Problem 3.12 Study Guide 1 Causes of Renal Failure 1. Discuss The Causes of Acute (Pre-Renal, Renal and Post-Renal) and Chronic Renal Failure
Problem 3.12 Study Guide 1 Causes of Renal Failure 1. Discuss The Causes of Acute (Pre-Renal, Renal and Post-Renal) and Chronic Renal Failure
Problem 3.12 Study Guide 1 Causes of Renal Failure 1. Discuss The Causes of Acute (Pre-Renal, Renal and Post-Renal) and Chronic Renal Failure
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Study Guide 1
Causes of renal failure
1. Discuss the causes of acute (pre-renal, renal and post-renal) and chronic renal failure
Renal failure refers to failure of excretory functions of kidney. It is usually, characterized by decrease in
glomerular filtration rate (GFR). If 50% of the nephrons are affected, GFR decreases only by 20% to 30%. It
is because of the compensatory mechanism by the unaffected nephrons. The renal failure may be either
acute or chronic.
Acute renal failure is the abrupt or sudden stoppage of renal functions. It is often reversible within few
days to few weeks. Acute renal failure may result in sudden life-threatening reactions in the body with the
need for emergency treatment. No time for the body to adjust to loss of kidney function
Causes:
Prerenal (70% of community-acquired acute kidney injury [AKI])
○ Volume loss (bleed, vomiting and diarrhoea, diuretics, primary hypoaldosteronism etc.)
○ ↓ cardiac output (AMI, cardiomyopathy, valvular cardiac disease, beta-blockers, high-output cardiac
failure etc.)
○ ↓ perfusion (renal artery and small vessel disease)
– Malignant hypertension, embolic disease, cyclosporin, transplant rejection, haemolytic uraemic
syndrome (HUS), vasculitis, ↑ calcium
Intrinsic renal (acute tubular necrosis [ATN] = 70% of hospital-acquired AKI)
○ Tubular disease (ATN, nephrotoxins, rhabdomyolysis)
○ Interstitial disease (sarcoid, SLE, infection, nephritis)
○ Glomerular disease (glomerulonephritis—Goodpasture's, SLE, post infections GN)
○ Vascular disease (malignant hypertension, scleroderma, HUS, PAN, renal vein thrombosis)
drug toxicity (e.g., aminoglycosides, amphotericin, cisplatin), and iodinated radiocontrast-induced
nephropathy. Contrast-induced nephropathy is the third most common cause of new-onset AKI in
hospitalized patients.
Postrenal
○ Urethra/bladder (benign prostatic hyperplasia [BPH], phimosis, stricture, cancer, nephrogenic bladder,
clot, trauma)
○ Ureter (vesicoureteral reflux, calculi, papillary necrosis, cancer, fibrosis, stricture, AAA, pregnant, IBD,
clot, trauma)
○ Infrarenal (crystals, protein casts)
Chronic renal failure:
Chronic renal failure is the progressive, long standing and irreversible impairment of renal functions. When
some of the nephrons loose the function, the unaffected nephrons can compensate it. However, when
more and more nephrons start losing the function over the months or years, the compensatory mechanism
fails and chronic renal failure develops.
CAUSES:
1. Chronic nephritis
2. Polycystic kidney disease
3. Renal calculi (kidney stones)
4. Urethral constriction
5. Hypertension
6. Atherosclerosis
7. Tuberculosis
8. Slow poisoning by drugs or metals.
2. Discuss the various stages of chronic kidney disease
and their clinical implications
The Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes
(KDIGO)guidelines state that CKD is defined by the presence of kidney damage or decreased kidney
function for three or more months, irrespective of the cause.
-Major marker of kidney damage or disease is micro albuminuria, most commonly used to assess
abnormal if albumin-to-creatinine ratio (ACR) is 30 mg/g (3.4 mg/mmol) or greater
-Glomerular filtration rate (GFR) is generally considered to be the best index of overall kidney function,
and declining GFR is the hallmark of progressive kidney disease. Dec GFR is <60ml/min per 1.73m2
Newer staging (up-to-date)
. In patients who are diagnosed with CKD using the criteria described above, staging of the CKD is done
according to :
●Cause of disease
Identifying the cause of kidney disease (eg, diabetes, drug toxicity, auto-immune diseases, urinary tract
obstruction, kidney transplantation, etc.) enables specific therapy directed at preventing further injury. In
addition, the cause of kidney disease has implications for the rate of progression and the risk of
complications
●Six categories of GFR (G stages)
●Three categories of albuminuria (A stages)
The addition of albuminuria staging to GFR staging is new since the original KDOQI classification scheme
was published . Albuminuria staging has been added because of the graded increase in risk for mortality,
progression of CKD, and ESKD at higher levels of albuminuria, independent of eGFR, without an apparent
threshold value (table at end with implication)
Older classification:mostly based on GFR levels (lecture)
-These three broad risk categories may help clinicians decide whether or not to refer their patients to a
nephrologist or specialist with expertise in caring for patients with CKD, and to develop a clinical action
plan
Epidemiology of renal failure in the Pacific. Prevention of kidney failure: what can be
done, and what are the limitations?
5.Discuss the major causes of renal failure in the surveys published in literature from the
pacific.
A questionnaire was sent to various countries in the Asian Pacific region and 10 countries responded. Data
from Australia and New Zealand was obtained from their registry report. The questionnaire requested
information on incidence, prevalence, transplantation rate, demographic data, causes of ESRD, causes of
death, and mortality rates for the years 1998 to 2000.
Diabetic nephropathy was the most common cause of ESRD in 9 of the 12 countries surveyed and 6 of the
12 countries had greater than 35% of their dialysis patients age 60 years and older
6.Compare the major causes of renal failure, found in the survey done twenty years ago
and from the survey done more recently
ACUTE
1. Dr. Ram’s – 1885
Medical causes of ARF (CWM hospital 1968 – 84)
7.Discuss reasons for the change in causes of renal failure over the last 20 years.
It has been argued that all industrializing societies undergo various "epidemiological transition" stages in
which the transition from Stage Two to Stage Three involves a change from "receding pandemics" to"
degenerative and lifestyle diseases". Continued globalization will mean that more populations in the
Pacific, and throughout the world, are adopting Westernized diets and lifestyles
The early studies by Prior and colleagues from throughout the Pacific Islands beginning in the 1960s clearly
showed that while diabetes was virtually non-existent in Polynesian populations maintaining a traditional
lifestyle, the reverse was true for the urbanized Polynesian populations
Due to rapid changes in lifestyle, risk factors such as obesity, unhealthy diets and physical inactivity have
become widespread throughout the region. This is particularly evident in the populations with the greatest
social and economic changes.
1983leptospirosis 1st AGN 2nd (ARF), CRFCGN, HTN, DM
1998DM 1st cause
Study Guide 2
1.Explain the two major aspects of renal acid-base balance and the role of the kidney in
maintaining a normal blood pH.
Every day, metabolism produces:
Volatile acid - 13 000mmol of CO2.
Fixed (non-volatile) acid- 50-80mmol of H+ [in the form of H2SO4, H3PO4, and NH4+].
The 2 major nephron events which regulate renal acid-base balance are:
1. Reabsorption of bicarbonate ions (HCO3 –)
2. Secretion of hydrogen ions (H+).
H+ is secreted into the lumen of proximal convoluted tubule, distal convoluted tubule and collecting duct.
Distal convoluted tubule and collecting duct have a special type of cells called intercalated cells (I cells)
that are involved in handling hydrogen and bicarbonate ions.
Secretion of H+ occurs by two pumps:
i. Sodium-hydrogen antiport pump - DCT
ii. ATP-driven proton pump – DCT & CD
About 4,320 mEq of HCO3 – is filtered by the glomeruli every day.
Chronic Vs Acute:
Acute:
-the PaCO2 is elevated above the upper limit of the reference range (ie, >45 mm Hg) with an accompanying
acidemia (ie, pH < 7.35)
Acute respiratory acidosis is present when an abrupt failure of ventilation occurs. Causes include::
- Central nervous system disease or drug-induced respiratory depression (HYPO)
- Inability to ventilate adequately, due to a neuromuscular disease or paralysis (eg, myasthenia
gravis, amyotrophic lateral sclerosis [ALS], Guillain-Barré syndrome, muscular dystrophy)
- Airway obstruction, usually related to asthma or chronic obstructive pulmonary disease (COPD)
Adaptation for Acute:
-Occurs within 5-10minutes
It originates exclusively from acidic titration of the body’s non-bicarbonate buffers (hemoglobin,
intracellular proteins and phosphates, plasma proteins):
CO2 + H2O ↔ H2CO3 ↔ HCO3- + H+
H+ + Buf- ↔ HBuf
where Buf- refers to the base component and HBuf to the acid component of non-bicarbonate buffers.
On average, plasma bicarbonate concentration increases by about 0.1 mEq/L for each 1 mmHg acute
increment in PaCO2; as a result, plasma hydrogen ion concentration increases by about 0.75 nEq/L for
each mm Hg acute rise in PaCO2
Chronic:
the PaCO2 is elevated above the upper limit of the reference range, with a normal or near-normal pH
secondary to renal compensation and an elevated serum bicarbonate levels (ie, >30 mEq/L)
Chronic respiratory acidosis may be secondary to many disorders, including COPD. Hypoventilation in
COPD involves multiple mechanisms, including the following:
-Decreased responsiveness to hypoxia and hypercapnia
-Increased ventilation-perfusion mismatch leading to increased dead space ventilation
-Decreased diaphragmatic function due to fatigue and hyperinflation
Adaptation for chronic: (basically kidney kicks in)
-requires 3-5days of sustained hypercapnia for completion
-upregulation of renal acidification mechanism in both proximal and distal segments of nephrons where:
Transient ↑ in urinary acid secretion (↑ ammonium excretion)
↑bicarb reabsorption
-transient ↑ in chloride secretionthis balances the ↑in bicarb conc in plasma leading to plasma anion
gap
On average, plasma bicarbonate concentration increases by about 0.3 mEq/L for each mm Hg chronic
increment in PaCO2; as a result, plasma hydrogen ion concentration increases by about 0.3 nEq/L for
each mm Hg chronic rise in PaCO2. Thus, at a given PaCO2 value, chronic adaptation provides better
defense of systemic acidity than acute adaptation
respiratory alkalosis: acute and chronic
Respiratory alkalosis is a disturbance in acid and base balance due to alveolar hyperventilation . Primary
hypocapnia is a synonymous term. PH > 7.45
Primary decreases in carbon dioxide production are generally attended by parallel decreases in alveolar
ventilation, thus preventing expression of respiratory alkalosis.
↑RR↓PaCO2 ↑bicarb (used up to buffer)/PaCO2 ratio↑PH
metabolic acidosis
is the acid-base imbalance characterized by excess accumulation of organic acids in the body, which is
caused by abnormal metabolic processes. Organic acids such as lactic acid, ketoacids and uric acid are
formed by normal metabolism
metabolic alkalosis
Metabolic alkalosis is the acid-base imbalance caused by loss of excess H+ resulting in increased HCO3-
concentration. Increased pH above 7.45
CAUSES:
1) Vomiting of gastric contents, due to loss of acids from
stomach in large amounts.
2) Increase in Aldosterone: Increased H+ loss in urine
3. Differentiate the metabolic acidosis in a patient with renal failure from someone with
diabetic ketoacidosis (DKA)
Normally, metabolic acids which are produced during normal daily metabolic reactions are excreted by the
kidney.
These excess H+ ions combine with PO4- or NH3 in the DCT and are eliminated in the urine.
In CRF, these H+ ions cannot be excreted: for the most part this is due to an inability on the part of the
kidney to produce NH3 in the DCT, which normally binds with secreted H+ ions to form NH4+ ion, for
excretion in the urine.
Thus, the acidosis of CRF results from an inability to excrete the normal complement of acids produced.
In ketoacidosis, on the other hand, metabolic acids are produced in abnormal amounts, by formation of
ketoacids during ketosis, and by formation of lactic acid during anaerobic metabolism in tissues poorly
perfused due to hypovolemia and dehydration.
Once adequate hydration is restored and the process of ketosis halted, these excess metabolic acids may
be eliminated by normal methods of excretion in the urine (or re-metabolized to their original substrate).
Study Guide 3
1. Discuss the physiological roles of calcium and phosphate
Calcium:
In a normal young healthy adult, there is about 1,100 g of calcium in the body. It forms about 1.5% of total
body weight. 99% of calcium is present in the bones and teeth and the rest is present in the plasma.
Approximately 99% of body calcium resides in the skeleton; the other 1% is present in the extracellular and
intracellular spaces. Normal blood calcium level ranges between 8.5 and 10.2 mg/dL/ 2.1-2.55 mmol/L or
4.1-5.2mEq/L
Types of calcium
in plasma: ionized/ diffusible (50%) vital for neural Act, muscle contraction, Cardiac activity, secretion
Non-ionize/ non-diffusibleas Ca bicarb (8-10%)
Calcium bound to albumin 40-42%
in bone: rapidly exchangeable calciumto maintain blood level
Slowly exchangeable/ stable calcium for bone remodelling
Calcium is very essential for many activities in the body such as:
1. Bone and teeth formation
2. Neuronal activity
3. Skeletal muscle activity
4. Cardiac activity
5. Smooth muscle activity
6. Secretory activity of the glands
7. Cell division and growth
8. Coagulation of blood.
Phosphate:
Phosphorus (P) is an essential mineral that is required by every cell in the body for normal function.
Phosphorus is present in many food substances, such as peas, dried beans, nuts, milk, cheese and butter.
Inorganic phosphorus (Pi) is in the form of the phosphate (PO4 ). Most of the phosphorus in the body is
found as phosphate. Phosphorus is also the body’s source of phosphate. In body, phosphate is the most
abundant intracellular anion.
IMPORTANCE OF PHOSPHATE
1. Phosphate is an important component of many organic substances such as, ATP, DNA, RNA and many
intermediates of metabolic pathways
2. Along with calcium, it forms an important constituent of bone and teeth
3. It forms a buffer in the maintenance of acid-base balance.
Total amount of phosphate in the body is 500 to 800 g. Though it is present in every cell of the body, 85%
to 90% of body’s phosphate is found in the bones and teeth. Normal plasma level of phosphate is 4 mg/dL.
2. Explain the roles of the following hormones in calcium and phosphate homeostasis
Vitamin D3
Calcitriol is a steroid hormone synthesized in kidney. It is the activated form of vitamin D. Its main action is
to increase the blood calcium level by increasing the calcium absorption from the small intestine
Calcitriol hormone increases absorption of phosphate from small intestine
Parathyroid hormone
The overall action of PTH is to increase plasma Ca++ levels and decrease plasma phosphate levels.
In the bone, PTH stimulates osteoclasts which break down the matrix of bone, releasing Ca2+ and PO4-
into the circulation, raising their levels.
In the intestine, PTH increases Ca2+ and PO4- absorption (as long as active vitamin D is present in
sufficient levels to facilitate this).
In the kidney, PTH stimulates reabsorption of Ca2+ and decreases reabsorption of PO4-, promoting PO4-
excretion.
The effect of this is to raise Ca2+ levels and decrease PO4- levels in the circulation.
Note that PTH also stimulates formation and release of calcitriol, the active form of vitamin D.
Calcitonin.
Calcium: It reduces the blood calcium level mainly by decreasing bone resorption
Phosphate: Calcitonin also decreases the plasma level of phosphate by inhibiting bone resorption and
stimulating the urinary excretion.
3. For three hormones in Q2, describe the
synthesis,
production or secretion,
the actions and effects on bone, intestine or kidneys
Parathyroid hormones
Produced at the parathyroid gland by CHIEF (PRINCIPAL) CELLS – non-granuler cells cell. clear cytoplasm,
large nucleus, contains mucous
Half-life and Plasma LevelParathormone has a half-life of 10 minutes. Normal plasma level of PTH is
about 1.5 to 5.5 ng/dL.
Synthesis
PTH secretion responds to small alterations in plasma Ca2+ within seconds through a unique Ca receptor
within the parathyroid cell plasma membrane senses changes in the extracellular fluid concentration of
Ca2+.
Prepro – PTH enter endoplasmic reticulum pro – PTH then enter Golgi body PTH
Metabolism
Sixty to seventy percent of PTH is degraded by Kupffer cells of liver, by means
of proteolysis. Degradation of about 20% to 30% PTH occurs in kidneys and to
a lesser extent in other organs.
Bone
Parathormone enhances the resorption of calcium from the bones
(osteoclastic activity) by acting on osteoblasts and osteoclasts of the bone.
Resorption of calcium from bones occurs in two phases:
i.Rapid phase
Rapid phase occurs within minutes after the release of PTH from parathyroid glands. Immediately after
reaching the bone, PTH gets attached with the receptors on the cell membrane of osteoblasts and
osteocytes. The hormone-receptor complex increases the permeability of membranes of these cells for
calcium ions. It accelerates the calcium pump mechanism, so that calcium ions move out of these bone
cells and enter the blood at a faster rate
ii.Slow phase
Slow phase of calcium resorption from bone is due to the activation of osteoclasts by PTH. When
osteoclasts are activated, some substances such as proteolytic enzymes, citric acid and lactic acid are
released from lysosomes of these cells. All these substances digest or dissolve the organic matrix of the
bone, releasing the calcium ions. The calcium ions slowly enter the blood. PTH increases calcium resorption
from bone by stimulating the proliferation of osteoclasts also.
Along with calcium resorption, PTH also increases phosphate absorption from the bones
Kidney
PTH increases the reabsorption of calcium from the renal tubules along with magnesium ions and
hydrogen ions. It increases calcium reabsorption mainly from distal convoluted tubule and proximal part of
collecting duct. PTH also increases the formation of 1,25- dihydroxycholecalciferol (activated form of
vitamin D) from 25-hydroxycholecalciferol in kidneys
Gastrointestinal Tract
PTH increases the absorption of calcium ions from the GI tract indirectly. It increases the formation of 1,25-
dihydroxycholecalciferol in the kidneys. This vitamin, in turn increases the absorption of calcium from GI
tract. Thus, the activated vitamin D is very essential for the absorption of calcium from the GI tract. And
PTH is essential for the formation of activated vitamin D.
Parathormone increases the absorption of phosphate from GI tract through calcitriol.
Vitamin D3
Liver form 25-hydroxyl cholecalciferolhas 2 isotopes vitamin D2 and D3..so D3 has high affinity
Kidney will form 1,25-dihydroxyl cholecalciferol as well as 24/25,dihydroxyl vit Dthese 24/25 inhibit prod
of VIT D3 (1,25 DOH). Cubulin, megalinabsorbed into kidney from urine
5. Explain how renal failure can lead to problems with calcium and phosphate
homeostasis.
Phosphate excretion falls in the very early stages of CKD. Retained phosphate then results in the release of
FGF23 and other phosphaturia agents by osteocytes as a compensatory mechanism.
FGF23 causes phosphaturia to bring the plasma phosphate level to within the normal range.
FGF23 also downregulates renal 1α-hydroxylase, reducing the action of activated vitamin D in increasing
intestinal absorption of phosphate. Despite consistently elevated levels of FGF23, phosphate levels in
blood will once again rise as CKD progresses
As CKD progresses, secondary hyperparathyroidism develops:
↓ renal production of 1α-hydroxylase ↓conversion of 25-(OH) 2D3 to active 1,25-(OH) 2 D 3
(1,25-dihydroxycholecalciferol).
1,25-(OH) 2 D 3 deficiency ↓ gut calcium absorption and fall in calcium.
↓ activation of vitamin D receptors in parathyroid glands by 1,25-(OH) 2 D3 increases the release of
PTH.
Retained phosphate also indirectly lowers ionized calcium (and probably directly via a putative but
unrecognized phosphate receptor), resulting in increased PTH synthesis and release.
PTH promotes reabsorption of calcium from bone and increased proximal renal tubular
reabsorption of calcium.
the rapid flow of tubular fluid through the collecting ducts prevents adequate water reabsorption
the rapid flow through both the loop of Henle and the collecting ducts prevents the countercurrent
mechanism from operating effectively to concentrate the medullary interstitial fluid solutes.
Therefore, as progressively more nephrons are destroyed, the maximum concentrating ability of the kidney
declines, and urine osmolarity and specific gravity (a measure of the total solute concentration) approach
the osmolarity and specific gravity of the glomerular filtrate.
The diluting mechanism in the kidney is also impaired when the number of nephrons decreases because
the rapid flushing of fluid through the loops of Henle and the high load of solutes such as urea cause a
relatively high solute concentration in the tubular fluid of this part of the nephron. As a consequence, the
diluting capacity of the kidney is impaired, and the minimal urine osmolality and specific gravity approach
those of the glomerular filtrate. Because the concentrating mechanism becomes impaired to a greater
extent than does the diluting mechanism in chronic renal failure, an important clinical test of renal function
is to determine how well the kidneys can concentrate urine when a person’s water intake is restricted for
12 or more hours
4. Revise the role of kidney in maintaining acid-base balance and discuss the
development of metabolic acidosis in CKD
Kidneys are the body’s 3rd line of defense in maintaining Acid base balance
HCO3- is reabsorbed in PCT and regenerated in DCT
H+ secreted in DCT as H2PO4 and in PCT & DCT as NH4+
In Acidosis Kidneys play main compensatory role:
1. Increase HCO3- reabsorption in kidney
2. ↑ regeneration (new synthesis) of HCO3- ions.
3. Kidney excretes excess H+ ion in large amounts in the form of NH4+ and H2PO4-
Osteitis fibrosa cystica – Osteitis fibrosa cystica is functionally characterized by high bone turnover due to
persistently high PTH. Activated osteoclasts cause bone resorption, cortical bone destruction, and fibrous
cysts formation. Osteoclast-like giant cells and vascularized fibrous tissue might replace bone marrow
resulting in Brown tumors, which are non-neoplastic lesions
Adynamic bone disease – Adynamic bone disease is characterized by low bone turnover with reductions in
both osteoblast and osteoclast activity and the skeleton becomes inert.
Osteomalacia – Osteomalacia is primarily characterized by decreased mineralization, causing an increase in
unmineralized osteoid. High remodeling rate: excessive osteoid formation with normal/little mineralization
low remodeling rate: normal osteoid production with diminished mineralization
Mixed uremic osteodystrophy – Mixed uremic osteodystrophy (MUO) is a term used to describe bone
biopsy findings of both high bone turnover and a disproportionate decrease in mineralization resulting in
increased osteoid
Osteoporosis - is caused by an imbalance of bone resorption and bone remodeling, leading to decreased
skeletal mass
Vascular Calcification in CKD
Extra-skeletal calcification is highly prevalent in CKD
Two types of vascular calcification
Intimal calcification leads to calcific plaques or circumferentially calcified atherosclerosis
Medial calcification is nonocclusive and leads to vascular stiffening
Pathogenesis of Vascular Calcification
Phenotypic switch vascular smooth muscle cells (VSMCs) osteo/chondrocytic-like cells lay down
collagen and noncollagenous proteins (ECM) intima or media Calcium and phosphorus incorporated
mineralization hydroxyapatite
Proinflammatory mediators, oxidative stress, altered vitamin D metabolism, and metabolic derangements
are significant contributors. Declining erythropoietin production causes anemia, which reduces oxygen
delivery to the myocardium.
Elevated renin level stimulates the secretion of aldosterone, increasing sodium and water reabsorption.
Hypertension is the result of excess sodium and fluid volume. Activation of RAAS release angiotensin 2
which is a vasoconstrictor causing further hypertension
Dyslipidaemia occurs early in CKD. CKD leads to a down regulation of lipoprotein lipase and the LDL-
receptor, and increased triglycerides in CKD are due to delayed catabolism of triglyceride rich lipoproteins,
with no differences in production rate
Atheromatous plaque and arterial calcification contribute to loss of vessel elasticity and obstruction and
are accelerated by the oxidative stress of CKD. Macrovascular disease is responsible for increased risk for
ischemic heart disease, left ventricular hypertrophy, congestive heart failure, stroke, & peripheral vascular
disease in individuals with uremia.
Pericarditis can develop from inflammation caused by the presence of uremic toxins. Accumulation of fluid
in the pericardial space can compromise ventricular filling and cardiac output.
80-90% of CKD patients develop LVH
Study Guide 5
1. State the effects of chronic renal failure on drug absorption, distribution, metabolism
and excretion (renal and non-renal effects
Absorption: process by which unchanged drug proceeds from the site of administration into the blood.
Affected by factors such as Lipid solubility, molecular size, degree of ionization (ionized are polar), PH of
environment
CRF effect:
Uremia and gut edema may cause nausea/vomiting or diarrhoea in patientsDecreases absorption of
drug taken orally
Uremia causes increased gut ammonia production makes gut environment alkalinedecreases absorption
of drugs that require acidic medium for absorption e.g. Iron
Distribution: the process of reversible transfer of a drug between one location and another
after being absorbed into blood, a drug may be distributed to tissues, depending on:
- blood supply to tissue
- permeability of capillaries, tissue membrane and perfusion
- lipid-solubility of a drug - lipid soluble drugs can easily cross capillary membrane into tissue
some drugs are bound to plasma proteinform drug protein complex:
Acidic drugs bind to albumin Basic drugs bind to α1-Acid glycoprotein
drug-protein complex can’t cross capillary membrane (too large) → not distributed to tissue
only free (unbound) drugs can cross capillary membrane → distributed to tissue » pharmacological effect
important to considerVolume of distributionvolume in which amount of drug in the body would eed
to be uniformly distributed to produce the observed concentration in the blood
CRF effect:
-Increased fluid accumulation may increase volume of distribution of water-soluble drugsImportant to
ensure adequate loading doses are given E.g. loading doses of Penicillins, Cephalosporins need to be
increased by 25-50%
-Albuminuria: loss of albumin in urinereduction in protein binding of many acidic drugs to albuminE.g.
penicillins, cephalosporins, aminoglycosides, frusemide and phenytoin (Avoid using high doses or
prolonged treatment with such drugs)
-Basic drugs bind mainly to 1-acid glycoprotein and this process is generally unaffected by CKDE.g.
metoprolol, codeine, ephedrine, phenobarbitione etc.
-Chronic renal failure also causes azotaemia: retained N compounds compete with drugs for protein
bindingResults in increased concentration of free drugs (esp. acidic drugs like Phenytoin)
-Renal impairment may alter tissue binding of certain drugs, e.g tissue binding of Digoxin decreases, thus
VD also decreases by approx. 50%-->Loading dose will need to be reduced
Hyperkalaemia will result in Digoxin toxicity
Metabolism: Drug modification or biotransformation by enzymes
A drug metabolized by liver to
inactive metabolites is not
significantly affected by a reduction
in renal excretion
However, for many drugs,
metabolites may be active, e.g. Glibenclamide
Most drugs are cleared by a combination of renal and non-renal clearance; few drugs are eliminated
entirely unchanged by the kidney
CRF effect:
-alterations in hepatic and extra-hepatic drug metabolism and transport occur during renal failure.
Reduction, hydrolysis and conjugation are slowedMay result in increased concentration of parent drug
-Many active or toxic metabolites depend on renal function for elimination; therefore they may
accumulate in RI E.g. Pethidine is converted to NorpethidineMay cause seizures if it accumulates- best to
avoid in RI
-Accumulation of uremic toxins and inflammatory cytokines may affect activity of cytochrome P 450
metabolic enzymes and of P-glycoprotein and organic anion-transporting peptides (OATPs). E.g. Results in
increase in bioavailability of meropenem, vancomycin and erythromycin
Excretion: Loss of drug from the body
age
body composition
disease state
gender
Example:
Thus, renal disease is likely to prolong the half-life of drugs cleared by the kidneys
GFR
GFR: amount of blood plasma filtered through the kidneys per minute ~125 mL/min
used clinically to guide management or adjustment of drug dosage
Generally, there is linear correlation b/w creatinine clearance and drug clearance
In patients with impaired renal function, dose adjustment can be based on creatinine clearance
Renal Clearance
most widely recognized formula for calculating CrCl and estimating renal function
Cockcroft-Gault formula:
If lean body weight is not available, ideal body weight can be used.
limitations: lack of validity in some populations, lack of reliability in severe malnutrition, obesity,
renal changes
alternative to CrCl is the eGFR (CrCL is not equivalent to eGFR*)
Calculating Ideal Body Weight
• Females: 45.5Kg+ 0.9Kg/cm for each cm above 152cm
• Males: 50Kg+ 0.9Kg/cm for each cm above 152cm
• Add 10% for a heavy frame, subtract 10% for a light frame
Categories of Impairment
• Severe impairment CrCl <10mL/min
• Moderate Impairment CrCl 10-25mL/min
• Mild Impairment CrCl 25-50mL/min
categorization for purpose of drug dosing- NOT for classification of chronic renal diseases
Drugs mainly eliminated by renal excretion
Drugs excreted largely unchanged in the urine include:
Screening in Fiji:
Kidney health triad BP + eGFR + Proteinuria
On first appointment, annually thereafter.
Cost of Renal Failure: who should be treated? Is a dialysis program sustainable in Fiji? The
public health perspective.
2. Discuss the cost implications of “renal replacement therapy”. its merits and demerits.
Haemodialysis
Pros of haemodialysis
When AV fistulas are used for vascular access, the risks complications of haemodialysis are reduced.
AV fistulas for haemodialysis can last many years, catheters for peritoneal dialysis and other forms
of vascular access, with usually no need for additional surgical intervention.
Haemodialysis at dialysis centres is done 3 times weekly leaving most of the week dialysis free.
Trained staff at the centres continuously supervise and monitor patient’s health and treatments
Haemodialysis at treatment centres allows for social interactions with people undergoing the same
process
Haemodialysis sessions can be used for work, reading and relaxation
Haemodialysis carries a relatively low risk of infection
Haemodialysis can also be done at home, at your own convenience. Haemodialysis done at home is
generally done daily, with assistance from a partner.
Nocturnal haemodialysis done at home is a relatively gentle form of treatment, leaving the patient
feeling stronger
Nocturnal haemodialysis allows for sense of normality and for regular work/school schedules
Cons of haemodialysis
If haemodialysis is done in a clinic, you will to travel to the clinic, and spend 3-4 hours there each
session.
Haemodialysis schedule must be stringently kept.
Travel is more complex, requiring advance planning and arrangements.
Diet and fluid restrictions must be adhered to strictly.
Fistula may seem ungainly and ugly to patient and can be at risk for infection
If undergoing home haemodialysis, a partner must be home, and must be involved in the nursing.
If done at home space, electrical and plumbing needs must be considered
Possible side effects include low blood pressure, shortness of breath and nausea.
Uses heparin bleeding disorders
Peritoneal dialysis
Pros
Gentler, slower dialysis with less side effects. Best option for any patients with heart disease.
A partner is not required.
CAPD and CCPD are interchangeable depending on your schedule.
Can dialyze during sleep
No need to go to centre three times a week
Comfort of being at home for treatment
No need to be stuck with needle each treatment like haemodialysis
Fewer food and liquid restrictions than haemodialysis
Don’t need to arrange for dialysis treatment at a centre when traveling
Cons
Treatments are done seven days a week.
Need to take have space in home to set up machine and store PD supplies
Need to be careful to not get PD catheter infected
PD can cause weight gain due to glucose in the dialysate (dialysis solution)
3. Discuss the challenges and complications of palliative care in renal failure patients
Integral to the precepts of palliative care is an interdisciplinary approach focusing upon physical comfort
(managing pain and other symptoms) and psychological, spiritual, and social support for the patient and
their family and community.
The goal of palliative care is to achieve the best possible quality of life by relieving suffering, controlling
symptoms, and restoring functional capacity, while maintaining sensitivity to personal, cultural, and
spiritual beliefs and practices ( to provide a support system to help patients live as actively as possible until
death)
Hospice care focuses on the care, comfort, and quality of life of a person with a serious illness who is
approaching the end of life. Like palliative care, hospice provides comprehensive comfort care as well as
support for the family, but, in hospice, attempts to cure the person's illness are stopped
The international kidney community is increasingly using the synonymous term "kidney supportive care"
rather than "kidney palliative care" to help reinforce the appropriateness of this kind of care throughout
the symptomatic illness trajectory and to distinguish it from end-of-life care
Benefits:
-experience lower symptoms burden at end of life, receive care consistent with their preference and to use
hospice services.
-palliative and hospice care in ESKD can ↓hospital care costs
Barriers:
-palliative and hospice care are underutilizedlate referral to hospice care once all treatment options are
exhaustedthis complicated transition
-uneven access to specialty palliative care services
-underdeveloped models of care for seriously ill patients with advanced CKD
-misaligned policy incentives
-In addition, nephrologists tend to be poorly trained in palliative care and often feel uncomfortable with
the care of dying patients
-patients lack understanding of the potential benefits of palliative and hospice care.
Components of kidney support care
1 Shared decision makingincorporate patients need + adapt care plans that facilitate patients life
2 Quality of life assessmentsymptom assessment regularly-3 monthly for non dialysis patients + fraility
of patients is assessed
3 Advance care planningshare personal values, life goals, and preferences regarding future medical care
and prepare them for periods of incapacity
4 Palliative and hospice care consultation
5 Terminal symptom management advance CKD have high symptom burden, As the patient's condition
deteriorates during the terminal phase, certain nonpharmacologic interventions become less realistic (eg,
exercise). Symptoms should be anticipated, with arrangement of appropriate prescriptions in place to
address symptoms as they occur.
- Painmost common complain 69%, opiods usedfentanyl, methadone
- Constipationw opioid usestool softeners, dietary changes and laxatives
- SOBpositioning of patients, fan blow at them gently, supplement oxygen, reassurance
- Anxiety, agitation & deliriumusually due to metabolic abnormalitiesused benzodiazepines for
anxiety, trazodone for agitation
- Myoclonus, muscle twitching and seizuresdue to opioids or uremic associated
- Nausea/ vomitinguse pro-kinetic agentmetoclopramide
- Respiratory tract secretionsaccumulate cuz weak to cough
- Pruritustopical/ emollients
Other challenges faced by patients at end of life:
Painelderly unwilling to report their pain because they believe its normal symptom
Depression45% of terminally ill patients w cancer have it, can lead to suicide, it makes their illness
worse. Anxiety coexists, demoralization can also occur. These symptoms occur due to the illness itself or
the treatment
Copingpatients face challenge coping with their disease on daily basis. Bod copers display a defensive
style which may include isolation, non-compliance avoidance, denial.
Dignity(worthy of honor, respect and esteem) for many patients dignity is related to level of
independence and autonomy so in terminally ill their dignity is gone
Otherssuch as anorexia, weakness, sexual dysfunctionall these lead to suffering more
Challenges faced by clinicians involved with end of life care:
-in adequate trainingneed to learn in engaging in difficult conversations
-in sufficient compensations
- personal discomfort with death
Study Guide 7
1.Discuss the different values of ethics
Principles or standards of behavior, one’s judgement of what Is important in life
What are the sources of Ethical Values?