1. AKI & CKD
Josh Exley

2. Learning Objectives Acute Kidney Injury Drugs and the Kidney
Chronic Kidney Disease

3. Normal Kidney function

4. Kidney Functions Excretory function Filter metabolites, toxins, drugs
Homeostatic function
Fluid balance
Electrolyte balance
Acid-base balance
Fluid regulation – ADH and aquaporins in the collecting duct
Acid-base – reabsorption of bicarbonate in urine, excretion of H+ ions

5. Kidney Functions Hormonal function
Renin – RAAS system and BP regulation
EPO
Metabolic
1, 25(OH) Vitamin D (Calcitriol) formation from 25 OH Vitamin D by 1α-Hydroxylase
Active Vit D – Promotes Ca2+ absorption in gut, renal tubule, bone

7. Where in the nephron is glucose reabsorbed?
PCT
What differentiates the thin and thick ascending limbs of the Loop of Henle?
Thick limb is impermeable to water, presence of Na/K/Cl contransporter

9. What is the role of Renin? Where is it made?
Converts angiotensinogen to Angiotensin 1
Juxtaglomerular apparatus, Afferent arteriole + DCT
What is the role of EPO?
Stimulates RBC production from precursors

10. Macula Densa – detects NaCl levels in DCT (due to decreased GFR)
Juxtaglomerular cells – specialised epithelium – produce renin in response to decreased pressure in afferent arteriole, decreased NaCl in DCT (due to decreased eGFR)

12. Acute Kidney Injury

13. AKI Rapid (within 48hrs) deterioration of renal function
Rise in serum creatinine >26micromol/L in 48 hours
>50% rise in serum creatinine over 7 days
Drop in urine output to 0.5ml/kg/hour for 6 hours
Results in failure of fluid, electrolyte and acid-base balance
Other functions are longer-term processes, less immediate consequences

14. Why is this important? 15% of adults in hospital have AKI
Potentially life-threatening
Hugely costly
Recognised and treated poorly
100x greater mortality than MRSA
20% of cases are avoidable
NCEPOD 2009 report

15. AKIN staging Stage Serum Creatinine Urine Output 1
Increase of ≥0.3 mg/dL (≥26.4 µmol/L) or 1.5- to 2-fold increase from baseline
< 0.5 mL/kg/h for >6 h 2
>2-fold to 3-fold increase from baseline
< 0.5 mL/kg/h for >12 h 3*
>3-fold increase from baseline
< 0.3 mL/kg/h for 24 h or anuria for 12 h
*Patients who receive renal replacement therapy are always stage 3
May have heard of RIFLE criteria – this supersedes that

16. Creatinine
Waste metabolite of creatine, formed from the natural breakdown of muscle cells
Formed at a relatively constant rate, dependent on muscle mass
Freely filtered and excreted exclusively by kidneys
Serum concentration dependent only on: amount produced, amount filtered (GFR)

17. Causes of AKI
Pre-Renal
Renal
Post-Renal

18. Pre-Renal Up to 80%
Anything reducing the amount of blood reaching the kidney
Nephrons functionally intact

19. Filtration is dependent on the glomerulus having a higher pressure than the Bowman space
Glomerular pressure depends on renal blood flow controlled by the afferent and efferent arteriole
Reduced renal blood flow causes ischaemia and cell death

20. Kidney auto-regulation
BP INCREASES
Afferent constricts
Efferent dilates
BP DECREASES
Afferent dilates
Efferent constricts
Can maintain GFR in remarkable variations of BP – from around systolic
NSAIDs and ACEi interfere with this – see later

21. Pre-Renal causes
Volume depletion – haemorrhage, burns, excessive diuresis, diarrhoea/vomiting
Systemic hypotension
Shock, sepsis, anaphylaxis
Severe HF, arrhythmias
Renal hypoperfusion – NSAIDs, ACE-I, renal artery stenosis, hepatorenal syndrome
Shock – hypovolaemic, cardiogenic, distributive, obstructive (obstruction of great vessels of heart – massive PE, tamponade)
Hepatorenal syndrome – severe liver disease (e.g cirrhosis) disrupts normal function of systemic haemodynamics + vasodilator and vasoconstriction mechanisms of the renal arteries, ultimately causing increased vasoconstriction. Liver disease also releases mediators which dilate vessels of the splanchnic circulation (supplying the gut) and thus away from the kidneys, under-pefusing them (also contributing to activation of vasoconstriciton mechanisms). Triad of: Deranged liver function, Kidney failure and circulatory abnormalities (e.g massive ascites)

22. Post Renal %
Obstruction of the passage of urine – from calyces to urethra
Increases tubular pressure, reducing the pressure gradient required for filtration
Pressure compresses and thins renal parenchyma leading to inflammation and altered blood flow, causing ischaemia – further damage
Usually insidious onset, may be acute if calculi with single functional kidney

23. Post-Renal
BPH
Tumours
Calculi
Neuropathic

24. Renal (Intrinsic)
Cytotoxic, ischaemic or inflammatory insult to the kidney with structural and functional damage
Classified on location of insult:
Glomerular – glomerulonephritis, mostly autoimmune
Interstitial – drugs, infection, systemic disease
Tubular – Acute Tubular Necrosis
Vascular – thrombosis, vasculitis, microangiopathies
Systemic diseases – lupus, sarcoid, leukaemia, lymphoma

25. Acute Tubular Necrosis
Most common cause of renal AKI
Causes:
Ischaemia – e.g as a result of pre-renal AKI
Nephrotoxic
lithium, aminoglycoside antibiotics, chemotherapy
Myeloma
Rhabdomyolysis
Leads to cell injury and death + inflammation + obstruction → releases cell mediators that cause intrarenal vasoconstriction → further hypoperfusion → loss of function
Gentamycin

27. STOP Sepsis & hypoperfusion Toxicity (Drugs/contrast) Obstruction
Parenchymal disease (Renal causes)

28. Symptoms Depends on underlying cause and severity Urine output
Usually oligouria or anuria
May have polyuria – tubular damage prevents reabsorption or osmotic effect of metabolites
Dehydration
Nausea/Vomiting
Confusion

29. Signs Accumulation of fluid and waste products Raised JVP
Pulmonary/Peripheral oedema
Electrolyte imbalance
Uraemia – itching, nausea & vomiting, confusion, tremors, acidosis, weakness
Evidence of causative mechanism
Obstruction
Sepsis
Heart failure
Systemic disease – rashes, arthralgia, weight loss

30. Investigations Urine dipstick Bloods Blood gas ECG
FBC
U&E
Lactate
Creatinine kinase
CRP
Blood gas
ECG
Microbiology – urine, blood
Don’t want to confuse you – investigations are dictated by history and clinical picture

31. Investigations Chest Xray Renal Ultrasound Immunology Myeloma screen
Renal biopsy

32. Management Stop nephrotoxic drugs Correct electrolyte imbalance
Strict fluid management
Fluids if dehydrated, diuretics if overloaded
Consider catheterisation for close monitoring
Correct underlying cause
Renal replacement therapy

33. Life-threatening Complications
Severe fluid overload
Hyperkalaemia
Metabolic acidosis
Spontaneous bleeding
Metabolic acidosis – cannot reabsorb bicarbonate effectively
Uraemia interacts with platelet activation and aggregation, preventing affective clotting

34. Hyperkalaemia Life threatening at >6.5mmol/L
Reduces myocardial excitability → impulse suppression
Bradycardia, followed by conduction abnormalities and eventual cardiac arrest
Calcium gluconate – stabilises membrane, cardioprotective
Insulin + Dextrose
Salbutamol nebuliser
Avoid potassium-sparing diuretics in anyone with baseline Potassium >5

35. Tall Tented T Waves
Later – bizzare broad QRS morphology, absent p waves, bradycardia

36. Indications for dialysis
Treatment-resistant hyperkalaemia
Severe metabolic acidosis
Symptomatic uraemia
Treatment resistant pulmonary oedema
80% mortality if dialysis required in AKI

37. What is the most common cause of AKI?
Pre-renal causes
What happens to the afferent and efferent arterioles when BP decreases?
Afferent dilates, efferent constricts
Where does creatinine originate from?
Breakdown of creatine, from muscle tissue

38. Drugs and the kidney

39. All aspects of pharmacokinetics can be affected by kidney disease
Drugs and the Kidney
All aspects of pharmacokinetics can be affected by kidney disease
Absorption
Distribution
Metabolism
Elimination
What is pharmacokinetics/dynamics?
Absorption – uraemia, gut oedema
Distribution – fluid retention = more solvent for water-soluable drugs, hypoproteinaemia – less drug binding
Metabolism – insulin metabolised by kidney
Elimination – less excretion, so accumulation of potentially harmful drugs/metabolites

40. Pharmacodynamics Adverse effects of drugs more likely:
Increased CNS sensitivity
Increased bleeding risk with anticoagulants
Increased risk of hyperkalaemia – ACEi, K+ sparing diuretics
Spironalactone, eplerenone

41. Assessment of Renal Function
Creatinine Clearance
eGFR

42. Creatinine clearance Ideally = 24hr urine collection
In reality = Cockroft-Gault equation using a single serum creatinine reading (estimated)
Used to adjust drug doses
Using serum creatinine is a poor marker of renal function – moderate impairment can exist with serum creatinine in the normal range
Used vs eGFR as it is fully validated. In practice it may be worthwhile comparing both

43. Cockroft-Gault equation
140−𝑎𝑔𝑒 ×𝐹×𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔 𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑖𝑛 𝑚𝑖𝑐𝑟𝑜𝑚𝑜𝑙/𝐿
F is a constant
In Men = 1.23
In Female = 1.04

44. Limitations of Cockroft-Gault
May overestimate creatinine clearance by 10-40%, particularly in severe impairment
As it originates from muscle:
Dependent on muscle mass
Exercise
Assumes constant rate of decline with age – less accurate in >85 years
Less accurate at extremes of BMI

45. Estimated GFR
Based on Modification of Diet in Renal Disease (MDRD) equation
Requires:
Age
Gender (men ↑ creatinine)
Ethnicity (Afro-Caribbean ↑ creatinine)
Usually automatically reported on a U&E, allowing easy assessment of renal function
More accurate than CrCl in CKD 3-5
Used in monitoring CKD

46. Common AKI causes - CANDA
Contrast
ACEi/AIIRB
NSAIDs
Diuretics
Antibiotics
Particularly gentamicin/vancomycin
Gentamicin = aminoglycoside
Vancomycin = glycopeptide
ABX + Contrast are directly nephrotoxic

47. NSAIDs
Inhibit COX enzyme, preventing production of Prostaglandins E2/D2
Prostaglandins are responsible for dilating afferent arteriole
In hypovolaemia/low BP state → no dilation → renal hypoperfusion

48. ACE inhibitors
Inhibits conversion of Angiotensin I to Angiotensin II in the lungs
Angiotensin II required to constrict efferent arteriole
Without efferent constriction → kidney can no longer maintain perfusion pressure → decrease in GFR

50. Drugs in AKI Drugs to stop ACEi/AIIRB NSAIDs
Metformin – NOT nephrotoxic, but causes lactic acidosis
Drugs to avoid
Contrast
Opioids (safest = oxycodone)
DMARDS e.g Methotrexate
AIIRB – losartan, candesartan
All Nice Men Can Open Doors

51. Dose Adjustment
Renally excreted – especially if narrow therapeutic index
Drugs with renally-cleared active metabolites
Management:
Decrease dose
Decrease frequency
Avoid altogether – different drug
Dose as normal – e.g secondary to sepsis where GFR will resolve
Digoxin, anti-epileptics
Opioids

52. CKD

53. Definition
Presence of kidney damage (albuminuria – ACR >65mg/mmol) or decreased kidney function (GFR <60ml/min/1.73m2) for 3 months or more
In most cases progressive and irreversible, but rate of progression can be slowed
Kidney failure = GFR <15ml/min/1.73m2, or the requirement of dialysis
ACR – albumin to creatinine ratio

54. Classification
Stage
Impairment
GFR (ml/min/1.732) 1
Normal
>90 2
Mild
89-60 3a
Mild-Moderate
59-45 3b
Moderate-Severe
44-30 4
Severe
30-15 5
Renal Failure
<15
Stage 4 – start planning for dialysis
Stage 5 – dialysis, transplant
Evidence = albuminuria/proteinuria, haematuria with proven renal origin, structural abnormality found on imaging, proven on biopsy
Patients with GFR >60 and no evidence of kidney disease DO NOT HAVE CKD

55. Some reduction in GFR as we age is normal

57. Causes Diabetes – 25% Glomerulonephritis – 15% Hypertension
Arteriopathic renal disease
Infective/Obstructive/Reflux
Familial - PCKD

58. Presentation Presents in three ways:
(Found routinely e.g diabetes/hypertension check-ups)
Anaemia
Acute-on-Chronic
Emergency from life-threatening complication of renal failure

59. Complications Fluid Overload Hypertension Hyperkalaemia Acidosis
Anaemia
Bone mineral disease
Increased Cardiovascular risk - calcification
Acidosis – reabsorption of bicarbonate decreased

60. Anaemia
Normochromic normocytic anaemia due to ↓ EPO production, worsens as GFR falls
Uraemia
Shorter RBC lifespan
Iron deficiency also common
poor absorption
uraemia-related bleeding, dialysis
impaired release from body stores
Uraemia

61. Hypertension Vicious cycle:
Common cause of CKD – glomerular + renal vasculature damage, decreased filtration gradient
CKD exacerbates HTN via volume expansion and increasing systemic vascular resistance
In non-diabetic, non-proteinuric patient: BP <140/90
In proteinuria (diabetes or not): BP<130/80
ACE inhibitors - first line
Large portion of total blood flow through kidneys, efferent arteriole constricts to maintain GFR

62. Bone Mineral Disease Raised phosphate – not excreted by kidneys
Release of FGF23
Increases phosphate excretion
Inhibits 1-α Hydroxylase
Overall low 1-α Hydroxylase production from CKD + Inhibtion by FGF23
Very confusing, lots of chemical mediators - this is the hyperparathyroid bone disease, other types exist – definitely do not need to know
High phosphate in itself lowers ionised calcium – binds to it forming Calcium phosphate which is not usable
Cardiovascular – increased calcification as raised phosphate binds to ionised calcium, and deposits in arteries
Decreased 1,25(OH) Vit D production
Main function = Increase serum ionised calcium (gut, kidney, bone)

63. Bone Mineral Disease Increased Parathyroid Hormone (PTH)
low serum ionised calcium
low 1,25(OH) Vit D
Increased Parathyroid Hormone (PTH)
Secondary hyperparathyroidism
Increased calcium reabsorption (bone + kidney)
Increased osteoclast activity
Presentation
Lytic bone erosions/cysts – ‘Moth-eaten appearance’
’Pepper-pot’ skull
Fractures – limbs + spine
Bone pain

64. Polycystic Kidney Disease
Autosomal dominant (1 in 1000)
Dysfunction in PKD genes
Protein involved in renal tubular and vascular development (+liver, brain, elsewhere)
Accounts for 10% of people on dialysis, renal failure aged 40-60
Presentation:
Polyuria
Loin pain
Hypertension
Enlarged bilateral kidneys
Frank haematuria following trauma
Autosomal recessive form – much more rare
Protein – called polycystin
Polyuria – issues with urine concentrating capacity
Supportive treatment, close monitoring

66. Management Surgical Transplant Conservative Exercise
Strict diet – low potassium, low phosphate
Medical
Treat complications
Extremely tight BP + glucose control
Phosphate binders
Renal replacement
Surgical
Transplant

67. Renal Replacement
Aims to mimic excretory function of normal kidney, not suitable for all
Haemodialysis
Formation of AV fistula
Blood separated from dialysis fluid by semi-permeable membrane, allowing diffusion down concentration gradient + continuous heparin infusion
Hypotension, access-related infection, N&V, headaches
Peritoneal Dialysis
Uses peritoneum as the semipermeable membrane, low tech, requires some residual renal function
Dialysis fluid placed in the peritoneal cavity, regularly changed
Peritonitis, catheter site inflammation
AV fistula – lower resistance vs capillary bed, so higher volume flow rates, theoretically less likely to stenose compared to synthetic grafts
Use a central vein (subclavian, jugular, femoral) if needed in an emergency
Peritoneal – continuous ambulatory (constantly present, changed 3-5x/day), Nightly (done automatically by machine whilst pt asleep),
Transplant – definitive tx, cadaveric or live (better donors) – 10 year survival 70-90%, acute rejection + complications less common

68. What CKD stage is a patient with GFR 38?
3b, Moderate-Severe
What CKD stage is a patient with GFR 61, with no symptoms of renal disease?
They do not have CKD
What is the most common cause of CKD?
Diabetes
Name 5 drugs that commonly cause AKI?
Contrast
ACEi
NSAIDs
Diuretics
Antibiotics – particularly..?