AKI & CKD Josh Exley

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

Normal Kidney function

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

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

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

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

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)

Acute Kidney Injury

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

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

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

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)

Causes of AKI Pre-Renal Renal Post-Renal

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

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

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 80-170 systolic NSAIDs and ACEi interfere with this – see later

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)

Post Renal 1-10% 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

Post-Renal BPH Tumours Calculi Neuropathic

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

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

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

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

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

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

Investigations Chest Xray Renal Ultrasound Immunology Myeloma screen Renal biopsy

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

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

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

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

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

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

Drugs and the kidney

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

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

Assessment of Renal Function Creatinine Clearance eGFR

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

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

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

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

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

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

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

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

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

CKD

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

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

Some reduction in GFR as we age is normal

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

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

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

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 http://jasn.asnjournals.org/content/23/10/1631.full Uraemia

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

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)

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

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

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

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

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..?