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HSS 3505 (2)
Lecture 11

HSS3505 Lecture 11: Patho – Renal Physiology

by OneClass1379467 , Fall 2016
19 Pages
86 Views
Fall 2016

Department
Health Sciences
Course Code
HSS 3505
Professor
Karen Phillips
Lecture
11

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Patho Renal Physiology (11)
How important is the kidney?
- Fluid regulation
o Blood pressure
o Cardiovascular output
o Imbalances
Congestive heart failure
Pneuomonia
Edema
o Acid/base balance
o Waste elimination
o Drug excretion pharmacology
Kidney Structure
- inner medulla and outer cortex
- nephrons: functional units located in renal cortex:
o renal corpuscle: filtering unit with glomerulus and glomerular capsule
o renal tubule: proximal convulated tubule, loop of henle, distal convulated
tubule
Renal Physiology
- urine production promotes homeostasis by regulating volume and composition of
blood
- three organic waste products:
o urea: most abundant waste
o creatinine: produced in skeletal muscle tissue
o uric acid: formed by recycling nitrogenous base from RNA molecules
Urine Formation
- kidneys return filtered fluid to internal environment through tubular reabsorption
- waste products are excreted in urine
- tubular secretion removes hydrogen ions and toxins faster than through filtration
Renal Disease
Congenital
o horseshoe kidney
o polycystic kidney disease
wilms tumor
Acquired
o Diabetic nephropathy
o Glomerulonephritis
o Kidney stones
o Kidney tumors
Wilms tumor
Renal cell carcinoma
o Pyelonephritis
o Renal failure
Acute renal failure
Chronic renal failure
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Congenital: Horseshoe Kidney
- affecting about 1 in 400 people
- in which a person’s two kidneys fuse together to form a horshoe-shape during
development in the womb
- complications-kidney stones, urinary tract infections
- often asymptomatic and discovered at autopsy
Congenital: Polycystic Kidney Disease
- progressive, genetic disorder
- characterized by the prescence of multiple cysts in both kidneys
- can also damage the liver, pancreas, rarely heart and brain
- autosomal dominant polycystic kidney disease (ADPKD) is generally a late-
onset disorder characterized by progressive cyst development and bilaterally
enlarged kidneys with multiple cysts. End stage renal failure (50%)
- autosomal recessive polycystic kidney disease (ARPKD) is much rarer than
ADPKD and is often fatal in utero or during the first month of life
Autosomal dominant polycystic kidney disease (ADPKD)
- mutations in PKD1 (85% cases) polycystin-1 (PC1) protein
- mutations in PKD2 (15%) polycystin -2 (PC2) protein
- transmembrane glycoproteins involved in Ca2+ signalling
- polycystins co-localize with fibrocystin at the primary cilia of renal epithelial
cells
- decreased Ca2 levels/signaling pathways subsequent accumulation of cAMP
- dysregulation of CFTR cl-channel involved in the formation of cysts
- increased cell proliferation and apoptosis
Autosomal recessive polycystic kidney disease (ARPKD)
- Approximately 30% of affected infants die in the neonatal period or within the
first year of life
- More than 50% of affected children progress to end-stage renal disease, usually in
the first decade of life
- Mutations in PKHD1
o Encodes fibrocystin (FC)
Mechanism Cyst Formation
- Disruption of the polycystin (PC) /fibrocystin (FC) pathway decreased Ca2+
levels
o stimulate adenylate cyclase (AC)
o inhibit phosphodiesterase (PDE) increased cAMP levels/PKA pathway
- activation of protein kinase A (PKA) stimulates cell proliferation by MAPK
pathway
- in polycystic kidney disease, cAMP-PKA signaling increases the permeability and
expression of CFTR Cl channels
o Cl effux from cell
o increases Na+ efflux from cell
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find more resources at oneclass.com
- water moves from cell into the lumen of the cyst
Diabetic Nephropathy
- progressive kidney disease caused by angiopathy of capillaries in the kidney
glomeruli
- characterized by nephrotic syndrome (protein in urine) and nodular
glomerulosclerosis (hardening of glomerulus)
- due to longstanding diabetes mellitus, and is a prime cause for dialysis in many
western countries
Glomerulonephritis
- inflammation of renal glomeruli caused by antigen-antibody reaction within
glomerular capillaries
- interaction of antigen-antibody activates complement and liberates mediators that
attract neutrophils
- actual glomerular injury is caused by destructive lysosomal enzymes that are
released from the leukocytes that have accumulated within the glomeruli
Kidney Stones
- also called renal calculi, are solid concretions (crystan aggregations) of dissolved
minerals in urine
- calculi typically form inside the kidneys or bladder
- nephrolithiasis: presence of calculi in kidneys
- urolithiasis: presence of calculi in the urinary tract
- obstruction with dilation or stretching of the upper ureter and renal pelvis
- spasm of muscle, severe episodic pain, most commonly felt in the flank, lower
abdomen and groin upon attempts to pass stone (urination)
- hematuria (bloody urine) is commonly present due to damage to the lining of the
urinary tract
- recurrence rates are estimated at about 10% a year, men are affected
approximately 4 times more often than women
- causes related to metabolic syndromes
Kidney Tumors: Wilms Tumor
- wilm’s tumor or nephroblastoma is a tumor of the kidneys that typically occurs in
children, rarely in adults
- treatment-removal of tumor/kidney
- Genetics:
- Mutations in WT1
o Wilms tumor protein
o Transcription factor
o Interactions with p53
Epigenetic/genomic alterations
Chromosome 11, 17, 19, chromosome x
Kidney Tumor Renal Cell Carcinoma
- renal cell carcinoma (RCC) is the most common form of kidney cancer
- collection of different types of tumors, each derived from various parts of the
nephron (epithelium or renal tubules)
o clear cell renal carcinoma (CCRCC)
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Description
Patho – Renal Physiology (11) How important is the kidney? - Fluid regulation o Blood pressure o Cardiovascular output o Imbalances  Congestive heart failure  Pneuomonia  Edema o Acid/base balance o Waste elimination o Drug excretion – pharmacology Kidney Structure - inner medulla and outer cortex - nephrons: functional units located in renal cortex: o renal corpuscle: filtering unit with glomerulus and glomerular capsule o renal tubule: proximal convulated tubule, loop of henle, distal convulated tubule Renal Physiology - urine production promotes homeostasis by regulating volume and composition of blood - three organic waste products: o urea: most abundant waste o creatinine: produced in skeletal muscle tissue o uric acid: formed by recycling nitrogenous base from RNA molecules Urine Formation - kidneys return filtered fluid to internal environment through tubular reabsorption - waste products are excreted in urine - tubular secretion removes hydrogen ions and toxins faster than through filtration Renal Disease Congenital o horseshoe kidney o polycystic kidney disease  wilms tumor Acquired o Diabetic nephropathy o Glomerulonephritis o Kidney stones o Kidney tumors  Wilms tumor  Renal cell carcinoma o Pyelonephritis o Renal failure  Acute renal failure  Chronic renal failure Congenital: Horseshoe Kidney - affecting about 1 in 400 people - in which a person’s two kidneys fuse together to form a horshoe-shape during development in the womb - complications-kidney stones, urinary tract infections - often asymptomatic and discovered at autopsy Congenital: Polycystic Kidney Disease - progressive, genetic disorder - characterized by the prescence of multiple cysts in both kidneys - can also damage the liver, pancreas, rarely heart and brain - autosomal dominant polycystic kidney disease (ADPKD) is generally a late- onset disorder characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts. End stage renal failure (50%) - autosomal recessive polycystic kidney disease (ARPKD) is much rarer than ADPKD and is often fatal in utero or during the first month of life Autosomal dominant polycystic kidney disease (ADPKD) - mutations in PKD1 (85% cases) – polycystin-1 (PC1) protein - mutations in PKD2 (15%) – polycystin -2 (PC2) protein - transmembrane glycoproteins – involved in Ca2+ signalling - polycystins co-localize with fibrocystin at the primary cilia of renal epithelial cells - decreased Ca2 levels/signaling pathways  subsequent accumulation of cAMP - dysregulation of CFTR cl-channel involved in the formation of cysts - increased cell proliferation and apoptosis Autosomal recessive polycystic kidney disease (ARPKD) - Approximately 30% of affected infants die in the neonatal period or within the first year of life - More than 50% of affected children progress to end-stage renal disease, usually in the first decade of life - Mutations in PKHD1 o Encodes fibrocystin (FC) Mechanism – Cyst Formation - Disruption of the polycystin (PC) /fibrocystin (FC) pathway decreased Ca 2+ levels o stimulate adenylate cyclase (AC) o inhibit phosphodiesterase (PDE) increased cAMP levels/PKA pathway - activation of protein kinase A (PKA) stimulates cell proliferation by MAPK pathway - in polycystic kidney disease, cAMP-PKA signaling increases the permeability and expression of CFTR Cl channels o Cl effux from cell o increases Na+ efflux from cell - water moves from cell into the lumen of the cyst Diabetic Nephropathy - progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli - characterized by nephrotic syndrome (protein in urine) and nodular glomerulosclerosis (hardening of glomerulus) - due to longstanding diabetes mellitus, and is a prime cause for dialysis in many western countries Glomerulonephritis - inflammation of renal glomeruli caused by antigen-antibody reaction within glomerular capillaries - interaction of antigen-antibody activates complement and liberates mediators that attract neutrophils - actual glomerular injury is caused by destructive lysosomal enzymes that are released from the leukocytes that have accumulated within the glomeruli Kidney Stones - also called renal calculi, are solid concretions (crystan aggregations) of dissolved minerals in urine - calculi typically form inside the kidneys or bladder - nephrolithiasis: presence of calculi in kidneys - urolithiasis: presence of calculi in the urinary tract - obstruction with dilation or stretching of the upper ureter and renal pelvis - spasm of muscle, severe episodic pain, most commonly felt in the flank, lower abdomen and groin upon attempts to pass stone (urination) - hematuria (bloody urine) is commonly present due to damage to the lining of the urinary tract - recurrence rates are estimated at about 10% a year, men are affected approximately 4 times more often than women - causes related to metabolic syndromes Kidney Tumors: Wilms Tumor - wilm’s tumor or nephroblastoma is a tumor of the kidneys that typically occurs in children, rarely in adults - treatment-removal of tumor/kidney - Genetics: - Mutations in WT1 o Wilms tumor protein o Transcription factor o Interactions with p53 Epigenetic/genomic alterations  Chromosome 11, 17, 19, chromosome x Kidney Tumor – Renal Cell Carcinoma - renal cell carcinoma (RCC) is the most common form of kidney cancer - collection of different types of tumors, each derived from various parts of the nephron (epithelium or renal tubules) o clear cell renal carcinoma (CCRCC) o mutations in VHL, PBRM1, SETD2, BAP1 – all genes located on 3p (21,25) o most common type of kidney cancer in adults o resistant to radiation therapy, chemotherapy Pyelonephritis - ascending urinary tract infection that has reached the renal pelvis - if the infection is severe, the term “urosepsis” is used interchargeably - requires antibiotic as therapy and treatment of any underlying causes or prevent recurrence - form of nephritis, may also be called pyelitis - extensive destruction of renal parenchyma due to a long-standing suppurative inflammation. The depression seen in the lower half of the specimen were caused by a staghorn calculus which has been removed Renal Failure - kidneys fail to function adequately - acute and chronic forms - detected by an elevated serum creatinine - decrease in the glomerular filtration rate (GFR) - problems frequently encountered are abnormal fluid levels in the body, deranged acid levels, abnormal levels of potassium, calcium, phosphate, hematuria (blood in the urine) and (in the longer term) anemia Acute Renal Failure - rapidly progressive loss of renal function, generally characterized by oliguria (decreased urine production) - quantified as less than 400mL per day in adults, less than 0.5mL/kg/h in children or less than 1 mL/kg/h in infants - body waters and body fluid disturbances - electrolyte derangement - pre-renal (causes in the blood supply): o hypovolemia (decreased blood volume) usually from shock or dehydration and fluid loss or excessive diuretics use o vascular problems, such as atheroembolic disease and renal vein thrombosis (which can occur as a complication of the nephrotic syndrome) - post-renal (obstructive causes in the urinary tract) due to: o medication interfering with normal bladder emptying o benign prostatic hypertrophy or prostate cancer o kidney stones o due to abdominal malignancy (eg ovarian cancer, colorectal cancer) o obstructed urinary catheter Causes 1. Prerenal - sudden and severe drop in blood pressure (shock) or interruption of blood flow to the kidneys from severe injury or illness 2. Intrarenal - direct damage to the kidneys by inflammation, toxins, drugs, infection, or reduced blood supply 3. Postrenal - sudden obstruction of urine flow due to enlargened prostate, kidney stones, bladder tumor, injury Chronic - progressive loss of renal function over a period of months or years through five stages - each stage is a progression through an abnormally low and deteriorating glomerular filtration rate, which is usually determined indirectly by the creatine level in blood serum Stages of Chronic Kidney Failure Stage 1 CKD: slightly diminished function; kidney damage with normal or increased GFR (>90mL/min/1.73m^2) Stage 2 CKD: Mild reduction in GFR (60-89 mL/min/1.73 m ) with kidney damage 2 Stage 3 CKD: Moderate reduction in GFR (30-59 mL/min/1.73 m ) Stage 4 CKD: Severe reduction in GFR (15-29 mL/min/1.73 m2) Stage 5 CKD: Established kidney failure (GFR <15 mL/min/1.73 m , or permanent renal replacement therapy (RRT) Causes of CKD - diabetic nephropathy - hypertension - glomerulonephritis -  together, these cause approximately 75% of all adult cases Treatment - goal of therapy is to slow down or halt the otherwise relentless progression of CKD to stage 5 - control of blood pressure and treatment of the original disease Renal Replacement Therapy (RRT) - encompass life-supporting treatments for renal failure - includes: o hemodialysis o peritoneal dialysis o hemofiltration and o renal transplantation - these treatments do not cure chronic kidney disease; they are palliative treatments Hemodialysis - method of removing waste products such as potassium and urea, as well as free water from the blood when the kidneys are in renal failure - can be an outpatient or inpatient therapy - routine hemodialysis is conducted in a dialysis outpatient facility Renal Transplantation - organ transplant of a kidney in a patient with end-stage renal disease - typically classified as deceased donor (formerly known as cadaveric) or living donor transplantation depending on the source of the recipient organ - kidney is the easiest organ to easily remove and implant - tissue typing relatively simple - live donors can be used without difficulty - in the event of failure, kidney dialysis has been available since 1940s - diabetes is the most common cause of kidney transplant, accounting for approximately 25% of those in the US - majority of renal transplant recipients are on some form of dialysis at time of transplant Patho Research Methods – Lecture 12 Experimental Approaches in Pathophysiology Use of animal in research - ethics - mouse models, generational studies, behavioural studies, lifespan studies Morphology and Anatomy - imaging, gross pathology, microscopy, histology Cell/Tissue Culture Molecular Biology - omics Forensic Science The Body Farm Why use animals for research? - animals serve as good models to help us understand how living tissues function and the biology underlying disease o the interaction of cells, tissues and organs within the body is very complex, and can often only be studied in the whole animal o physiological systems and pathophysiological processes - only by understanding how disease or injuries affect living organisms can we develop treatments or cures - animal models used to: o help researchers understand the fundamental ways in which diseases affect living tissue o develop and test treatments for illness or injury o train future scientists and physicians - we also study animals to learn more about animals - biodiversity, animal behaviour, veterinary medicine, reproduction Cant Computer Models and Cell Cultures Replace Animal Research? - computer models and cell cultures are good for screening and are used frequently - such models cannot replicate complicated interactions in the whole system - final testing depends on studies in animals; sometimes it is required by law - animal and non-animal models used in conjunction achieve the best answer Can Results from Animal Studies Really Be Applied to Humans? - there are many similarities between animals and humans. Examples include: o immune function in mice o cardiovascular function in dogs - animals provide index of safety o Nuremberg Code mandates that animal studies precede and support human studies o Declaration of Helsinki mandates that medical research on humans must be supported by preceding animal research - Nearly all medical advances of the past century started with research in animals Canadian Council on Animal Care (CCAC) - national peer-review organization responsible for setting, maintaining and overseeing the implementation of high standards for animal ethics and care in science throughout Canada - CCAC has developed guidelines for the care and use of experimental animals and has also established assessment panels to oversee the use of animals in universities, government laboratories, and commercial labs The Three Rs - widely accepted internationally as the ethic of animal experimentation - Replace: avoid or replace the use of animals wherever possible - Reduce: employ strategies that will result in fewer animals being used and which are consistent with sound experimental design - Refine: modify husbandry or experimental procedures to minimize pain and distress Animal Research Ethics - animal care committees o each university, research institution o evaluate protocols on basis of  skill/training of animal users, pain control, numbers of animals used, endpoints - tricouncil grant agencies (CIHR, NSERC, SSHRC) o specific guidelines on animal/human research o must obtain ethics approval - university wont release grant funds without ethical approval Animal Care - housing considerations o animal behaviour o experimental conditions o animal welfare - enrichment o toys, things to chew, places to climb, hide - animal care staff o veterinarians  monitor health of all animals in facility o vet techs – cage changing, food, training of staff/students, research protocols, maintain facility Animal Models - non-human animal that has a disease or injury that is similar to a human condition - transgenic animal – created with genes absent or overexposed - animal model created by drugs/virus/pathogen/surgical manipulation - naturally occurring animal with a disease or genotype mimicking human relevant condition Why is the Mouse such a popular Animal Model? - genetically similarly to humans (95-98%) - can be genetically manipulated to mimic virtually any human disease or condition o Jackson laboratory maintains 7000+ genetically defined strains o Gain of function (transgenesis) o Loss of function (knock out) o Change of function (knock in) - can be inbred to yield genetically identically strains - accelerated lifespan, with one mouse year equaling about 30 human years; their entire life cycle can be studied within 2-3 years - been used in biomedical research for nearly a century; physiology well understood - cost-effective and efficient research tool o small, they reproduce quickly, and they are relatively easy to handle and transport Transgenic Animals - mutant animals carrying experimentally introduced foreign genetic elements in all their cells, including the germline o may be mice or other animals - knock out mouse: a transgenic mouse in which the normal gene is missing or engineered so that is not transcribed or translated. Knocks out that gene - knock in mouse: a transgenic mouse in which the engineered “transgene” is subtly manipulated to: - a) alter the function of the gene - b) change the transcription rate to overproduce/underproduce gene product - c) create a fluorescent gene product to map its distribution in tissue - conditional knock out (knock in) mouse: a transgenic mouse in which the transgene is knocked out (or in) in specific tissues, at a specific developmental stage or in response to an exogenous substance Mouse Genome - mammalian - 20 chromosomes - 2.6 gb - 25000 genes - 99% have human counterpart Lifespan or Generational Assays Mouse Life Cycle - 4-day oestrus - 20-day gestation - 4-8 pups per litter - 2-8 litters per female - 7 weeks to sexual maturity - 2-3 year lifespan Applications of transgenic mice - transgenic mice are often generated to address the role a gene plays in a biological process a the level of the whole organism: o to confirm the role of a gene mutation o to help unravel the molecular mechanisms that control gene expression o to help unravel the biochemical in vivo mechanisms and the origin of disease o to develop an animal model to test therapeutic strategies Imaging Techniques - real-time tracking disease progression - metabolism studies – uptake of labelled glucose for example
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