Kidney Physiology Lecture PDF

Kidney Physiology Lecture Presented by Ronald Castelino A/Prof in Clinical Pharmacy [email protected] The University of Sydney Page 1 The University of Sydney Page 2  LEARNING OBJECTIVES – The aim of this session is to provide you with enhanced knowledge and skills to...

Kidney Physiology Lecture Presented by Ronald Castelino A/Prof in Clinical Pharmacy [email protected] The University of Sydney Page 1 The University of Sydney Page 2  LEARNING OBJECTIVES – The aim of this session is to provide you with enhanced knowledge and skills to assess patient’s renal function and manage patients with chronic kidney disease, end stage kidney disease and acute kidney injury. It will also provide an introduction to renal replacement therapy. – Lecture 1& 2 – List the main functions of the kidney – Describe & interpret the tests used to investigate kidney function – Acute Kidney Injury (AKI) The University of Sydney Page 3  URINARY SYSTEM – Kidneys x 2 – Urinary bladder – temporary storage for urine – Ureter x 2 – urine transport: kidney to bladder – Urethra – urine from bladder to external The University of Sydney Page 4  – What are the functions of the kidney? The University of Sydney Page 5  – Functions of the kidney – Excretory functions – Endocrine functions – Regulatory functions – Metabolic functions The University of Sydney Page 6 ― Kidneys-Two sections ― Outer cortex ― Inner medulla ― The functional unit of the kidney is Nephron ― Approximately one million in each kidney ― capable of forming urine ― Two major components: – Glomerulus – Tubular system Proximal tubule Diluting segment Distal tubule Collecting duct The University of Sydney Page 7 The University of Sydney Page 8  Arcuate branches ― Renal blood supply: ― 20% of the cardiac output ― Blood flow to the medullary region is poor at the best of time; risk of hypoxia significant Afferent ― Vascular supply: arteriole ― renal arteries— interlobar arteries— Efferent arcuate arteries— interlobular arteries Arteriole ― afferent arterioles— glomerular capillaries—efferent Peritubular arterioles—peritubular capillaries capillaries The University of Sydney Page 9  Steps in urine formation ― Filtration: ― Filtration only takes place in the renal corpuscle. ― 180 liters of fluid is filtered by the nephrons in one day!! ― Reabsorption ― Reabsorption occurs when filtered material is moved back into the blood, ― Secretion ― while secretion removes selected material from the blood and places it in the filtrate. The University of Sydney Page 10 11 The University of Sydney Page 11 12 The University of Sydney Page 12  ― The glomerulus is a high-pressure filtration system composed of a specialized capillary network. ― Blood supplied to the glomerulus through the Afferent Arterioles (AA) and removed by the Efferent Arterioles (EA) ― Large molecules are generally unable to pass through the glomerular membranes ― It generates an ultra filtrate that is free of blood and significant amounts of blood proteins. ― Ultra filtrate passed into the tubular system for processing eg reabsorption of water & electrolytes, regulation of concentration, etc ― Glomerular filtration rate (GFR) is a key marker of renal function ― Index of renal function would thus ideally measure GFR The University of Sydney Page 13  GFR usually maintained by factors such as cardiac output, SNS tone, blood pressure, vascular volume, etc Glomerulus Afferent arteriole Efferent arteriole Urine Output The University of Sydney Page 14  Reduction in any of these drivers will lead to reduced GFR and hence urine production Glomerulus Afferent arteriole Efferent arteriole The University of Sydney Page 15  ― A feedback mechanism that keeps renal blood flow (RBF) and GFR constant despite changes in arterial blood pressure. ― As RBF increases, GFR increases, leading to an increase in NaCl delivery to the macula densa. ― a feedback loop through the macula densa to the juxtaglomerular cells of the afferent arteriole results in increased vascular tone, decreased renal blood flow and a decrease in GFR. ― NaCl to the macula densa then decreases leading to relaxation of the afferent arteriole (increasing glomerular hydrostatic pressure) and increases renin release from juxtaglomerular cells of afferent and efferent arterioles ― renin increases angiotensin I, then converted to angiotensin II which constrict efferent arteriole increasing hydrostatic pressure returning GFR to normal The University of Sydney Page 16  The kidneys have inbuilt physiological defense measures to counteract reduced inflow using Prostaglandins and Angiotensin II In conditions of stress to the kidneys (eg CKD, DM, HTN, CCF) these mechanisms become increasingly important to maintain GFR. PGs ATII Glomerulus Efferent arteriole Afferent arteriole Constriction Dilation The University of Sydney Page 17  Physiology of renal blood flow The University of Sydney Page 18  Urine = GF –TR+ TS The University of Sydney Page 19 The University of Sydney Page 20  Urine = GF –TR+ TS The University of Sydney Page 21  + - arterial pressure Glomerular hydrostatic pressure GFR Proximal tubule NaCl reabsorption macula densa NaCl renin angiotensin II afferent arteriolar efferent arteriolar resistance resistance The University of Sydney Page 22 The University of Sydney Page 23  Q&A The University of Sydney Page 24 Evaluation of Kidney Function Presented by Ronald Castelino A/Prof in Clinical Pharmacy [email protected] The University of Sydney Page 25 The University of Sydney Page 26  Evaluate organ function Determine extent of kidney disease (stage) Determine appropriate management (action plan) if kidney disease is an issue Determine appropriate dose for drugs excreted through the kidney Prevent further damage by using nephrotoxic agents The University of Sydney Page 27  Glomerular filtration rate (GFR): is the rate (volume per unit of time) at which ultra filtrate is formed at the glomerulus. GFR primary measure of renal function & hence critical knowledge to evaluate drug dosage Normal is 100 to 120 ml/min Cannot be measured directly An Ideal filtration marker should be filtered with no reabsorption or secretion Filtration markers: Exogenous (e.g. Inulin, sinistrin, iohexol, iothalamate) Endogenous (e.g. Serum Creatinine, Cystatin C) The University of Sydney Page 28  – Creatinine – Urea – Substances which we measure that give approximations Note: Albuminuria and Haematuria are signs of kidney damage and may also used in the diagnosis of kidney diseases The University of Sydney Page 29  Urea End product of protein and amino acid catabolism – serum urea concentrations are influenced by both rate of protein breakdown and renal urea excretion Filtered at glomerulus & reabsorbed in tubules (40-60%) A relatively insensitive marker of renal function Usually measured along with serum creatinine The University of Sydney Page 30  Reference Interval for Creatinine Male 60-120 micromol/L Female 50-110 micromol/L Waste product of muscle metabolism — formed by the liver via breakdown of creatine (from muscle) — usually produced at a constant rate dependent on muscle mass Excreted by kidney - glomerular filtration (10% via secretion) — SCr is both a reflection of both muscle mass and kidney function — SCr is inversely proportional to glomerular filtration rate — doubling of SCr (even within the reference range) represents a 50% reduction in renal function Good indicator of renal function (better than urea) The University of Sydney Page 31 The University of Sydney Page 32 Serum Creatinine may be quite misleading as the sole measure of renal function Alternative methods of evaluation necessary eg Creatinine Clearance, eGFR The University of Sydney Page 33  Case Examples – Example 1: – An 80 year old, 172 cms height, 70 kgs and a SCr of 100 micromol/L will have a creatinine clearance (CrCl) of 52 ml/min – A 20 year old, 172 cms height, 70 kgs and a SCr of 100 micromol/L will have a CrCl of 104 ml/min – Example 2: – Mrs SP presents to RHH with throbbing headache & nausea. She is 32 years old, 60kgs, 165 cms – PMH: liver transplant at 2, previous rejection, migraine, depression & reflux – On tacrolimus 3mg m & 2mg n, amitriptyline 25mg n, esomeprazole 40mg m, prednisolone 7mg m, nicotine patches The University of Sydney Page 34  Case Examples – Example 2 Continued: – GP ordered tacrolimus levels. Tacrolimus levels were 37.8 micrograms/L (very high-so referred to RHH) – Patient states that she bought fluconazole for thrush from pharmacy – SCr: 51 micromol/L (Day 1), 96 micromol/L (Day 2) – CrCL: 133 ml/min (Day 1), CrCl: 70 ml/min The University of Sydney Page 35  (140- Age (yrs)) X Weight (kg) Creatinine Clearance = (ml/min) 0.815 X Serum Creatinine(micromol/L) X 0.85 for women Assumptions: relatively stable renal function; normal muscle mass for age, sex, weight; Recommended for renal dosing of medications Not corrected for BSA The University of Sydney Page 36  IBW needed for Cockcroft & Gault calculation as creatinine produced by muscles, and hence relies on muscle mass only IBW men (kg) = 50 + (0.9 x height in centimetres > 152 cm) IBW women (kg) = 45.5 + (0.9 x height in centimetres > 152 cm) Note: if individual is under IBW, use actual body weight in calculation (not IBW) The University of Sydney Page 37  Grade Creatinine Clearance Mild 25-50 mL/min Moderate 10-25 mL/min AMH 2021 Severe 60mL/min/1.73m2 – More appropriately categorises individuals with respect to long-term clinical risks of end-stage kidney disease, CHD, stroke and all cause mortality than MDRD. – Has now replaced MDRD equation as the automated eGFR reporting – Is reported with every request for SCr in individuals aged 18 years or more. – Other newer markers such as Cystatin C and U-NGAL are available in other countries – Currently not used in Australia The University of Sydney Page 39  – Protein and albumin – Evaluation of urinary protein or albumin is now a standard tool to characterize the severity of CKD and to monitor the rate of disease progression – Excessive amounts of proteins in the urine also indicates increased cardiovascular risk – Persistent proteinuria or albuminuria that is present on at least 3 occasions over a period of 3 to 6 months is now considered a principal marker of kidney damage The University of Sydney Page 40  – Urine ACR predicts renal and CVD risk – Urine ACR is more sensitive than Protein: Creatinine Ratio (PCR) – Albuminuria is present if two out of three ACR tests are positive – CKD is present if albuminuria is persistent at least for 3 months – Hematuria – In many people, haematuria is related to menstruation or UTI – Persistent haematuria, or haematuria in conjunction with other indicators of kidney damage needs further investigation – Dipsticks may be used as a screening The University of Sydney Page 41 The University of Sydney Page 42 The University of Sydney Page 43  – Factors other than CKD known to increase albuminuria – Urinary tract infection (UTI) – High protein intake – CCF – Heavy exercise (within 24 hours) – Drugs (NSAIDs) – Hematuria – In many people, haematuria is related to menstruation or UTI – Persistent haematuria, or haematuria in conjunction with other indicators of kidney damage needs further investigation – Dipsticks may be used as a screening The University of Sydney Page 44  Drug Dosage Adjustment in Kidney Impairment – Dose reduction of some drugs is recommended for people with reduced kidney function – eGFR provides a valid estimate of kidney drug clearance and is widely available on laboratory reports. – If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. – For drug dosing in very large or very small people, it may be preferred to calculate an eGFR that is not normalised to 1.73m2 body surface area (BSA). The University of Sydney Page 45  Drug Dosage Adjustment in Kidney Impairment – eGFR provides a valid estimate of kidney drug clearance and is widely available on laboratory reports. – For most drugs in clinical practice eGFR vs CG equations has no major difference in dosage recommendations – Caution is advised in special groups (amputees, obesity, pregnancy) or when dealing with narrow therapeutic index drugs – Important to focus on the patient-related, disease-related and medication-related characteristics and use clinical judgment The University of Sydney Page 46  Q&A The University of Sydney Page 47 Kidney Disease: Acute Kidney Injury Presented by Ronald Castelino A/Prof in Clinical Pharmacy Renal Pharmacist, Blacktown Hospital, NSW [email protected]; [email protected] The University of Sydney Page 48 The University of Sydney Page 49  LEARNING OBJECTIVES – Understand the categorisation of the causes of AKI – Identify risk factors for AKI – Identify medications associated with AKI – Formulate preventive strategies to decrease the risk of developing AKI – Formulate a therapeutic plan to manage AKI and its complications – Prerequisites Before commencing this session you should have an understanding of: kidney blood flow, glomerular filtration and plasma clearance Tubular function and urine production The University of Sydney Page 50 Acute Kidney Injury / Renal Failure The University of Sydney Page 51  – Abrupt decline in renal function leading to an increase in serum concentrations of urea, creatinine & other substances (occurs over a period of days) – Common - occurs in 2% to 7% of all hospital admissions – and in up to 36% to 67% of critically ill patients – very common amongst the elderly – may occur in someone either with previously normal renal function or as an acute and unanticipated deterioration in function in a patient with previously established chronic kidney disease (“acute on chronic”) The University of Sydney Page 52 The University of Sydney Page 53 The University of Sydney Page 54 The University of Sydney Page 55  AUSTRALIAN CRITERIA FOR AKI The University of Sydney Page 56  STRATIFICATION OF AKI The University of Sydney Page 57  Diagnosis of AKI The University of Sydney Page 58  Estimating Kidney Function in AKI – Difficult because commonly used SCr based equation are not appropriate (assume stable SCr) – Other equations such as Brater and Jeliffe may be more accurate than Cockcroft-Gault but less tested The University of Sydney Page 59  Three categories of AKI – Pre-renal (40-80% of cases) – diseases characterized by renal hypo perfusion in which the integrity of renal parenchymal tissue is preserved – Intra-renal or intrinsic (10-50% of cases) – diseases involving renal parenchymal tissue – Post-renal or obstructive (160mg frusemide), but cease if no response – for AIN, avoid offending agent in future The University of Sydney Page 71 72 The University of Sydney Page 72  – Post-renal – relieve obstruction – All patients with significant AKI also require attentive management of volume, electrolyte (esp K+) and acid- base status, and nutrition – Renal replacement therapy (RRT, dialysis) may be required in cases of severe AKI (hyperkalaemia, volume overload, severe acidosis, or overt uraemia) The University of Sydney Page 73 74 The University of Sydney Page 74  – Severe hyperkalaemia (K+ >6.5 mmol/L) is a medical emergency because of the risk of life threatening cardiac arrhythmias The University of Sydney Page 75  Problem Management Fluid volume disturbance Rehydrate (hypovolaemic); withhold fluid/high dose diuretic (hypervolaemic); dialysis (resistant pulmonary oedema) Metabolic disturbances Hyperkalemia IV calcium; bicarbonate; glucose+insulin; ion exchange resin; dialysis Acidosis Bicarbonate; dialysis Uraemic symptoms Dialysis Infection Antibiotics Nutritional deficiencies Enteral nutrition; parenteral nutrition; dialysis The University of Sydney Page 76  – Optimising drug therapy for patients with AKI is challenging – Factors that need considerations include; residual drug clearance, accumulation of fluids, and dialysis. – For renally cleared drugs (>30% elimination unchanged in the urine), particularly for drugs with narrow therapeutic range, serum drug concentration and pharmacodynamic response is necessary. The University of Sydney Page 77  Q&A The University of Sydney Page 78  Case Examples – An 84-year-old lady was admitted to a major teaching hospital with complaints of chest pain. Cardiac issues were ruled out following ECG and Troponins. She was diagnosed to have GORD and 2was also noted to have an AKI on admission (eGFR: 14ml/min/1.73m 2. ). Previous GP results 6 months ago was 54ml /min/1.73m – Was discharged with Esomeprazole 40mg BD, Gaviscon 20ml TDS prn with a discharge eGFR of 24ml – Aprrox 5 months later presents to Blacktown hospital with similar complaints. eGFR:12ml – Medication history reports 6-8 tabs of QuickEze (each with 750mg Calcium), taking Gaviscon and also Vitamin D 2 Caps for osteoporosis – Diagnosis: Calcium Alkali Syndrome, treated with Pamidronate and hydration. Discharge eGFR of 52ml/min – Clinical Tip: Always ask for OTC and other drugs – https://onlinelibrary.wiley.com/doi/epdf/10.1002/jppr.1873 The University of Sydney Page 79