of body creatine
Most creatinine is found in muscle
Serves as energy storage reservoir for conversion to ATP
Excretion relatively constant per day in a given individual
Normal is 0.7 – 1.5 mg/dL (bigger person with bigger muscle will be larger)
How does creatinine compare to BUN? Why?
Slightly better estimate of glomerular function than BUN
LESS affected by kidney perfusion (NOT reabsorbed)–> only secreted in tubules
**if you could only pick ONE test you’d pick a creatinine over a BUN
What causes pre-renal increase in creatinine?
- Increased synthesis!
Muscle hypertrophy Muscle necrosis Anabolic steroid use High meat diet Intense exercise
- Decreased renal perfusion (CHF, hypotension, shock)
What cuases post-renal increase in creatinine?
UT obstruction
What is a normal BUN: creatinine ratio?
10-20:1
What does an elevated BUN:Cr ratio indicate? What dose a normal ratio indicate?
Elevated BUN:Cr ratio in PRE-RENAL CONDITIONS
-Due to disproportionate increase in proximal urea reabsorption which accompanies the reabsorption of water (80:20)
Normal ratio in RENAL DISEASE 40:4
When do you use FeNa? How do you calculate it? What does a FeNa less than one indicate? What if FeNa> 2 indicate? Why?
Additional calculation to assist in the differential diagnosis of pre-renal versus renal disease (ATN)
Fe Na = Urine Na x plasma Cr x 100/ Urine Cr x plasma Na
FeNa < 1.0 % favors pre-renal
FeNa >2.0 % favors ATN
Na retention is appropriate renal response to renal ischemia (pre-renal), but this is impaired with ATN; the tubules fail and the urine Na concentration is high (>40mEq/L)
What is a normal proteinuria?
Normal urine up to 150 mg/24 hours
1/3 albumin (MW 69,000)
1/3 small globulins (MW<60,000)
1/3 Tamm-Horsfall protein (tubular secretion)
*You can have proteins in urine and NOT be sick
How do you test for proteinuria?
- Urine dipstick
- Sensitive only to ALBUMIN (won’t detect light chains)
- pH dependent (false + in ALKALINE urine)
- False + with gross HEMATURIA or dilute urine - Acid precipitation
- Detects albumin and globulins (ie-light chains)
- False + with gross hematuria and some meds
Can you have proteinuria w/out renal disease?
YES!
- Postural (orthostatic)
3 - 5% of young adults - Transient
- Functional
- Heavy exercise, cold exposure, fever
- -< 0.5 gm/24hrs
- -Hyaline and granular casts
- -Resolves in 2 - 3 days
What diseases can cause proteinuria w/out renal disease?
Congestive heart failure
< 0.5 gm/24hrs
Massive obesity
Constrictive pericarditis
Renal vein thrombosis
If you do see protein in the urine, can you guess whether it’s related to glomerular or tubular disease?
Maybe…
Glomerular pattern: albumin, small globulins
- Globulins reabsorbed with normal tubular fxn
- May be in nephrotic range (> 3.5 gms/24hrs)
Tubular pattern: Beta2 microglobulin
~1 - 2 gms/24hrs (never reaches nephrotic range)
What percent of people have congenital anomalies of the UT? What causes congenital anomalies?
10% of people are born with urinary tract malformations
May be hereditary or acquired during gestational development
What is the most common type of congenital anomaly in kids? In adults?
Renal dysplasia and hypoplasia account for ~20% of chronic kidney disease in children
Polycystic kidney disease accounts for ~10% of chronic kidney disease in adults
What is agenesis of the kidneys?
Bilateral agenesis incompatible with life
Unilateral agenesis compatible with normal function
What is hypoplasia of the kidney?
Failure of development of the kidney to a normal size
Bilateral or unilateral
No scarring* with a DECREASED NUMBER of renal lobes (6 or less) required for true hypoplasia
Most cases are acquired (show scarring)
What is an ectopic kidney?
Typically just above the pelvic brim or in pelvis
What is a horseshoe kidney?
Fusion of the upper (10%) or lower poles (90%) to form a single horseshoe-shaped kidney
1 in 500 – 1,000 autopsies
What is cystic disease of the kidney?
Hereditary or acquired
Relatively common
May lead to chronic kidney disease
May be confused with malignancy (solitary cyst can be confused w/ renal cell carcinoma)
What is cystic renal dysplasia?
Unilateral or bilateral
Gross: Enlarged, multi-cystic, and irregular
Micro:** UNDIFFERENTIATED mesenchyme, CARTILAGE, immature collecting ductules, and variably sized CYSTS lined by flattened epithelium
Most cases also have lower tract anomalies
SPORADIC disorder
What is the most important cystic renal kidney disease to remember?***
Autosomal dominant polycystic kidney disease
Hereditary, affecting 1/400-1,000 live births
Autosomal dominant inheritance
Bilateral disease, involving only a portion of the kidney initially
Renal failure in <2% by age 40 years
Renal failure in 75% by age 75 years
Multiple expanding cysts destroy renal parenchyma
What are the genetics of adult PCKD?
Two main gene abnormalities:
- PKD1 gene on chromo 16p13.3
- 80 - 85% of cases
- Encodes POLYCYSTIN 1, a protein that functions in CELL-CELL/CELL- MATRIX INTERACTIONS (integral membrane protein) - PKD2 gene on chromo 4q21
- 10 - 15% of cases; less severe
- Encodes POLYCYSTIN 2, a protein which acts as a nonspecific CALCIUM PERMEABLE CHANNEL
Primary cilia on tubular cells contain both POLYCYSTINS (keep tubular cells oriented in the right plane, if they’re not oriented correctly pumps won’t be on the right membrane)
If you have mut–> tubular cells secrete things in wrong space> cysts > disruption of intracellular ca> tubular cell death
What does adult PCKD look like gross and micro?
Gross: Bilaterally enlarged kidneys (may be huge!) that look like a bag of cysts
Micro: Cysts with variable lining (arise from tubules throughout the nephron), normal parenchyma present between cysts
How does adult PCKD present clinically?
Asymptomatic/pain/hematuria
What are extra-renal anomalies in adult PCKD? WHich is most important?
Liver cysts (40% of patients)
- **Intracranial berry aneurysms
- -Cause death in 4 – 10% of PCKD patients
Mitral valve prolapse (20 – 25% of patients)
