miller - renal disorders.pdf
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D R A D R I A N G M I L L E R
R O Y A L L I V E R P O O L H O S P I T A L
An Introduction to Kidney Disorders
Aims of this session
• To briefly revise kidney function
• To revisit means of assessing kidney function
• Gain an understanding of common kidney disorders
• Understand pre-renal, intra-renal and post-renal
concepts
• Learn how to investigate and manage renal
disease
• Apply knowledge to clinical scenarios (cases)
Important points to remember
• Renal disease is rarely straight-forward – this session
will not teach you everything you need to know but
were afraid to ask about renal disease
• Use the references cited to expand your knowledge
• Use Textbooks (Tietz, Marshall etc)
• Make a friend of the kidney and its role in health
and disease
• Although sometimes (!) complicated, the kidney’s role is
crucial to understanding many disease processes
• Use a multi-disciplinary approach to clinical problems
THE KIDNEY – A REFRESHER
KIDNEY FUNCTIONS
• Maintains water and electrolyte homeostasis
• Controls volume and composition of ECF
• Removes water-soluble waste products and toxins
• Nitrogenous compounds
• Maintains acid-base balance (excretion of H+)
• Produces (and responds to) chemical messengers
• Role in Vitamin D metabolism
• Role in haemoglobin synthesis
When renal function is impaired, for WHATEVER reason, it
will hinder the kidney’s ability to perform these functions
KIDNEY FUNCTIONS
• Maintains water and electrolyte homeostasis
• Sodium, glucose, bicarbonate reabsorption
• Potassium, phosphate, acid (H+) excretion
• Water control
• Electroneutrality
In order to function, the kidney needs…
• Adequate perfusion (blood supply)
• Positive pressure differential at the glomerulus
• Viable, semi-permeable glomerular membrane
• Intact, functioning tubular endothelium
• Channels
• Transporters
• Gradients (electrochemical, concentration)
• Clear passage for filtrate to travel
• Appropriate hormonal activity (and ability to
respond)
• Energy!
ASSESSING RENAL FUNCTION
Which function to measure….?
•Ability to maintain water and electrolyte balance?
•Ability to select what is allowed to enter the tubule?
•Ability to remove waste products?
•Ability to produce (and respond to) chemical mediators?
ASSESSING RENAL FUNCTION
Broadly divided into:
•Assessment of glomerular filtration
• Ability to remove waste products
•Assessment of glomerular integrity
• Ability to select what is allowed to enter the tubule
•Assessment of tubular cell function
• Ability to reabsorb or secrete compounds
• Ability to respond to stimulation
AT THE MACROSCOPIC LEVEL
• Imaging studies are used to indicate anatomical
changes
• Radiography
• Ultrasonography
• CT, MRI
• Angiography
• Urinalysis is a simple way to indicate renal pathology
• Appearance (cloudy? Bloody? Strange colour? Smell?)
• Specific gravity and osmolality
• pH
• Protein
• Sediment
• Other substances
AT THE MICROSCOPIC LEVEL
• Immunological analysis
• Auto-antibodies against renal components
• Immuno-histochemical analysis
• Biochemical analysis is the mainstay of renal
investigations
ASSESSING GLOMERULAR FILTRATION
• As Biochemists, our frontline test measures the ability
of the kidneys to excrete nitrogenous (azotemic)
waste products.
Creatinine Urea
Borne from the (uneasy) relationship between serum creatinine
concentration and glomerular filtration rate. Urea used as a side-kick.
Although beyond the scope of this lecture to discuss the advantages and disadvantages of estimating glomerular
filtration rate (eGFR) as a function of serum creatinine
concentration (and other confounding variables), it would be
prudent to read the following:
Assessing Kidney Function — Measured and Estimated Glomerular Filtration Rate
L. Stevens et al., New England Journal of Medicine (2006), 354 2473-83
Creatinine and glomerular filtration rate: evolution of an accommodation
C. Diskin, Annals of Clinical Biochemistry (2007), 44 16–19
“Creatinine clearance is not and has never been synonymous with
GFR, and no regression analysis will make it so, because the
serum creatinine depends upon many other factors than filtration”.
ASSESSING GLOMERULAR INTEGRITY
• Detection of compounds not normally present in the urine due
to the selectivity of the glomerular basement membrane
• Albumin is the predominant plasma protein responsible for many physiological functions (solute transport, oncotic pressure
etc). Normally not filtered at the glomerulus due to
• Size (~66 kDa)
• Charge (net negative charge)
• It’s presence in urine signals
loss of glomerular integrity
• “Microalbuminuria”
Used to monitor CKD
ASSESSING TUBULAR FUNCTION
The most common tests of tubular function assess:
•Ability to excrete an acid load (Urine pH e.g. RTA)
•Ability to concentrate urine (Urine osmo. e.g. SIADH, DI)
•Ability to respond to hormones (plasma and urine
electrolytes e.g. Addison’s)
•Ability to reabsorb solutes (urine glucose e.g. DM)
NB. Many re-absorption mechanisms are saturable. The presence of
small molecular weight solutes in the urine that aren’t normally there
may reflect over-production rather than under-reabsorption e.g.
• Glucose in Diabetes Mellitus
• Amino acids in some inborn errors of metabolism
RENAL DISORDERS
Acute Renal Failure (ARF)
• More recently referred to as “Acute Kidney Injury” (AKI)
• Describes a clinical scenario of kidney failure that develops over hours or days (as opposed to weeks or months)
• May be superimposed on established, chronic renal failure
(CRF) and is then referred to as “acute on chronic” RF
• Traditionally separated into three major groups
• Pre-renal (insult occurs before the kidneys)
• Renal (intrinsic, tubular dysfunction)
• Post-renal (blockage of the flow of urine to the ureters/bladder)
Acute Kidney Injury
J. Kellum. Crit Care Med (2008), 36 [Supplement] S141–S145
Reminder: in order to function, the kidney needs…
• Adequate blood/fluid supply
• Positive pressure differential at the glomerulus
• Viable, semi-permeable glomerular membrane
• Intact, functioning tubular endothelium
• Clear passage for filtrate to travel
• Appropriate hormonal activity (and ability to
respond)
• Energy
In Pre-Renal Conditions
• Adequate blood and fluid supply?
• Positive pressure differential at the glomerulus?
Pre-renal ARF implies some form of
hypoperfusion which may be a result of:
• Dehydration
• Haemorrhage or thrombosis
• Renal artery stenosis
• Acute cardiac failure
• Sepsis
Pre-renal ARF can be considered an appropriate response to
hypovolaemia, conserving water and sodium at the expense of GFR
N O T A V A I L A B L E I N P R I M A R Y C A R E ( N O T A L W A Y S A C C U R A T E I N S E C O N D A R Y C A R E ! ! )
FLUID BALANCE CHARTS!
INTRINSIC RENAL FAILURE
Due to their high metabolic rate, the kidneys are extremely vulnerable to
ischaemia – prolonged episodes may cause renal damage that persists
after the underlying cause has been resolved - termed “Acute Tubular
Necrosis”
Causes of intrinsic renal failure
• Glomerulonephritis
• Goodpasture’s disease
• Systemic Lupus Eryth’s (SLE)
• Cryoglobulinaemia
Not exactly ―common‖
• Pre-renal causes of ATN
• Drugs
• Tubular nephritis
• Sarcoidosis
• Poisoning
• Rhabdomyolysis
• Etc
A lot more common
POST-RENAL FAILURE
• Obstruction is the most common cause of post-
renal failure. The main culprits are:
• Renal calculi
• Retroperitoneal fibrosis
• Invasive bladder carcinoma
• Benign or malignant prostatic disease (males)
A very un-holy
trinity!!
SOME FEATURES OF ARF
Metabolic Feature Clinical Feature
Retention of nitrogenous waste
products
Nausea, vomiting, disturbance
of consciousness, coma
Retention of sodium and water
(usually with hyponatraemia)
Peripheral and pulmonary
oedema, ascites, pleural
effusion
Hyperkalaemia ECG changes (peaked or
“tented” T waves, flat P waves,
QRS depression), muscle
weakness, paralysis
Retention of acid (metabolic acidosis)
Kussmaul breathing, hypotension
INVESTIGATING ARF/AKI
• Urine dipstick testing for blood and protein suggest glomerular
disease
• What if no urine is available?
• Guidelines suggest serum creatinine and urine output are the
best biomarkers of AKI
UK Renal Association – Guidelines issued in March 2011
MULTI-DISCIPLINARY APPROACH
• Clinical
• PMH
• Medications
• Biochemistry
• Urinalysis – protein and
blood
• U&E, Calcium, phosphate, CRP, CK, LFT
• Arterial blood gases
• Haematology
• Red cell casts
• Full blood count
• Microbiology
• Cultures and serology
• Immunology
• Auto-antibody screens
(ANCA, Anti-GBM etc.)
• Cryoglobulin
MANAGEMENT OF ARF/AKI
• Establish whether acute, chronic or acute-on-
chronic
• Identify whether pre-renal and resuscitate with fluids
• Discontinue nephrotoxic drugs
• Treat metabolic complications
• Exclude urinary tract obstruction
• Investigate for intrinsic disease
• Involve Nephrologists! Prognosis can be very poor.
Acute Renal Failure
R. Hilton. BMJ (2006), 333 p 7572
CHRONIC RENAL FAILURE
(CRF)
CHRONIC RENAL FAILURE
• Unlike ARF/AKI, the onset of CRF is much more
gradual, presenting over months and years
• Usually asymptomatic (initially, at least)
• Only presents when renal functional threshold is crossed
• Usually secondary to other pathologies
• Natural decline of GFR with age
• In many cases, progresses to End-Stage Renal Failure (ESRF)
• Although there are many causes of CRF, the clinical
features tend to be similar as the condition reflects
the decline in the number of functioning nephrons
Causes of CRF
• There are many, classified into 4 groups:
• Vascular disease
• Renal artery stenosis
• Glomerular disease (primary or secondary)
• Primary - Membranoproliferative glomerulonephritis
• Secondary – DM, SLE, BJP, Auto-immune etc
• Tubulointerstitial disease
• Drugs (allopurinol), infections, sarcoidosis, heavy metals
• Urinary tract obstruction
• Stones, tumours, fibrosis
Effects of CRF
CRF
Acid-base disturbances
Calcium, phosphate,
magnesium
Endocrinopathies (thyroid,
gonadal)
Carbohydrate and lipid
metabolism Retention of nitrogenous waste
products
Sodium and water
disturbances
Potassium metabolism
Management of CRF/CKD
• Control the underlying co-morbidity
• Slow progression of kidney disease
• Anti-hypertensives etc
• Prevent complications (CV, anaemia etc)
• Strict diet, supplementation
• Prepare for renal replacement therapy (dialysis,
transplant)
www.kidney.org
CLINICAL CASES
Remember!!
• Always consider (pre-)analytical causes
• Patient demographics
• Past medical history
• Presenting symptoms
• Where the patient has come from?
• Medications
• Multi-disciplinary approach
• Multi-condition appreciation!
A wise old Biochemist once said:
―When you hear hooves, think horses not zebras!‖
i.e. common things happen often, rare things happen rarely
Case 1
• KB, 50 years old, female.
• Sample received from Cardiology Outpatients
• Clinical details: “HF, fluid retention”
• Medications not stated
• Assumptions?
Biochemistry
Date Sodium (135-145 mmol/L)
Potassium (3.5-5.5 mmol/L)
Urea
Creatinine
19/08/11 144 4.3 28.4 181
21/09/11 142 4.2 27.1 199
11/10/11 142 4.8 28.6 214
What else do we need?
• Are there any Biochemistry tests we’d like to add
on?
• Are there any haematology or immunology tests
we’d like to do?
• What’s the diagnosis?
• How do we manage patients with this condition?
Case 2
• CC, 34 years old, female.
• Patient location: Ward 6
• Clinical details: “HD”
• Medications not stated
Biochemistry
Analyte Range 15/09/11 06/10/11 06/10/11
Sodium 135 -145 mmol/L 138 139 139
Potassium 3.5 - 5.5 mmol/L 4.0 6.4 3.7
Urea 2.5 - 7.0 mmol/L 2.9 25.5 2.2
Creatinine 50 - 130 µmol/L 146 735 127
Phosphate 0.70 - 1.40 mmol/L N/A 1.04 N/A
Calcium 2.20 - 2.60 mmol/L N/A 2.53 N/A
Hb 11.8 – 16.7 d/dL 11.2 10.9 N/A
25 (OH) Vit D >50 nmol/L N/A 60 N/A
Diagnosis and Management
• What is going on in this patient?
• How are these patients managed?
• Dialysis
Management (continued)
As mentioned earlier:
• Dietary interventions
• Reduced potassium, phosphate, sodium, protein etc
• Controlling blood pressure
• ACEIs/ARBs
• Reduce CV risk
• Statins, lipid-lowering agents, anti-coagulation therapy
• Control renal bone disease
• Monitoring markers of turnover
• Vitamin D
• Monitoring other complications
• Anaemia
Case 3
• RD, 55 years old, male.
• Patient location: Ward 2B
• Clinical details: None supplied
• Medications not stated
Biochemistry & Haematology
Analyte Range 17/10/09 10/10/11
Sodium 135 -145 mmol/L 133 127
Potassium 3.5 - 5.5 mmol/L 3.8 4.7
Urea 2.5 - 7.0 mmol/L 9.8 17.9
Creatinine 50 - 130 µmol/L 156 244
Phosphate 0.70 - 1.40 mmol/L 1.01 1.22
Calcium 2.20 - 2.60 mmol/L 2.14 2.45
Hb 11.8 – 16.7 d/dL 10.1 9.6
hsTrop T <14 ng/L N/A 561
Diagnosis and Management
• Acute-on-chronic renal failure
• Presents a “double whammy” to the kidneys
• Management revolves around treating the acute
insult while protecting the remaining renal function
• Prognosis is poor
Case 4
• JT, 38 years old, male.
• Patient location: Ward 5Y
• Clinical details: “Ca GI, post-chemo”
• Medications not stated
Biochemistry
Analyte Range 07/10/11 11/10/11 12/10/11
Sodium 135 -145 mmol/L 125 116 114
Potassium 3.5 - 5.5 mmol/L 4.2 4.5 3.9
Urea 2.5 - 7.0 mmol/L 3.3 23.2 22.5
Creatinine 50 - 130 µmol/L 45 338 241
Phosphate 0.70 - 1.40 mmol/L 0.51 1.92 1.46
Calcium 2.20 - 2.60 mmol/L 2.17 1.72 1.86
Bilirubin 2 - 17 µmol/L 179 205 206
Summary - Learning points
• Look at the whole picture (and just the facts!)
• Gain an appreciation for homeostatic mechanisms
and what can go wrong
• Many medications are nephrotoxic (very rare that
clinicians tell us what a patient is taking)
• Knowing what each ward’s speciality is can help
• Familiarising with Consultants names also.
• Think multi-disciplinary!
• Renal impairment affects many organ systems