Unit 10: Diabetic Nephrogy Flashcards
What is the role of hyperglycemia in activating the immune system and what are the consequences of this in diabetic nephropathy?
Hyperglycemia - production of reactive oxygen species and activation of pathways such as protein kinase C and AGE.
Causes inflammation - characterised by immune cells, cytokines and chemokines, including TGFbeta, VEGF - leads to inflammation fibrosis and increased vascular permeability.
Causes podocytopathy and intraglomerular hypertension resulting in proteinuria.
Increase in fibroblasts and chronic tubular injury as epithelial-mesenchymal celll transformation triggers in tubules.
What is the pathophysiology/ mechanism underpinning type 1 diabetes?
Is a combination of genetic and environment risk factors.
T cells react against beta cell antigens (breach of tolerance).
Brings about a cellular response against the antigen - resulting in the destruction of pancreatic beta cells due to autoimmune mechanism and inflammation - leading to a loss or reduction in insulin levels.
What are the consequences of low insulin in type 1 diabetes on the cellular level?
GLUT 4 is an insulin-dependent - transporter - is not inserted into cell membrane so cells cannot take up glucose from blood stream
lack of glucose in adipose tissue decreases fat synthesis and increases fat breakdown - FA are released into the blood and oxidised to ketone bodies
Hyperglycaemia leads to symptoms of diabetes.
What are the different antibodies in type 1 diabetes?
Anti-GAD (precurdor for glutamic acid required for GABA which causes release of insulin)
Anti- inslet cell antibodies
Anti-insulin antibodies
What are some of the genetic predispositions to type 1 diabetes?
Failure in maturation of T cells - results in escape of self reacting T cell - APECED
Mutation in HLA gene so better presents beta cell antigen to T cell (HLA-DQ and HLA-DR)
What are some hypothesised environmental triggers to type 1 diabetes?
Molecular mimicry - cross reactivity between forien antigen and beta cell antigen
Virus, toxin or repeated stress on the beta cells - results in crytpic antigen release - causing autoimmunity.
What are the key clinical presentations of T1DM?
Polyuria
Polydipsia (increased thirst)
Polyphagia
Weight Loss
Lethargic and Fatigue
Blurry visions
Nocturia
25% - Diabetic keotacidosis - vomittting and in severe cases coma.
Severe cases - altered mental status and deep and laboured breathing
What is the pathogenesis of type 2 diabetes mellitus?
Combination of genetic and life style risks - including obesity and inactivity
Increased levels of intraperitoneal visceral fat
Fat as an endocrine organ secretes Inflammatory markers, adipokines and free fatty acids
Complex mechanism can increase insulin resistance - beta cells respond to counteract this by increasing more insulin
Overtime, FFAs also inhibit GLUT2 on Beta cells so reduce glucose import, so unable to response to high blood glucose so reduced insulin secretion, become fatigued as insulin resistance increases - this leads to relative insulin deficiency and eventually absolute insulin deficiency - these patients present with hyperglycemia.
However, cant utilise blood glucose triggers physiological response observed in starvation - can cause diabetic ketoacidosis.
What are some risk factors for type 2 diabetes?
Age - older individuals beta cell mass declines so predisposed to insulin resistance as remaining beta cells become fatigued
Medications - corticosteroids, anti-psychotics and progestine only oral contraceptives
Obesity, lack of exercise, fatty diet
Genetic - high risk if first degree family relative
Gestational diabetes or given birth to a baby over 9 pounds
Are African American, hispanic or latina.
What are the common clinical presentations of type 2 diabetes?
Polyuria - nocturia
Fatigue
Polydipsia
Weight loss
Blurred vision
Ithciness around the genital area or regular bouts of thrush
Slow to heal cuts or ulcers
What are the microvascular complications of type 2 diabetes?
Retinopathy - blurred vision, risk of cataracts and glucoma, hyperglycemia causes damage to small blood vessels at the back of the eye - cause vision loss
Nephropathy - characterised by albuminuria across all stages, early GFR is elevated then progressively declines - riske of renal osteodystrophy, low calcium, high phosphate, high PTH, low VitD
Peripheral neuropathy - loss of sensation particularly in hands and feet, gangrenes and infected foot wounds due to damage to peripheral nerve and the supply blood vessels from hyperglycemia.
What are the macrovascular complications of type 2 diabetes?
Brain - increased risk of stroke, TIA and cognitive impairment
Heart - increase risk of coronary artery disease
Lower limb problems - peripheral vascular disease, narrowing of blood vessels - reduce blood flow to feet can result in slow healing feet wounds.
Main underlying factor - is causative of atherosclerosis due to hyperglycemia
Describe the micturition reflex when not urinating?
Not urinating - detrusor is relaxed (stimulated by sympathetic lumbar splanchnic nerve via hypogastric plexus and pelvic nerve NA at beta 3 receptors), internal urethral sphincter is contracted (sympathetic activation by NA alpha 1 receptors),
external urethera sphincter is contracted and the pelvic flood muscle maintain continence (stimulation of pudendal nerve S2,3,4)
Describe the micturition reflex when urinating
urination - bladder has filled, stretch receptors are activated and can relay to the spinal cord and brain. Activates the spinobulbospinal reflex
Parasympathetic pelvic nerve (ACh) causes contraction of the detrusor muscle, relaxation of the internal urethral sphincter parasympathetic, relaxation of the external urethra sphincter (pudendal nerve inhibition)
Parasympathetic - cause peristaltic contraction of smooth muscle in the urethra cause urination.
May be aided by valsalva manoeuvre to increase intrabdominal pressure.
What is meant by glycated haemoglobin?
Slow non-enzymatic covalent attachement of glucose to haemoglobin
What is the use of Hb1Ac blood test?
Uses levels of Glycated haemoglobin accepted as the international standard method for assessing glycemic control over the course of 3 months (or 120 days - is reflective of the life span of the rbc) and reflects.
Hyperglycemia causes Hb1Ac to increase - reflect previous three months, but one month before has the greatest effect on result
is directly proportional to ambient blood glucose concentration.
How to interpret HbA1C results?
A rise of 11mmol/mol in HbA1c is equivalent to a rise of 2mmol/L of blood glucose
Normal is below 42mmol/mol or 6%
Pre-diabetes is 42 to 47 or 6-6.4%
Diabetes is 48mmol/mol of over 6.5% or over
What factors can make Hb1Ac results inaccurate?
Factors that affect red blood cell lifespan
Low when low rbcs lifespan - sickle cell anemia, thalassemia
High when high rbcs life span - pernicous anemia, folate deficiency.
What is eGFR and how is it measured?
Is the flow of substance from blood from the glomerulus into the Bowman space over a specified period of time - rate of blood flow through the kidney.
Assessment of renal function
Estimated using renal markers such as creatinine (endogenous) CysC(endogenous) and inulin.
This is because we can predict the level that should be found in the blood and compare this to the level there actually is - hence determine the level of excretion from the kidney
What equations are commonly used when calcuating GFR?
Children: schwarts equation
Adults: Cockcroft-gualt equation
MDRD study equation
CKD_EPI equation
How does eGFR relate to the stage of kidney failure?
Stage 1 - Normal or high is above 90
Stage 2 - Mildly decreases 60-89
Stage 3a - 45-59ml/min
Stage 3b - 30 to 44
Stage 4 - 29-15
Stage 5 - below 15
Unit - ml/min
What is creatinine clearance?
How can it be used to estimate renal function?
The volume of blood plasma cleared of creatinine per unit of time
Used as value of renal function as can estimate the level of creatinine that should be present in the blood and urine - hence can compare to actual value.
What is the difference between creatinine clearance and eGFR?**
Creatinine clearance - creatinine specific - results can be skewed by other pathologies such as muscle damage - must be accounted for.
Creatinine clearance tend to be higher than eGFR particularly as eGFR declines.
GFR is preferred in clinical practice because it is easier to measure as creatinine clearance requires 24-hour urine collection.
What is the use of the albumin:Creatinine ratio to test for renal dysfunction?
Albumin is not normally found in the urine, creatinine is usually found in the urine.
If albumin is elevated indicates proteinuria - a sign of podocyte dysfunction indicative of damage to the filtration barrier
Hig value - indicates renal pathology - most often due to diabetes mellitus
Should be tested at diagnosis with DM and annually from then onwards