Kidney Disease Flashcards
What is GFR? How is it calculated?
GFR = volume filtered by glomeruli, per unit time - corresponds to the arterial blood volume entering the kidney and being filtered (hard to measure)
Instead we focus on a substance that is completely filtered into the urine in order to calculate GFR (amount in renal artery will correspond to the amount in the urine)
Creates the following relationship - relates the substances that we’re measuring e.g. creatinine.
GFR = (Conc. Urine x urine ouput)/(Conc. Plasma)
Looking at the ratio between creatinine in the urine and the plasma – provides an indication of the rate of filtration and thus a window into the level of functioning of the nephrons
What are the four requirements for the substance that is used to measure GFR?
- Must not alter GFR
- Freely filtered at glomerulus
- Not reabsorbed / actively secreted in nephron
- Not metabolised / produced by kidney
Why do we measure GFR in the first place?
- Provides an assessment of global renal function
- Pathology causing loss/damage to glomeruli affects kidney generally – GFR loss correlated with general loss of function
- Guides management in chronic kidney disease (CKD)
- Rate of decline predicts need for renal replacement therapy
- Used to guide dosing of potentially toxic (renally cleared) drugs
What are examples of exogenous substances that can be used to calculate GFR?
As a whole, not commonly used.
What are two endogenous substances that are used to calculate GFR?
Creatinine - more commonly used
* Small molecule (113 Da)
* Produced at relatively constant rate (muscle metabolism)
* Some active tubular secretion
* Long established role in GFR measurement
Cystatin C
* Small protein (13kDa), inhibitor of proteases
* Produced by all nucleated cells
* No significant tubular secretion/absorption
* 10-20x more expensive to measure (than creatinine)
* Relatively new method of measuring GFR
Why is it challenging to calculate GFR by measuring urine Creatinine and volume?
Requires 24 hour urine collection
- Inconvenient for patient
- Inaccurate: may not be complete, may be mis-timed
- Imprecise: involves combination of imprecision from 4 variables…
Futhermore… At very low GFR (advanced renal failure) there is further inaccuracy
* less creatinine filtered
* amount creatinine secreted becomes proportionally much larger
So if we don’t measure urine creatinine/volume, how can we measure GFR?
Use plasma creatinine to estimate GFR (eGFR)
Based on the assumption that there is a recipricol relationship between plasma creatinine and GFR
- Low GFR means that there is more creatinine in the blood
- Higher GFR will results in more clearance and thus a lower plasma creatinine concentration
Very large inter-individual differences caused by differences muscle mass (production of creatinine) so must be taken into consideration
What are some examples of different equations used to calculate eGFR?
Cockcroft‐Gault equation - plasma creatinine, weight, age, and sex - Often used to adjust dosing for renally excreted drugs with potential toxicity
MDRD eqaution - most commonly used - only really accurate for people with a certain level of GFR impairment – most useful for GFR is less than 60ml.
EPI equation - provides more reliable measurments - equation accurately estimates GFR up to 90ml - not commonly adopted across the UK
When do the eGFR equations lose applicability?
- Children
- Pregnancy
- Very elderly – neither study included these groups
- Muscle mass extremes (frail, amputee, heavily built)
- Rapidly ‐ changing renal function
- Very low GFR
How is CKD diagnosis made? How is the staging of CKD performed?
Diagnosis of CKD usually requires eGFR consistently to be less than 60 mL/min/1.73 m2
But can involve eGFR >60 if any of:
- Persistent proteinuria / microalbuminuria
- Haematuria - blood
- Renal anatomical/genetic abnormality e.g. biopsy - proven GN, or PKCD
Staging uses both eGFR and urinary albumin to creatinine ratio (ACR)
What is the definition of acute kidney injury?
An abrupt loss of renal function
Commonly characterised by acute:
* oliguria & increases in plasma urea & creatinine
* Often accompanied by a loss in ability to regulate water, electrolyte & acid-base balance.
Do we use eGFR to detect acute kidney injury? How do we stage it?
eGFR is not a good measure for acute kidney injury - eGFR is better for more longer term changes
To pick up on AKI…
* We look at plasma creatinine - requires establishing creatinine baseline - looking for a reduction of 50% or more from baseline
* Decreased urine output
If we don’t have previous baseline – we use reference ranges –high degree of error
Combine degree of creatinine rise (using lab-computer based algorithm) and clinical context to gauge the severity of AKI
Used table to stage – considers clinical context and creatinine rise
What are some important renal tubular functions that we can assess?
- Acid-base homeostasis
- Electrolyte homeostasis
- Fluid balance and sodium
- Urine concentrating ability
What is the pH of the urine normally? What condition is associated with the failure of acid-base homeostasis? How can we test for it?
Urine is usually significantly more acidic than plasma
pH urine less than 5.5 vs. pH plasma 7.35 ‐7.45
Renal Tubular Acidosis (RTA) type I can lead to pH urine more than 5.5
* Distal tubular cells unable to secrete H+ - leading to acidification of blood
* Many possible causes: autoimmune, paraproteinaemia, nephrocalcinosis etc.
Test - Ammonium chloride loading test (rarely used!)
* Used to confirm suspected RTA type I
* NH4Cl administration leads to metabolic acidosis
* If pHurine >5.5 persists then RTA type I confirmed
How could one examine whether hypokalaemia (electrolyte imbalance) was due to a renal problem?
Electrolyte homeostasis – key function of kidney
Many different sources of electrolyte disorders – GI, shifts into cell, renal etc. – need to investigate to figure where the problem is coming from
Example: Hypokalaemia, K+ less than 3.5 mmol/L
- Spot urine K+ less than 20 mmol/L (no excess being excreted) usually excludes renal loss
- Often a spot urine is not sufficient as concentrations vary throughout the day… so we either need a 24 hour urine collection and measure creatinine to correct for variability in urine conc e.g. fractional excretion of phosphate (FEP)
What are plasma and urine sodium used for? If the plasma is hyponatraemic, what do urine sodium values above and below 30mmol/L tell you?
Plasma sodium – more an indicator of fluid balance, rather than total body sodium - hypernatraemia tends to reflect water deficit, rather than sodium overload
Urine sodium can be used to determine if tubular function appropriate
How is the kidney’s urine concentrating ability measured?
Concentrating ability - Assessed by measuring urine osmolality (and plasma osmolality for comparison)
Loss of urine conc ability may be accompanied by polyuria
What do you expect will happen to urine vs. plasma osmolality in CKD, acute tubular necrosis, DM and diabetes inspidus?
Expect that the osmolality of the urine to be greater than the plasma given that the urine should be more concentrated.
Advanced renal failure and tubular necrosis – kidneys are unable to concentrate the urine – urine osmolality = plasma osmolality
Diabetes – urine osmolality is the same or greater plasma osmolality – osmotic diuresis – pulls water into urine (extra glucose exerts osmotic pull)
Diabetes insipidus – urine osmolality is lower than plasma - very dilute urine
How do we test for diabetes inspidus?
DI involves failure of action of vasopressin (or ADH)
May be cranial (hypothalamic/pituitary pathology), nephrogenic (tubular problem)
Involves withholding fluids over several hours
* Normal response: plasma osmolality static, urine osmolality rises i.e. kidney conc urine
* DI: plasma osmolality will rise… urine remains dilute
Cranial DI should be responsive to DDAVP (synthetic vasopressin)
What is dipstick urinanalysis used for?
Point of Care test - Rapid, simple, convenient, cheap
Can measure…
* Glucose (diabetes?)
* Ketones (ketoacidosis?)
* Protein (albumin) – not as sensitive as lab measurement
* Blood (detects Hb: calculi, bladder ca., glomerulonephritis)
* Leukocytes (UTI)
* Nitrites (produced by nitrate-‐reducing UTI bacteria)
* Bilirubin (jaundice)
* Urobilinogen (absent in cholestatic jaundice)
* pH
Do proteins normally enter into the filtrate? Are they reabsorbed? What happens in pathological states?
Normal
* Glomeruli prevent passage of most large plasma proteins
* Tubules actively re‐absorb/catabolise low MW proteins
Renal pathology may lead to:
* Increased glomerular permeability – increasing urinary albumin, detectable levels of large MW proteins not normally found in urine
* Decreased tubular protein reabsorption – increased conc. of low MW proteins
How is proteinuria detected?
- Dipstick tests – can’t quantify across time – this case we need protein lab measurements
- Lab-based albumin/creatine ratio – protein:creatine ratio (PCR) or albumin:creatinine ratio (ACR - can be used to classify CKD)
Creatinine is used to adjust for urinary conc
What is microalbuminuria?
Microalbuminuria - albumin levels too low to be picked up by dipstick but can be detected in the lab
Note – these changes can occur transiently – so if this is present you need to take measurements across time to confirm diagnosis
Important for prevention of significant diabetic nephropathy
What are the functions of the glomeruli, tubules and interstitium?
- Glomeruli (filtering units)
- Tubules (reabsorption)
- Interstitium (the ‘bit in between the tubules’). Mainly comprises microvascular capillaries in health)
Label the structures in the following diagram of a glomerulus.
How is acute kidney injury defined?
AKI is defined as any of the following:
* Increase in serum creatinine by > 26.5
μmols/L in 48 hours or,
* Increase in serum creatinine by > 1.5x baseline creatinine within last 7 days or
* Urine volume < 0.5ml/kg/hr for 6 hours - decreased
Mainly used creatinine - important for staging as shown in the attached image.
oliguric – little or anuric – no urine
Why is AKI important to study?
AKI is COMMON (affects 7% of hospital inpatients) and has adverse consequences:
* Increased length of stay in hospital
* Increased morbidity
* Increased hospital & post-discharge mortality
* Very costly (~£500 million/annum)
Is severe AKI independently associated with CKD and end-stage renal disease?
Severe AKI is independently associated with adverse renal outcomes:
- Increased incidence of chronic kidney disease
- Increased incidence of end-stage renal disease
Is AKI a diagnosis?
No! It is a syndrome - we need to think about what is causing the dysfunction.
How can we divide the causes of AKIs in three ways?
PRE-RENAL - reduced real or ‘effective’ blood volume
RENAL - glomerulus, tubules and interstitium
POST-RENAL - obstruction – multiple levels (e.g. ureter, bladder etc)
What are some pre-renal causes of AKI?
Hypovolaemia (low blood volume) - e.g. bleeding, 3rd space fluid losses, over-enthusiastic diuretic therapy!
Hypotension e.g. septic/cardiogenic shock, liver failure
Reduced renal blood supply secondary to severe renovascular disease (±ACEI) - stenosis, dissection of the abdominal aorta
ACEi blocks RAAS system - results in reduced renal perfusion - can be damaging therefore.
How can renal obstruction be investigated?
Imaging is used to investigate obstructions
Renal Ultrasound can detect obstruction
CT scan with contrast can also be used to examine accumulation of constrast in kidney - Hydronephrosis (accumulaiton of urine in the kidneys)
What is a myeloma kidney?
Myeloma kidney - causes intrarenal obstruction
B-cell dysplasia – one antibody produced – antibody accumulation/precipitation in the kidney – leads to obstruction
Myeloma – silent condition that can take out kidneys quite quickly – think about this when other common signs aren’t present
Renal AKI cause - what is acute tubular injury?
Acute tubular injury - Commonest cause of AKI in hospitals and can complicate everything previously discussed!
Caused by…
1. Tubular toxins, eg gentamicin, cisplatinum, NSAIDs, radio-contrast dye
2. Severe prolonged hypotension (sepsis, MI)
3. Renal hypoperfusion e.g. elderly patient on ACEI, diuretic who has diarrhea and vomiting - common cause due to low oxygen levels in the medulla!
Recovery from ATI - Initial oliguria then may exhibit polyuric recovery phase (watch electrolytes)
Histology - cell debris in granular casts - tubular cells dying and accumulating in the tubules.
Renal AKI cause - What are some tubulointerstitial causes?
Interstitium – think allergy - Acute allergic interstitial nephritis
- DRUG-RELATED e.g. PPIs, (omeprazole) antibiotics, diuretics, NSAIDs
- May have an eosinophilia - no rash
- Often respond well to steroids
Hard to diagnose – no rash or other sign – look at eosinophil level with no signs of any other allergic reaction
Renal AKI causes - what is a glomerular cause of AKI?
Glomerular causes
Rapidly progressive glomerulonephritis (RPGN)
Immune driven and characteristized by glomerular crescents – space full of immune cells - characteristics
Loss nephrons cant make new ones
Renal AKI causes - what is a vascular cause of AKI?
Haemolytic uraemic syndrome (HUS) - can be..
* E coli related (E coli O157)
* Familial cases (genetic aetiology)
Characterisitc - Glomeruli full of thrombus
What investigations could we consider performing on an AKI patient?
- Urine dipstick – simple BUT important (blood, protein)
- Blood tests - shown in image
- Urine culture
- Renal Ultrasound - if obstructed then decompress
- Renal biopsy (AKI and normal sized kidneys)
- Angiography ± intervention
What are some equations that are used to calculate eGFR?
MDRD or CKD-EPI normally used
CKD-EPI - serum creatinine, sex, age and race (also a version using cystatin C instead of creatinine) - race co-efficient removed in 2021
What are the different stages of CKD?
90-120 - normal Kidney function or stage 1 kidney disease - differential between these two is an abnormal kidney radiology or biopsy or protein in urine
60-90 - Similar thing for stage 2 kidney disease – you are also looking for other markers - abnormal kidney radiology or biopsy or protein in urine
Different for Stage 3, 4 and 5 – no additional tests needed – enough for kidney disease diagnosis
From stage 3 onwards – patient normally gets a referral
ESRD – end stage renal disease – stage I – transplant or dialysis (dialysis normally started when we reach an eGFR of 6-10)
How is CKD staged?
Consider both GFR and proteinuria to determine which patients require treatment.
Both proteinuria and GFR is a marker and cause of kidney disease
How does proteinuria cause kidney disease?
How proteinuria can cause kidney disease…
Proteinuria – cells that take up protein in filtrate become overworked – causing inflammation, cell death and fibrosis – replacement of cells - chronic interstitial fibrosis
Use RAAS – opens efferent arteriole – reducing glomerular pressure - less protein going through
What is the relationship between hypertension and CKD?
Hypertension is both a cause and a consequence of CKD - HTN causes renal disease & Renal disease results in hypertension
Complications of hypertension - Causes Left Ventricular Hypertrophy / Stroke / End-organ damage- eyes/ kidneys
BP treatment goals - adjusted for DM/proteinuria
- “normal” -130/80
- DM / Proteinuria - 125/75
Attached graph - shows relationship between GFR loss per year for different BP values
Why is the associaiton between hyperkalaemia and CKD? What should we do to prevent it?
CKD – inability to excrete K+ - resulting in hyperkalaemia - important to monitor
- Hyperkalaemia common as GFR declines < 25
- Hyperkalaemia can occur if GFR >25 if diabetes + type 4 Renal tubularacidosis, ACE inhibitors (stops K+ excretion) or high K+ diet are present.
Prevention
* Dietary advice re High K foods
* Potassium binders – used in people that need to stay on ACEi in heart failure – binds to potassium – but expensive
How do we treat renal osteodystrophy in CKD patients?
- Phosphate restrict – vegan diet and binders (phosphate binders) – reduce meat and dairy - Phosphate binds to Ca2+
- Vitamin D therapy – alfacacidol (already has hydroxylation) - increase Ca and decreased PO4
- Monitor PTH
- Parathyroidectomy – removal of parathyroid is an option
What are the consequences of high phosphate levels (hyperphosphataemia)?
We see vessel calcification (medial calcification)- resulting in non-compliant vessels, systolic hypertension (L vent hypertrophy) and diastolic hypotension (myocardial ischaemia)
Calciphylaxis - calcium accumulates in small blood vessels of the fat and skin tissues - causing blood clots, painful skin ulcers and may cause serious infections that can lead to death
What is the association between CKD and cardiovascular disease?
Increased risk of cardiovascular death and death from all causes as CKD progresses
List shows a range of cardiovascular risk factors that arise in response to CKD.
Which CKD patients should referred on to the renal clinic?
- Any patient with rapid increase in creatinine/ hypertension
- People with haematuria (blood) & rising creatinine/proteinuria and/or hypertension
- Stage 3 CKD with hypertension/ proteinuria /haematuria/ rising creatinine
- Any stage 4/5 CKD who is suitable for treatment
Late referral patients do considerably worse
Anaemia / renal bone disease / dialysis access
What are the two types of dialysis?
Haemodialysis - treatment to filter wastes and water from your blood
Peritoneal dialysis - At home method – peritoneal space filled with fluid (allows for exchange) and then waste fluid is removed
