Kidney disease

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

Functions of the kidney

• Excretory functions

  • metabolic wastes: urea, creatinine

  • Excretion of bioactive substances (hormones, foreign substances, drugs)

  • Toxins

• Endocrine functions

  • Erythropoietin

  • Renin

  • Prostaglandins

• Regulatory functions

  • Water balance

  • Electrolyte balance & acid-base balance

    • Sodium

    • Potassium

    • Chloride

    • Bicarbonate

    • Calcium

    • Magnesium

• Metabolic functions

  • Vitamin D (1 alpha,25 dihydroxy cholecalciferol)

  • Vitamin D is produced from the skin

The kidney

• 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

Renal anatomy

Renal physiology

Steps in urine formation

• Filtration:

  • Filtration only takes place in the renal corpuscle.

  • 180 litres 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.

Filtration (golmerular function)

• 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

Physiology of renal blood flow

GFR usually maintained by factors such as cardiac output, SNS tone, blood pressure, vascular volume, etc

Reduction in any of these drivers will lead to reduced GFR and hence urine production

• 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 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.

Assessment of kidney function

• 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 kidney function & hence critical knowledge to evaluate drug dosage

• Normal is 100 to 120 ml/min

• Filtration markers:

  • Exogenous (e.g. Inulin)

  • Endogenous (e.g. Serum Creatinine, Urea)

Endogenous markers

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

Creatinine:

• 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)

Drug dosing in kidney disease

• GFR is the key clinical measure of kidney function.

• In general, for drugs that are excreted by the kidney, a decrease in GFR is associated with a decrease in drug clearance and the dosage needs to be reduced.

• The GFR can be quantitated in multiple ways.

  • Each has advantages and disadvantages.

• The measured GFR (mGFR) is the gold standard, but it is resource intensive and expensive.

• So, the estimated GFR (eGFR) is used to classify and monitor the severity of chronic kidney disease

• This adjustment depends on the severity of the disease and what proportion of the drug is eliminated by the kidneys.

• The estimated glomerular filtration rate can generally be used to guide dose adjustment in patients with stable kidney function.

• However, the formula can be misleading in some patient subsets and other approaches are required.

• At extremes of body mass, the estimated glomerular filtration rate can under- or overestimate kidney function. It may need to be adjusted for body surface area, particularly for drugs with a narrow therapeutic range.

Serum creatinine-based formulae

• GFR can be assessed using serum creatinine-based formulae – Cockcroft-Gault and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).

IBW:

men: 50 + (0.9 x height cm> 152cm)

women: 45 + (0.9 x height cm> 152cm)

CG formula

• CG Formula is not routinely used currently

• Because eCrCl was validated against measured CrCl based on 24-hour urine collection, it overestimates the actual GFR given that creatinine is both filtered and secreted in the nephron tubules.

• By 2010 most laboratories in Australia were using a newer creatinine assay standardised to isotope dilution mass spectrometry (IDMS) which resulted in a 10–20% decrease in creatinine concentrations.

• Therefore, there will increase the eCrCl compared to what would have been calculated pre-2010.

• May be recommended for some select drugs (e.g. Dabigatr

eGFR-CKD-EPI

• The CKD-EPI formula estimates GFR because it was validated against GFR measured using exogenous filtration markers.

• It incorporates age and sex into a relatively complicated formula.

• eGFR is automatically calculated and reported by the laboratory.

• The units for the automated eGFR are mL/min/1.73 m2

Which formula to use for drug dosing

• Important to note neither is a perfect representation of the true value of the GFR.

• Second, the eCrCl and automated eGFR do not give exactly the same results and eCrCl generally overestimates mGFR.

• For patients with a body surface area that is substantially different from 1.73 m2, the eGFR can be de-indexed to give units of mL/minute

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

• Depends upon proportion of drug eliminated by the kidney, risk of adverse effects, duration, and if the drug has active or toxic metabolites that rely on kidney for elimination

• Dose adjustment in kidney impairment usually involves increasing dosing interval or reducing dose

• Important to focus on the patient-related, disease-related and medication-related characteristics and use clinical judgment

Drug dosing consideration in AKI

• Optimising drug therapy for patients with acute kidney injury (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.

Acute kidney injury (AKI) (acute renal/kidney failure, ARF)

• 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”)

Major risk factors for acute kidney injury (AKI)

Stratification of AKI

Diagnosis of AKI

Types of AKI-pathophysiology

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 (<10% of cases)

  • diseases associated with acute obstruction of the urinary tract (i.e. ureters, urethra etc)

ACE I and NSAIDs

ACEI & ARBS block ATII which dilates the efferent arteriole and decreases glomerulus filtration pressure

NSAIS block prostaglandins which then constricts the afferent arteriole

Clinical manifestations

• frequently occur late in the course and are often not apparent until renal dysfunction has become severe

  • early signs often non-specific and occur in addition to other clinical conditions

  • hypertension, oedema (esp. in patients who are fluid overloaded)

  • anorexia, fatigue, nausea and vomiting, and pruritis (uremia)

  • a decline in urine output or dark-coloured urine oliguria and/or anuria

Note: High mortality – non-oliguric AKI better prognosis

AKI: prevention (SADMANS)

• Identification of high-risk individuals

• Optimisation of renal perfusion

  • volume expansion and/or fluid therapy where appropriate

  • vasopressors (e.g. adrenaline, dopamine) may be used once intravascular volume has been restored (patchy evidence however)

• Avoidance of nephrotoxins wherever possible (and close monitoring when not)

  • includes drugs, and combinations of drugs, e.g. triple whammy

• Specific circumstances (examples)

  • once daily dosing of aminoglycosides

  • allopurinol and rasburicase to prevent tumour lysis syndrome

  • Amphotericin whenever possible; limiting dose, rate of infusion.

• Recognise that patients with pre-existing renal impairment are at higher risk of developing further renal insufficiency—treat and monitor accordingly

• Temporarily withhold nephrotoxins (especially ACE-I, ARBs, NSAIDs) and diuretics (to prevent dehydration) when patients become unwell—either in the community or in hospital

• SADMANS group of drugs

• Ensure that patients remain adequately hydrated, to maintain renal perfusion

• Remember to monitor renal function after starting, or increasing the dose, of ACE-I or ARBs (check one to two weeks later)

• Where necessary, adjust drug doses in patients with renal impairment

• Monitor drug levels when using aminoglycoside (gentamicin) and/or glycopeptide (vancomycin) antibiotics - and adjust dose accordingly

• Hydrate the patient and consider using N-acetyl cysteine before procedures entailing radiological contrast media

AKI: management

The most important step is to reverse the cause (which will depend on the type of AKI)

• Pre-renal

  • improve perfusion, remove offending medications

• Intrinsic

  • treatment of ATN primarily supportive

    • no specific therapeutic intervention has been found to hasten recovery of kidney function

  • use of diuretics to convert patients from oliguric to nonoliguric ATN not associated with improved outcomes

    • may be helpful in volume management (need high doses e.g. >160mg frusemide), but cease if no response

  • for AIN, avoid offending agent in future

• Post-renal

  • relieve obstruction

• All patients with significant AKI also require attentive management of volume, electrolyte (esp K+) and acidbase status, and nutrition

• Renal replacement therapy (RRT, dialysis) may be required in cases of severe AKI (hyperkalaemia, volume overload, severe acidosis, or overt uraemia)

Management of hyperkalaemia + other AKI complications

(blood potassium levels are too high and can cause life-threatening heart arrhythmias, muscle weakness, and paralysis)

• Severe hyperkalaemia (K+ >6.5 mmol/L) is a medical emergency because of the risk of life threatening cardiac arrhythmias

Chronic kidney disease (CKD)

• CKD is defined as kidney damage or GFR below 60ml/min/1.73m2 for 3 months or more irrespective of the cause.

• CKD is

  • a long-term health condition (months/years), preventable in many cases

  • glomerular & tubular damage

  • asymptomatic until much of the kidney function is lost

  • compensatory and adaptive mechanisms maintain acceptable health until GFR is ~10 to 15 ml/min

CKD: risk factors

CKD: major causes

Clinical manifestations

CVD in patients with CKD

General Management

Management of CKD

Preserving renal function: hypertension

• both symptomatic of advanced CKD and pathogenic

  • lowering BP delays the rate of progression

• ACEIs/AT2RAs are generally the best agents (esp in diabetic nephropathy), CCB (dihydropyridine) are also preferred.

• most patients will require at least 2 drugs, probably more

• Key take home message: ACEis/ARBs are first line agents in patients with CKD but can also be nephrotoxic.

• As long as kidney function does not deteriorate by more than 25% (eGFR) of baseline within 2 months of initiation they are ok to continue.

• OR potassium does not exceed by 6mmol/L they are ok to continue. They are renoprotective in the long run

Preserving renal function: proteinuria/albuminuria

• degree of proteinuria correlates with rate of progression , and is the most reliable prognostic factor in CKD

  • absence of significant proteinuria or remission indicates favourable prognosis

• low-protein diets are not promoted (little benefit)- but avoid high protein diets (aim for 0.6-0.8g/kg/day)

Management:

• ACEI/ARBs, reduce salt, SGLT2i, Finerenone

Lipids and CKD

• CKD is associated commonly with substantial abnormalities of lipid metabolism, including increased LDL, TG, VLDL, and reduced levels of HDL cholesterol.

• Dyslipidaemia is more severe in individuals with albuminuria

• Management:

  • Evaluate lipid profile in newly diagnosed CKD

  • If aged ≥50 years with any stage of CKD (irrespective of lipid levels)

    • Statin if eGFR is > 60 mL/min/1.73m2

    • Statin/ezetimibe combination if eGFR is ≤ 60 mL/min/1.73m2

  • If aged < 50 years with any stage of CKD (irrespective of lipid levels):

    • Statin if presence of one or more of: coronary disease, previous ischaemic stroke, diabetes or estimated 10-year incidence of fatal or non-fatal myocardial infarction above 10%

Glucose control

Four pillars of diabetic kidney disease

Four pillars of kidney disease cont…

Metabolic acidosis

• Kidney essential in maintaining acid–base balanc

• usual symptom is SOBOE not explained by pulmonary oedema or anaemia

  • chronic acidosis in people with <30ml/min/1.73m2 also aggravates hyperkalaemia, inhibits protein anabolism & accelerates bone calcium loss and associated with increased morbidity

• seldom requires treatment unless

  • [bicarb] ~<15 mmol/l, pH ~<7.30,

• Sodium bicarbonate (SodiBic 840mg capsule) occasionally used

  • Typical starting dose 1 cap od/bd increasing up to 2 bd if needed to keep bicarb >22mmol/L

  • but carries a substantial sodium load

  • typically not required in dialysis

Hyperkalaemia management

• If K+>7.0 mmol/L (3.5-5.0 mmol/L) → ECG changes → → cardiac arrest

  • Calcium gluconate 10% (10-20mL) IV → stabilises myocardium

  • Insulin (soluble) 10-20 units + glucose 50% (50mL) → stimulates K+ uptake into cells

  • Sodium (or calcium) resonium 15g TDS-QID po or enema → binds potassium & releases calcium

• Chronic:

  • removal of drugs contributing to hyperkalaemia

  • reducing potassium dietary intake

  • Correct acidosis

  • increasing potassium elimination

    • K+ wasting diuretics (thiazides/loop)

    • cation exchange resins (polystyrene sulfonate, Resonium )

Managing complication - vitamin D and phosphorous metabolism

• Kidney intricately involved in bone metabolism

  • phosphate excretion

  • vitamin D activation

• Abnormalities in these parameters results in

  • bone pain, increased incidence of bone fractures and deformity, myopathy and muscle pain, and ruptures of tendons

  • calcification in lungs (impaired pulmonary function, pulmonary fibrosis & hypertension, right ventricular hypertrophy, and cor pulmonale),

  • heart and coronary arteries (IHD and CHF),

  • other vascular sites

• May be evident with GFR <40mL/min

• Goals of treatment

• maintain near-normal [Ca 2.2-2.6mmol/L] and [PO4 0.8-1.5mmol/L]

• prevent secondary hyperparathyroidism

• Management strategies

• dietary phosphate restriction

• PO4--- binding agents

• vitamin D therapy

• calcimimetics

• dialysis

Managing complication - vitamin D and phosphorous metabolism: phosphate and calcium management

Phosphate management:

• dietary restriction of protein often reduces PO4 intake

• PO4 binding agents

  • Binds to dietary phosphate to prevent absorption

  • Calcium containing preparations (e.g. CaCO3)

  • Sevelamer & Lanthanum available for patients on dialysis

  • Aluminium hydroxide (not first line due to accumulation and risk of encephalopathy)

Calcium:

• If phosphate is controlled, calcium will typically remain in normal range

• If level is low with normal phosphate consider vitamin D supplementation

• Hypercalcaemia associated with increased risk of vascular calcification

Vitamin D therapy (calcitriol, paricalcitol):

• suppresses PTH secretion and stimulates GI calcium absorption

• care to avoid hypercalcaemia (less risk with paricalcitol) – monitor levels closely

• If kidney function is still intact cholecalciferol can be used

• Cholecalciferol may still be used for 25OH Vitamin D deficiency including in combination with calcitriol in advanced CKD

Calcimimetics (cinacalcet)

• rapidly suppresses PTH secretion without increasing calcium absorption (risk of hypocalcaemia)

• Cinacalcet can be used to treat hyperparathyroidism for individuals on dialysis

• PBS delisted from August 2015

Managing complication - anaemia

• Anaemia common in CKD

  • Due to reduced EPO synthesis

  • Reduced absorption of iron

  • Resistance to the action of erythropoietin stimulating agents (ESA)

• Targets:

  • Hb 100-115g/L

  • Prior to commencing erythropoietin stimulating agents (ESA), trial of iron supplementation is recommended maintaining transferrin saturation (TSAT) >20% and ferritin between >100 μg/L

  • Once ESA commenced, maintain: Ferritin 200-500 μg/L; TSAT 20-30%

• Treatment can decrease morbidity/mortality, reduce LV hypertrophy, increase exercise tolerance, increase QOL

• May sometimes respond to Fe infusions, but commonly managed using ESA

  • Use ESA cautiously- higher Hb levels associated with increased risk of cancer, death, cardiovascular events, and hospitalisation for CHF

  • Hb should not exceed 130 g/L (increased risk of CV events)

  • Note: AMH recommends not to exceed 120g/L

  • TREAT (Trial to reduce cardiovascular events with Aranesp Therapy) failed to show a benefit in outcomes, but treatment with ESAs was associated with increased stroke (NEJM 2009;361)

• Most patients using ESA will also require Fe, and potentially folate and/or B12

  • Ensure transferrin saturation 20%-30% and ferritin between 100 and 500μg/L

• 4 ESAs currently marketed in Aust:

  • Darbepoetin alfa (Aranesp)

  • Epoetin alfa (Eprex)

  • Epoetin beta (NeoRecormon)

  • Methoxy polyethylene glycol-epoetin beta (Mircera)

• All marketed for treatment of anaemia associated with CKD

• All appear to have similar efficacy, most differences related to duration of action, e.g. Eprex dosed twice weekly, Aranesp once weekly and Mircera once monthly

Determining when dialysis is needed

A mnemonic, AEIOU, is a simplified way for determining when dialysis needs to be initiated

• Acidosis refractory to medication

• Electrolyte abnormality (particularly hyperkalemia)

• Intoxicants that are removed through dialysis

• Overload (or volume overload) refractory to diuretics

• Uremia (which causes the symptoms of kidney failure)

Dialysis - general

• Progression of uraemic symptoms and/or hyperkalaemia will result in ESKD patients requiring dialysis or transplant

• Two main modalities exist

  • peritoneal dialysis (PD)

    • catheter is inserted into abdominal cavity

    • dialysate is run into abdomen and left for 30 minutes

    • run into a collecting bag »Multiple times per day

  • haemodialysis (HD)

    • blood (heparinised) pumped through dialyser (artificial kidney) and returned to patient.

    • Multiple times per week for hours

Haemodialysis

In hemodialysis, blood is pumped from the body through a machine where chemistries are balanced and waste and fluid are removed.

The blood is then returned from the machine to the body.

AV fistula:

• The preferred access for hemodialysis is an AV fistula.

• A surgical connection is made between an artery and vein.

• The high pressure and fast flow from the artery traverses through the newly connected vein.

• As the access matures, the vein gets larger. It will allow for placing two needles in the access and fast blood flow to facilitate dialysis.

• The enlarged vein allows for blood flow rates of > 400 mL / min.

Haemodialysis - advantages and disadvantages

Peritoneal Dialysis (PD)

Peritoneal dialysis can be done in two ways.

• Through manual exchanges, known as continuous ambulatory peritoneal dialysis (CAPD).

• Overnight, through a cycler, known as automated peritoneal dialysis (APD)

• The lining of the peritoneal cavity is covered in small capillaries that act as a natural filter.

• In peritoneal dialysis, a catheter is placed in this cavity to allow clean, chemically balanced fluid to be infused.

• This fluid helps draw out waste, balance chemistries, and remove excess fluid.

• The now dirty fluid is drained and replaced by clean fluid to start the process again.

Peritoneal Dialysis (PD) - advantages and disadvantages