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