MS2 renal/pulm Flashcards
3 overlaping kidney systems (from cranial to caudal)
- The pronephros ( rudimentary and nonfunctional)
- The mesonephros (function for a short time during the early fetal period)
- The METANEPHRONS** (forms the permanent kidney) ; problems with this part will result in kidney problems
Summary of renal embryology
- Excretory system
- Kidney develops from what 2 sources
- how many nephrons
- when does urine production begin?
Excretory system
A. Kidney develops from 2 sources
- metanephric mesoderm, which provides excretory units
- urethritic bud, which gives rise to the collecting system
B. Nephrons are formed until birth, at which time there are approx 1 million in each kidney
C. URINE PRODUCTION BEGINS EARLY IN GESTATION, SOON AFTER DIFFERENTIATION OF THE GLOMERULAR CAPILLARIES, WHICH START TO FORM BY THE 10th WEEK
D. At birth the kidneys have a lobulated appearance, but the lobulation disappears during infancy as a result of further growth of the nephrons, although there is no increase in their number
Accessory (Aberrant) renal arteries
Some patients may have renal arteries from the aorta that during development did not appropriately
regress and which supply a specific portion of the kidney.
Any disruption to that specific artery will result in ischemia to the supplied portion of the kidney.
Arteries may obstruct urine flow at the pelviureteral junction leading to dilation of the calyces and pelvis known as
HYDRONEPHROSIS.
Horseshoe kidney
Found in 1/600 patients
Begins its ascent but the inferior mesenteric artery gets in the way
Results in a kidney that is most commonly fused at the
lower poles (90%) forming a U-shaped structure
Higher likelihood of developing a nephroblastoma
(Wilms tumor)
Isthmus typically lies anterior to the aorta and inferior
vena cava and posterior to the inferior mesenteric artery
Multicystic dysplastic kidney
- if you have in 2 kidneys (incompatible with life). In 1 kidney, it might be felt as an abdominal mass. Many not be severe enough to be detect
Ducts are surrounded by undifferentiated cells
Nephrons fail to develop and ureteric bud fails to branch so collecting ducts never form
The kidney is replaced by cysts and does not function.
Bilateral is incompatible with life.
Most common cause of a mass in a newborn, although most are nonpalpable at birth.
Polycystic kidney disease (AD vs AR)
ARPKD
• Progressive condition seen in 1/40,000 births
• Cysts form from collecting ducts
• Kidneys become large
• Results in renal failure in infancy or childhood
ADPKD
- cysts in kidney (all segments of the nephron) and can present with hemorrhage. Can feel these kidneys on physical exam. VERY HUGE - creatine problems to other organs by pressing on them.
- CAUSE RENAL FAILURE IN ADULTHOOD
- Cysts form from all segments of the nephron
- Cause renal failure in adulthood
- More common, 1/1,000 but less progressive than ARPKD
Pelvic kidney
Function of kidney is not affected. People don’t know they have this problem
• The ascent of kidneys from the sacral region to their normal
anatomical position results from the disproportionately rapid
growth of the caudal end of the embryo.
• A pelvic kidney does not leave its original pelvic developmental area.
Renal Agenesis
Incompatible with life (failure of kidney development)
- Failure of kidney development (bilateral renal agenesis) due to the failure of formation of the ureteric bud
- Associated with Potter syndrome; Results in anuria, oligohydramnios, and pulmonary hypoplasia
o Common characteristics include:
Abnormal facies
Atresia of duodenum and trachea
Cardiac anomalies
Cleft lip and palate
Low-set ears
Seminal vesicle, uterine, vaginal, and vas deferens abnormalities
o Not compatible with life
Wilm’s tumor
• Kidney cancer arising in fetus or by 5 years of age • Mutations in WT1 on 11p13
• WAGR syndrome is:
Wilms tumor Aniridia Genitourinary anomalies Mental Retardation
• Denys-Drash syndrome Renal failure Pseudohermaphridism Wilms tumor
***Very aggressive malignancy that can develop in kids
Bifid (double ureter)
o Two distinct ureters arising from the kidney, which either fuse along their courses or with two different insertion points into the bladder.
o Results from early division of the metanephric blastema.
Describe the following kidney issues
- Double pelvis
- Ectopic ureteric orifice
- Megaloureter
- Ureteropelvic junction obstruction
* **What is most common site of obstruction
- Double pelvis
o Two renal pelvises emanate from the renal hilum and immediately fuse to form one ureter. - Ectopic ureteric orifice
o A ureter enters the seminal vesicle or prostatic urethra (or vagina), instead of the bladder.
o Patient will consequently present with incontinence. - Megaloureter
o Abnormally enlarged ureter - Ureteropelvic junction obstruction (People have normal lives with this, you might not even see anything till postmortem)
o Area between the kidney and the ureter
o Last segment of the fetal ureter to canalize
o Most common site of obstruction**
o Presents prenatally as hydronephrosis; may present as a palpable abdominal mass.
o Evaluate with US, VCUG
o Diuretic renography (renal scan plus diuretic) measures the emptying time from the kidney
o Patients may require pyeloplasty to remove the atretic segment and reattaching the ureter.
12 clinical manifestations of renal diseases
A. Azotemia – elevation of blood urea nitrogen (BUN) and creatinine usually due to decreased glomerular filtration rate (GFR) due to many renal and other disorders
- Prerenal azotemia – hypoperfusion of kidneys impairing renal function (caused by? - CHF)
- Renal azotemia – from intrinsic renal disease
- Postrenal azotemia – obstruction of urine flow beyond the level of the kidney (caused by?- BPH)
B. Uremia – when failure of the renal excretory system causes clinical signs and symptoms in other systems (e.g UREMIC PERICARDITIS)
C. Nephritic syndrome – described below
D. Rapidly progressive glomerulonephritis – nephritic syndrome with rapid decline of GFR
E. Nephrotic syndrome – described below
F. Asymptomatic hematuria and/or proteinuria – due to mild glomerular abnormalities
G. Acute renal failure
1. Oliguria or anuria 2. Azotemia 3. Rapid onset, frequently reversible
H. Chronic renal failure
I. Prolonged signs and symptoms of uremia
II. Generally progression from normal renal function to end-stage renal disease is through four stages:
a. DIMINISHED RENAL RESERVE; GFR ~50% of normal. BUN & Cr are normal
b. RENAL INSUFFICIENCY; GFR is 20-50% of nml. +Azotemia, anemia, htn
c. CHRONIC RENAL FAILURE; GFR < 20-25% of nml. Loss of renal regulation of volume and solute concentration a) Edema b) Metabolic acidosis c) Hyperkalemia - cause dysarrthymhias d) Uremia with neurologic, GI, CV system symptoms
d. END-STAGE RENAL DISEASE
1) GFR < 5% of nml 2) Terminal stage of uremia
I. Renal tubular defects – Polyuria, nocturia, electrolyte disorders
J. Urinary tract infection
1. Bacteruria and pyuria 2. Affecting kidney (pyelonephritis) and/or bladder (cystitis)
K. Nephrolithiasis (kidney stones) – pain, hematuria, possible recurrence
L. Urinary tract obstruction and renal tumors
Approach to renal disease
A. Tissue involvement (4)
B. Extent of involvement (2)
C. Type of involvement (5)
D. Method of examination (3)
A. Tissue Involvement
- Glomerulus
- Tubules
- Interstitium
- Vasculature
B. Extent of Involvement
- Kidney
- Glomeruli
C. Type of Involvement
- Cellularity
- Inflammation
- Fibrosis / hyaline / other deposits
- Necrosis / atrophy
- Structural alteration
D. Method of Examination (usually from kidney biopsy)
- Light microscopy - disease process and development
- Immunofluorescence - etiology
- Electron microscopy - structural alteration
Polycystic kidney disease - ADPKD
General Genetics; PKD 1 vs PKD 2 - which is more common? More severe? Pathogenesis Morphology Clinical features (3)
a. General
1) Common, 1:400-1000 live births
2) Always bilateral
3) Causes 5-10% of cases of chronic renal failure
b. Genetics – at least two genes
1) PKD1 (16p13.3)
a) 85% of cases are due to a mutation in PKD1 b) Encodes polycystin-1 – integral membrane protein c) More severe disease d) Average age of end-stage renal disease / death = 53 years
2) PKD2 (4q21)
a) ~15% of cases due to a mutation in PKD2 b) Encodes polycystin-2 – integral membrane protein c) Less severe disease d) Average age of end-stage renal disease / death = 69 years
c. Pathogenesis – not established
d. Morphology
1) Bilaterally enlarged kidneys (sometimes greatly)
2) External surface is covered with cysts
3) Cysts arise from tubules throughout the nephron
4) Microscopically: functioning nephrons between cysts
e. Clinical features
1) Enlarged kidneys on physical exam
2) Pain (from expanding cysts or passing blood clots), hematuria (from hemorrhage into cysts) or asymptomatic until renal insufficiency develops
3) Extrarenal anomalies
a) Liver cysts – seen in 40% of patients b) Berry aneurysms c) Cardiac valve anomalies – 20-25% of patients
Polycystic kidney disease - ARPKD
- gene?
- morphology
- clinical
Autosomal-recessive (childhood) polycystic disease (ARPKD)
a. PKHD1 gene (6p21-p23) encodes fibrocystin – integral membrane protein, function unknown
b. Morphology
1) Kidneys enlarged
2) Cut surfaces are sponge-like because of numerous cysts arising from collecting ducts BUT
3) External surface is smooth (unlike ADPKD)
4) LIVER CYSTS ALMOST ALWAYS PRESENT
c. Clinical
1) Four subcategories: perinatal, neonatal, infantile, juvenile
2) Perinatal and neonatal most common
a) Infant born with enlarged, cystic kidneys b) Death in infancy or childhood (Lung hypoplasia -Lung not develop??
3) HEPATIC FIBROSIS in SURVIVORS
List 6 Medullary cystic disease
- Medullary sponge kidney
a. Adults b. Cystic dilations of collecting ducts in medulla c. May result in hematuria, infection, urinary calculi OR asymptomatic d. Renal function not affected - Nephronophthisis (next flashcard)
- Adult-onset medullary cystic disease
a. Similar in morphology but distinct from nephronophthisis b. Autosomal dominant c. Two genes MCKD1 and MCKD2 - Acquired (dialysis-associated)
a. NUMEROUS CORTICAL and MEDULLARY CYSTS AFTER PROLONGED DIALYSIS, 0.5-2 cm b. Clear fluid contents and may contain calcium oxalate crystals c. Likely due to tubular obstruction by fibrosis or oxalate crystals d. Asymptomatic – usually e. Renal cell carcinoma – rarely (7% of patients) develops in wall of cyst - Simple renal cysts
a. Single or multiple, cortical, 1-5 cm
b. Microscopic HEMATURIA OR asymptomatic
c. No clinical significance BUT must distinguish from tumors on imaging. 1) Smooth contours 2) Essentially always avascular 3) Give fluid (rather than solid) signal on radiography - Renal cysts in hereditary malformations syndromes (tuberous sclerosis, von hipped Lindau - in renal cell carcinoma?)
Medullary cystic disease - nephronophthisis
- most common cause of what
- 3 variants
- pathogenesis
- morphology
- clinical features
Nephronophthisis
a. Group of progressive renal disorders
b. Most common cause of genetic renal disease in children and young adults
c. Three variants
1) Sporadic, nonfamilial
2) Familial juvenile nephronophthisis (most common)
3) Renal-retinal dysplasia (15%)
d. Pathogenesis
1) Seven genes identified
2) Autosomal recessive
3) NPH1, NPH2 and NPH3 are mutated in juvenile form
e. Morphology
1) Small kidneys, granular surface
2) Cysts predominantly at corticomedullary junction
3) Cortex: tubular atrophy, thickening of basement membranes of distal and proximal tubules, interstitial fibrosis
4) RESULT: renal insufficiency, chronic renal failure, end-stage renal disease
f. Clinical features
1) First symptoms: Polyuria and polydipsia – unable to concentrate urine
2) Also: Sodium wasting and tubular acidosis
3) May have extrarenal involvement – ocular motor abnormalities, retinal dystrophy, liver fibrosis, cerebellar abnormalities
4) Progression to terminal renal failure, 5-10 years
5) May be difficult to diagnose: cysts are too small to see on imaging
Glomerular review
- function of glomerulus
- how many percent of blood go to glomerulus
- arterial side of circulation
- structure of GBM (3 parts)
- plasma vs glomerular filtrate (diiff)
Glomerulus; function is to FILTER
- 20% of all blood; < 0.5% of body mass
- Blood (capillary) → pre-urine (Bowmans space).
- arterial side of circulation; afferent arterioles in, efferent arteriole out. Blood then goes to remainder of kidney
- structure of GBM; Fenestrated endothelium, basement membrane, epithelial cells with foot processes
- Plasma vs glomerular filtrate; Plasma has more proteins than glomerular filtrate
Nephritic Syndrome
Pathogenesis
Clinical (6)
Diseases presenting as primarily nephritic syndrome (3)
Nephritic Syndrome Pathogenesis
- Inflammatory rupture of glomerular capillaries
- Bleeding into urinary space
- mild to moderate proteinuria and edema
Clinical
- HEMATURIA, red cell casts in urine, oliguria, azotemia, HTN mild to moderate, maybe proteinuria and edema
Diseases (NEPHRITIC SYNDROME)
- Post strep infectious glomerulonephritis
- Nonstreptococcal Acute Glomerulonephritis
- RPGN ( Rapidly progressive - CRESENT - glomerulonephritis) Type I, II, III
Acute proliferative (post strep) glomerulonephritis
Clinical presentation Pathogenesis Light Microscopy Immunofluorescent microscopy Electron microscopy
Vs
Non infectious
Acute proliferative (post strep) glomerulonephritis
General
- 1-4 weeks post strep skin or pharynx infection
- Children 6-10 yrs
Etiology and Pathogenesis
- IMMUNE COMPLEX MEDIATED
Light microscopy
- PROLIFERATION
- DIFFUSE NEUTROPHIL AND MONOCYTE INFILTRATION
Immunofluorescence
- GRANULAR DEPOSITS OF IgG, IgM, C3, MESANGIUM AND ALONG GBM
- “HUMPS” of electron dense Ag-Ab complex deposits, EPITHELIAL SIDE OF BASEMENT MEMBRANE (SUBEPITHELIAL)
Clinical
- hematuria, hx of strep, periorbital edema
RPGN
***3 types Clinical presentation Pathogenesis Light Microscopy Immunofluorescent microscopy Electron microscopy
RPGN (CRESENT); Rapidly Progressive glomerular Nephropathy ***IMMEDIATE WORSE PROGNOSIS
Overview
- RUPTURES IN GBM
- MOST CASES IMMUNOLOGICALLY MEDICATED
Classification
- type I (Anti-GBM antibody); anti GBM Abs
- type II (IMMUNE COMPLEX DEPOSITION)
- Type III (NO anti-GBM or immune complexes)
Light microscopy - CRESENTS
Immunofluorescence
- Type I; Linear GBM for Ig and complement
- type II; granular immune deposits
- type III; little or no deposition
Electron microscopy
- ruptures in GBM
Clinical; Goodpasture -HEMOPTYSIS
Nephrotic syndrome
4 types
Presentation
Pathophysiology
Nephrotic Syndrome
- Clinical; PROTEINURIA (>3.5 gm/day)
Diseases presenting as nephrotic syndrome
- Membranous Nephropathy
- Minimal change disease
- Focal segmental glomerulosclerosis (FSGS)
- Membranoproliferative glomerulonephritis (MPGN)
Nephrotic syndrome - Membranous glomerulonephropathy
Clinical presentation Pathogenesis Light microscopy Immunofluoresent microscopy Electron microscopy
Overview
Patho - immune complex mediated
Light microscopy - Diffuse thickening of glomerular capillary wall
Immunofluorescence; granular IgG and C3
Electron microscopy
- Deposites btw GBM and epithelial cells
- SPIKES AND DOMES
Nephrotic Syndrome _ Minimal change disease
Clinical presentation Pathogenesis Light microscopy Immunofluoresent microscopy Electron microscopy
Minimal change disease
Overview - most common cause of NEPHROTIC syndrome in children
Light microscopy; NO CHANGE
Immunofluorescence; NO Ig or complement DEPOSITS
Electron microscopy
- EFFACEMENT OF FOOT PROCESSES of visceral epithelial cells
Clinical features
- RESPOND RAPIDLY TO CORTICOSTEROID TX
Nephrotic syndrome - FSGS
Clinical presentation Pathogenesis Light microscopy Immunofluoresent microscopy Electron microscopy
FSGS - Focal Segmental Glomerulosclerosis
Patho; VISCERAL EPITHELIAL DAMAGE
Light microscopy,
- SCLEROSIS (focal)
- Segmental
- affected capillary loops collapse
- Segmental HYALINOSIS
Immunofluorescence
- IgM and C3 in Sclerotic areas +/- mesangium
Electron microscopy
- Diffuse effacement of foot processes
- focal detachment of epithelial cells and denudation of GBM
Clinical course
- POOR RESPONSE TO CORTICOSTEROID TX
Nephrotic syndrome - MPGN (Type I vs Type II)
Clinical presentation Pathogenesis Light microscopy Immunofluoresent microscopy Electron microscopy
MPGN - Membranoproliferative Glomerulonephritis
Primary (idiopathic), (type I and II)
Secondary is always type I
Patho
Type I
- Immune complexes
- activation of classical and alternative complement pathways
Type II
- activation of alternative complement pathway
Light microscopy
- Proliferation of mesangial cells
- proliferation of capillary endothelium
- Glomerular capillary wall has a “TRAM-TRACK” appearance
Immunofluorescence
- Type I; C3 in granular pattern. IgG, C1q and C4 may also be present
- Type II; C3. NO IgG or C1q or C4
Electron microscopy
- Type I; Subendothelial electron-dense depositis, may also be mesangial and subepithelial deposits
- Type II; Deposition of dense material into GBM . RIBBON LIKE
Identify 3 Isolated Urinary Abnormalitis
Pathogenesis
Clinical features
Morgphology (LM, Immunofluorescence, EM)
- IgA Nephropathy
- Patho; Genetic or acquired abnormality of immune regulation
- Light microscopy; Mesangial widening due to proliferation and endocapillary proliferation
- Immunofluorescence; MESANGIAL DEPOSITION of IgA. C3, properdin, IgG, IgM often. Dense deposits in mesangium
- Clinical features; HEMATURIA - Alport Syndrome
- Patho; abnormal alpha 3, alpha 4, alpha 5 chains of collagen IV. Defective assemble of collagen IV
- Electron microscopy; Early lesion - GBM thinking. Fully developed disease - GBM alternating thick and thin. Splitting and layering of lamina densa
- clinical features; hematuria, Red cell casts. HEMATURIA with progressive to chronic renal failure. nerve deafness, Eye disorders - Thin Basement Membrane Lesion
Glomerular lesions associated with systemic diseases (4)
- Lupus nephritis; various possible clinical manifestations
- Henoch-Schoenlein Purpura
- Diabetic Nephropathy
- Amyloidosis
- deposits of abnormal proteins (amyloid) in the mesangium and glomerular capillary walls
- eventually the glomerulus is completely obliterated
- also see deposits in renal interstitium and vessel walls
- may present with nephrotic syndrome
- may die of uremia from destruction of glomeruli
The potassium balance (external vs internal balance)
**what is the goal
External K+ Balance—Excretion must equal intake
- The relationship between dietary K+ intake and K+ excretion determines external K+ balance. The dietary intake of K+ is approximately equal to that of Na+, 80 to 120 mEq/day. This K+ intake is more than the entire K+ content of the ECF, which is only ∼70 mEq/l. For the plasma K+ content to remain constant, the body must excrete K+ through renal and extrarenal mechanisms at the same rate as K+ ingestion. The kidneys excrete 90% to 95% of the daily K+ intake; the colon excretes 5% to 10%.
Internal K+ Balance—Buffer the rise of ECF K+
- Maintaining normal intracellular and extracellular [K+] requires not only the external K+ balance just described, but also the appropriate distribution of K+ within the body. Most of the K+ is inside cells-particularly muscle cells, which represent a high faction of body mass-with smaller quantities in liver, bone, and red blood cells.
What induces cellular K+ uptake?
What about K+ excretion?
Cellular K uptake
- Distribution of ingested K+: Upon ingestion K is rapidly taken up by cells, primarily the liver and the muscles. Dietary K load momentarily cause hyperkalemia. This increase is rapidly buffered by K uptake by the cells. The kidneys slowly catch up and increase excretion
- ***Increased Na/K ATPase activity increases cellular K uptake
K excretion
Renal tubular sites of potassium reabsorption and secretion. Potassium is reabsorbed in the proximal tubule and in the ascending loop of Henle, so only about 8 percent of the filtered load is delivered to the distal tubule. Secretion of potassium into the late distal tubules and collecting ducts adds to the amount delivered; therefore, the daily excretion is about 12 percent of the potassium filtered at the glomerular capillaries. The percentages indicate how much of the filtered load is reabsorbed or secreted into the different tubular segments.
What happens to reabsorption/secretion in following conditions
- The K+ depleted state (e.g kids)
- The K+ repleted state (e.g diet rich in potassium)
- The K+ depleted state (e.g kids)
- K+ is reabsorbed ALL along the nephron (PT, TAL, CCTs)
- K+ Reabsorption by Intercalated Cells Occurs Through Apical K+ Uptake Mediated by an H-K Pump—which means that ↑K+ uptake will cause H+ loss
A. The proximal tubule reabsorbs most of the filtered K+ through two paracellular mechanisms:
- Solvent drag- driven by Na reabsorption
- Electro-diffusion- in S3 of the PCT luminal positivity drives out K+
B. The TAL of the loop of Henle reabsorbs K+ by both paracellular and transcellular mechanisms:
- Transcellular- NKCC2
- Paracellular- luminal positivity
C. The CCTs reabsorb K+ in response to K+ depletion:
- A transcellular process mediated by the α intercalated cells. This is an active process mediated by an apical ATP-driven H-K pump. The α intercalated cells are also responsible for H+ secretion. K+ depletion is often associated with accelerated secretion of H+ and the development of hypokalemic alkalosis. - The K+ repleted state (e.g diet rich in potassium)
- K+ excretion is regulated by ALDOSTERONE (increase) and by changes in cell [K+] in Principal cells in the COLLECTING DUCT.
A. Na+ transport (stimulated by aldosterone) into the cell—↑↑luminal negativity—K+ loss
B.↑ENaC or ↑Na-K-ATPase will ↑K+ loss
C.Antidiuretic hormone (ADH) inserts H2O channels in the luminal membra
*****ALDOSTERONE PROMOTES K+ SECRETION
Since aldosterone stimulates K+ secretion and Na+ reabsorption, how can normal balance for Na+ and K+ be maintained independent of each other?
For example, in response to an increase in K+ intake, K+ excretion increases & K+ balance is restored but there is transient Na+ retention.
Are there factors, other than diet that can modulate K secretion?
- Increase aldosterone secretion and increase cell K+ in principal cells
- Increased luminal flow increases K+ secretion (e.g diuretics)
- Increasing delivery of Na+ to the collecting duct stimulates Na+ reabsorption, making the lumen more negative. A more negative lumen potential favors K+ secretion
Effect on K+ secretion of changes in urine flow to the collecting duct
- Increased urine flow that occurs with extracellular volume expansion, osmotic diuresis, or administration of several diuretic agents (e.g., acetazolamide, furosemide, thiazides) leads to enhanced K+ excretion (kaliuresis).
- Almost uniformly, increased urinary flow is also associated with increased Na+ excretion (natriuresis), so that both solutes appear in increased amounts in the urine.
- When luminal flow is low, then as K+ moves from the principal cell to the lumen, luminal [K+] rises rapidly to a steady-state level, thereby inhibiting further K+ diffusion from the cell. Thus, total K+ secretion is relatively low. When luminal flow is high, it sweeps newly secreted K+ downstream. The resulting fall in luminal [K+] steepens the K+ gradient across the apical membrane and consequently increases passive K+ flux from cell to lumen.
- Increased luminal flow also increases the Na+ delivery to tubule cells, thus raising luminal [Na+] and enhancing Na+ uptake. This incremental supply of Na+ to the principal cell stimulates its Na-K pump, increases basolateral K+ uptake, and further increases K+ secretion. Also, increased Na uptake depolarizes the luminal membrane increasing luminal negativity and increasing electrochemical driving force for K+ secretion
ACID BASE DISTURBANCES AFFECT K+ BALANCE
- effect on alkalosis/ acidosis on K+ in the blood (hyper or hypokalemia)
- effect of change in K+ in blood on alkalosis/acidosis
- As a rule, acidemia leads to hyperkalemia as tissues release K+. We can think of this K+ release as an “exchange” of intracellular K+ for extracellular H+, although a single transport protein generally does not mediate this “exchange”
- ** Acidosis induces hyperkalemia and decreases K secretion, thus compounding the hyperkalemia
- *** Alkalosis induces hypokalemia and increases K secretion, thus compounding the hypokalemia
Summarize the 3 factors that promote K excretion
- Aldosterone: K directly activates adrenal cortex:-
a. Stimulates the basolateral Na/K ATPase increasing [K]i
b. Stimulate apical ENaC that ↑luminal negativity- promoting K excretion
c. Aldo ↑apical membrane K conductivity - Luminal flow affects K excretion: increases with increased and vice versa:-
a. Increased luminal flow reduces luminal [K] around the principal cells thus promoting K
excretion
b. Increased luminal flow ↑Na delivery to, and Na reabsorption by, principal cells, thus increasing luminal negativity and promoting K excretion - Alkalosis promotes K excretion and acidosis retention:-
a. Alkalosis drives up intracellular pH that activates Na/K ATPase in all cells, including principal cells
b. High pH ↑conductance of apical K channels c. Thus, alkalosis not only produces systemic hypokalemia but also worsens it by promoting K excretion by the kidneys
Summarize High points of HYPOKALEMIA VS HYPERKALEMIA
1.HYPOKALEMIA:-
1.1. ↑Renal excretion—hyperaldosternosim; K+-wasting diuretics (acetazolamide, osmotics,
NKCC2-blockers, thiazides and thiazide-like drugs); Cushings (high corticosteroids will activate mineralocorticoid receptors)
1.2.GI losses of fluids (vomiting, diarrhea)—loose K+ in GI secretions—also volume loss
activates RAAS and aldosterone excretes K+
1.3.Transcellular movement—alkalosis
1.4.Treatment—
1.4.1.K+ and volume replacement (to “switch off” aldosterone)
1.HYPERKAEMIA:-
1.1.↓Renal excretion—renal failure (↓GFR); hypoaldosternosim; K+-sparing diuretics (spironolactone, eplerenone, amiloride)
1.2.Cell lysis (recall, cells have a LOT of K+)—rhabdomyolysis; leukemias and lymphomas; cell-
death after cancer chemotherapy; reperfusion after ischemia spills K+ into the blood stream 1.3.Transcellular movement—acidosis 1.4.Treatment—
1.4.1.Glucose with insulin—push K+ into the cells 1.4.2.Na-HCO3—alkalosis pushed K+ into the cells 1.4.3.IV Calcium gluconate—stabilizes the cardiac membrane and can prevent arrhythmias 1.4.4.β2-agonist (albuterol)—push K+ into the cells 1.4.5.Potassium binding resins (Kayexalate)—binds K+ in the small intestines and prevent its reabsorption into the circulation
1.4.6.Dialysis
- Calcium vs Phosphate homeostasis
- 2 things that increase calcium absorption
- how does hypercalcemia affect NKCC and luminal positivity?
- how does renal failure affect Ca and phosphate
- Calcium absorption lead to phosphate excretion
- 2 things that increase calcium absorption (While preventing phosphate absorption)
- parathyroid
- vitamin D - Hypercalcemia blocks NKCC2 and dissipates luminal positivity in the TAL—↓Ca2+ resorption
- Renal failure - decrease GFR
- Hyperphosphatemia
- hypocalcemia (Will activists PTH - activate osteoclasts - renal osteodystrophy)
HIGH POINTS Ca2+ and Pi
- Kidneys resorb majority of Ca++ filtered—resorption is passive in the proximal tubule and the TAL—active in the DCT where its stimulated by parathyroid hormone and activated vitamin D.
- 1.Hypercalcemia blocks calcium resorption via the basolateral calcium sensing receptor (CaSR)
- Phosphate, on the other hand, is excreted by the kidney (in large amounts on a Western diet)
- 1.Phosphate resorption—the proximal tubule reabsorbs most of the filtered phosphate by the transcellular route (NaPi transporters)
- 2.FGF23 and parathyroid hormone reduce Pi resorption in the proximal tubule
What happens in renal failure
1. ↓GFR—↓urine flow, which will allow for more phosphate reabsorption
2.↓GFR—↓phosphate filtration, which will reduce phosphate excretion
3.Kidneys cannot make enough activated vitamin D3
LEAD TO
1.High [Pi]p will ionize with Ca++ and reduce [Ca++]p (double product)
2.Less Ca++ is absorbed (less vitamin D3)
3.Combined (1 and 2) lower serum Ca++ and activate PTH
LEAD TO
1.High PTH is bad news for the body and causes renal osteodystrophy
2.This is characterized by bone remodeling (osteoclast activation) and abnormal deposition on the vasculature (altering the structure of the vasculature)
Summary of changed in CKD with treatment
Kidney functions (5)
- Sodium balance
- Potassium excretion
- Acid excretion
- Calcium/phosphate balance
- Erythropoiesis
CKD (abnormalities)
- Sodium retention and volume overload
- Hyperkalemia
- Metabolic acidosis
- Increase phosphate and PTH, decrease serum calcium and calcitrol
- Anemia
Treatment
- Sodium restriction diuretics
- DIetary restriction. avoid NSAIDs
- Sodium bicarbonate
- Phosphate binders and calcimemetics
- Erythropoiesis-stimulating agents; iron replacement
Summary of urea cycling
Glomerulus PT Ascending/descending Thin loop Thick ascending limb DT MCD Excreted
- **What happens to urea in kidney failure
- plasma creatinine vs GFR vs urea
- what ration of BUN/creatinine indicate renal failure
- Glomerulus - urea freely filtered; 100% = amount filtered
- PT - 50% reabsorbed (solvent drag, facilitated diffusion)
- Ascending/descending Thin loop - 60% secreted from interstitium into loop (UT-A2)
- Thick ascending limb - No transport of urea
- DT - 110% present; no transport of urea
- MCD ; 70% reabsorbed - 60% into interstitium (UT-A1); increased by ADH (AVP), 10% into vasa recta
- Excreted; 40% of filtered load
* ** Urea transport is passive in all nephron segments, following the urea concentration gradient. Urea crosses cell membranes by facilitated diffusion.
- As renal disease progresses and GFR declines, serum creatinine increases. Clinicians measure PCr to follow changes in GFR.
- Plasma creatinine is a function of GFR—rises linearly with falling GFR
- In renal disease, as GFR declines, less creatinine is filtered so the concentration of creatinine in the serum gradually increases. (As creatinine level increase linearly, urea will also increase disproportionately due to decrease in GFR)
- Increase serum BUN/creatinine > 20:1 (prerenal azotemia)
Urine Concentration & Dilution: The Countercurrent Multiplier
- Function of the countercurrent mechanism
- osmolarity through the kidney tubule
- what are the functions of the loop of henle that contribute to the countercurrent mechanism (4)
- what hormone dictates if urine is dilute or concentrated
- *** What 2 things help with water conservation
- what 2 parts of tubules are impermeable to water
- what is the maximal effect of NaCl transport in the thick/thin ascending limb
Function of the countercurrent mechanism
- The function of the countercurrent mechanism is to create urine with an osmolality different from serum osmolality
- To conserve water (the usual physiological condition), the countercurrent mechanism generates urine with osmolality greater than plasma (concentrated urine).
- To excrete excess water, the countercurrent mechanism generates urine with osmolality less than plasma (dilute urine)
- A concentrated urine is produced when ADH is present in the plasma (the usual physiological condition).
- In the absence of ADH a dilute urine is produced.
Tubule Fluid Is Isosmotic in the Proximal Tubule, Becomes Dilute by the End Loop of Henle, and Then Either Remains Dilute or Becomes Concentrated by the End of the Collecting Duct
- The Loop of Henle helps creates urine with an osmolality different from plasma
Functions of the loop of Henle that contribute to the countercurrent mechanism: The countercurrent “multiplier” is located in the Henle’s loop:-
- The descending limb is impermeable to solutes, but freely permeable to water.
- The ascending limb reabsorbs large quantities of NaCl & is impermeable to water.
- Reabsorption of NaCl without water creates a dilute urine.
- The thick ascending limb is called the “diluting segment”.
ADH dictates the urine will be dilute or concentrated….but, recall, water needs ΔOsm to cross compartments
- The interstitial around Henle’s loop provides the ΔOsm for water to cross compartments
- The medullary interstitium in the juxtaglomerular nephrons is hypertonic, with tonicity increasing towards the hairpin loop
Hypertonic medullary interstitium & ADH are required for renal water conservation
- Medullary Hypertonicity “Draws” Water Out (FORCE)
- ADH Provides Water Permeability
Dilute urine is a consequence of withdrawal of ADH
- In the absence of ADH the IMCD becomes impermeable to water.
Importantly, this does not dissipate the medullary hypertonicity.
tALH and TAL are impermeable to water (Diluting segment - because water can’t leave where as NaCl leaves - permeable)
The maximal effect of NaCl transport in the thick/thin ascending limb is to create a gradient of 200 mOsm/Kg between the urine and the interstitium (B+A)
- The NKCC2 (TAL) actively generates this transepithelial gradient of NaCl while the tALH contributes by passive transport. Remember that the tALH and the TAL are impermeable to water.
How is this single effect, of generating a 200 mosmole/l gradient, magnified? The answer lies in the properties of the tDLH that is impermeable to salt, but freely permeable to H2O
- Urine in descending limb equilibrates osmotically with interstitium
- flow of urine moves hyperosmotic urine into ascending limb
- urine in descending limb equilibrates osmotically with interstitium, again.
** Repeat the cycle enough number of times and you have hypertonic medulla
Urine osmolality rises and then falls along the nephron
Summarize - changes in urine osmolarity
Urine osmolality rises and then falls along the nephron
Urine is ALWAYS iso-osmolar (300 mOsmoles/l) at the end of PT, hyperosmolar (>300) at tDLH and hypo-osmolar (<300) at the end of TAL
Thin descending limb is is freely permeable to water which is drawn out due to progressively increasing interstitial osmotic gradient
Thin ascending limb is water impermeable and freely allows passage of NaCl; thus at the end of this segment urine has the same osmolarity as the interstitium at this point, usually ≈ 350-450 mOsmoles/l
TAL (NKCC2 channels) avidly reabsorb solutes without much water reabsorption; thus making the urine hypo-osmolar (always)(referred to as the diluting segment)
DCT also reabsorbs NaCl and further dilutes the urine
Role of urea in urinary concentration
- *Is ADH present in hydration or dehydration
- *What is the diluting vs concentrating segment
Problem: If NaCl is the only contributor to the interstitial hyperosmolarity, tALH cannot passively transport NaCl out (no diffusion gradient) of the lumen (remember, NaCl is the principal solute in the lumen).
Presence of Urea draws water out of the tDLH, concentrating urine with NaCl. Now at the tALH NaCl concentration is much higher than the interstitium and passive diffusion of NaCl from the lumen to the interstitium can happen.
Remember, the TAL does not face this conundrum as there NaCl transport is active.
Urea, at the tip of the loop augments overall interstitial osmolarity and increases the renal capacity to concentrate urine
ADH, concentrates urine directly (by AQP2) but also aids water reabsorption by increasing urea in the medullary interstitium
(ADH-UT-A1)
- The urea that accumulates in the interstitium is secreted into the tALH and is again reabsorbed at the IMCD, aided by ADH. This is urea recycling
- ***ADH increases urea recycling
ADH
- Over hydration; No ADH
- Dehydration; ADH present
Segment
- TAL; directly diluting segment and indirectly concentrating segment
- IMCD; directly concentrating segment
Free water clearance
- positive vs negative
- in presence of loop diuretics?
Remember—If urinary osmolality is greater than plasma—free water clearance is said to be negative
Remember—If urinary osmolality is less than plasma —free water clearance is said to be positive
With loop diuretics; Free water clearance = 0 (patient is peeing plasma)
- Generation of either positive or negative free water clearance depends on NaCl reabsorption in thick ascending limb of loop— generates the medullary hypertonicity:- Damage to the renal medulla or administration of loop diuretics diminishes the capacity to concentrate or dilute urine—free water clearances goes toward zero (urine osmolality approaches the value for plasma osmolality). PATIENT PEES PLASMA
Regulation of osmolality
- *Normal control of ADH secretion is via what?
- *Several Non-osmotic stimuli also enhance AVP? (How)
AVP (ADH) Increases Water Permeability in All Nephron Segments Beyond the Distal Convoluted Tubule
- Arginine vasopressin is the principal regulator of osmolality, which also co-regulates effective circulating volume
- Synthesized in the supraoptic & the paraventricular nucleus of the hypothalamus
- Secreted from the posterior pituitary
Distal Nephronal segments have high water permeability, only in the presence of AVP
ADH (AVP) binds to, and activates, V2 receptor on the collecting ducts of the nephrons and increases cAMP →this leads to recycling of AQP2 & UT-A1 to the luminal membrane
Through V1 receptor AVP induces vasoconstriction and platelet aggregation
Normal control of ADH Secretion is via the osmoreceptors
- Osmoreceptors normally control urine water excretion—they are very sensitive to small changes in plasma osmolality.
- An increase in plasma osmolality stimulates ADH secretion—ADH travels to the kidney and makes the collecting ducts permeable to water.
- Normally ADH is present in the plasma and the kidneys are conserving water (urine osmolality is greater than plasma osmolality)
Several Non-osmotic Stimuli Also Enhance Arginine Vasopressin Secretion
- Reduced Effective Circulating volume
- When ECF decrease significantly, ADH is stimulated even if plasma osmolarity is falling
- In day to day life plasma osmolarity changes are much more potent stimuli for ADH release; however, after 20% blood loss, falling MAP & volume depletion are stronger stimuli
- This is also because apart from retaining water and increasing volume AVP is a vasoconstrictor and can sustain MAP in face of falling CO
- Shift the AVP response curve to left or right is dependent on the state of the circulation
* *Inresponse to heart failure or hypovolemic shock, the kidney conserves NaCl and water
Other non-osmotic regulators of AVP:
- Pain, nausea, and several drugs:- morphine, nicotine, and high doses of barbiturates stimulate AVP secretion.
- Alcohol and drugs that block the effect of morphine (opiate antagonists) inhibit AVP secretion and promote diuresis
- High levels of chorionic gonadotropins sensitize the hypothalamic nuclei to release AVP at lower plasma osmolarity. This leads to mild water retention in pregnancy. Also seen right before the bleeding phase of the menstrual cycle.
Summarize ADH and free water clearance HIGH POINTS
- ADH increases water permeability of ALL nephron segments after distal convoluted tubule (DCT)—action of V2 receptors
- 1.Primary effect—↑AQP2 channels into the cell membrane 1.2.Additional effects—↑NKCC2 activity in the TAL; ↑urea permeability in the collecting duct
- ↑Plasma osmolarity and ↓intravascular volume are two key stimulators of ADH release
- SIADH—too little ADH; Diabetes insipidus—not enough amount, or defective action of ADH
- Free water clearance (CH2O)—if urine osmolarity > plasma osmolarity, CH2O is NEGATIVE—urine is concentrated (seen with high ADH)
- Free water clearance (CH2O)—if urine osmolarity < plasma osmolarity, CH2O is POSITIVE—(seen with low ADH)
- Free water clearance (CH2O)—if urine osmolarity ≈ plasma osmolarity, CH2O is zero (seen with loop diuretics)
Diseases associated with abnormal regulation of ADH (2)
• Too little ADH activity
– Leads to excessive water loss in urine, excessive urine volume of dilute urine and increase in plasma sodium – DIABETES INSIPIDUS
• Too much ADH activity
– Leads to too much water reabsorption, hyponatremia and potential hypervolemia – patients with brain injuries (SIADH) and patients on loop diuretics
Diabetes Insipidus
Central diabetes insipidus
Desmopressin (DDAVP)
Nephrogenic Diabetes Insipidus
Diabetes Insipidus
A. failure to reabsorb necessary amounts of water
B. Symptoms; 1) large volume 3.5 - 20 L/d of dilute urine are produced 2) blood volume decrease, [Na+] increase and osmolality increase but 3) Consequent extreme thirst, and polydipsia, make net changes in BV and osmolality small - only 1-2%
C. 2 causes; 1) Deficient ADH secretion (<85% norm) - CENTRAL (or hypothalamic or pituitary) DI. 2) Decreased sensitivity of kidney to ADH - NEPHROGENIC DI
Central Diabetes Insipidus
A. Deficiency or absence of ADH
B. Treatment; Hormone replacement
Lifelong treatment necessary for most patients
- Vasopressin (ADH), V1 and V2; NOT USED FOR DI
- Desmopressin; V2»V1. Longer half life - DRUG OF CHOICE
Desmopressin - DRUG OF CHOICE
- selective for V2 (cAMP) over V1 (Ca2+). Longer half life. IN 2x
- Other uses; – Nocturnal enuresis (bed-wetting). – Treatment of von Willebrand disease (type I) and hemophilia A (see blood coagulation lecture)
- toxicity; Water intoxication, - must restrict water intake
Nephrogenic Diabetes Insipidus
• “Nephrogenic” signifies that the DI results from
an inability of the kidney to respond to ADH
• Results from
– Genetic defects in ADH receptor or aquaporin-2
– Drug side effect, e.g. Li+, demeclocycline
• Does not respond to DDAVP
• TREATMENT:
– Paradoxically, both types of diabetes insipidus can be
treated with thiazide diuretics!!
– Volume of urine produced can be decreased by 50%
How can a diuretic that increases urine production decrease urine production?
Why do thiazides work?
VASOPRESSIN/ADH “ANTAGONISTS”: (DRUGS that INDUCE DIABETES INSIPIDUS)
How can a diuretic that increases urine production decrease urine production?
• Important to recognize that over the long term, the urine volume must parallel fluid intake
- Consequently in order to decrease the volume of urine produced one must decrease fluid intake
• What would happen if a DI patient stopped drinking?
– Would become hypovolemic, BP ↓ and then NE and ATII produced would stimulate Na+/H would decline
• Why does a person with DI drink so much?
– They become very thirsty
• What stimulates thirst?
– Increase in plasma [Na+] and hypovolemia
– However, a 2-3 % increase in plasma [Na+] has same effect as a 10-15% decrease in blood volume
– This high sensitivity to small changes in [Na+], allows blood volume to be maintained in DI
Why do thiazides work?
- Since the DCT is impermeable to H 2O, the diuretic effect of HCTZ results from more Na+ in the collecting duct, which reduces the gradient for water reabsorption (Na+ holds water in the lumen)- less H2O absorption in the CD (↓gradient).
– Since, in DI H2O cannot be absorbed in CD anyway:-
HCTZ will not act as a “diuretic”, but as a “natriuretic”.
– Its only effect will therefore be to lower plasma [Na+], and this will decrease thirst and water intake
VASOPRESSIN/ADH “ANTAGONISTS”: (DRUGS that INDUCE DIABETES INSIPIDUS)
• Under certain conditions, ADH activity can be “too high” leading to hyponatremia
- SIADH - patients with brain injuries - hypovolemia
- Advanced CHF and cirrhosis with ascites patients on loop diuretics (RAAS activated, ADH increase)
- Hyponatremia - cells swell, e.g in brain
- We need “ADH antagonist” to increase water loss and treat/prevent the hyponatremia
VASOPRESSIN/ADH “ANTAGONISTS”: (DRUGS that INDUCE DIABETES INSIPIDUS)
• CONIVAPTAN and TOLVAPTAN
– “VAPTANS” the first real vasopressin receptor antagonist
• Lithium (Li+) (Eskalith®, 1970) and DEMECLOCYCLINE (Declomycin®)
– Not true antagonists, but they…
– Block adenylate cyclase in CD and thereby block action of ADH/vasopressin - DI
Medications; action/indication/administration
CONIVAPTAN (Vaprisol)
Lithium (Li+) Carbonate (Eskalith)
DEMECLOCYCLINE (Declomycin)
CONIVAPTAN (Vaprisol)
- Action; V1A and V2 antagonist
- INDICATION – treatment of hyponatremia
~Since it lowers blood volume, only use in euvolemic and hypervolemic patients
~Use is contraindicated in hypovolemic patients, and also in patients with CHF
- ADMINISTRATION; Continuous IV infusion for maximum of 4 days, hence only used in hospitalized patients
Lithium (Li+) Carbonate (Eskalith)
- USE: Off-label use for tx of hyponatremia
~SIADH (e.g. CNS injury)
• MAJOR/USUAL INDICATION
~Antimanic drug (see CNS pharm notes)
~Significant toxicity if [Li]plasma >1mM
- SIDE EFFECT: 30% patients - diabetes insipidus
~ Renal handling analogous to sodium
~Re-absorbed by CD cells via Na+ channels
~Tx: thiazides, but lower Li+ dose, as reuptake in PT↑
DEMECLOCYCLINE (Declomycin)
• Tetracycline antibiotic with unique property
• SIDE EFFECT
– Diabetes insipidus, mechanism same as Li+
• USE - off-label use for tx of hyponatremia
– SIADH (e.g. from CNS injury)
– Heart failure, liver disease (cirrhosis) patients with elevated ADH
• Less toxic and effects more predictable than Li+
Acute tubular injury (previously known as acute tubular necrosis)
General
- most common cause of?
- is it reversible?
- Most common etiologies (2)
ATI - Acute tubular injury
General
- Most common cause of acute kidney injury (AKI)
- Accounts for 50% of cases of AKI in hospitalized patients
- REVERSIBLE; however if it has progressed long enough, it might not be reversible
- Characterized by acute renal failure and tubular injury
- Most common etiologies
A. ISCHEMIA - due to decreased or interrupted blood flow
- vasculitis; microscopic polyangiitis (MPO ANCA)
- malignant HTN
- Systemic thrombotic conditions ; HUS, TTP, DIC
- hypotension, shock
- Dehydration
B. Direct toxic injury to tubules; exo vs endogenous
1) Exogenous (5)
I. Drugs, heavy metals, radiocontrast dyes; Aminoglycerides (gentamicin), NSAIDs, ACEI, cyclosporine, cisplatin, Amphotericin B
II. Heavy metals; mercury, lead
III. Organic solvents; carbon tetrachloride
IV. Ethylene glycol (antifreeze)
V. Radiocontrast dye
2) Endogenous (3)
I. Hemoglobin (hemolysis)
II. Myoglobin (skeletal muscle injury)
III. Monoclonal light chains (multiple myeloma)
ATI - Acute tubular Injury
Pathogenesis - critical events in both etiologies (2)
- Tubular epithelium injury
a. Loss of cell polarity (Na,K+-ATPase delivers Na+ to distal tubule →vasoconstriction
b. Recruitment of WBCs which add to injury
c. Injured epithelium
1) Detaches from basement membrane and causes luminal obstruction→ ↑tubular pressure, ↓GFR
2) Glomerular filtrate leaks back into interstitium →↑interstitial edema → ↑interstitial pressure → further damage to tubule - Persistent, severe disturbances in blood flow - intrarenal vasoconstriction due to;
- RAAS
- Increased Na+ delivery to DT (tubuloglomerular feedback)
ATI - acute tubular injury
Morphology (gross vs microscopic)
- Gross - enlarged, swollen kidneys, pale cortex, hyperemic medulla
- Microscopic
A. Focal tubular epithelial necrosis along the nephron, with skip areas.
B. Occlusion of lumen by casts
I. DT and collecting duct
II. Casts; a) pigmented granular b) eosinophilic hyaline - composed of tamm-horsfall protein (normally secreted by cells of ascending thick limb and distal tubule)
C. Changes specific to etiology
I. Ischemic;
a) patchy, short segments of tubular necrosis in straight segment of PT and Thick ascending Lino of loop of henle
b) Rupture of basement membrane (tubulorrhexis)
c) Interstitial edema
d) accumulation of WBCs in dilated vasa recta.
II. Toxic;
a) continuous tubular necrosis in PT and straight segment of PT
b) No tubulorrhexis (BM rupture)
c) Distinctive morphologic changes associated with certain toxins
- MERCURIC CHLORIDE; large eosinophilic inclusions. Later - calcifications
- CARBON TETRACHLORIDE; accumulation of neutral lipids in injured cells
- ETHYLENE GLYCOL; ballooning, vacuolar degeneration of PCT; calcium ocalate crystals in tubular lumens
- LEAD; large acidophilic nuclear inclusions, little calcification, no crystal formation
d) Evidence of epithelial regeneration as condition progresses
ATI - Acute tubular Injury
Clinical course
- Initiation
- Maintenance
- Recovery
- Prognosis
- Initiation
- Lasts ~36 hrs
- Dominated by medical, surgical or obstetric precipitating event
- Slight decrease in urine output and rise in BUN - Maintenance
- Lasts 5-7 days
- Oliguria 40-400 ml/day
- salt and water overload, rising BUN, hyperkalemia, metabolic acidosis
- may need dialysis - Recovery
- 10 to 14 days
- steady increase in urine volume to a profuse diuresis (up to 3L/day)
- Loss of water, sodium, potassium through still injured but recovering tubule epithelium
- increased vulnerability to infection
- eventually tubular function is restores, concentrating ability improves, BUN and creatinine return to normal levels - Prognosis
- Nephrotoxic - depends on; 1) Magnitude and duration of injury 2) damage to other organs like liver or heart 3) ~95% recover with appropriate supportive care
- Ischemic; in shock, extensive burns, other causes of multi organ failure, mortality rate is >= 50%
Tubulointerstitial nephritis
General Summarize causes (4)
General
- Involves inflammatory injuries of the tubule and interstitium, onset is often insidious, manifested by azotemia (increased BUN/creatinine)
- May be acute or chronic
- Distinguished from glomerular diseases by:
a. Absence of nephritic or nephrotic syndromes
b. Presence of defects in tubular function; 1) Impaired ability to concentrate urine 2) salt wasting 3) Diminished ability to secrete acids (metabolic acidosis)
Causes of tubulointerstitial nephritis
- Infections; acute (E.coli) and chronic pyelonephritis
- Drug and toxin induced tubulointerstitial nephritis
- Metabolic diseases causing tubulointerstitial nephritis (urate nephropathy and nephrocalcinosis)
- Neoplasms (multiple myeloma)
Tubulointerstitial nephritis
Infections - acute pyelonephritis
General
Routes of infection (2)
- Acute pyelonephritis
a. Acute inflammation affecting the tubules, interstitium and renal pelvis
b. One of the most common diseases of the kidney
c. A serious complication of lower urinary tract infection (cystitis) d. Caused by the same microbes as lower UTI
1) 85% are gram-negative bacilli, normal flora of colon
a) E. coli (by far most common) b) Proteus spp. c) Klebsiella spp.
d) Enterobacter spp.
2) Gram(+): Enterococcus faecalis, Staphylococcus spp.
3) Virtually any bacterial or fungal agent
4) Immunocompromised: viruses
Routes of infection
1. Hematogenous - seeding kidneys from localized or systemic infection, less common
- ASCENDING INFECTION - most common
A) Urethra; bladder
i) MORE COMMON IN WOMEN BECAUSE OF SHORTER URETHRA II) via instrumentation in either sex (urinary catheter, cystoscope etc)
B. Bladder - kidney
I) Urinary tract obstruction and urine stasis; outflow obstruction - incomplete emptying - urine stasis - growth of bacteria that have entered the bladder
II) Vesicoureteral reflux; a) incompetent vesicoureteral valve b) congenital or acquired c) during micturition, urine empties through urethra and refluxes into ureter
III) Intrarenal reflux; most common in upper and lower poles because of flattened tips of papillae
IV) Imaging - cystourethrogram
Tubulointerstitial nephritis
Infections - acute pyelonephritis Morphology Associated risk factors Presentation Transplant pts
Morphology
1) Patchy, interstitial suppurative inflammation
2) Intratubular aggregates of neutrophils
3) Neutrophilic tubulitis
4) Tubular necrosis
5) Complications
a) Papillary necrosis
i. Mainly in DM, sickle cell disease
ii. Grossly - tips to distal 2/3rds of papillae show grey white to yellow necrosis
III. Microscopically - coagulative necrosis
B) Pyonephrosis ; Pelvis, calyces and ureter are filled with pus due to partial or complete obstruction high in urinary tract
C) Perinephric abcess; extension of suppurative inflammation through the renal capsule into perinephric tissue
6) Healing
- acute inflammation is replaced by chronic inflammatory cells (macrophages, plasma cells and lymphocytes)
- Then replaced by scar associated with inflammation, fibrosis and deformation of the underlying calyx and pelvis
Associated risk factors
1) Urinary tract obstruction (congenital or acquired)
2) Instrumentation of urinary tract (most often catheterization)
3) Vesicoureteral reflux
4) Pregnancy
5) Gender and age
- <1 yr, more common in males from congenital abnormalities
- 1-40yrs; more common in WOMEN (SHORTER URETHRA)
- >40 yrs; increasing in men due to prostatic hyperplasia and instrumentation
6) Preexisting renal lesions
7) Diabetes mellitus
8) Immunosuppresion, Immunodeficiency
Presentation
1) Sudden onset of pain at the costovertebral angle
2) Fever, malaise
3) Sx of lower UTI; dysuria, frequency, urgency
4) UA; WBCs, leukocytes (indicates upper UTI)
Transplant pts; polyoma virus from reactivation
Chronic pyelonephritis
General (2 forms)
Morphology
Clinical features
a. Chronic tubulointerstitial inflammation and scarring involve the calyces and pelvis
b. May be unilateral or bilateral
c. Important cause of kidney destruction in children with severe lower urinary tract abnormalities
d. TWO FORMS
1) Reflux nephropathy ; most common form of pyelonephritis scarring. Occurs early in childhood as a result of UTI and congenital vesicoureteral and intrarenal reflux
2) Chronic obstructive pyelonephritis; recurrent infections and obstructive lesions. Results in recurrent inflammation and scarring.
Morphology
1) Irregular scarring; if bilateral then asymmetrically scarred
2) Coarse, discrete, corticomedullary scars overlying dilated, blunted or deformed calyces, and flattening of papillae
3) Most scars in upper and lower poles, same as intrarenal reflux 4) Microscopic:
- tubules with areas of atrophy, hypertrophy, dilation
- Thyroidization; dilated tubules filled with casts resemble thyroid colloid
- Interstitium; inflammation and fibrosis (LYMPHOCYTES)
- vessels; i) In scarred areas - show intimal sclerosis. II) If htn is present then show hyaline arteriolosclerosis throughout kidney
- Glomeruli; ischemic changes only
Clinical features
- Silent onset or s/s of recurrent acute pyelonephritis (back pain, fever, pyuria, bacteriuria)
- Gradual onset of renal insufficiency and hypertension
- Loss of tubular function, concentrating ability, leads to polyuria, nocturia
- May develop a secondary focal segmental glomerulosclerosis (example of nephrotic syndrome)
A cause of tubulointerstitial nephritis
Drug and toxin -induced tubulointerstitial nephritis
- does it cause AKI? How? (3)
- acute drug induced interstitial nephritis; triggered by? Pathogenesis? Morphology? Clinical? NSAID associated nephropathy?
Drug and toxin -induced tubulointerstitial nephritis
- Second most common cause of acute kidney injury (after pyelonephritis)
- Three ways that toxins & drugs trigger AKI
- interstitial immunologic reaction e.g acute hypersensitivity nephritis induced by methicillin
- acute tubular injury
- subclinical, cumulative injury to tubules, takes years to develop chronic renal insufficiency - Acute drug-induced interstitial nephritis
A. Triggered by synthetic penicillins (methicillin, ampicillin) and other synthetic antibiotics (rifampin), diuretics (thiazides), NSAIDs, miscellaneous (allopurinol, cimetidine), analgesic nephropathy (mostly historical significance, due to phenacetin which is now off the market in most countries)
B. Pathogenesis
- Idiosyncratic immune mechanism
- Not dose related
- Late phase reaction of an IgE mediated (type I) hypersensitivity OR
- T cell-mediated (type IV) delayed hypersensitivity
C. Morphology
1) Interstitium; edema, mononuclear infiltrates (lymphocytes, macrophages), eosinophils and neutrophils may be present, maybe nonnecrotizing granulomas
2) Tubules; Lymphocyte infiltration. Necrosis and regeneration - varying degrees
3) Glomeruli - normal except with NSAIDs then minimal change disease and nephrotic syndrome
Clinical
- Onset is ~15 days after drug exposure
- Fever, eosinophilia (may be transient), rash (25% of pts), renal abnormalities (hematuria, mild proteinuria, leukocyturia including eos)
- Rising serum creatinine or AKI with oliguria in ~50% of pts, more often older pts
- Recovery follows withdrawal of offending drug
- Necrotic papillae may be excreted causing hematuria, sx of obstruction
NSAID associated nephropathy
- Renal complications are uncommon
- Nonselective NSAIDs; renal effects are due to inhibition of cox dependent prostaglandin synthesis
- Selective COX-2 inhibitors spare GI tract but affect kidneys because COX 2 is expressed in the kidney
- Renal syndromes include;
- acute kidney injury; due to decreased synthesis of vasodilators prostaglandins - ischemia
- acute hypersensitivity interstitial nephritis
- acute interstitial nephritis and minimal change disease - due to hypersensitivity reaction affecting interstitium
- membranous nephropathy with nephrotic syndrome
A cause of tubulointerstitial nephritis
Metabolic diseases causing tubulointerstitial nephritis (2)
- Urate nephropathy - 3 types
A. Acute uric acid nephropathy
- Caused by precipitation of uric acid crystals in the collecting ducts - obstruction of nephrons - acute renal failure
- Often seen in leukemia or lymphoma when first treated with chemotherapy (tumor lysis syndrome); a) drugs kill cancer cells b) nucleic acids are released from dead cells and broken down, producing uric acid
B. Chronic urate nephropathy (gouty nephropathy)
- monosodium urate crystals precipitate in distal tubules, collecting ducts and interstitium (due to acidic environment)
- Crystals stimulate a granulomatous response with giant cells
- Crystals obstruct tubules causing cortical atrophy and scarring
C. Nephrolithiasis; uric acid stones are present in 22% of gout pts - Nephrocalcinosis
A. Disorders associated with hypercalcemia induce formation of calcium stones and deposition of calcium in kidney; Hyperparathyroidism, multiple myeloma, Vit D intoxication, metastatic cancer, excess calcium intake (milk alkali syndrome)
B. May lead to chronic tubulointerstitial disease and renal insufficiency via; loss of concentrating ability, tubular acidosis, salt losing nephritis
A cause of tubulointerstitial nephritis
Neoplasms
- renal insufficiency occur in how much of patients with what neoplasm?
- factors contributing to renal damage (4)
- morphology
- clinical features
NEOPLASMS ; Light chain cast nephropathy (multiple myeloma)
1. Renal insufficiency occurs in ~50% of pts with multiple myeloma
2. Factors contributing to renal damage
A. Bench-Jones proteinuria and cast nephropathy
I) Ig light chains are directly toxic to epithelial cells
II) Light chain nephropathy;
- light chains and tam horsfall proteins lead to laryngeal tubular casts
- Obstruct tubular lumens
- induce an inflammatory reaction
B. Amyloidosis of AL type - formed from free light chains, usually gamma type
C. Light chain deposition disease - kappa type deposit in GBMs, mesangium, tubular basement membrane
D. Hypercalcemia and hyperuricemia
Morphology
A. Bence Jones tubular casts
- Pink to blue, amorphous
- fractured, concentrically laminated, distend the tubular lumens
- may be surrounded by multinucleated giant cells, inflammation, fibrosis
B. amyloidosis
C. Nephrocalcinosis
Clinical features
A. Chronic kidney disease may develop slowly OR
B. Acute kidney injury with oliguria may develop suddenly
C. Bence-Jones proteinuria occurs in 70% of multiple myeloma pts
Conclusion Of CKD (Shapiro)
- Understand and cite the classification of chronic kidney disease (CKD).
- Understand how GFR can be measured and estimated.
- Enumerate the complications of end stage renal disease (ESRD) as well as the implications of CKD to overall health.
- List the factors that predict the development and progression of CKD.
- Recite the major features of the symptom complex of uremia which complicated ESRD.
- Understand and discuss the concept of “trade off” in the pathogenesis of uremia.
- CKD is staged based on eGFR and albuminuria.
- eGFR is assessed by formulae using the SCr (+/- serum Cystatin C), age and gender along with race.
- MDRD is probably best.
- Patients with CKD experience much more CV disease than those without CKD.
- CKD progression occurs with hypertension, proteinuria and progression of underlying disease.
- Uremia is a symptom complex involving virtually all organs. The involvement of the CV, bone, and hematopoietic systems have been best characterized.
- It is believed that “trade off” explains the inherent nature of CKD to progress as well as cause the uremic syndrome.
Renal Vascular Diseases
Benign Nephrosclerosis
- Pathogenesis
- Morphology; microscopic
- Clinical features
Benign Nephrosclerosis
Pathogenesis
- Medial and intimal thickening ; due to hemodynamic changes (hypertension), aging, genetics
- Hyaline deposition in arterioles
Microscopic
- Narrowed lumens of arterioles and small arteries due to thickening and hyalinization of walls
- Scarring, glomerular sclerosis, loss of tubules alternate with preserved parenchyma; causes granular surface appearance
- Fibroelastic hyperplasia; medial hypertrophy, reduplication of elastic lamina, myofibroblastic tissue in intima
Clinical Features
- May be mild proteinuria
- Rarely causes renal insufficiency EXCEPT in; pts in African descent, pts with more severe HTN, pts with another underlying disease esp diabetes
Malignant Hypertension
Morphology
Clinical features
Histology (2)
Malignant Hypertension
Morphology
- Gross; “FLEA-BITTEN” appearance of kidney from petechial hemorrhages on cortical surface
Clinical features
- Punctate hemorrhages
- Poor cortical demarcation
- swelling, edema
Histology (2)
- Fibrinous necrosis of arterioles
- Vessels walls appear eosinophilic, granular
- Stain positive for fibrin - hyperplastic ArteriOLOsclerosis
- “Onion skinning” appearance of walls arteries and arterioles
- due to elongation and proliferation of concentrically arranged smooth muscle cells and layers of collagen
- luminal narrowing, may be thrombosis
Renal Artery Stenosis
Pathogenesis
Morphology
Clinical course
Renal Artery Stenosis
Pathogenesis
- UNILATERAL constriction decreases intrarenal circulation/ blood pressure
- cells of juxtaglomerular apparatus release renin
- Angiotensin II (vasoconstrictor) is produced causing HTN
- Aldosterone conserves Na+ and subsequently H2O
Morphology
- Atherosclerotic plaque occlusion (70%)
- more common in men
- advancing age
- diabetes - Fibromuscular dysplasia of renal artery
- women
- 3rd and 4th decades - Ischemic kidney
- reduced in size, crowding of glomeruli, atrophic tubules, interstitial fibrosis
- protected from effects of HTN
Clinical course
- resembles essential HTN
- elevated plasma or renal vein renin levels
- 70-80% cure rate with intervention
Thrombotic microangiopthies (2)
Pathogenesis
- HUS - Hemolytic Uremic Syndrome ; typical and atypical
- TTP - thrombotic thrombocytopenic purpura
Pathogenesis
HUS; Tissue dysfunction resulting from formation of microthrombi - vascular obstruction - tissue ischemia
HUS - ENDOTHELIAL INJURY - platelet activation and thrombosis
A. Typical
- Endothelial injury triggered by shiva-like toxin
- Associated with consumption of contaminated food
B. Atypical - Excessive activation of complement from;
- Inherited mutation of complement-regulatory proteins
- Acquired causes (scleroderma, HTN, chemo, immunosuppressive drugs, radiation)
TTP - PLATELET AGGREGATION from very large multimers of vWF
A. Deficiency of plasma metalloprotease ADAMTS13 (cleaves multimers of vWF)
- AutoAbs to ADAMTS13 (most common)
- Inherited deficiency of ADAMTS13
Thrombotic microangiopthies (2)
Clinical Features
Clinical Features Typical HUS - After intestinal infection with E.coli strain 0157-H7 - Most often in children - flu like symptoms or diarrhea - then symptoms of bleeding - severe oliguria and hematuria - microangiopathic hemolytic anemia - thrombocytopenia - +/- neurological symptoms - ~50% with HTN - Manage with dialysis - Renal fxn recovers in weeks
Atypical HUS
- Adults
- > 50% have inherited deficiency of complement regulatory proteins
- most common; factor H deficiency
- ~half have relapsing course progressing to ESRD
- conditions occasionally associated with atypical HUS; anti phospholipid Ab syndrome, pregnancy post parturition, vascular renal disease - sclerosis and malignant HTN, chemo and immunosuppresion, irradiation of kidney, +/- neurological symptoms, distinguish from TTP by normal ADAMTS13 plasma levels
TTP
- Pentad of fever, neurologic symptoms, microangiopathic hemolytic anemia, thrombocytopenia, renal failure
- adults >40 yrs, F>M
- CNS involvement is dominant feature
- Renal involvement ~50%
- Mortality <50% with exchange transfusions and immunosuppression
Thrombotic microangiopthies (2)
Morphology
Acute vs Chronic
Acute (Typical and atypical HUS, TTP)
A. Cortical necrosis, subcapsular petechaie
B. Microscopic
- Glomerular capillaries occluded by thrombi
- Capillary walls thickened by endothelial cell swelling and cell debris
- disruption of mesangial matrix
- interlobular arteries/arterioles; fibrinoid necrosis and occluding thrombi
Chronic (Atypical HUS, TTP)
A. Scarring of renal cortex
B. Microscopic
- thickening of glomerular capillary walls
- splitting of GBM (tram-tracking)
- thickening of artery and arteriole walls, persistent hypoperfusion, atrophy, renal failure, HTN
Atherosclerotic Ischemic
Renal disease
Atherosclerotic Ischemic
Renal disease
- bilateral renal artery disease
- common cause of chronic ischemia, renal insufficiency in older adults, +/- HTN
- surgical intervention preserves remaining renal function
Atheroembolic Renal disease
Atheroembolic Renal disease
- Embolization of atherosclerotic plaque fragments into renal vessels esp. arcuate and interlobular arteries
- Follows intervention (AAA repair, aortic valve angioplasty) in elderly pts with severe atherosclerotic disease
- May cause acute renal failure in pts with already compromised renal function
Cholesterol Emboli
Cholesterol Emboli
- Arterial seeding of fragmented atherosclerotic plaque to small arterioles
- Clear clefts of cholesterol seen embolized to small vessels
Sickle cell Disease Nephropathy
Sickle cell Disease Nephropathy
- Hematuria
- Proteinuria
- Diminished concentrating ability is common
- Seen In homozygotes and heterozygotes
Diffuse cortical necrosis
Diffuse cortical necrosis
- Uncommon
- follows catastrophic conditions such as abruptio placenta, septic shock
- cortex only
- massive ischemic (coagulative) necrosis
- May have intravascular and intraglomerular thromboses
- rapidly fatal without supportive treatment
- Rare complication of massive hemorrhage
- usually results from obstetric emergency
- complete bilateral cortical necrosis
Renal Infarct
Renal Infarct
- End organ circulation, very limited collateral circulation
- Most infarcts are due to emboli; left heart is a common source
- Morphology; typical of infarcts - Mary be single or multiple, wedge shaped, soft pale yellow Well demarcated after 24hr, eventually replace with scar tissue
- Clinically silent or positive pain, tenderness, hematuria
Total renal Infarction
Total renal Infarction
- entire kidney is Infarct Ed
- vascular compromise at main renal artery
Obstructive uropathy
- general
- common causes (9)
General
- may be sudden or insidious, partial or complete, unilateral or bilateral
- At any level of the urinary tract
- Intrinsic or extrinsic
Common causes
- Congenital abnormalities - structures, mental stenosis
- Urinary calculus
- BPH
- Tumors; prostate, bladder. Tumor of contiguous tissues - cervix, uterus
- Inflammation - prostatitis, uretitis, urethritis
- Sloughed papillae or blood clots
- Pregnancy
- Uterine prolapse
- Functional d/o’s; e.g neurogenic (SCI, DM)
Obstructive uropathy
HYDRONEPHROSIS
- general
- morphology
- clinical features (5)
- Dilation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to the obstruction to urine outflow
- Initial functional alterations are tubular
Morphology
A. If obstruction is sudden and complete, mild dilation of pelvis and calyces, sometimes atrophy of renal parenchyma
B. If partial or intermittent; dilation is progressive
C. Early - dilation and significant interstitial inflammation
D. Chronic; 1) Cortical tubular atrophy 2) Interstitial fibrosis 3) Blunting of spices of pyramids
e. Far advanced - kidney becomes a thin - walled cystic structure
Clinical Features
- Acute obstruction may be painful from dilation of collecting system and renal capsule
- Unilateral obstruction may remain silent because unaffected kidney can maintain adequate renal function
- Bilateral partial obstruction; a) concentrating ability affected first b) presents with polyuria and nocturia
- Bilateral complete obstruction; a) presets with oliguria or anuria b) fatal without intervention
- Relief of obstruction in the early stages leads to return of normal renal function - may have postobstructive diuresis
Obstructive disease
UROLITHIASIS
General
4 main types
General
- affects 5-10% of Americans sometime in their lifetime
- May occur anywhere in the urinary tract but most often in kidney
- M>F, peak age 20-30 yrs
- Familial predisposition
- All stones have an organic mucoprotein matrix
- Most important fact in stone formation; INCREASED URINARY CONCENTRATION OF THE STONE’S CONSTITUENTS SUCH THAT IT EXCEEDS THEIR SOLUBILITY (SUPERSATURATION)
4 Main Types
- Calcium oxalate and phosphate stones (70% of stones)
- Mostly idiopathic hypercalciuria (50%). Others are hypercalciuris and hypercalcemia > hyperoxaluria > enteric (hyperabsorption of calcium in gut)
- Hyperuricosuria (20%)
- hypercitraturia
- no known metabolic abnormality
- RADIOPAQUE (picked up on spiral CT) - Magnesium ammonium phosphate stones (aka struvite, 15% of stones)
- formed secondary to infections by urea splitting bacteria; Proteus, some staphylococci
- conversion of urea to ammonia alkaline the urine
- magnesium ammonium phosphate salts precipitate at the higher pH
- Form some of the largest, “staghorn” stones which occupy the renal pelvis
- RADIOPAQUE - Uric acid stones (5-10%)
- common in pts with hyperuricemia e.g gout and leukemia (high cell turnover)
- >50% of these stones occur without hyperuricemia - may be in persons with urine pH <5.5, uric acid is insoluble in acidic urine
- RADIOLUCENT - Cystine stones (1-2%)
- Cystinuria due to genetic defect in renal reabsorption of AA
- Precipitate at a low urinary pH
Obstructive disease
UROLITHIASIS
Morphology
Clinical features
Morphology
- unilateral in ~80% of pts
- sites; calyces, pelvises, bladder
- stones in renal pelvis tend to stay small, 2-3 mm
- Progressive accretions may result in a cast of the pelvis and calyces known as a staghorn calculus
Clinical features
- may be asymptomatic pr cause severe renal colic and abdominal pain
- may cause significant renal damage
- stone predispose the pt to UTI
Renal tumors
Identify 3 benign tumors
- Renal papillary adenoma
- small adenoma arising from the renal tubular epithelium
- found commonly, 7-22% at autopsy
- histologically the same as low-grade papillary renal cell carcinoma
- size is prognostic of metastasis,<3cm rarely metastasize - Angiomyolipoma
- Arising from perivascular epithelioid cells
- consist of vessels, smooth muscle and fat
- associated with familial tumor syndrome tuberous sclerosis (25-50% of t.s pts)
- susceptible to spontaneous hemorrhage - Oncocytoma
- large, eosinophilic cells with benign appearing nuclei, large nucleoli
- arise from the intercalated cells of the collecting duct
- 5-15% of renal neoplasms
- Gross; tan to red brown, homogeneous and usually well encapsulated with a CENTRAL SCAR, may be large
Renal tumors
Malignant (3)
- Renal Cell Carcinoma
- Urothelial carcinoma of renal pelvis
- Wilms tumor
Malignant renal tumor
Renal cell carcinoma (RCC)
Epidemiology
Risk factors (7)
Major types (5) - classier by histology, cytogenetics, genetics
Epidemiology
- 65k new cases/yr
- 13k deaths/yr
- 85% renal cancers
- older individuals (6-7 decade); M:F - 2: 1 (males smoke more)
Risk factors (7)
- tobacco; most significant (2x incidence)
- obesity
- HTN
- Unopposed estrogen
- exposures; asbestos, petroleum products, heavy metals
- renal factors; ESRD, CKD, acquired cystic disease, tuberous sclerosis
- familial variants (4@ renal cancers); Von hipped lindau, hereditary leiomyomatosis and renal cell cancer syndrome, hereditary papillary carcinoma, birth Hogg dube syndrome
Major types (5) - classier by histology, cytogenetics, genetics 1. Clear cell carcinoma; most common type. Cells have clear or granular cytoplasm. Nonpapillary. 95% sporadic although can be familial. 98% have deletion on 3p, deleted area includes VHL gene (Von Hippel lindau), even in sporadic tumors. 80% show mutations in non deleted VHL allele
- Papillary carcinoma; 10-15% of RCC. Papillary growth pattern. Not associated with 3p deletions. Sporadic form - trisomies 7 and 17, loss of Y in males. Familial form - associated with MET proto-oncogenes on chromosome 7. Frequently multifocal in origin, unlike clear cell
- Chromophobe carcinoma; 5% of RCC. Cells have prominent cell membranes, pale eosinophilic cytoplasm, halo around nucleus. Arise from collecting duct intercalated cells, like oncocytoma. Excellent prognosis
- Xp1 1 translocation carcinoma; Genetically distinct, translocations of the TFE3 gene located at Xp11.2. Young patients, Clear cytoplasm with papillary architecture
- Collecting duct carcinoma; <= 1% of RCC. Arise from collecting duct cells in medulla. Malignant cells forming glands in a prominent fibrotic stroma
Malignant renal tumor
Renal cell carcinoma (RCC)
Morphology; clear cells vs papillary vs chromophobe
Clinical Features
- classic triad?
Morphology
- Most common in poles of kidney
- Clear cell RCC
- usually unilateral and solitary
- bright orange-yellow-gray-white, spherical, distorts renal outline
- well circumscribed
- tumor cells - abundant clear or granular cytoplasm containing glycogen and lipids
- Tumor may enlarge and extend into ureter
- Tends to invade renal vein and IVC, even extend to right side of heart - Papillary RCC
- Arise from distal convoluted tubules
- May be multifocal and bilateral
- cuboidal cells arranged in papillary formation s
- interstitial foam cells in papillary cores - Chromophobe RCC
- pale eosinophilic cells with perinuclear halo in solid sheets
- largest cells around blood vessels
Clinical features
A. Classic triad; costovertebral pain, palpable mass, hematuria (all three present in only ~10% of pts)
B. Hematuria - early but may be intermittent, microscopic
C. Constitutional sx when tumor reached >= 10cm: fever, malaise, weakness, weight loss
D. Often found incidentally (CT or MRI for another indication)
E. Syndromes of abnormal hormone production; polycythemia, hypercalcemia, HTN
F. 25% of tumors have metastasized at time of diagnosis; Lung (>50%), bone (33%), regional LNs, liver, adrenal, brain
G. Prognosis and treatment
- 5 yr; 70%, 95% if no distant metastasis, 60% if renal vein invasion or extension into pernephric fat
- Radical or partial nephrectomy (to preserve renal function)
- TK and VEGF inhibitors for metastatic disease
Malignant renal tumor
UROTHELIAL CARCINOMA OF RENAL PELVIS
- Originates from urothelial of renal pelvis
- ~5-10% of primary renal tumors
- Transitional cell tumors
- Present early with hematuria, possible outflow obstruction
- Histologically identical to tumors of the urinary bladder urothelial
- May be multiple, 50% have history of or concomitant urinary bladder tumor
- … Commonly infiltrate wall of pelvis and calyces
- 5 year survival; 50-100% for low grade tumors, 10% for high grade, infiltrating
Malignant renal tumor
Wilms tumor
General
Morphology
Clinical features
Wilms tumor
General
- Most common primary renal malignancy in children
- Fourth most common pediatric malignancy
- Peak incidence; 2-5 yrs of age, 95% of tumors present 10 yrs of age
- large mass, usually unilateral but 5-10% are bilateral
- most cases are sporadic (90%), ~ 10% are associated with syndromes;
1. WAGR syndrome - a) wilms, aniridia, genital abnormality, mental retardation. B) Lifetime risk of developing Wilms = 33% c) Deletion of 11p13, location of WT1 (Wilms tumor-associated gene) and PAX6 (Aniridia)
2. Denys-Drash Syndrome; a) gonadal dyspenesis, early onset nephropathy b) ~90% risk for Wilms tumor c) Mutation in WT1
3. Beckwith-Wiedemann syndrome; a) Organomegaly, macroglossia, omphalocele b) mutations in regions of 11p15.5, multiple genes “WT2”
Morphology
1. Classic triphasic combination of cells
A) Blastermal - small, blue cells
B) Stromal - fibrocystic or myxoid
C) Epithelial - primitive tubes and glomeruli
2. Anaplasia; large, hyperchromatic, paleo morphia nuclei + abnormal mitoses; a) 5% of tumors b) correlates with the emergence of resistance to chemo
Clinical features
- large abdominal mass, unilateral or crosses the midline if large enough
- presenting symptoms; hematuria, pain in abdomen after trauma, intestinal obstruction , HTN
- 2 year survival = 90% survival > 2 yrs implies cure
- Important to identify and manage anaplasia
3 parts of the lower urinary tract
**state accompanying conditions
- Ureters
- congenital anomalies
- inflammations
- tumors and tumor like lesions
- obstructive lesions - Urinary Bladder
- congenital anomalies
- inflammations
- metaplasia
- neoplasia
- obstruction - Urethra
- inflammation
- tumor and tumor Iike lesions
Ureters
Normal
COngenital anomalies (3)
Tumors (benign vs malignant)
Obstruction (obstructive lesions - intrinsic vs extrinsic)
Ureters; Normal
- Narrowing at; ureteropelvic junction, crossing iliac vessels, where ureters enter bladder
- Note; Ureter enters bladder in an oblique manner which allows the enclosing bladder musculature to act like a sphincteric valve, blocking the reflux of urine even in a distended bladder
Ureters; Congenital Anomalies
- Double ureters
- usually associated with duplication of renal pelvis
- Usually unilateral and are joined in the wall of the bladder
- Usually no clinical significance - Ureteropelvic junction obstruction
- Children, boys more than girls
- 20% are bilateral
- most common cause of hydronephrosis in infants and children - Diverticula
- Saccular outpouching of urethral wall
- Urinary stasis in the sac may be a reservoir for bacteria causing recurrent infections
- But most are asymptomatic
Tumors/tumor like lesions
1. Benign
- fibroepithelial polyps
- leiomyomas
2. Malignant; majority are urothelial (transitional cell) carcinomas)
A. Urothelial carcinoma
- Rare in the ureter
- Resemble transitional cell (urothelial cell) tumors in renal pelvis, calyces, urinary bladder
- risk factors; smoking, occupational exposure (aniline dyes), phenacetin
Obstruction
- causes hydroureter and hydronephrosis
- may be acute (calculus) or chronic (tumors, sclerosing retroperitoneal fibrosis)
Obstructive lesions
- Intrinsic; calculus, strictures, tumors, blood clots, neurogenic
- Extrinsic; pregnancy, periureteral inflammation, endometriosis, tumors, sclerosing retroperitoneal fibrosis
Sclerosing retroperitoneal fibrosis
- fibrotic proliferative inflammatory process encasing the retroperitoneal structures
- causes hydronephrosis
- middle to late age, M>F
- 70% idiopathic
- can be associated with IgG4-related disease
- drugs (ergot derivatives), adjacent inflammatory conditions (Crohn’s), malignancy (lymphomas)
- microscopy; fibrous tissues, infiltrate of lymphocytes, plasma cells, eosinophils
- tx; corticosteroids, urethral stents
Urinary Bladders
Congenital anomalies (4)
Congenital anomalies
- Vesicoureteral reflux; most common and serious congenital anomaly
- Diverticula
- Evagination of bladder wall
- 1cm to 5-10 cm
- acquired are most often associated with obstruction due to BPH
- asymptomatic or serve as a reservoir for bacteria - Exstrophy
- developmental failure of anterior wall of abdomen and bladder
- bladder communicated with or lies on surface of abdomen - Urachal anomalies
- Urachus; canal that connects fetal bladder with allantois, obliterated after birth
- totally patent/persistent; a fistula connecting the bladder and umbilicus
- central portion persists; urachal cyst, carcinoma may arise in cyst
Urinary bladder
Inflammation (Cystitis)
- common agents
- risk factors
- morphology
- clinical features
- special forms (2)
- Common agents
- E.coli, proteus, klebsiella, Enterobacter
- TB cystitis
- Candida albicans, cryptococcal agents
- Schistosomiasis; middle eastern countries
- adenovirus, chlamydia, mycoplasma
2, Risk factors; female sex, bladder calculi, urinary
obstruction, DM, instrumentation
- Morphology
- acute; neutrophilic infiltrate
- chronic; persistent infection, mononuclear infiltrate
- hemorrhagic cystitis; chemotherapy, adenovirus
- follicular cystitis; not related to infection, presence of lymphoid follicles in mucosa and wall
- eosinophilic cystitis; nonspecific subacute inflammation with eosinophils, but may be due to systemic allergic reaction
4. Clinical features A. Triad of symptoms - Frequency (~15-20 min) - Suprapubic pain (lower abdomen) - Dysuria; pain, burning with urination
- Special forms
A. Interstitial cystitis (Chronic Pelvis Pain Syndrome)
- women more than men
- intermittent, often severe suprapubic pain, frequency, urgency, hematuria, dysuria
- cystoscopy; a) Early - fissues, punctate hemorrhages in mucosa b) Late - classic, ulcerative phase, chronic mucosal ulcers (hunner ulcers)
- Late; transmural fibrosis, contracted bladder
- Biopsy to rile out carcinoma
B. Malakoplakia - Morphology
A. Gross; Slightly raised, soft, yellow mucosal plaques 3-4 cm in diameter
B. microscopic; large foamy macrophages, multinucleated giant cells, lymphocytes
C. Laminated mineralized concretions (calcium in lysosomes), michaelis- Gutmann bodies, seen within macrophages
Urinary bladder
Metaplastic lesions
- Common lesions
- Brunn nests
- Urothelium grows into lamina propia
- Urothelial cells in the nest undergo metaplasia - Cystitis cystica; Urothelial cells retract to form cystic space lined by urothelium
- Cystitis Glandularis; urothelial cells undergo metaplasia to cuboidal/columnar/goblet cell epithelium, resembling intestinal metaplasia
- Squamous metaplasia; response to injury
- Nephrogenic metaplasia/nephrogenic adenoma; response to injury, cuboidal epithelium and tubular proliferation of luminal propria
* **MAY BE CONFUSED FOR CANCER
Bladder tumors
General
risk factors (6)
Main tumor (types)
Other cancers
General
- M>W, 3:1
- developed nations > developing nations
- urban > rural
- 80% of pts aged 50-80 yrs
- 95% epithelial in origin
Risk factors
A. Cigarette smoking - most important risk factor, increases risk 3-7x, smaller risk with other tobacco products
- occupational exposure to Arya amines; dye, rubber and leather industries
- schistosomiasis haematobium; Egypt, Sudan, 70% SCC, 30% TCC
- long term analgesics
- long term exposure to cyclophosphamide; immunosuppressive agent, induces hemorrhagic cystitis
- Irradation
Bladder tumors
1. urothelial tumors;
- urothelial carcinoma in situ
- Papillary urothelial carcinoma, low grade
- Papillary urothelial carcinoma, high grade
- Papillary urothelial neoplasm of low malignant potential
(PUNLMP)
- urothelial papilloma
- inverted urothelial papilloma
- urothelial proliferation of uncertain malignant potential (hyperplasia)
- urothelial dysplasia/Atypia
- Other associated cancers
- squamous cell carcinoma
- mixed carcinoma
- adenocarcinoma
- small cell carcinoma
- sarcoma
Bladder tumors
- Molecular genetics
- Two distinct precursor lesions to invasive urothelial
carcinoma
Molecular genetics
• Gain-of-function mutation in FGFR3: Mutation
leads to activation of tyrosine kinase, usually
found in low grade papillary carcinomas
• Loss-of-function mutations in TP53 and RB tumor
suppressor gene: usually high grade, muscle
invasive tumors
• Activating mutation of HRAS oncogene
• Loss of genetic material on chromosome 9
- Two distinct precursor lesions to invasive urothelial
carcinoma
A. Noninvasive papillary Tumors - more common
B. Flat, noninvasive urothelial carcinoma (aka carcinoma in situ, CIS)
Bladder tumor morphology
- Papilloma
- Inverted papilloma
- PUNLMP
- Low grade papillary urothelial carcinoma
- High grade papillary urothelial carcinoma
- Carcinoma in situ (CIS, flat urothelial carcinoma)
- Papilloma
- Uncommon, young, 0.5-2cm.
- exophytic; attached to mucosa by a stalk
- consists of papillae with a core covered by normal; appearing urothelium
- may recur - Inverted papilloma
- benign
- extend into lamina propia - PUNLMP (Papillary urothelial neoplasms of low malignant potential)
• Histologically similar to papilloma but with
thicker urothelium than papilloma
• Larger than papillomas
• Rarely progress to a higher grade - Low grade papillary urothelial carcinoma
• Orderly appearance • Evenly-spaced, cohesive cells • Mild atypia • Scattered hyperchromic nuclei, some mitotic figures • Rarely invade - High grade papillary urothelial carcinoma
• Architectural disarray and loss of polarity • Discohesive cells • Large hyperchromatic nuclei • Anaplasia • Atypical mitotic figures • Higher incidence of invasion into muscular layer • Higher risk of progression • Significant metastatic potential (after invasion) - Carcinoma in situ (CIS, flat urothelial carcinoma)
• Cytologically malignant cells within flat urothelium • No invasion of basement membrane • Discohesive cells, shed into urine • 50-75% of cases progress to invasive cancer
Pathological staging
Ta, ‘Tis, T1, T2, T3a, T3b, T4
- Ta: Noninvasive, papillary
- Tis: Carcinoma in situ (noninvasive, flat)
- T1: Invasive, into lamina propia
- T2: Invasive, into muscularis propia
- T3a: Microscopic extravesicle invasion (into perivesical fat)
- T3b: Grossly apparent extravesicle invasion
- T4: Invasive, into adjacent structures
Other types of bladder tumors
- Embryonic rhabdomyosarcoma
- Leiomyosarcoma
Bladder tumors clinical features and treatment (invasive vs non invasive)
- Embryonal rhabdomyosarcoma (Sarcoma botryoides)
• Most common sarcoma of infancy or childhood
• Grape like, muscle origin
• Cambium layer
• Deeper hypocelluar and myxoid stroma - Leiomyosarcoma
• Most common bladder sarcoma in adults
• Fascicles of malignant spindle cells
Clinical features
- painless gross or microscopic hematuria; most frequent sign (70-90%)
- may see dysuria, frequency
Treatment
- Non invasive; a) routine biopsy b) intravascular chemotherapy c) radiotherapy
- Invasive; surgical resection
Bladder obstruction
Types
Morphology (early vs late)
Bladder - Obstruction
• BPH/Carcinomas • Cystocele of bladder • Congenital urethral narrowing/stricture • Inflammatory (urethra/bladder) • Bladder tumors • Secondary invasion (cervix/vagina) • Mechanical obstruction: foreign body/stones • Injury to bladder innervations
Morphology
• Early: Some thickening of bladder wall, normal mucosa.
• Late: Individual muscle bundles enlarge, trabeculation
of bladder wall.
Urethra
Inflammation (2)
Tumors
- benign vs malignant
Urethra Inflammation 1. Urethritis • Gonococcal • Non-gonococcal; E. coli, Chlamydia, Mycoplasma • Pain, itching, frequency
- reactive Arthritis (Reiter Syndrome)
- Arthritis, conjunctivitis, urethritis
Tumors
1. Urethral caruncle; • Inflammatory • Small, red, painful mass in external urethral meatus, typically in older females • Histology: Vascular, fibroblasts, leukocytes • May ulcerate and bleed • Tx: surgical excision
Benign vs Malignant 1. Benign: Papillomas/condylomas 2. Malignant: • Rare • Proximal: Urothelial origin • Distal: Squamous cell origin
Basic Acid-Base Physiology
- acid vs base
- pH
- body buffers
- K equation (Henderson)
- Henderson-Hasselback equation (just added logs)
- pH depends on what 2 factors
- Effect of CO2 accumulation on pH
An acid donates a proton whereas as a base accepts it
H2CO3 ⟷ H+ + HCO3-
pH is a measure of H+ concentration and is mathematically calculated as pH = -log10 [H+]
Body buffers are primarily weak acids (along with their conjugate bases) that have incomplete dissociation. **Buffer system maintain the pH balance by responding to dramatic changes in pH
CO2 + H2O ⇋ H2CO3 ⇋ H+ + HCO3- Or, CO2 + H2O ⇋ H+ + HCO3-; K = [H+][HCO3-]/[CO2]
[CO2] = 0.03PCO2
K = [H+][HCO3-]/0.03PCO2
**Ignore water in the equation because concentration of water is so high in the body
**Henry’s law is when you convert a gas to a solution so [CO2] = 0.03
**PCO2 = 40
Therefore K = [H+][HCO3-]/1.2
- From Henderson-Hasselbach’s equation:
- For a solution containing a weak acid- pH = pK + log base/acid
- therefore, for CO2 + H2O ⇋ H+ + HCO3- = pH = pK + log [HCO3-]/[CO2]
- = pH = 6.10 + log [HCO3-]/0.03PCO2
pH = pK + log [HCO3-] / 0.03PCO2
- pH is maintained by a ratio of bicarb (kidneys) and CO2 (lungs). 20:1 will always keep pH at 7.4
*****IF CO2 ACCUMULATES in a closed system, pH will decrease. However, our body is an open system to we have minimal changes to out pH
Renal regulation of HCO3-
- What absorbed filtered bicarb
- Human body generates what? (5)
- What is the principal job of the kidney ? What is the supplement job of kidney ?
- Kidneys reabsorb almost all of the filtered HCO3-
- Human body generates:-
- Potential volatile acid- CO2
- Non-volatile acid
- Non-volatile bases
- Dietary acid load
- (Dietary acid + metabolic acid)-metabolic bases = 70 mM/day H+ - Hco3- Reabsorption Is The Principal Action Through Which Kidneys Maintain Acid-Base Balance.
- supplement job of kidney is to regenate the bicarb that was consumed in step 1
Identify job of transport system (and where it works)
- Sodium Hydrogen exchanger
- H-ATPase (what activates this)
- Effects of aldosterone (3)
- Is all H+ secreted that is excreted?
- Sodium hydrogen exchanger transports H+ in the PT and TAL
- Na-H-antiport (NHE): Principal mechanism in the PT (80% HCO3- absorbed and the TAL (20% HCO3- absorbed). Also notice the basolateral Na/HCO3 co transport - H+ secretory system; alpha intercalated cells in the cortical collecting tubule/duct
- H-ATPase: Principal mechanism in the intercalated cells (less so in TAL). Also notice the basolateral Cl/HCO3 exchanger and the H-K- antiport (secondary H+ secretor) - Aldosterone has 3 effects
A. Directly stimulate H-ATPase
B. Increase Na-K- ATPasem which increase Na gradient to enter the cell
C. Increase ENaC activity and number - increase luminal negativity - more H+ can be secreted - Not ALL H+ secreted are excreted in urine—a vast majority are resorbed (recycled to reclaim bicarb in the body)
- Proximal Tubule and the TAL secretes H+ to reclaim all HCO3- No H+ is Excreted at this step
Summarize the principal job of kidneys is reabsorb Ig bicarb (FIRST STEP IN RENAL REGULATION OF ACIDE-BASE BALANCE)
The apical membrane Na/H anti-porter mediates most of HCO3- absorption in the P.T.
These anti-porters are inhibited by lithium and amiloride.
The Na/H anti-porter is exquisitely sensitive to H+ concentration on the inside (cytoplasmic side) of the vesicle.
NHE3 is the Na/H anti-porter subtype predominantly responsible for aforementioned actions.
NHE3 activity stimulated by AngII and endothelin; inhibited by PTH and PKA.
Summarize Sunday step of renal regulation
The second step, in renal regulation of acid-base balance, is the generation of new HCO3- that involves secretion & then excretion of H+*
- need what 2 buffers
- Net acid excretion
The Second Step: Generation of “new bicarbonate” and EXCRETION of H+ needs urinary buffers phosphates and ammonia are those buffers
- **Whenever an H+ secreted into the tubular lumen combines with a buffer other than HCO3- the net effect is addition of a new HCO3- to the blood **
- Filtered H2PO4 and creatinine are titrable proton acceptors and that are protonated primarily in the proximal tubule. The H+ is exchanged for Na by the NHE. This step leads to synthesis of one new molecule of HCO3-
- Metabolically-derived NH3 is the second (and more important) proton acceptor in the tubular fluid. NHE in the proximal tubule and H+-ATPase in the distal tubular segments (intercalated cells) allow H+ movement into the tubular lumen. Protonation of NH3 also leads to synthesis of one new molecule of HCO3-.
- Combined titrable and non titrable (NH4+) acid secretion equals the amount of new HCO3- synthesized by the kidneys
N.A.E (Net Acid excretion)
- N.A.E. = rate of NH 4+ excretion + rate of titratable acid (T.A.) excretion minus rate of HCO3- excretion
- N.A.E. = (U NH4+)(V) + (T.A.)(V) - (UHCO3-)(V) (Units for all terms are microEq/min; V = urine flow, ml/min)
- The physiological significance of N.A.E. is that it equals the net amount of new HCO 3- generated by the kidney:
- For each NH4+ excreted, 1 new HCO3- is added to renal venous blood
- For each H+ excreted combined with HPO4- - ( = T.A.) one HCO
3- is addedto the renal venous blood.
- Subtracting the amount of HCO3- excreted gives the NET amount of new
- HCO3- added to the renal venous blood.
How does pH affect renal acid secretion ?
- Falling pH, cortisol and endothelin stimulate H+ secretion (in tubular cells) and HCO3- reabsorption
- this is by increase in NHE activity and increase cell to lumen gradient for H+ secretion - Increasing the [H+] gradient from cell to lumen increases H+ secretion. This effect occurs in all nephron segments that secrete H+.
- The renal response to increased dietary acid intake is increased net acid excretion
- Increased PaCO stimulates HCO3- reabsorption since CO2 activates H+ secretion that is central to HCO3- reabsorption
- Elevated PCO2 directly stimulates H+ secretion
- 1.As acids consume HCO3- and generate H2CO3 and then CO2, this directly activated PT cells to increase NHE activity, in the short term, and expression in the long term.
- Acid production and consumption of HCO3- ↓ pH & stimulates H+ secretion and glutamine metabolism
- 1.↓ extracellular pH decreases tubular cell pH and increases NHE activity in the PT cells. This also increases NH3 production in the distal tubules.
- 2.Also, Na/HCO3- is activated in face of ↓pH.
- 3.HCO3- consumption by metabolic acid ↑ lumen to interstitium HCO3- gradient, thus ↑ HCO3- reabsorption.
- Overproduction of a base will have the opposite effects.
Effect of hypo/hyperkalemia on acid excretion
- Hypokalemia causes metabolic alkalosis:
- 1.Transcellular shift of H+ in “exchange” for K+
- 2.Increased activity of H-K-ATPase
- 3.Increased activity go NHE3 2.Hyperkalemia causes acidosis:
2.1.Transcellular shift of H+ in “exchange” for K+ is the major cause
3.Important—effects of primary acid base disorders on K+ are much more
pronounced than the effects of primary K+ homeostatic disorders on acid-base balance.
**By causing intracellular acidosis, hypokalemia increases NH3 activity. Hypokalemia causes metabolic alkalosis. High aldosterone causes alkalosis. Hypovolemia causes metabolic alkalosis
Urinary Anion Gap
- what is the rule of thumb
- when will you have positive vs negative anion gap
ELECTRONEUTRALITY has to be maintained
- Normally measured urinary cations and anions: Na+, K+, Cl-
- NH4+ is also present but can’t me measured
- Normal anion gap = [Na]u + [K]u - [Cl]u Cations MUST EQUAL Anions
- We have an unmeasured cation and thus, URINARY ANION GAP MUST BE A POSITIVE NUMBER
- In metabolic acidosis new HCO3 has to be synthesized by the kidneys i.e. NH4+ excretion must increase (the unmeasured cation)
- Cl- excretion also increases to maintain electroneutraility
- We still cannot measured NH4+ however, [Cl]u has increased
- Thus, we now have NEGATIVE URINARY ANION GAP
- Acidemia with normal urinary anion gap could suggest impaired renal NH4+ excretion(type I renal tubular acidosis or hypoaldosteronism)
- In metabolic acidosis if the UAG is positive then it signifies impaired renal NH4+ excretion i.e. renal cause of acidosis
In metabolic acidosis if the UAG is positive then it signifies impaired renal NH4+ excretion i.e. renal cause of acidosis
Summarize types of Renal tubular Acidosis (Type 2)
- Pathology
- Cause
- Urine pH
- plasma K
- Proximal RTA (TYPE 2)—the proximal tubule is dysfunctional and cannot absorb all the HCO3- it is supposed to
- 1.Normally, the proximal tubule reabsorbs almost ALL HCO3- till the concentration of bicarbonate in the glomerular filtrate and plasma exceeds 26-28 mmol/L (true in euvolemia, not in hypovolemia). After this points, bicarb is NOT reabsorbed and starts to appear in urine.
- 2.In TYPE 2 RTA, this mechanism is altered and proximal tubule can reabsorb only 16-17 mmol/L of bicarb. Thus, plasma bicarb drops and the system comes to a new equilibrium at a lower plasma [HCO3-]. Thus, self-limiting acidosis.
- 3.There are one of three possible mechanisms—↓NHE, ↓Carbonic Anhydrase, ↓Na-K- ATPase in the proximal tubule—all three invariably linked to ↓Na+ resorption and activation of RAAS.
- Proximal RTA (TYPE 2)—causes:
- 1.Genetic defects in the proximal tubule—Fanconi’s syndrome
- 2.Multiple myeloma—likely the most common cause
- Urinary acidification is normal i.e. urine pH is <5.3—this is because distal nephron is still functional and is excreting protons
- Plasma K+ is low—hypokalemia—due to aldosterone activation as a consequence of Na+ wasting
- Diagnostic test—infuse Na-HCO3—as soon as plasma concentration of bicarb exceeds the capacity of the proximal tubule to reabsorb bicarb, urine will become alkaline (bicarbonate will start appearing in urine)
In metabolic acidosis if the UAG is positive then it signifies impaired renal NH4+ excretion i.e. renal cause of acidosis
Summarize types of Renal tubular Acidosis (Type 1)
- Pathology
- Cause
- Urine pH
- plasma K
- Distal RTA (TYPE 1)—the distal tubule is dysfunctional and cannot excrete protons
- 1.Normally, the distal tubule acidifies urine by excreting protons in urine via the H-ATPase transporter. These protons then bind to NH3 and appear in urine.
- 2.Most common cause of TYPE 1 RTA is defective H-ATPase in the collecting ducts
- 3.Since H+ cannot be secreted, K+ excretion increases to balance thenluminal negativity created by Na+ reabsorption in the collecting ducts—hypokalemia is the result.
- 4.Diagnosis—urine pH is >5.3 and Na-HCO3 infusion does not affect it
In metabolic acidosis if the UAG is positive then it signifies impaired renal NH4+ excretion i.e. renal cause of acidosis
Summarize types of Renal tubular Acidosis (Type 4)
- Pathology
- Cause
- Urine pH
- plasma K
- Renal tubular acidosis due to hypoaldosteronism—
- 1.Aldosterone activates Na+ reabsorption in the collecting duct, thus creating luminal negativity. This then favors K+ and H+ secretion
- 2.Aldosterone also activates H-ATPase, thus ↑H+ secretion 1.3.Hypoaldosteronism leads to academia and hyperkalemia—
- 3.1.↓luminal negativity
- 3.2.↓H-ATPase
- 3.3.↓K+ channel activity
Summary of role of kidney in normal acid base balance
**Big picture
The kidneys generate 50 – 100 mEq/day of new HCO3- to replace the HCO3- lost by reaction with metabolic H+ .
- Plasma HCO 3- is freely filtered; 99% is reabsorbed.
- HCO3- reabsorption is coupled to H+ secretion in proximal tubule, thick ascending loop of Henle, & collecting duct. stimulated by increased PCO Increased in hypovolemia.
- HCO3- generation derives from glutamine catabolism. is stimulated by a high protein diet and acidosis.
Acid-base balance
- importance
- pH of arterial blood
- death occurs with what pH levels
Acid-base balance is important for metabolic activity of the body
- pH of arterial blood = 7.35 - 7.45. Alterations have effects on normal cell function
- pH <6.8 or >8.0 death occurs
- Buffers
Which is predominant in extracellular compartment - Non-bicarbonate buffer system
- Buffers
- A buffer has the ability to minimize changes in pH when H+ are added or removed from the system
- E.g. H+ + A- ↔ HA
- Body buffers are primarily weak acids (along with their conjugate bases) that have incomplete dissociation. By extension, best buffers are those who have pK as close to physiological pH as possible i.e. close to 7.4.
- Two physiological buffer systems ensure tight regulation of body pH: between 7.36-7.44
- IT’S AN IMPERFECT SYSTEM AS ACID-BASE PROBLEMS ARE QUITE COMMON IN THE CLINICS
*** The Bicarbonate Buffer System Is the Major ECF Buffer System
PH = pK + log [HCO3-] / 0.03 PCO2
- To keep the pH of the biological systems near normal the ratio of HCO3-/CO2 has to be kept constant, acutely. Acute regulation of the pH primarily involves a respiratory compensation. Hyperventilation during acidosis to remove excess CO2 and hypoventilation during alkalosis to retain CO2
- For long term pH regulation the kidneys maintain HCO3- concentration and the lungs CO2
- Non-bicarbonate buffer system
1.Half of the buffering capacity is contributed by non-bicarbonate
buffers
1.1.Intracellular and extracellular proteins especially, albumin and Hb
1.2.Phosphate: H2 PO41-↔ H++ +HPO42-
1.3.Bone is basic: is composed of com-pounds such as sodium
bicarbonate and calcium carbonate—and thus, dissolution of bone
releases base. This release can buffer an acid load, although at the expense of bone density, if it occurs over an extended period. In contrast, bone formation, by consuming base, helps buffer excess base.
Summarize 2 jobs of the kidney in acid/base balance
- Reabsorb ALL filtered HCO3- (98% of the job)
- Excrete protons - make new HCO3- (2% of the job)
***Both are activated in ACIDOSIS by; increased transcellular gradient for H+ secretion, increased cortisol, increase endothelium
Review the regulation of tubular acidification in the following states
- Hypokalemia
- Hyperkalemia
- Hypokalemia
Hypokalemia: causes systemic alkalosis AND increase proximal renal tubular HCO3 absorption AND increase distal nephron acidification.
1.1.Transcellular shift of H+ as cells take up protons and extrude K 1.2.This intracellular increase in protons increases NHE Vmax ,thus absorbing more HCO3 in the PT
1.3.Hypokalemia activates H-K ATPase in the distal nephron thus, increasing distal renal tubular acidification
1.4.Hypokalemia is usually secondary to hyperaldosteronism, which increases H-ATPase activity - Hyperkalemia
Hyperkalemia: causes systemic acidosis AND reduces proximal renal tubular HCO3 absorption AND reduces distal nephron acidification.
1.1.Transcellular shift of H+ as cells take up K and extrude protons 1.2.This intracellular decrease in protons decreases NHE Vmax ,thus absorbing less HCO3 in the PT
1.3.Hyperkalemia suppresses H-K ATPase in the distal nephron thus, decreasing distal renal tubular acidification
1.4.Hyperkalemia is usually secondary to hypoaldosteronism, which decreases H-ATPase activity
Common characteristics of metabolic and respiratory acidosis
Acidosis stimulates renal HCO3- generation and renal H+ secretion . Increased HCO3- generation in mostly due to increased renal glutamine metabolism
**Acidosis increases renal tubular H+ secretion by increasing
Tubular cell [H+] and the cell to lumen H+ gradient
the activity of the Na+, H+ antiport (proximal tubule & loop)
the activity of the H+ ATPase (intercalated cells in collecting duct)
Metabolic acidosis
Xters Major causes (3) Buffering Compensation (timeframe)**** Winter’s rule for compensation in metabolic acidosis
Metabolic acidosis is characterized by
low arterial pH (normal 7.40, range of 7.35-7.45) and
low serum HCO 3- concentration (normal 24 meq/L, range 22-28 meq/L)
The low pH and serum HCO 3- concentration result from excess H+ added to the ECF (or by loss of HCO3-)
Major causes of metabolic acidosis
- Increased acid generation; lactic acidosis, ketoacidosis (uncontrolled DM, excess alcohol intake or fasting), ingestion (methanol, ethylene glycol, aspirin, toluene - inhalant abuse)
- Loss of HCO3-; diarrhea (stool contains HCO3-), proximal tubular acidosis (inability to reabsorb filtered HCO3-)
- Diminished renal acid excretion; renal failure, distal tubular acidosis (inability to excrete daily acid load)
Buffering
- It has an immediate (respiratory) and delayed component (renal)
- LOWER SERUM BICARB and INCREASE SERUM K+
Compensation
- respiratory compensation; <12hrs
- Renal compensation; takes 3-5 days for full renal response
- *In simple metabolic acidosis, serum pH, [HCO3-] and PCO2 are all reduced =, uncompensated and compensated
- Metabolic acidosis leads to hyperkalemia and intracellular K+ depletion. The total amount of K+ in the body is decreased, but some K+ shifts from cells to ECF causing hyperkalemia or maybe normokalemia in chronic acidosis.
Winter’s rule for compensation ***
Expected pCO2 = 1.5 x [HCO3] + 8 Range (+/- 2)
E.g. What is the expected PCO2 in a patient with acidosis
and HCO3 of 12 mEq/L? Remember, this is pulmonary compensation, usually occurs rapidly. = 1.5 * 12 = 18 + 8 = 26±2 mmHg
Remember
- combined disorder; both metabolic and respiratory acidosis or alkalosis
- Mixed disorder; metabolic acidosis and respiratory alkalosis presenting at same time and vice versa
Anion gap
- useful in what diagnosis
- what is normal value
- when can anion gap be increased (2)
- when is anion gap positive vs negation
Anion gap - useful in diagnosis of metabolic acidosis
The concept of the anion gap is based on the fact that there must be equal concentrations of cations and anions in the serum.
Anion gap = [Na+] - ([Cl-] + [HCO3-])
Anion gap = 142 – (105 + 25) = 12
Ion concentrations are mEq/L. Normally the anion gap is mostly due to protein, primarily albumin.
- The anion gap may be increased by Hyperalbuminemia
**When there is loss of volume (HCO3-), body will gain NaCl
Think HCO3 loss: 1. Volume loss and kidneys try to retain
NaCl (Diarrhea) 2.Renal HCO3 loss and kidneys absorb
more chloride to maintain electroneutrality - Serum anion gap increases if a measured anion is replaced by an unmeasured one
Anion gap positive vs negative
- Positive; measured cations (Na+, K+) > measured anions (Cl-)
- Negative; measured cations are still the same but the measured anion has increased (Cl) to maintain urinary electroneutrality.
High Anion gap acidemia vs Normal anion gap acidemia
1. High Anion Gap acidemia Lactic acidosis Ketoacidosis Salicylate poisoning Methanol Ethylene glycol
- Normal Anion Gap acidemia
- HCO3- loss: Diarrhea, Renal tubular acidosis
- Renal failure
- Ammonium chloride
Respiratory acidoses
Causes (2)
Buffering
Compensation
Respiratory acidosis is defined as a disorder that causes an elevation in arterial PCO2 and a reduction in serum pH resulting from retention of CO2
- Interference with pulmonary CO
a. Chronic obstructive pulmonary disease
B. Emphysema
C. Chronic bronchitis
D. Severe asthma
2. Interference with ventilation A. Neuromuscular diseases B. Chest wall disorders such as severe kyphoscoliosis C. Obesity hypoventilation syndrome D. Obstructive sleep apnea E. Central nervous system depression - Drugs (narcotics, barbiturates, etc) - Neurologic disorders (encephalitis, brainstem disease, trauma)
Buffers
- Assume for a second that no other buffer exists—both, H+ and HCO3- will rise and the reaction will rapidly come to an equilibrium.
- If both increase by only 40 nano-moles (thats 10-9 of a mole) it doesn’t even put a dent in the bicarbonate concentration (24 milli-moles/L), but doubles the H+ concentration (40 nano-moles/L). Since pH is ONLY -log10[H+], pH will drop through the floor.
- Thus, we will NOT be able to buffer any rise in CO2
- As you increase PCO2 and form carbonic acid (H2CO3), bicarbonate cannot neutralize the H+. ∴ [H] and [HCO3-] rise and pH falls.
- However, intracellular buffers and non-bicarbonate buffers can neutralize the carbonic acid and thus prevent large reductions in pH.
- HCO3- levels increase slightly as a consequence
- ***In respiratory acidosis, there is increase in CO2. This lead to increase in HCO3- but its not enough to satisfy the equation. 1 FOR 10
- **Renal compensation (4 FOR 10)
Summary of compensation vs buffering
1. Intracellular buffering of CO 2
increases serum [HCO3-] 1mEq/L per 10 mm Hg increase in PCO2 (1 for 10 rule)
2. When full compensation has happened, expected HCO3- in chronic respiratory acidosis: The [HCO3] will increase by 4 mmol/l for every 10 mmHg elevation in pCO2 above 40mmHg (the 4 for 10 rule)
Metabolic alkalosis
Causes
Types (3)
Why does the kidney “allow” metabolic alkalosis when it can excrete HCO3-
Causes
Metabolic alkalosis is defined as a disorder that causes elevations in the serum HCO 3- concentration and pH. Most frequent cause is loss of H+ ions from the body
Types
- GI Hydrogen loss (vomiting, nasogastric sunction) - Norovirus
- Renal Hydrogen loss ( hyperaldosteronism, loop/thiazide diuretics)
- Intracellular shift of H+; hypokalemia
Why does the kidney “allow” metabolic alkalosis when it can excrete HCO3-
- MA is almost always caused by loss of H+ and Cl loss is a usual accompaniment. MA is almost always hypochloremic.
- Perpetuation of MA requires impairment in renal HCO3- excretion.
- ↓GFR can can ↑ HCO3- reabsorption and prevent its excretion- volume loss
- ↑ HCO3- reabsorption:• Chloride depletion • Hypokalemia • ↑Aldosterone
ECF depletion effect:
• Activation of the RAS/SNS increases Na reabsorption in the PT through ↑activation of NHE
• RAS activates aldosterone that increases secretion of H+ in the
cortical collecting tubules (Aldosterone stimulates the H+ ATPase in the intercalated cells of the collecting duct)
Cl depletion is more responsible for increase HCO3- reabsorption
• ↓Cl reduces the activity of NKCC2 resulting in activation of the RAAS
Metabolic alkalosis
Rule for compensation ***
Expected pCO2 = 40 + 0.7 x [ΔHCO3]of 1 mEq/L
E.g. What is the expected PCO2 in a patient with alkalosis and HCO3 of 36 mEq/L? Remember, this is pulmonary compensation, usually occurs rapidly.
= 0.7* (36-24) = 0.7x 12 + 40 = 48 mmHg (+/- 2)
Respiratory alkalosis
Causes
Buffers
Compensation
Causes
- Respiratory alkalosis is defined as a disorder that causes a reduction in arterial PCO2 and an increase in pH
Causes ; ***Usually IATROGENIC (caused by ventilator)
1. Hyperventilation
Drug induced
Neurological conditions that increase ventilation
Anxiety, pain, fear
2. Occurs commonly with mechanical ventilation Symptoms may include dizziness, confusion and seizures.
**You pass out from a panic attack because there is decreased CO2 which lead to vasoconstriction of cerebral vessels (hypoperfuson)
- As you decrease PCO2 and use carbonic acid (H2CO3) [H] falls and pH rises and the system rapidly comes to equilibrium, however at a high pH
- However, intracellular buffers and non-bicarbonate buffers can provide H+ to combine with HCO3- and form carbonic acid which can then dissociate to carbon dioxide to provide for excessive loss of CO2 by the lungs. this buffers the rise in pH
- As H+ are combining with HCO3- its levels decrease slightly
Buffering
- Buffering is due to H+ leaving cells
- Loss of H+ from cells decreases intracellular [H+]. H+ from cells reacts with serum [HCO 3-] which decreases 2mEq/L per 10 mm Hg decrease in PCO 2. CO2 is excreted by the lungs
Compensation ; RENAL
- Intracellular buffering of CO 2 decrease serum [HCO3-] 2
mEq/L per 10 mm Hg decrease in PCO2 (2 for 10 rule)
- When full compensation has happened, expected HCO3- in chronic respiratory alkalosis: The [HCO3] will decrease by 5 mmol/l for every 10 mmHg fall in pCO2 below 40mmHg (the 5 for 10 rule)
How to differentiate between partial compensation and combined disorder
Respiratory compensation is always acute, if the lungs are functional. Thus, if respiratory compensation was expected and didn’t happen fully, respiratory acidosis is complicating metabolic acidosis or respiratory alkalosis is accompanying metabolic alkalosis.
Renal compensation takes 2-3 days to fully develop. Within this time frame, lower than expected HCO3 in respiratory acidosis, or higher than expected in respiratory alkalosis, can be deemed partial compensation. After this window, however, it’s considered a combined acid-base imbalance.
Remember, even with full compensation the pH WILL NOT BE NORMALIZED
Case A 78-year-old woman with no history is brought to the ER, unconscious 1.pH = 7.4 2.[HCO3] = 36 mEq/L 3.PCO2 = 60 mmHg
Clearly the Pt has respiratory acidosis. Now, if this is acute then HCO3 should have been 26 (24 + 1 for 10). If this is chronic then HCO3 should have been 32 (24 + 4 for 10). However, HCO3 is 36. The Pt has mixed acid-base imbalance: She has respiratory acidosis with metabolic alkalosis. E.g. She has long standing COPD and is being treated with thiazides for hypertension.
Suspect mixed acid-base disorder (acidosis and alkalosis) if the pH is normal but PCO2 or HCO3- is abnormal. They might appear at normal or expected values but remember, pH RARELY RETURNS TO NORMAL JUST BY COMPENSATION OR BUFFERING.
Summarize various respiratory physical exam findings
4 sounds
Percussion abnormalities
Abnormalities in other systems
Finding on fingers?
§ You must know this!!
- Rhonchi are lower pitched “musical noises”. They are caused by airway obstruction, usually with mucus secretions. (E.G FROM PRODUCTIVE COUGH)
- Wheezes are higher pitched noises. Also secondary to airway obstruction, usually more from airway swelling (as in asthma).
- inspiratory wheezing is upper airway while expiratory wheezing is usually trachea area. - Crackles (also called rales) suggest fluid in the lung parenchyma (fluid from heart failure, infection).
- Fine dry crackles (velcrow like sound) seen with scarring and interstitial processes.
Percussion abnormalities – effusion or consolidation causes decreased resonance. Increased air (as in pneumothorax or emphysema) cause increased resonance.
Look for abnormalities in other systems. For example - crackles from heart failure will likely be accompanied by abnormal cardiac findings.
Clubbing of the fingers can be seen with congenital heart disease,
pulmonary fibrosis, lung cancer. **sometimes it can mean nothing
Looks for increased AP diameter of the chest, suggesting chronic
hyperinflation. (COPD, air trapping)
Physical exam resp findings
What do they following indicate
- Rales (wet crackle)
- Fine crackles
- Rhonchi
- Wheezing
***MUST KNOW
§ Rales (wet crackles) suggests infiltrate or edema.
§ Fine crackles suggest interstitial disease.
§ Rhonchi suggest secretions in the airway.
§ Wheezing suggests airway swelling (as in asthma).
Respiratory
Normal anatomy
- how many lobes in right vs left lung
- main function
NORMAL ANATOMY
A. Right lung with 3 lobes; (heavier, more problems occur here)
B. Left lung with 2 lobes (including the lingula)
C. Main function- exchange different gases between inspired air and blood
D. Trachea branches out to right and left main stem bronchi (more likely to aspirate into the right main stem bronchus)
E. Bronchi (HAVE CARTILAGE AND SUBMUCOSAL GLANDS) lead to bronchioles which do not have cartilage or submucosal glands
F. Bronchioles lead to terminal bronchioles
G. Terminal bronchioles lead to the acinus
H. Acinus (terminal respiratory unit)
1. Contains respiratory bronchioles which lead to alveolar ducts
2. Alveolar ducts lead to alveolar sacs (alveoli)
I. General histology
- Respiratory tree lined by ciliated pseudostratified columnar epithelium. ***exception - vocal cord lines by stratified squamous epithelium
- Cartilaginous airways with mucus-secreting goblet cells and submucosal glands
J. Alveolar histology
- Capillary endothelium
- Basement membrane
- Interstitium
- Alveolar epithelium; a) Type I pneumocytes (flat epithelial cells); cover 95% of alveolar surface and b) Type II pneumocytes (cuboidal epithelial cells) - produce surfactant and repair
- Alveolar macrophages - esp smokers
K. Dual circulation with pulmonary and bronchial arteries
- blood vessels are lined by endothelial cells
- airways lined by epithelial cells
- pleural is lined by mesotheliom cells
Pulmonary defense mechanisms
- Pulmonary tract defense mechanisms
- Factors affects our pulmonary defense mechanism
- Pulmonary tract defense mechanisms
A. Nasal clearance - sneezing or blowing
B. Tracheobronchial clearance by cilia; epithelial mucociliary action
C. Alveolar clearance by macrophage; phagocytosis - Factors affects our pulmonary defense mechanism
A. Loss or suppression of cough reflex (coma, drugs, pain)
B. Injury to mucociliary apparatus (ciliary dysfunction, smoking, viruses)
C. Interference with alveolar macrophages (alcohol, smoking)
D. Pulmonary congestion and edema
E. Accumulation of lung secretions (cystic fibrosis)
Chronic diffuse interstitial (Restrictive) Diseases
General
General
- Disorders with inflammation and fibrosis of the alveolar wall interstitium leading to restrictive lung disease
- Dyspnea, tachypnea and eventual cyanosis without wheezing (obstruction)
- Classic features are reduced carbon monoxide diffusing capacity, lung volume and compliance
- Chest X-rays show bilateral infiltrative small nodules, irregular lines or ground-glass shadows
- Advanced disease leads to secondary pulmonary hypertension, cor pulmonale (right sided failure) and end-stage lung or honeycomb lung
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases - IPF General Pathogenesis Morphology/histology Clinical
**FIBROBLASTIC FOCI
IPF - Idiopathic Pulmonary Fibrosis
a. Clinicopathologic syndrome with characteristic radiologic, pathologic and clinical features
b. Histologic pattern that of usual interstitial pneumonia (UIP) also seen in connective tissue diseases, hypersensitivity pneumonia & asbestosis
c. Pathogenesis
1. Etiology unknown but most likely caused by repeated cycles of epithelial activation/injury by certain agents
2. Inflammation causes abnormal epithelial repair leading to fibroblastic/myofibroblastic proliferation (“FIBROBLASTIC FOCI”)
3. Abnormal repair due to fibrogenic TGF-beta, which is released by Type I alveolar epithelial cells
4. TGF-beta1 negatively regulates telomerase activity - increased epithelial cell apoptosis - cycles of cell death and repair
5. Caveolin-1, which is an inhibitor of TGF-beta, is decreased in epithelial cells and fibroblasts in IPF
D. Morphology/Histology
- Cobblestone pleural surface with firm rubbery cut surfaces
- Mostly involves lower lobes near subpleural regions and along interlobular septae
- Early stage with fibroblastic foci with temporal heterogeneity (layers of normal and abnormal lung)
- Late stages with dense fibrosis and cystic spaces lined by hyperplastic Type II pneumocytes (honeycomb lung)
- Usually see coexistence of both early and late lesions
- May see mild/moderate inflammation, squamous metaplasia, smooth muscle hyperplasia and pulmonary HTN
E. Clinical
(1) Insidious onset of dyspnea on exertion and dry cough
(2) Later see hypoxemia, cyanosis and clubbing
(3) Most patients between 40-70 years of age at diagnosis
(4) Unpredictable course with median survival of about 3 years
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (2)- Nonspecific Interstitial Pneumonia (NSIP)
General
Etiology
Morphology/histology (cellular/fibrosing pattern)
Clinical
**compare differences with IPF/UIP - NO FIBROBLASTIC FOCI, RESPOND WELL TO STEROIDS
Nonspecific Interstitial Pneumonia (NSIP)
a. Also with characteristic radiologic, pathologic and clinical features
b. Etiology unknown
c. Morphology/Histology
(1) Cellular pattern; (a) Uniform/patchy mild to moderate chronic inflammation (b) Better prognosis than with fibrosing pattern
(2) Fibrosing pattern; (a) Diffuse/patchy interstitial fibrosis WITHOUT temporal heterogeneity in UIP (b) NO fibroblastic foci and honeycomb lung
d. Clinical
(1) Months of dyspnea and cough
(2) Most patients between 46-55 years of age (younger than IPF/UIP)
(3) Much better prognosis than in patients with UIP
* ***RESPONDS TO STEROID
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (3)- Cryptogenic Organizing pneumonia (previously known as BOOP)
Etiology
General
Morphology/histology
Clinical
**MASSON BODIES (organizing pneumonia pattern with no temporal heterogeneity)
Cryptogenic Organizing Pneumonia (previously known as BOOP)
a. Etiology unknown
b. Common response to various infections or inflammatory lung injury (e.g. viral/bacterial pneumonias, inhaled toxins, drugs, etc.)
c. Morphology/Histology
(1) Patchy subpleural or peribronchial airspace consolidation
(2) See intra-alveolar polypoid plugs of loose organizing
connective tissue (Masson bodies) WITHOUT temporal heterogeneity
(3) NO interstitial fibrosis or honeycomb lung
d. Clinical
(1) Acute onset of cough and dyspnea
(2) Most need steroid treatment for > 6 months
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (4) - Pulmonary involvement in connective tissue diseases
Pulmonary involvement in connective tissue diseases
a. Include rheumatoid arthritis, scleroderma and systemic lupus erythematosus
b. Can occur in many different patterns (UIP, NSIP, organizing pneumonia, bronchiolitis)
c. May occur in 30-40% of rheumatoid arthritis patients
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (5) - Pneumoconioses
General
Pathogenesis **AREAS OF FIBROSIS - SILICOSIS
Coal workers pneumoconiosis; **LARGE AREAS OF FIBROSIS - PROGRESSIVE MASSIVE FIBROSIS
**different types
Clinical
Pneumoconioses
a. Diseases caused by organic and inorganic particulates as well as chemical fumes and vapors
b. Pathogenesis
(1) Disease development depends on various physical factors
(a) Amount of dust retained determined by concentration
in ambient air, duration of exposure and effectiveness of clearing mechanisms
(b) Size, shape and buoyancy of particles
(c) Particle solubility and physiochemical reactivity
(d) Possible additional effects of other irritants
(2) Remember- most dangerous particles measure 1-5 um
(a) Smaller particles more readily enter pulmonary fluids
rapidly reaching toxic levels causing acute lung injury
(b) Larger particles persist longer causing fibrosis (silicosis)
c. Coal Workers’ Pneumoconiosis
(1) Asymptomatic anthracosis
(a) Accumulation of carbon pigment in macrophages along
lymphatics and lymphoid tissue in miners, tobacco smokers and urban dwellers
(b) Does not produce a cellular reaction
(2) Simple CWP with little/no pulmonary dysfunction
(a) See coal macules (1-2 mm) with carbon-laden
macrophages and larger coal nodules with collagen
(b) Macules and nodules along the respiratory bronchioles
(c) Upper lobes & upper zones of lower lobes more affected
(d) Leads to centrilobular emphysema
(3) Complicated CWP (progressive massive fibrosis)
(a) In a background of simple CWP developing over years
(b) See multiple blackened scars > 1 cm (up to 10 cm) in lung parenchyma
(c) Composed of dense collagen, carbon pigment & necrotic centers
(4) Clinical
(a) Usually a benign disease course (b) Mild forms of complicated CWP without loss of
function exist (only 10% of simple CWP progress to complicated CWP)
(c) More advanced forms of CWP lead to pulmonary
hypertension and cor pulmonale even WITHOUT further exposure
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (5b) - Pneumoconioses 5b. Silicosis General Pathogenesis Morphology/histology Clinical
**wildly seen in the world, nodules, capsules
Silicosis
(1) Caused by inhalation of crystalline silicon dioxide (silica)
(2) Most prevalent chronic occupational disease worldwide
(3) Seen in sandblasters and mine workers years after exposure
(4) Pathogenesis
(a) Silica in crystalline and amorphous forms
(b) Crystalline form much more fibrogenic (incl. quartz)
(c) Silica causes macrophage to release various mediators
(e. g. IL-1, TNF, O2-derived free radicals, fibrogenic cytokines)
(5) Morphology/Histology
(a) Early stage barely palpable nodules in upper lung zones (b) Later stage see nodules coalescing to form hard
collagenous scars made of concentric layers of hyalinized collagen with a dense capsule
(c) Lesions may involve hilar lymph nodes and pleura with
thin calcifications (eggshell calcifications)
(6) Clinical
(a) X-ray: fine nodularity in upper lung areas (b) Dyspnea occurs after development of massive fibrosis (c) Associated with increased incidence of tuberculosi
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (5c) - Pneumoconioses 5c. Asbestos related disease General Pathogenesis Epidemiology Morphology/Histology
- *DOME BELL SHAPED FIBERS. BLUE STAIN ON IRON STAIN
- can see plaques
(1) Asbestos exposure linked to fibrous pleural plaques, pleural effusions, interstitial fibrosis, lung and laryngeal carcinoma, mesothelioma
(2) Pathogenesis
(a) Depends on concentration and physical properties (size,
shape, solubility) of the fibers
(b) 2 types of fibers- serpentine (chrysotile) and amphibole
(c) Serpentine form: most prevalent form; curly flexible
soluble fibers; removed by upper respiratory mucociliary apparatus
(d) Amphibole form: least prevalent form but more
pathogenic; stiff and brittle fibers; penetrate deep into the lung interstitium
(e) Both fibrogenic but only the amphibole form is
associated with mesothelioma
(f) Inhaled fibers cause initial injury at the bifurcations of small airways where they penetrate macrophage
(g) Macrophage are activated releasing chemotactic factors
and fibrogenic mediators leading to widespread fibrosis
3) Epidemiology
(a) Exposure leads to 5 fold increase in lung carcinoma
(b) Exposure + smoking leads to 55 fold increase in lung ca
(c) Exposure leads to 1000 fold increase in mesothelioma
(4) Morphology/Histology
(a) See diffuse interstitial fibrosis similar to UIP
(b) Asbestos bodies- golden-brown elongated asbestos fibers coated with iron-containing protein from macrophage
(c) Initial fibrosis around respiratory bronchioles and alveolar ducts extending airspaces extending to alveolar sacs and alveoli
(D) Finally creates enlarged airspaces with fibrous walls (honeycomb pattern)
(E) Disease begins in the lower lobes with the middle and upper lobes possibly affected later
F) Pleural plaques are the most common manifestation of asbestos exposure; dense collagen with calcium mostly on anterior & posterolateral parietal pleura & diaphragm
G) Pleural plaques DO NOT contain asbestos bodies
- Clinical
(a) Dyspnea with productive cough
(b) Symptoms usually > 20 years after asbestos exposure
(c) Chest x-ray: irregular linear densities
(d) Asbestosis + lung or pleural cancer = grim prognosis
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (6) - Therapy-induced lung disease
Therapy-induced lung disease
- **certain drugs cause bronchospasm, pulmonary
edema, DAD (diffuse alveolar damage), organizing pneumonia and INTERSTITIAL FIBROSIS
a. Bleomycin (antineoplastic drug) can cause lung damage and fibrosis
b. Amiodarone (anti-arrhythmic drug) causes pneumonitis in 5-15%
c. Acute radiation pneumonitis occurs in 10-20% of patients 1-6 months later (fever, profound dyspnea, pleural effusion)
d. Chronic radiation pneumonitis (diffuse alveolar damage with epithelial cell atypia and pulmonary fibrosis) can also occur
Chronic diffuse interstitial (Restrictive) Diseases
Fibrosing diseases (7) - Caplan syndrome
Caplan syndrome
a. CW Pneumoconiosis + rheumatoid arthritis
b. See lung nodules with possible central necrosis
c. Syndrome can also occur in asbestosis and silicosis
• Describe the role of neutrophils, macrophages (M1 vs M2) and lymphocytes in the regulation of acute/chronic inflammation
Difference between acute vs chronic infections
1. Acute; neutrophils (60%). Neutrophils perform PHAGOCYTOSIS to kill bacteria, and die by APOPTOSIS
- Macs; monocyte 9%. Macrophage control when to transition from acute to chronic infections
A. M1;
- kills ingested and intracellular bacteria (CD40 bind CD40L Th1 effector to produce INTERFERON GAMMA TO KILL THE CELL).
- “Angry macrophages” activated by interferon gamma.
- Also produce cytokines like IL1, IL12, IL23 to stimulate inflammation.
B. M2;
- not efficient in killing intracellular bacteria.
- Produce IL10 and TGF-beta which are anti-inflammatory cytokines - Chronic; Lymphocyte 30% . Lymphocytes, recirculate back to lymphatics and blood if they don’t encounter the cognate antigens (much longer lifespan than neutrophils)
• Describe the physiology, microbiology, and pathology of CFTR mutations and their impact on CF lung disease
**Pathogens associated with CF - CGD (NADPH oxidase defect) vs Cl ion transport defect
Physiology - cystic fibrosis chloride ion channel
• Cystic fibrosis transmembrane conductance regulator (CFTR) (chromosome 7)
• Chloride channel transports Cl- in and out of cells.
• Basic defect is due to the mutations in CFTR that cause difficulty to move Cl- across the membrane.
• Increased Cl ion outside the cells, increased the Na ion
reabsorption.
• A thin layer of mucus on top of the airway, small intestine
(meconium ileus), and pancreatic duct become dehydrated and sticky due to CFTR mutation.
Pathology - Cystic fibrosis lung disease
● Thick dehydrated mucus production in airways
● Chronic obstructive pulmonary disease
● Bronchiectasis with pulmonary exacerbations
● Recurrent lung infections
● Bronchopneumonia
● Gradual lung function deterioration (FEV1)
Microbiology - BAL (bronchoalveolar lavage) fluid from a patient with CF ***REPEATED ACUTE INFECTION
- Inflammatory cells (neutrophils)
- IL-8, LTB4, C5a, IL-17, PGP, bacterial products
- TNF-a, IL-1b and GM-CSF
- Decreased cough clearance
- Impaired apoptosis and efferocytosis
- Neutrophil elastase and oxidants in BAL
- IL-10 downregulated in BAL
Pathogens associated with CF (cystic fibrosis)
- CGD (NADPH oxidase defect)
- Catalase positive bacteria
- Staphylococcus aureus
- Burkholderia (Pseudomonas) cepacia
- Serratia marcescens
- Nocardia
- Aspergillus - CF (Cl ion transport defect)
- Pseudomonas aeruginosa
- Staphylococcus aureus incl. MRSA
- Nontypable Haemophilus influenzae
- Burkholderia cepacia (poor prognosis for lung transplant)
- S. maltophilia
- Achromobacter
• List common antibiotic resistance mechanisms of bacteria
- Describe entry (2)
- Destroy antibiotics
- Altered target (3)
- Describe entry (2)
- Build a physical barrier by limiting the diffusion of antibiotics through a viscous layer of polysaccharide (biofilms). Decrease entry
- Alterations that affect permeability (ie, decrease the intracellular concentration of antibiotic) are used by a variety of antibiotics. This can involve a decreased influx or an increased efflux from the bacterial cell. Decrease entry. - Destroy antibiotics
- Inactivation of the antibiotic through hydrolysis (eg, β-lactamases that cleave the β-lactam ring of penicillins, cephalosporins and carbapenems)-Destroy antibiotics - Altered target (3)
- Synthesis of modified LPS that resists action of peptide antibiotics-Altered target.
- Chemical modification of the antibiotic through acetylation, phosphorylation, or adenylylation (eg, chloramphenicol acetyl transferase that transfers an acetyl group from acetyl CoA to chloramphenicol, resulting in its inactivation). Altered target.
- Alteration of antibiotic targets through mutation (eg, the alteration of a single amino acid in ribosomal protein S12, which prevents streptomycin binding to the 30S ribosome subunit without affecting protein synthesis). Altered target
CF
Beta - lactamase CF antibacterial therapy immunodeficiency in CF CF clinical trials Summary of CF lung disease
Beta - lactamase
1. Major mechanism in Gram-negative pathogens
2. May be plasmid- or chromosomally-mediated
- Most are plasmid-mediated
- “AmpC” β-lactamases may be encoded on chromosome of
“SPACE” organisms (Serratia marcescens, Pseudomonas
aeruginosa/Proteus spp., Acinetobacter spp., Citrobacter spp.,
Enterobacter spp.)
3. Main types of β-lactamases: (3)
A. Penicillinases inactivate penicillins
B. “Extended-spectrum β-lactamases” (ESBLs) inactivate most β-
lactams except for carbapenems
C. Carbapenemases (e.g., OXA, KPC, metallo-β-lactamases) inactivate carbapenems
CF antibacterial therapy
• P. aeruginosa is naturally resistant to many antibiotics. ***
• Resistant strains often emerge during therapy.
• Combination therapy (double coverage) with different mechanisms of action: Intravenous administration of anti-Pseudomonas penicillin, ticarcillin or piperacillin (b-lactam), plus an aminoglycoside, eg. gentamicin or amikacin (acute pulmonary exacerbations).
• Inhaled tobramycin and oral azithrommycin.
Immunodeficiency in CF
• Innate immunity: complement, macrophages, and neutrophils (mucociliary clearance defect).
• Antigen presentation by APC (dendritic, macrophages and B cells) (possible).
• Adaptive immunity: T and B cells. Th2-Th17 axis. Elevated levels of IgG1-4, IgM, and IgA, indicating that the germinal center of LN is functional with isotype switching. Fc portion of antibodies are fine.
• Reduced opsonic phagocytosis with CF sera indicates
that affinity maturation due to somatic hypermutation (AID) may not be functional.
• Clonal expansion is not an issue. The issue is clonal
expansion with not produce good antibodies.
CF clinical trials
● Gene therapy
● Broad anti-inflammatory modulator
● Antibacterials with anti-inflammatory properties
● Modulators of intracellular signaling (IL-10, INF-g)
● Inhibitors of neutrophils influx (Anti-IL-8 and anti-IL-17)
● Inhibitors of neutrophil products (DNase)
● Anti-oxidants
● Anti-proteases
Summary of CF lung disease
- CF lung disease is characterized by repeated acute inflammation with excessive neutrophils in the interstitial space.
- Biofilm formation reduces efficacy of both antimicrobial therapy and immune responses, and also causes the chronic presence of bacteria.
- Acute inflammation is part of innate immunity which as limited specificity. Uncontrolled acute inflammation eventually leads to structural damage resulting in bronchiectasis and lung abscess.
- The key to cure the CF lung disease lies in the production of antibodies with improved specificity (more effective binding). Immunotherapy, CAR-T, chimeric antigen receptor of T cells; CTLA-4 and PD-1 *** TO PRODUCE LIFELONG IMMUNITY
TB
Primary vs secondary
Adaptive responses to Intracellular bacteria
Primary TB
• Tuberculosis is caused by inhalation of aerosolized Mycobacterium spp including M. tuberculosis.
• Initial exposure causes the primary TB with the
formation of focal caseating necrosis in the lower
lobe of lung and hilar lymph nodes.
• Foci undergo fibrosis and calcification forming Gohn
complex.
• Generally asymptomatic and PPD positive.
Secondary TB due to the reactivation
• HIV and aging are two major risk factors.
• Occurs at the apex of lung and can spread to any tissue.
• Forms cavitary foci of caseous necrosis; May also lead to miliary pulmonary TB or TB bronchopneumonia.
• Fevers and night sweats
• Cough with hemotypsis
• Weight loss
• Biopsy-granuloma and AFB positive bacilli
Adaptive responses to Intracellular bacteria (2)
1. Prototypical response to intracellular bacteria is TH1
- IFN- g activates macrophages to destroy phagocytosed microbes
- MAC-produced IL-12 activates NK cell which produces IFN-g
- IL-12 causes the differentiation of T cell o TH1 cell which produces IFN-g
- TH1 cell CD40L activates macrophages (APC) via CD40
- GC-LN: TH1 cell CD28 binds to B7 on macrophage (APC) for co-
stimulation
- GC-LN: TH1 cell CD40L co-stimulates B cells (APC) via CD40
- GC-LN: IFN-g induces opsonizing and complement-binding Ab
isotypes via affinity maturation (somatic hypermutation) and isotype switching
2. Phagocytosed bacteria also stimulate CD8+ T cell responses if bacterial Ags are transported from phagosomes into the cytosol
- CTLs can kill infected cells
• Describe the formation and pathogenesis of granuloma in TB; Understand the caseating vs noncaseating granuloma and its use in the differential diagnosis
Pathogenesis of granulomas
A. Infection before activation of cell mediated immunity
B. Initiation and consequences of cell mediated immunity
2 types of granuloma
1. Caseating granulomas
• Bacteria: Mycobacterium tuberculosis, Treponema
pallidum, Listeria monocytogenes (granulomatosis infantiseptica)
• Fungi: Aspergillus, Blastomyces, Coccidioides, Cryptococcus, Candida, and Histoplasma
• Helminthic infection: Schistosoma mansoni, S. japonicum, the liver granulomas form around the parasite eggs.
- Noncaseating granulomas
• Reaction to foreign materials
• Sarcoidosis (lung, offending antigen unknown)
• Beryllium exposure
• Crohn disease (offending antigen unknown, contrast to UC)
• Cat scratch disease (Bartonella henselae with neutrophils)
• Mycobacterium leprae
TB treatment regimen - first Line drugs
HIV and TB
MDR and XDR TB
Summary of TB
TB treatment regimen - first Line drugs
- For pulmonary TB; 3 or 4 drugs for 2 months followed by 2 drugs for 4 months;
- RIF, INH, PZA and EMB for 2 months
- INH and RIF for 4 months - DOT is important to ensure adherence and reduce resistance
- For extrapulmonary disease or with HIV treatment may be longer
- For LTBI one drug is used; usually INH for 9 months
HIV and TB
- TB is leading killer of HIV-positive people causing one fourth of all HIV-related deaths
- HIV-infected;
- 30 times more likely to progress to TB disease
- 40% develop TB disease 2-3 months after exposure
- TB increases risk of HIV progression - Associated with multi-drug resistant TB (MDR-TB)
MDR and XDR TB
- Drug resistant Mtb is a result of selection of naturally resistant bacilli from a large population of tubercle bacilli
- improper use of TB medications; Non-adherence, inadequate dose of drugs, inappropriate single drug therapy - MDR TB; resistant to isoniazid and rifampin
- XDR TB; resistant to isoniazid and rifampin + a FLUOROQUINOLONES + one injectable second line agent (kanamycin, amikacin, capreomycin)
Summary of TB
- TB is caused by infections by an intracellular bacterium. The primary infection starts with bacterial colonization in alveolar macrophage via respiratory droplets.
- Initial exposure causes the formation of caseating granuloma in the lower lobe of the lung and hilar lymph nodes.
- Macrophage will produce IL-12 and TFN-a which causes the naïve T cells to become Th1 which produces IFN-g
- IFN-g activated macrophages are called epithelioid histiocytes.
- Reactivation of TB can disseminate to other body sites, bone marrow, spleen, kidney, and CNS, all with formation of caseating granulomas
• Describe the diagnosis and treatment of TB
TB diagnosis
1. Immuno-diagnosis:
- tuberculin skin test (TST), PPD. Be careful about false positive. Delayed type hypersensitivity (cell-mediated)
- In vitro IFN-r release assays. Specific antigen (early
secreted antigen target-6 ESAT-6, culture filtrate protein 10
(CFB-10), test true positive.
2. Chest X-ray: primary vs. secondary.
3. Microscopy: Acid fast bacilli (AFB stain of sputum)
4. PCR
5. Culture: gold standard, but takes 3-4 weeks.
TB treatment • Anti-TB drugs: 6 MONTHS - Isoniazid (INH). - Rifampin (RIF). - Pyrazinamide (PZA) - Ethambutol (EMB). • Prophylaxis • Vaccination with attenuated M. bovis [bacille Calmette-Guerin (BCG)]
Respiratory pharmacology
- Mechanism of asthma
Mechanisms of Asthma
• Increased numbers of inflammatory cells in the airway: TH2 cells, eosinophils, and B lymphocytes (produce IgE), mast cells
• Release more than 100 inflammatory mediators
• Inflammatory mediators → induce bronchoconstriction
• Cholinergic reflexes → bronchoconstriction
• Hypertrophy/hyperplasia of airway smooth muscle cells
• Vasodilation, plasma leak → edema
• Chronic inflammation leads to structural changes
• Subepithelial fibrosis (basement membrane thickening)
• Hyperplasia of mucus-secreting cells
**AIM OF DRUGS IS TO SUPPRESS BRONCHIOCONSTRICTION
Classification of Asthma severity
Intermittent vs persistent mild vs persistent moderate vs persistent severe
- Intermittent
o Symptoms less than 2 days per week
o Nighttime awakenings less than 2 days per month
o Interference with normal activity—none
o FEV1 greater than 80% of predicted
o Albuterol inhaler used less than 2 days per week
o Exacerbations requiring systemic corticosteroids (0 to 1 per year) - Persistent Mild
o Symptoms more than 2 days per week
o Nighttime awakenings 3 to 4 times per month
o Interference with normal activity—minor limitation
o FEV1 greater or equal to 80% of predicted
o Albuterol inhaler used more than 2 days per week, but not daily and not more than 1 time per day
o Exacerbations requiring systemic corticosteroids (more than 2 per year) - Persistent Moderate
o Symptoms are daily
o Nighttime awakenings more than once per week
o Interference with normal activity—some limitation
o FEV1 60-80% of predicted
o Albuterol inhaler used daily
o Exacerbations requiring systemic corticosteroids (more than 2 per year) - Persistent Severe
o Symptoms are throughout the day
o Nighttime awakenings are often (7 times per week)
o Interference with normal activity—extremely limited
o FEV1 less than 60%
o Albuterol inhaler used several times per day
o Exacerbations requiring systemic corticosteroids (more than 2 per year)
Routes of drug delivery to the lungs (3)
Inhalation (types) vs nebulizer vs oral
Inhalation therapy: • 10 to 20% of the drug is inhaled • 80 to 90% of the drug is swallowed • Use of large-volume spacer will reduced the amount of drug being deposited on the oropharynx (reduce oral and systemic side effects (this particularly important when it comes to inhaled corticosteroids)) • Metered dose inhalers • Space chambers • Dry powder inhalers
• NEBULIZERS (useful for treating extreme exacerbations of asthma or COPD when airway obstruction is extreme). Also useful for delivering drugs to infants and small children
• ORAL ROUTE (have to give a much larger dose compared to inhaled dose to get the same effect). Theophylline has be given by the oral route
- e.g Some meds may be given as a syrup to children
