patho2: mod1: lecs 6-7

acute kidney injury (AKI)

acute kidney injury (AKI)

• abrupt loss of kidney function within a few days

• reversible nephron damage

• pre-renal

• intra-renal

• post-renal

chronic kidney disease

• a progressive loss of function of more and more nephrons that gradually decreases overall kidney function

• permanent damage to nephrons

  • diabetic kidney disease

  • leads to end-stage renal disease

  • dialysis (fewer than 360,000 functional nephrons)

• caused by: diabetes, hypertension

• waste products such as creatinine and urea accumulate in the plasma in proportion to the number of non-functioning nephrons

markers of renal disease

• low urine output (oliguria)

• low GFR

• high serum creatinine

• hypocalemia

• hypokalemia

• elevated cystatin C

cystatin C

• a non-glycosylated, protease inhibitor

• produced by all nucleated cells and exhibits a stable production rate

• it has shown promise as a replacement for serum creatinine in estimation of GFR

• after glomerular filtration, it is fully catabolized in the proximal renal tubule and is not returned to blood

• when GFR decreases, levels begins to rise proportionately

clinical presentation of acute renal injury

• heterogenous group of disorders characterized by deterioration in renal function (decreased GFR)

• oliguria: variable

• other: hematuria, proteinuria, edema, hypertension

hematuria

• gross: when you can physically see the blood in urine

• microscopic: when you cannot see the blood in urine, but it is still there

pre-renal acute kidney injury

• sudden reduction in renal blood flow to the kidney (renal hypoperfusion) that causes loss of kidney function

• nothing wrong with the kidney itself

• can be caused by sepsis, trauma, bleeding, or poor cardiac output

intra-renal acute kidney injury

• nephron damage (direct damage to the kidney)

• acute tubular necrosis (ATN)

• acute glomerulonephritis

  • immune response that damages glomerular epithelial cells and basement membrane → proteinuria, hematuria

  • decreases Kf (by blocking fenestrations) and decreases GFR

    • strep infection

    • antibody-antigen complexes are insoluble to the glomerulus

• prolonged ischemia

• toxins, drugs, infection,

• nephrotoxins: heavy metals such as lead, cadmium, mercury, chromium

• anti-freeze (ethylene glycol)

acute glomerulonephritis

• 3rd most common cause of end-stage renal disease

• requires prompt diagnosis, as it can rapidly progress to permanent kidney disease if left undiagnosed

• treatment includes

  • control of inflammation

    • eg. corticosteroids, fish oil

  • inhibition of fibrosis

    • ACE inhibitors, angiotensin 2 receptor blockers, statins, antioxidants

post-renal acute kidney injury

• problem occurs after the kidney

  • urinary tract obstruction

    • kidney stones

    • enlarged prostate

    • tumors

    • injury

    • fluid build up in the nephron

urinary tract obstruction

• decreased urine flow

• blockage leads to a backflow of urine back into the urinary tract

• this results in increased pressure in the urinary system, which impairs the function of the kidneys and leads to nephron damage

• prolonged blockage can result in renal dysfunction

hydronephronesis

• swelling of the kidney due to urine back up

kidney stones

• calculi

• location: calyces, urethra, bladder

• can be made of calcium oxalate & phosphate, uric acid, struvite/infection (alkaline urine), or cysteine

• symptoms include pain and hematuria

• damage to the renal papillae

fluid build up throughout the nephron

• GFR decreases

• pressure of bowman’s space decreases → pressure of glomerular capillaries decreases

• decreased net pressure across glomerular capillaries

• causes physical damage to nephrons

precipitation from urine

• when the concentration of certain substances exceeds their solubility limits in the urine, they can no longer remain dissolved and instead separate out to form solid crystals → the formation of kidney stones or other types of urinary calculi

• often supersaturated solution exists in renal system because it favors crystal formation

urine precipitation

• calcium oxalate

• uric acid

• calcium phosphate

tubular fluid (loop of Henle) precipitaiton

• calcium phosphate

inhibitors of crystal formation present

• citrate

• pyrophosphate

• magnesium ion

• osteopontin protein

• tamm-horsfall protein

promoters of crystal formation present

• dead cells/tissue

• secondary crystallization

  • eg. calcium phosphate can precipitate on calcium oxalate crystals

• aggregation of multiple small crystals into larger ones

low pH inhibits which crystal formations?

• calcium phosphate and struvite crystals

low pH promotes which crystal formations?

• uric acid and cysteine crystals

tamm-horsfall glycoprotein (THP)

• most abundant urine protein, with multiple roles in renal physiology and bladder protection

• protects against bacterial UTI by blocking bacterial adherence to the bladder epithelium

Randall’s plaques

• act as a starting point for the formation (crystallization) of calcium oxalate on calcium phosphate in the Loop of Henle

collecting duct epithelium attachment

• protein or lipid “receptors” for calcium oxalate crystallization

  • calcium oxalate

micturition (urination) process

• two processes

  • filing phase

  • voiding phase

• sensations of bladder fullness are conveyed to the spinal cord by the pelvic and hypogastric nerves

detruser

• parasympathetic nervous system

• smooth muscle on the wall of the bladder

• allows the bladder to contract to excrete urine or relax to hold urine

• involuntary

• filling phase: relaxed

• voiding phase: contracting

internal sphincter

• sympathetic nervous system

• involuntary smooth muscle

• controls urine flow from the bladder to the urethra

• filling phase: contracting

• voiding phase: relaxed

external sphincter

• somatic nervous system

• voluntary movement

• surrounds the opening of the bladder to the urethra and relaxes to allow urine to pass

• filling phase: contracting

• voiding phase: relaxed

intra-renal glomerulopathy

• nephritic: immune complexes

• nephrotic: podocyte dysfunction

acute kidney injury early clinical manifestations

• initial symptoms: fatigue and malaise

• loss of excretory capacity and accumulation of water, electrolytes, and nitrogenous wastes

• pre-renal azotemia: elevated BUN/serum creatinine

• urinalysis: no casts detected

• maximal urinary concentration: 1500 mOsm/L

• may progress to acute tubular necrosis (ATN) without proper treatment

urinary casts

• microscopic cylindrical structures produced by the kidney and present in the urine in certain disease states

• they form in the distal convoluted tubule and collecting ducts of nephrons, then dislodge and pass into the urine, where they can be detected by microscope

• made of white blood cells, RBCs, kidney cells, or other substances

azotemia

• an elevation of nitrogenous products (BUN/creatinine) in blood and other secondary waste products in the body

• raising the level of nitrogenous waste is attributed to the inability of the renal system to filter (decrease in GFR) such waste products adequately

• typical of both acute and chronic kidney injury

acute kidney injury later clinical manifestations

• frank acute tubular necrosis: dyspnea, orthopnea, heart (sound S3), edema

• progressive elevation of serum creatinine

• urinary casts can be found

• urine osmolality

• fractional excretion of Na (as low as 1%)

orthopnea

• difficulty breathing (dyspnea) while laying flat specifically

prostatitis

• swelling, inflammation, and enlargement of the prostate gland, which is situated directly below the bladder in men

• often causes painful or difficult urination

• influences how urethra removes bladder pressure to void

• treatments: antibacterial agents or agents to relax the internal sphincter

  • alpha-1 blockers: tone down SNS activity

  • PDE inhibitors: smooth muscle relaxation

chronic kidney disease (CKD) effect on body fluids

• generalized edema due to water and solute retention

• failure to excrete metabolites, excess ions, “toxins”

  • acidosis: reduced excretion of non-volatile acids lowers plasma pH

  • increased levels of urea, creatinine, and uric acid in plasma (non-protein nitrogen)

  • increased levels of potassium, phosphates, sulfates, and phenols due to reduced renal excretion

CKD early stages

• large drops in GFR result in little increases in plasma creatinine

CKD later stages

• modest decreases in GFR result in large increases in plasma creatinine

causes of CKD

• acute kidney failure

• nephritis

• renal artery obstruction

• kidney stones

• nephrotic syndrome

• polycystic kidney disease

• diabetic neuropathy

• hypertension

• atherosclerosis

nephritis

• a condition in which the nephrons, the functional units of the kidneys, become inflamed

nephrotic syndrome

• a condition defined by massive proteinuria (>40mg/m2/hr) responsible for hypoalbuminemia (less than 30g/L), with resulting hyperlipidemia, edema, and various complications

• usually caused by damage to glomerular capillaries

diabetic kidney disease (DKD)

• leading cause of kidney failure worldwide

• genetic and environmental factors

• hyperglycemia-induced metabolic alterations

  • changes in energy utilization

  • mitochondrial dysfunction

• blood pressure control slows disease progression

  • angiotensin receptor blockers, ACE inhibitors

molecular causes of diabetic kidney disease (DKD)

• changes in microvasculature

  • hyalinosis: the presence of a glassy or homogeneous substance (hyaline) in renal arterioles

• loss of podocytes and hypertrophy

• tubular epithelial atrophy

• basement membrane thickening

• inflammation

• hypertrophy of mesangial cells and podocytes

• dedifferentiation of podocytes

• albuminuria

hyalinosis

• several degenerative processes that affect various cells and tissues, resulting in the formation of rounded masses ("droplets") or relatively broad bands of substances that are homogeneous, translucent, refractile, and moderately to deeply acidophilic

• may occur in the smooth muscle of arterioles

• causes arteriole narrowing

mesangial cells

• provide structural support to the capillaries within the glomerulus

• play a role in regulating blood flow within the glomerulus by contracting or relaxing

• can engulf and remove particles, contributing to the maintenance of a clean glomerular environment (phagocytosis)

what does DKD originate from?

• metabolic dysregulation: molecular mechanisms behind hyperglycemia and free fatty acid levels

• increased polyol and hexosamine pathways

• excessive Glucose-3-Phosphate

  • ↑ PKC

  • ↑ advanced glycation endproducts

    • PARP

    • NADH

mitochondrial effects of DKD

• oxidative phosphorylation

• reactive oxygen species

• effects on mitochondrial gene transcription (epigenetics) leads to long term changes in mitochondrial function

membranous nephropathy of glomerular capillary

• a kidney disorder where the glomerular basement membrane (GBM) becomes thickened due to the deposition of immune complexes

• thickened due to sub-epithelial deposits

• nephrotic

post-infectious glomerulonephritis

• following a bacterial infection, the immune system responds by producing antibodies to fight the bacteria

• immune complexes can circulate in the bloodstream and eventually get deposited in the glomeruli, particularly in the sub-epithelial space which can thicken the basement membrane

• sub-epithelial deposits

lupus glomerulonephritis

• the immune system attacks the glomeruli in the kidneys

• this immune response can cause inflammation and damage to the kidney tissue

• sub-endothelial deposits cause inflammation of the glomeruli

IgA nephropathy

• mesangial deposits

• mesangial deposits refer to the accumulation of substances in the mesangium, particularly in the spaces around mesangial cells

• the immune system produces excessive amounts of immunoglobulin, leading to the formation of immune complexes in the mesangium

• the subsequent inflammation can lead to kidney damage over time

• nephritic

goodpasture’s syndrome

• autoimmune

• immune system mistakenly produces antibodies that bind to and attack the glomerular basement membrane (GBM), which can lead to kidney damage

nephritic disorders

• characterized by inflammation of the glomeruli

• only some proteinuria

• immune complex deposits: subendothelial or GBM

  • cellular inflammatory reaction

nephrotic disorders

• characterized by increased permeability of the glomerular filtration barrier, leading to significant proteinuria

  • an episode of infectious diseases, particularly the upper respiratory tract, is found as a triggering factor in almost half of cases, an allergic reaction in a third of cases and more rarely, an insect bite, vaccination, treatment psychological stress

  • immune complex deposits: epithelial

    • no cellular inflammatory reaction

endothelial cell dysfunction

• altered permeability results in albuminuria

  • disruption of fenestrated glomerular epithelium and glycocalyx

  • thickened basement membrane

  • hyalinosis: dysfunctional vessels

  • mesangial cell hypertrophy

  • mesangial cell extracellular matrix

loss of podocytes and dedifferentiation

• podocyte death via apoptosis

• hypertrophy of remaining podocytes

• dedifferentiation of remaining podocytes

• progressive thickening of the basement membrane

• overall, there is a alteration in podocyte function

  • podocytes normally determine what gets filtered in the nephron

  • proteinuria

hemodialysis

• a machine is used to filter waste products out of the blood, doing what healthy kidneys normally would do

• the default treatment for patients with end stage renal disease

• short-term goals correct electrolyte balance, metabolic acidosis, correct fluid state, and remove toxins

• long term goals optimize the patients’ functional status, control BP, prevent uremia, and improve survival

• usually performed at a dialysis center three times per week for 3-4 hours

how hemodialysis functions

• uses a semipermeable membrane to filter waste products from blood

• soluble movement by diffusion down concentration gradient causing blood solute concentration to fall

  • wastes are diluted into dialysate

  • dialysate flows in the opposite direction to blood flow

  • dialysate is discarded

peritoneal dialysis (PD)

• a part of the abdomen called the peritoneum is used to filter waste out of the blood internally

• can be done at home

• the peritoneal cavity is filled with diasylate

  • waste products diffuse into dialysate through the mesentery

  • dialysate stays in the abdominal cavity

  • the dialysate is removed and discarded

  • change dialysate 4 times a day

side effects of dialysis

• low blood pressure

• taking on extra fluids between treatment

• heart disease

• nausea and vomiting

• dry or itchy skin due to high phosphorus

• restless leg syndrome

• muscle cramps