Week 6 Flashcards
Functions of the kidneys
Homeostasis:
-water/fluid
-electrolytes
-acid-base
-blood pressure
-elimination of waste
-excretion of drugs and drug metabolites
Metabolic/endocrine:
-synthesis of hormones
— vitamin D
— erythropoietin
—renin
Measurement of glomerular filtration rate
Gold standards but not used clinically
Exogenous filtration markers:
-e.g inulin, 51Cr-EDTA
-require injection or infusion
-require multiple sample collection
-cumbersome, intrusive
Endogenous filtration markers:
-eg urinary clearance of creatinine
-requires accurate timed urine collection and matched serum sample
-cumbersome and error prone
Only used rarely for specific purposes when clinical decisions depend on accurate knowledge of GFR
Estimation of GFR from serum creatinine
Creatinine from breakdown of muscle and gets cleared by kidneys
Limitation 1:
-Non linear relationship between serum creatinine and GFR. Small changes in serum creatinine value can mean large changes in GFR
Non renal determinants of serum creatinine include:
-age
-sex
-ethnicity
-body habitus
-diet
Limitation 2:
-creatinine is an end product of muscle turnover, creatinine generation is proportional to muscle mass
-creatinine can also be derived from dietary meat or creatinine supplements
Quantification of proteinuria
Injured, inflamed or damaged glomerulus/kidneys will leak protein
Bad prognostic factor in terms of progression of cKD, increase risk CVD and mortality
Concentration of any analyte in urine is heavily influenced by concentration or urine
Measure total amount: protein excretion in 24 hrs urine sample
Measure ratio to reference analyte (known conc.): protein:creatinine ratio or albumin:creatinine ratio to estimate protein in urine
Definition of chronic kidney disease
CKD is defined as abnormalities of kidney structure or function, present for> 3 months with implications for health
Albuminuria
Urine sediment abnormalities- blood or RBC casts
Structural abnormalities etc
Decreased GFR
Classification of CKD
Stage 1: normal kidney function GFR>90ml/min but proteinuria or blood etc
When estimating GFR with creatinine cant go up to 120 as EGFR increases confidence of measurement decreases
Moderate stage 3A 3B- CKD with reduced renal function
Severe stage 5 GFR<15
Irreversible loss of renal filtration function (loss of nephrons)
Progressive loss of renal filtration function if untreated irreversible damage
Stage 5 CKD end stage renal failure
Insufficient renal function to sustain life/health
Haemodialysis, peritoneal dialysis
Kidney transplantation
Death
Relative risks for adverse outcomes
Knowing if someone has proteinuria helps determine the cause
Helps narrow down investigations and find cause CKD, do biopsy because we’re looking to see the type of inflammatory disease so can treat appropriately
Proteinuria increases rate at which CKD progresses
Who has renal disease
Common with Uk population
Significant proportion unrecognised
Important risk factors are:
-age
-social deprivation
-black or south Asian ethnicity
-hypertension
-diabetes
-smoking
Causes of CKD
Diabetes- diabetic kidney disease
Hypertension/ischaemic
Glomerulonephritis
Genetic
Other
Diabetic nephropathy
Diabetic kidney disease
Renal disease occur 40% patients with type I and 2 diabetes
40% patients with ESRF in US and 20% in Europe
Associated with poor diabetes control and hypertension
Characterised by proteinuria
Correlation with diabetic retinopathy
If you have microvascular disease elsewhere likely to get it in kidneys
Pathology of diabetic nephropathy
Thickening of basement membrane
Mesangial expansion . Get collagen deposits and fibrosis
-hyperglycaemia stimulates increased matrix production by mesangial cells
-stimulation of TGF-beta release
Glomerulosclerosis due to intraglomerular hypertension or ischaemic damage
Hyperglycaemia causes vasodilation of afferent arterioles increasing glomerular pressure (so people with diabetic KD at first hyperfiltrate slight increase in GFR) then causes damage with time starts to develop proteinuria and reduce kidney function
Natural history of diabetic nephropathy
Onset of diabetes:
-increased GFR
-reversible albuminuria
-increased kidney size
After ~5 years :
-increased glomerular basement membrane thickness
-mesangial expansion
Mircoalbuminuria and rising blood pressure
11-23 years: onset proteinuria
13-25 years: rising serum creatinine
15-27 years: ESRF
Inevitable decline in renal function over 7-10 years
Treatment diabetic nephropathy
Treat underlying cause: good blood sugar control (diet and medications)
Reduce proteinuria: ACE inhibition and SGLT2 inhibitor
Limit cardiovascular risk: control blood pressure, treat hyperlipidaemia stop smoking etc
Hypertensive nephropathy
Vascular remodelling (atherosclerosis, intimal thickening) leading to narrowing of blood vessels and glomerular ischaemia
Glomerular hypertension causing injury and sclerosis over prolonged periods
Progressive kidney disease, progressive fibrosis
Thickened intima
Segmented sclerosis scarring glomeruli more lesions, more scarring nephrons, lose functional nephrons progressive CKD
Renovascular disease
Because of atherosclerosis can disrupt blood supply to kidneys
Renal artery stenosis
Likely to have hypertension and CVD cKD due to other reasons as well
Glomerulonephritis
Immune mediated injury to glomeruli
Characteristic changes in kidney histology and immunohistochemistry
Typically blood and/or protein in urine
Immunocomplex formation and deposition in glomeruli that causes damage
Many different disease processes:
-e.g IgA nephropathy (most common)
-can be associated with infection (e.g streptococcus, HIV)
-can be part of systemic disease process (e.g systemic lupus erythematosus, vasculitis)
Autosomal dominant polycystic kidneys
Most common genetic cause
Autosomal dominant most common manifests in adulthood
There are recessive forms too that manifest in childhood
Large cysts, large kidneys, very painful. Cysts can rupture- painful can cause haematuria
Loss nephrons due to cysts displacing functional tissue
Affects ~1 in 1000 people
Other causes of CKD
-Medications (NSAIDs, chemotherapy, others)
-recurrent urinary tract infection
-urinary outflow obstruction- common, benign hyperplasia
-trauma uncommon
-interstitial nephritis
-recurrent/persistent acute kidney injury
Complications related to CKD
Increased mortality, cardiovascular disease and hypertension. Altered drug handling
Anaemia, vitamin D, phosphate and parathyroid disturbance
Acidosis, hyperkalaemia
Fluid retention, uraemia
Cardiovascular risk in CKD
Traditional risks: diabetes, hypertension, dyslipidaemia, smoking
Non classical risks: endothelial dysfunction, inflammation, oxidative stress, catabolic state
CKD-related risks: fluid retention, anaemia, hyperparathyroidism, vascular calcification
Hypertension
Multiple mechanisms:
-sodium retention
-volume expansion
-renin-angiotensin-system activation
-sympathetic nervous system activation
-endothelial dysfunction
Accelerates decline of kidney function
Contributes to cardiovascular risk (stroke, myocardial infarction, heart failure)
Management:
-moderate salt intake
-RAS blockade
-diuretics
-other anti-hypertensive medications
Vitamin D, calcium and parathyroid hormone in renal failure
Vitamin D not activated in kidneys
So serum calcium not increased
Constant secretion of PTH and bone resorption
Cycle repeats not corrected autonomous production PTH by parathyroid glands. Secondary and tertiary hyperparathyroidism
Major risk factor for calcium deposition in blood vessels
Renal bone disease
Brown tumour
Rugger jersey spine
Ectopic calcification
Calcium depositions in blood vessels
Risk factor of CVD
How to manage mineral bone disease
Correct global vitamin D deficiency if present (colecalciferol, ergocalciferol)
Supplement activated vitamin D (Alfacalcidol, calcitriol)
Control high phosphate levels (dietary restriction, phosphate binders)
Offer calcimimetics -stop producing PTH
Last resort: parathyroidectomy
Anaemia
Impact:
-impaired quality of life
—reduced exercise capacity
—impaired cognition
-increase risk of left ventricular hypertrophy
-increase CV disease in patients with CKD and anaemia vs those with CKD without anaemia
Management:
-correct iron deficiency if present, helps RBC production
-recombinant erythropoietin: supplement what kidneys cant produce stimulate bone marrow to produce RBCs
Bicarbonate- carbonic acid buffer system
PH= pK+logHCO3-/H2CO3-
With progressive kidney disease you fail to excrete H+, reabsorb serum HCO3- and metabolic acidosis
Increase CO2 removed by lungs to maintain pH
Metabolic acidosis
Impact:
-increased respiratory rate
-acute-life threatening metabolic dysfunction
-chronic- loss of bone and muscle mass
Management :
- sodium bicarbonate
-dialysis (or transplantation)
Hyperkalaemia
Enormous functional reserve to excrete potassium
Severe hyperkalaemia when GFR<10ml.min
Due to:
-excessive load
-interference with potassium excretion
— acidosis with volume contraction
— diabetic nephropathy
Alterations in membrane excitability
Cardiac arrhythmias
ECG changes:
-tall T waves
- long QRS interval
-long PR interval
-cardiac arrest
How to manage hyperkalaemia
Input side:
-dietary potassium restriction
-potassium binders- dont use in clinical practice
Output side:
-dialysis (or transplantation)
Determinants on when to start:
-how patient feels- degree of uremia
-losing weight, vomiting etc
-EGFR<10ml/min
Sodium and fluid retention
Loss of nephrons reduces ability to excrete salt and water
Major cause of hypertension and fluid overload
Sodium must be within normal range for normal neurological function
High or low sodium leads to confusion, fits and coma
Failure of fluid homeostasis
Inability to concentrate urine (early):
-loss of diurnal rhythm of urine excretion
Inability to excrete water load:
-dilutional hyponatraemia
-oedema- pitting oedema, painful
-hypertension
How to manage fluid overload
Input side:
-salt restriction
-fluid restriction
Output side:
-diuretics
-dialysis or transplant
Uraemia- accumulation of metabolic waste products
Accumulation of toxic waste products:
-retention nitrogenous waste (urea)
-numerous other known and unknown compounds (urate, phosphate, TNF-alpha, IL-6, p-crestless sulfate, beta2-microglobulin)
Life threatening consequences of uraemia:
-encephalopathy- metabolic flap- asterixis
-pericarditis- cardiac tamponade
Retention of drugs and drug metabolites
Many drugs metabolised and or excreted by the kidney
Consequences of impaired renal clearance:
-prolonged duration of action
-toxicity from high drug levels
Insulin-> hypoglycaemia
Opiates-> reduced consciousness and respiratory arrest
Antibiotics-> encephalopathy
Lithium-> vomiting, tremors, confusion
Digoxin-> arrhythmia
Acute kidney injury
Sudden deterioration in kidney function
Timing: hours, days, weeks has to be less than 3 months
Spectrum: mild drop in renal function to complete loss of kidney function (kidney failure)
May result in failure to maintain, fluid , electrolyte and acid base balance
Formerly known as acute renal failure
Differentiate from cKD
AKI staging
Stage 1: creatinine >26umol/L in 48 hours. Urine output <0.5ml/kg for >6 hrs
Stage 2: 100-200% increase creatinine. Urine < 0.5 for >12 hrs
Stage 3: >200% increase >357 creatinine. Urine <0.3ml/kg >24 hrs or Anuria for 12 hours. Needs dialysis
How common is acute kidney injury
AKI is present in: up to 1 in 5 emergency admissions into hospital have or develop AKI
The incidence is increasing: improved detection, electronic alerts, increasing elderly population who are at risk
Cost of AKI: accounts for 1 billion/year, 1% of NHS budget
Impact and importance
100000 deaths in hospital per year associated with AKI
~ 20% of these deaths could potentially be prevented with appropriate treatment and care
1 in 5 emergency admissions has AKI
Community acquired versus hospital acquired
Associated with very high mortality
AKI causes chronic kidney disease
Patients with AKI are more likely to develop ESRD
Patients with AKI and CKD are even more likely to develop ESRD
Risk factors for AKI
Age> 65 years
History of:
-chronic kidney disease
-diabetes
-heart failure
-liver disease
Reliance on other for fluid intake
Context:
-sepsis
-hypovolaemia
-hypotension
-dehydration
-reduce fluid intake
Drugs:
-diuretics, ACE inhibitors/ARBs, blood pressure medication, metformin, NSAIDs, gentamicin, acyclovir, contrast
Causes of AKI
Pre-renal: perfusion failure
Intrinsic: intrinsic disease of the kidney
Post-renal: obstruction of urinary system
Pre-Renal causes
Hypovolaemia: eg dehydration, gastrointestinal losses, haemorrhage, burns
Hypotension: eg sepsis
Renal artery occlusion
Hypervolaemic states associated with reduced renal perfusion: heart failure, liver failure
Drugs that reduce BP, circulating volume or renal blood flow e.g ACE inhibitors, NSAIDs, diuretics, antihypertensives
Renal autoregulation
Afferent and efferent arteriole vasoconstrict and vasodilate controlling flow through kidney
Perfusion failure
Low BP and low blood volume kidney responds by afferent dilation good perfusion and urine production
But if very low BP and very low blood volume, very low renal perfusion and very low urine production= pre renal failure/ perfusion failure
In context of low blood pressure due to ACE/ARB block renin angiotensin system RAS blockade, lose afferent dilation and efferent constriction, low blood flow, cant perfuse glomerulus properly, lack of urine production
Treatment of perfusion failure
Restore tissue perfusion:
-fluid volume replacement
—blood, IV fluids
-blood pressure support (inotropic drugs)
-restore arterial patency
-stop exacerbating drugs
—RAS blockade
—stop NSAID
Obstruction POST renal
Benign prostatic hypertrophy most common
Tumours:
-intrinsic eg bladder, ureter
-extrinsic e.g prostate, cervix
Fibrosis
Stones- rare to have bilateral so not most common
Treating obstruction- unblocking the pipes
Nephrostomy
Bladder catheter
Urinary stent
Renal causes
Diseases that damage the tubules, interstitium, glomeruli
-acute tubular necrosis most common
-acute interstitial nephritis
-drugs: antibiotics, NSAID, chemotherapy
-infection: HIV, hepatitis B/C, post-streptococcal, endocarditis, COVID-19
-systemic disease: vasculitis, lupus, myeloma
-glomerulonephritis (blood an or protein present on urine dipstick)
Nephrotic syndrome
Complete loss filtration barrier
Leak lots protein
Hypoalbuminaemic
Lose oncotic pressure so get oedema
Present with oedema, low albumin in blood, protein in urine
No cellular proliferation
Insidious onset
Nephritic syndrome
Inflammatory disease in kidneys typically presents with rapidly progressive glomerulonephritis
Blood/protein in urine
Less protein than nephrotic syndrome
More inflammation, rapid reduction in kidney function
Cellular proliferation and immune complex deposition
Abrupt onset
Causes of death
Infection
Other underlying disease: eg cancer, cardiovascular diabetes
Hyperkalaemia
Acidosis
Pulmonary oedema
These can be managed by dialysis, potassium lowering drugs
Prevention, assessment, management
Identify those at risk of AKI early
-patient related risk factors
-admission related risk factors
-intervention/treatment related risk factors
Monitoring:
-urine output
-input/output
-weights
Management:
-starts with identification and recognition of AKI risk
-fluid balance
-fluid intervention oral and iV
-exclude obstruction
-urine dipstick
-treatment of underlying problems
-stopping Nephrotoxic drugs and context specific drugs
-ongoing monitoring and treatment adjustment
-ongoing monitoring and fluid intervention adjustments
-referral
Dialysis
Indications:
-fluid overload
-hyperkalaemia
-severe metabolic acidosis
-severe uraemia
Unresponsive to medical management
Removal of poisons/toxins
What is renal replacement therapy RRT
Life supporting treatment for renal failure
-acute vs chronic
Dialysis:
-haemodialysis
-peritoneal dialysis
Transplantation
What do kidneys do
Filtration and excretion
-electrolyte balance, fluid balance, acid-base balance
BP regulation
Regulation of RBC production
Vitamin D activation
When is RRT necessary
Failure to perform filtration/excretion functions-> potentially life threatening consequences
Chronic kidney disease stage 5
-Irreversible damage to the kidneys, requiring long term life sustaining therapy
Acute kidney injury
-Severe, potentially reversible, kidney “shut down”
-temporary life sustaining therapy
Important emergency RRT indications
Hyperkalaemia- resistant to treatment
Severe pulmonary oedema- resistant to treatment
Severe acidosis- resistant to treatment
Severe uraemia- pericarditis, seizures
Ingestion of dialysable poisons eg ethylene glycol
What can RRT replace
Dialysis: filtration and excretion: electrolyte balance, fluid balance, acid-base balance. Only to GFR 15ml/min
Transplantation: filtration and excretion, BP regulation, regulation of RBC production, vitamin D activation
What is dialysis
Separation/movement of particles in a liquid based on their ability to pass through a semipermeable membrane
Membranes used in dialysis:
-synthetic e.g. polysulfone can vary size of pores
-biological eg peritoneum, peritoneal dialysis, can’t alter membrane, people differ in composition
Use different types of forces to enable clearance of small and bigger solutes to enable clearance of fluids
Can add buffers e.g lactate that buffers H+ to correct acidosis
How do particles move across the membrane
Diffusion- solvent moves by concentration gradient
Ultrafiltration- solution moves by pressure gradient
Can apply hydrostatic pressure to one side semi permeable membrane so water moves across membrane
Osmosis- water moves by concentration gradient, peritoneal dialysis
Can also have convection, solute drag, small solutes move across with fluid if the fluid is moving with high flow rate can eliminate small solutes effectively e.g urea. Used in haemodialysis
Haemodialysis
Intermittent: 4 hours 3x a week, outpatient
Extracorporeal (outside the body)
Hospital/outpatient, some dialyse at home (need right water treatment)
RRT of choice is usually haemofiltration continuous dialysis at slower flow rate which if you have haemodynamic instability is more gentle
Diffusion, ultrafiltration and convection
Lots of fibres increase surface area
Countercurrent gradient
Blood travels on one side of dialysis membrane
Dialysis fluid passes on other side of dialysis membrane
Haemodialysis can change membrane pore size
E.g high flux dialysers-> large pores, enhanced middle molecule clearance
What do you need for haemodialysis
Patient
Access to blood
Dialyser
Dialysis machine
Ultra-pure water
Dialysis nurse
Access to blood haemodialysis
Acute setting: temporary dialysis catheter/vascath, NB: clotting
Chronic setting: long term dialysis catheter/tunnelled line, arterio-venous fistula/graft
AV fistula and AV graft
AV fistula: anastomose vein and artery, vein gets arterialised gets bigger and tougher wall so dialysis needles dont collapse the vein. Radial A to cephalic vein, brachial A to cephalic vein, brachial A to basilic vein
AV graft: synthetic material connecting artery to vein, can needle the graft, clots eventually, fistula better
Ultrapure water
Free from:
-chlorine
-heavy metals
-XS Mg/Ca
-endotoxins
-bacteria
Dialysis nurse
Machine set up
Patient connection
Monitoring
Troubleshooting
Patient disconnection
Crucial
Peritoneal dialysis
Continuous therapy
Corporeal (inside body)
Semi permeable membrane- peritoneum
Home therapy
Diffusion, osmosis, convection
Membrane pores: individual variability, cant predict or change
Aquaporins- water movement
Peritoneal dialysis fluid
“Iatrogenic ascites”
Carried out in peritoneal space
Fluid:
-hypertonic -> osmotic gradient :
— glucose
—starches e,g icodextrin, cant equilibrate so water only moves in one direction
-diffusion gradient: K+, Na+, urea
-acid/base: lactate
Dialysis and acid-base
Blood [H+]= low (freely diffuses into tissues)
Can’t remove acid load by filtration alone
Alkali added to patient from dialysis solution:
- concentration of alkali is greater than in plasma
-lactate, acetate, bicarbonate
-lactate and acetate metabolised to CO2 and H2O and H+ consumed and buffer generated
-in CAPD lactate used as buffer metabolised in Krebs cycle to pyruvate
CAPD and APD
CAPD: continuous ambulatory peritoneal dialysis
- manual exchanges eg 2-3L 4x daily, 3 a day one at night
APD: automated peritoneal dialysis
-intermittent overnight
-6-8 hours 4-6 fill/drain cycles
Considerations for peritoneal dialysis
Age, older age more frail, lose vision and dexterity so may not be able to do dialysis themselves, assisted peritoneal dialysis
Previous abdominal surgeries/stomas
Polycystic kidney disease- space considerations
Home:
-water source next to bedroom, hand washing prevent infections
-storage for fluid
HD vs PD
Equally effective
Patient choice
HD: short intermittent treatment time, hospital therapy, defined fluid removal. Access complications, lifestyle disruption, holiday considerations, stricter diet, muscle cramps/fatigue, haemodynamic instability
PD: continuous/daily treatment gentle clearance, less haemodynamic instability, home therapy, more liberal diet, holiday flexibility. Access peritonitis risk, peritoneal sclerosis, membrane failure risk, home storage of kit
Problems with dialysis HD
Access:
-clotting
-central venous stenosis
-infection- lines»_space;AVF:
—bacteraemia
—endocarditis
—osteomyelitis/discitis
Haemodynamic instability
Fatigue
Problems with dialysis PD
PD tube dysfunction:
-constipation
-migration
-occlusion e.g fibrin
Infection:
-peritonitis- cloudy fluid
-gram +ve>-ve
Membrane failure
Encapsulating peritoneal sclerosis EPS
The biggest problem with dialysis
20% patients will die each year
Cardiac disease:
-LVH due to hypertension, anaemia, fluid overload
-calcification of arteries, lipid abnormalities
Infection (secondary immunodeficiency)
Anaemia
Bone disease
Malnutrition
NB. Conservative management is a treatment option for ESRF
Transplantation
Treatment of choice for ESRF
Improved QOL, improved survival
Recovery of renal function, including EPO and vitamin D production
Iliac fossa insert ureter into bladder and blood supply into aorta
Discuss with all patients unless absolute contraindications present
Live donor- careful assessment
Deceased donor - waiting list
Timing: pre-emptive= better outcomes, limited by donor pool
Assessment of potential transplant recipient
Age
Age-related comorbidity: frailty scoring
Cardiovascular risk
Immunosuppression risk- malignancy (2-5 years remission)
Surgical factors:
-BMI>30 challenging operative perspective and bone closure perspective
-vascular anatomy and intraabdominal space PKD
Immunological factors-> previous sensitisation ?ABOi
Patient needs to be fit for major surgery and chronic immunosuppression
Contraindications of transplants
Absolute contraindications:
-high peri-operative mortality
-poor life expectancy
-active malignancy
Relative contraindications:
-coronary or cerebrovascular disease
-recurrent disease
-non compliance
Transplant complications
Early/medium term:
-CV morbidity/mortality
-infection
-rejection
Long term: additional
-increased CVD risk
-Tx-associated DM
-opportunistic infections/viral reactivation
-malignancy esp non-melanoma skin cancer and virus associated eg PTLD (EBV)
Transplant immunology
Donor and recipient must be matched:
-species
-blood group antigens (ABO)- not always possible to desensitise
-HLA antigens: class I A/B, class II DR
Reduce alloimmune responses (detection of non-self)
Matching HLA antigens
Tissue typing -> analysis of recipient HLA types (blood- leukocytes)
Pre-existing anti HLA antibodies-> calculated reaction frequency cRF%:
-testing recipient serum against panel of common HLA antigens
-identifies ‘highly sensitised’ patients-> pregnancy, transfusions, previous transplants
Crossmatching: done just before transplant:
-identifies recipient pre formed Abs against specific donor antigens
-‘virtual’- recipient serum reactivity against donors known HLA alleles (BEAD assay)
-‘wet’ or ‘leukocyte’ cross match- recipient serum reactivity against donor leukocytes CELL assay
Immunosuppression
Required even if ‘well matched’
Up to 30-40% may still reject but treatable
Main goal is to reduce T cell alloimmune responses- reduce ability of T cells to mount effective responses to non self antigens, increase infection risk, decrease ability to fight off infection, increase risk cancer
Induction v maintenance
Triple therapy:
-CNI (calcineurin inhibitors) eg tacrolimus
-antiproliferative agents eg mycophenolate MMF, azathioprine
-corticosteroids- prednisolone
Basiliximab (induction)- anti CD25 (IL-2Ra)
Induction immunosuppression considerations
Infection risk:
-CMV-> valganciclovir
-fungi/oral thrush -> nystatin
-pneumocystis-> co-trimoxazole
High dose steroids:
-GI protection-> PPI
-bone protection-> calcium supplementation
