Kidney Flashcards
What are the three functions of the kidney?
Excretory
Endocrine
Metabolic
What is the term renal function mean?
Excretion, endocrine, metabolic functions
What is the purpose of excretory functions of the kidney?
Regulate fluid, electrolyte, and acid-base balance
Remove metabolic waste products & foreign
chemicals from blood for urinary excretion
How is the excretory function of the kidney achieved?
Filtration
Reabsorption
Secretion
How does blood enter the glomerulus?
Afferent arteriole
What is Glomerular Filtraiton?
Filtered via the hydrostatic pressure through the capillaries that form the glomerulus into the bowman capsule
What is the filtrate composed of?
~20% of plasma entering the glomerulus, fluids, electrolytes, small molecules
What is not in the filtrate or shouldnt be?
Largle molecules and proteins such as blood cells
How does blood leave the kidney/
Efferent arteriole
What is the composition of filtrate?
– Glucose
– Electrolytes
– Amino acids
– Water
– Urea
– Uric acid
– Creatinine
– Protein
What is the process of reabsorption/
Substances out of the renal tubules back into the blood capillaries
What is reabsorption include?
Water, NaCl, K, HCO3, urea, amino acids, glucose
Which substances are secreted?
H+, K+, uric acid, certain drugs
How are substances secreted?
Active transport mechanisms, Diffusion
Which ion is the kidney responsible for secreting for acid-base balance
H+
What is the kidney responsible for with respect to reabsorption
HCO3-, Bicarbonate
What is the response in Acidosis?
In response to excess acid, kidneys reabsorb all
filtered bicarbonate and produces new
bicarbonate
What is the response of alkalosis
In response to too little acid, kidneys excrete
bicarbonate to restore H+ concentration to
normal
The endocrine functions of the kidney involve?
Blood pressure control, RBC production
What are the Key renal blood pressure mechanisms?
RAAS, ADH, ANP
- Renin-Angiotensin-Aldosterone System
(RAAS) - Antidiuretic hormone (ADH)
- Atrial natriuretic peptide (ANP)
What does increases renin lead to?
– Vasoconstriction
– Sodium and water retention
What does angiotensin II do?
evokes vasoconstriction of the efferent
arteriole, to increase glomerular hydrostatic pressure
What is Prostaglandin E2 and I2?
Produced by the kidney in response to
decreased blood flow
What does Prostaglandin E2 and I2 do?
Cause vasodilation, specifically of the afferent
arteriole, to increase renal perfusion
– Why NSAIDs decrease kidney function
- Also promote the secretion of renin
What is aldosterone?
Primary role is to stimulate tubule reabsorption of
sodium
What does Aldosterone indirectly do?
– Increases potassium excretion
– Increases H+ excretion
What is ADH?
Secreted by the posterior pituitary in response to
increased blood sodium levels / low blood volume
What does ADH do?
Increases water permeability of the collecting
ducts, promoting water reabsorption
leads to kidneys excreting more concentrated urine
What is antidiuresis?
Very concentrated urine
What is ANP?
Released in response to increased stretch of
the heart muscle
What does ANP do?
Opposes the actions of RAAS by causing
vasodilation and increased renal excretion of
sodium (opposite effect of aldosterone)
What are the three main metabolic functions of the kidney?
i. Metabolism of endogenous compounds (e.g.,
insulin)
ii. Vitamin D activation
iii. Gluconeogenesis
In CKD Vitamin D activation is?
Impaired
What does Vitamin D insufficiencies lead to/
– Leads to disruption of the calcium-
phosphorus-parathyroid hormone balance
and renal bone disease
What is Gluconeogensis?
Production of glucose from amino acids
Why do we check renal functions?
Early recognition of CKD
Adjust Drug doses
Monitoring nephrotoxic medications
What is creatinine?
a by-product of muscle metabolism
that is primarily eliminated by glomerular
filtration
What happens tot he SCr when the GFR is low?
Increased as this is a measurement of Cr in the serum (Blood)
What is the equation for classifying the severity of kidney disease?
CKD-EPI
What is the CKD-EPI measurment?
The CKD-EPI Creatinine Equation for Glomerular Filtration Rate (GFR) estimates GFR based on serum creatinine.
What is the equation used for making renal dose adjustmemnts?
Cockcroft-Gault
What is the Cockcroft-Gault equation?
Calculates CrCl according to the Cockcroft-Gault equation. For use in patients with stable renal function to estimate creatinine clearance. (ml/min)
The CKD-EPI equation is used to estimate kidney
function in a patient receiving dialysis True of False?
False, Given that the machine is filtering, we can no longer estimate kidney function. It is no longer relevant. CKD-EPI is out of the door.
Which equations are generally utilized?
CKD-
EPI and Cockcroft-Gault equation
To calculate CrCl for the purpose of DRUG/DOSE
ADJUSTMENT, use
COCKROFT-GAULT
To calculate eGFR to STAGE CKD use,
CKD-EPI
Which key component was removed from the 2012 to 2021 CKD-EPI
Have removed ‘race’ from the equation
What is the normalized or indexed eGFR?
Uses the mean standardized BSA of 1.73m^2
Recommended for CKD staging/progression
Units mL/min/1.73m^2
What is the schwartz calculation used for?
GFR for pediatrics
What is urea?
BUN produces as a break down product of protein
Does Urea truly measure GFR?
No because it is reabsorbed
Is urea increased or decreased in renal impariemnt?
BUN is increased in renal impairment
What is BUN affected by?
– dietary protein
– GI bleeding
– hydration status (HIGH urea means LOW water;
dehydration)
What is proteinuria?
This is a marker of kidney damage since protein should never pass the kidney membrane
What type of protein is lost in the urine
– ↑ albumin excretion sensitive to kidney damage from diabetes,
hypertension, glomerular diseases
LMW globublin in tubulointerstitial kidney disease
A small amount of albumin in the urine is
Normal
How do we screen albuminuria?
Albumin creatinine ratio (ACR)
What is the mg/mmol for A1
<3 mg/mmol
What is the mg/mmol for A2 category
3-30 mg/mmol
What is the mg/mmol for A3 category
> 30mg/mmol
What is Urinalysis
Provides info about the physical and chemical
composition of urine
What is the Urinalysis
Colour, cells, and crystals
What are the four different casts?
RBC, WBC, Fatty, and Granular
What is Urinary eosinophils indicate?
Interstitial neprhritis
What does glucose indicate in urine
Indicative of diabetes/DKA
What is leukocyte esterase and nitrite
positive in UTIs
Acute kidney injury is?
– A sudden decline in renal function (hours or days)
as evidenced by changes in laboratory values (SCr,
BUN, and urine)
What is Anuric?
less than 50 mL/day urine output
What is Oliguric
- less than 500 mL/day urine output
What is Non-Oliguric?
- greater than 500 mL/day urine output
How long AKI take to develop and what develops
After development of AKI, may take up to 4 days
before an ↑ in SCr is observed
What is the criteria of AKI?
Change in SCr
Risk factors for AKI?
Anything that decreases blood flow to the kidneys
Most common causes of AKI
Pre-Renal
Intra-Renal or Intrinsic
Post-Renal
What is the most common form of AKI?
Pre-Renal AKI
What causes decreased kidney perfusion?
– Intravascular volume depletion (e.g., hemorrhage,
dehydration, burns, diuretic therapy)
– Decreased effective circulating volume (e.g., HF, cirrhosis)
– Hypotension (e.g., vasodilating medications, septic shock)
– Decreased glomerular filtration pressure (ACEi/ARBs +
NSAIDs)
What are the 4 types of intrinsic AKI?
Acute Tubular necrosis
Acute Interstitial nephritis
Acute Glomerulonephritis
Vascular kidney injury
What can cause intrinsic AKI?
Ischemia, Toxins, Disease
What are the causes of Post-renal KAI?
Nephrolithiasis (Kidney stones)
Prostate enlargement
Cervical cancer tumors
Drugs that crystallize
What drugs can crystallize and cause Post renal AKI?
Sulfonamides, Acyclovir, MTX
What are the lab values of AKI? (4)
Increases in SCr, BUN, acidosis, and hyperkalemia
What is FENa
Fractional excretion of sodium
FENa will ___ with pre-renal AKI
Decrease because of the activation of the RAAS system
FENa will ___ with tubular damage
Increase
What can be observed in urinalysis?
Cellular debris or casts
Other tests that can be done for the diagnosis of AKI
Renal ultrasound
Kidney biopsy
- invasive, only used if necessary
What is the goal of therapy for AKI?
Prevent further renal injury
Minimize extra renal complications
Facilitate recovery of renal function bake to baseline
Treatment for Pre-renal failure include (General)
Hydration
BP support
Fluid removal
Stop or hold drugs that impair kidney function/urine flow
Treatment for intrinsic renal failure
Discontinue offending agent
Manage underlying autoimmune disease
What is the post renal failure treatment?
Catheter to restore urine flow
Identify and remove obstruction
Adequate hydration when giving drugs with potential to crystallize
What is the #1 concern of AKI?
Hyperkalemia
What is the potassium range in an individual
3.5-5mmol/L
What do we see in AKI/CKD with respect to lab levels (Potassium)
Hyperkalemia
At what potassium level are we concerned with?
> 7mmol/L
What is the mild treatment of Hyperkalemia
Kayexalate, furosemide to increase urinary excretion
If severe hyperkalemia what do you do?
hospital
Just need to regulate everything
When do we Dialyze in AKI?
AEIOU
Acidosis, Electrolye abnormalities, Toxic ingestions, fluid overload, uremia
What are the clinical guidelines we use to help with Kidney related questions
KDIGO, Canadian society of nephrology, KDOQI (USA)
What are the 4 causes of CKD?
Diabetes, Hypertension, Immune/Inherited, Other etiology
What is the Definition of CKD?
GFR ≤ 60 mL/min/1.73m2 for 3 months or more,
with or without kidney damage
OR
Kidney damage for ≥ 3 months, with or without
decreased GFR, as evidenced by pathological
abnormalities, abnormalities in blood or urine, or as
seen by renal imaging
What is something we need to rule out with respect to CKD?
Remember low eGFR may be explained by an AKI –
may need to rule-out
What are the two ways we can stage CKD?
GFR and Albuminuria
What is the the values for he GFR for each category?
What are the Albuminuria categories for kidney function
HOw do we stage CKD?
How can CKD be staged?
Generally is asymptomatic hence screening required
What Can occur at stages 3 and 4 of CKD?
– Low energy, fatigue, confusion
– Foaming, tea-coloured, blood or cloudy urine
– Edema
– Shortness of breath
– Pruritis
Which stages of CKD are generally managed in primary care
Stage 3a-3b, 30-59ml/min
Which stages of CKD are generally managed with a nephrologist?
Stage 4-5 <30ml/min
What is the average rate of decline for individuals with CKD?
between 2.3 to 4.5
mL/min/1.73m2 per year in the MDRD study
What are associated with a faster rate of CKD progression?
Lower GFR and greater albuminuria
What diseases can cause quicker rates of kidney damage?
Diabetic nephropathy, glomerular diseases, polycystic
kidney disease, and kidney disease in transplant
recipients tend to progress more quickly
What diseases can cause slower progression of CKD?
Hypertensive kidney disease and tubulointerstitial
diseases tend to progress more slowly
What are non-modifiable factors of CKD?
African american race, male, advanced age, family history
What are modifiable factors of CKD?
– Uncontrolled hypertension
– Poor blood glucose control
– Proteinuria
– Smoking
– Obesity
How rapidly can untreated hypertension cause CKD decline?
12ml/min/year
If BP is less then 130/80 what GFR decline can we expect?
1-2ml/min/year
What are the blood pressure targets for individuals with high BP and CKD (Not on dialysis)
120
What is the target BP for individuals with kidney transplant?
130/80
What is the blood pressure targets for people with diabetic CKD?
130/80
What is the BP target for adults with polycystic kidney disease?
110
What is the BP target for high risk patients
<120
What is the acronym AARF?
Who is not suitable for blood pressure lowering?
What lifestyle recomendations from HTN Canada should be followed?
Salt restriction to 2000mg Sodium (5g of salt) per day
What other lifestyle recommendations are made for decreasing blood pressure?
Excersize, weight reduction, alcohol consumption
What are the first line BP agents for individuals with Kidney disease?
– ACE-i/ARBs
– diuretics
– long-acting CCBs
What factors should be considered for blood pressure management for individuals with kidney disease?
Consider comorbidities, stage of CKD, degree of
albuminuria, type of CKD when selecting therapy
What is the first line treatment for HTN if a
patient has proteinuria?
a. ACE-i/ARBs
What are the benefits of Ace/Arbs?
Reduce BP and flomerular cap pressure,
Reduce proteinuria
For Diabetes and non diabetes what are the htn first line therapy for kidney disease with albuminuria guidelines?
– Diabetic kidney disease – if ACR > 3mg/mmol
(category A2, aka microalbuminuria)
– Nondiabetic proteinuric CKD – if ACR > 30mg/mmol
(category A3, aka macroalbuminuria)
What are the CI of Ace/Arb therapy
– Angioedema
– Bilateral renal artery stenosis
– Pregnancy
What precautions should be taken when on ace/arb therapy
– Intravascular fluid depletion
* Reduce/hold dose if severe vomiting, diarrhea, fluid depletion
– eGFR <30mL/min/m2
– Hypotension (caution if BP <110/70)
– Hyperkalemia (K+ > 5.5 mmol/L)
What are the monitoring parameters of ACE/ARB therapies? (4)
Why shouldnt Acei/Arb therapy be used in combination therapy?
Because it can lead to a worsened renal outcomes
Why should DRI not be used in CKD/Renal disease?
More adverse events including non fatal stroke, renal complications, hyperkalemia nad hypotension
What are the steroidal MRAs?
Spironolactone, eplerenone
What are the non-steroidal (Selective)
Finerenone
What is the benefit of Finerenone?
Much higher specificity for MR vs glucocorticoid androgen receptors
Reduction in albuminuria while javing less side effects
Which population should we consider using finerenone?
T2DM, eGFR >25ml/min, normal K+ levels and albuminuria >3
What is the concerning side effects associated with finerenone?
Hyperkalemia.
Which combination is generally recommended with finerenone
SGLT2 inhibitor, but not a lot of evidence
What is the usage of furosemide in CKD?
fluid retention, needs ot be dosed though every 6 hours
What is chlorthalidone>
Studied for stage 4 CKD. Hypokalemia and orthostasis though
Hypertensive agent
What is the benefit of using DHPCCBS?
Preferred over thiazides in combination with ace/arb therapy with patients with diabetes
Good CV benefits
No evidence for CKD progression slowing
What is the DHPCCB we should know?
Amlodipine?
What is the non-DHP CCBs?
Diltiazem and verapamil
What do nonDHP CCBs do?
Shown to decrease proteinuria but not to the same extent as ACEis
No evidence for slowing ckd progression
What role do BB play in CKD?
CV protection in patients with CKD, renal dose adjustement once CrCL approaches 30ml/min
What is clonidine?
Alpha 2 agonists that is good as adjunctive therapy for HTN bc no DIs with commonly used BP meds
What is the alpha 1 blockers?
Terazosin prazosin
What are terazosin and prazosin used for?
Adjunctive therapy for elevated BP in CKD patients
May consider in patients with prostatic hypertrophy
Alpha 1 antagonist
What are the direct vasodilators?
Hydralazine, Might be used as adjunct but MANY side effects
What is the Role of Proteinuria in CKD Progression?
Linked with progression of diabetic and non diabetic CKD
High risk of progressing to kidney failure
An indicator of subclinical cardiovascular disease
What does microalbuminuria do?
Predicts loss of kidney function
Why is it important to identify patients at category A2 albuminuria?
so appropriate therapy (ACE-i or ARB) can be instituted to slow progression
What is considered mild proteinuria loss?
Mild 150-500mg (Cat 2)
What is considered moderate proteinuria loss?
> 500mg Cat 3
WhatWhat is considered nephrotic proteinuria loss?
> 3grams of albumin excretion or >2200mg/24hours
What is Nephrotic syndrome?
Associated with hyperlipidemia, hypoalbuminemia, generalized edema, thromboembolic risk, foamy urine
What are examples of kidney diseases associated with proteinuria?
- Diabetic nephropathy
- Hypertensive kidney disease
- Primary glomerular diseases (e.g., Minimal Change
Disease, focal and segmental glomerulosclerosis, IgA
nephropathy) - Lupus nephritis
- Post-streptococcal glomerulonephritis
How is kidney disease associated with proteinuria sometimes treated?
Treated with steroids or immunosuppressants
ACE-i/ARBs for select patients with
no hypertension why?
– Reduce glomerular capillary pressure and volume
– Possible direct effect on podocytes to ↓ proteinuria
What is considered First-line therapy for kidney diseases with proteinuria?
– Diabetic or hypertensive kidney disease with category A2 or A3 albuminuria
– Other kidney diseases with proteinuria
What is the potential new role for SGLT2i in proteinuria kidney disease?
Dapagliflozin was well tolerated and showed major improvement in those with ESKD
What is the treatment recommendations in accordance to the CCS guidelines for CKD?
How often is one screened for CKD with diabetes?
- 5 years after diagnosis of T1DM
- At time of diagnosis for T2DM
What is the threshold of ACR used for staging nephropathy?
What does blood glucose control do?
Prevents and delays progression of diabetic nephropathy
What measurements will be less accurate in patients with advanced CKD? (G4-G5)
Hb A1C
What does metformin do with respect to renal disease?
CV benefit
What dosage of metformin do we see in individuals with eGFR 15-29ml/min?
500mg/day
What is the dosing of metformin?
What benefits does sglt2 inhibitors have in CKD?
Evidence for CV benefits AND for reducing the progression of CKD in patients with DM
At what level does SGLT2 inhibitors not have glucose secreting effects in the kidneys?
eGFR >20ml/min
When can SGLT2 inhibitors be initiated?
- Not to be initiated if eGFR <20mL/min, but may be continued until dialysis
- Can continue with a modest initial ↓ eGFR (≤30%)
What are the dosages for SGLT2 inhibitors?
Which SGLT2 inhibitor has the lowest eGFR?
Empagliflozin
What evidence is their for GLP-1 agonists for kidney disease?
FLOW trial, but data is not yet available (used semaglutide as their study)
What does smoking do with respect to CKD?
Smoking increases progression of CKD
– Mechanisms: ↑ BP & HR, ↓ renal blood flow
(constriction), vascular injury
What nephrotoxins should be avoided in CKD?
- NSAIDs, COX-2 inhibitors
- lithium
- aminoglycosides
- amphotericin B
- calcineurin inhibitors
- cisplatin
What drugs should you avoid combining with nephrotoxins?
Ace-i/Arb, NSAIDS, Diuretics
When should dyslipidemia be treated?
> 50 years old with eGFR <60 & not on dialysis:
Tx with low-dose statin or statin/ezetimibe combo irrespective
of LDL level
When should dyslipidemia be treated?
> 50 years old with CKD and eGFR >60
Tx with statin
When should dyslipidemia be treated?
18–49 year old with CKD:
– Tx with statin treatment if estimated CV risk is >10% (high)
(e.g., prior CV event or diabetes)
Do statins have benefit to slowing CKD progression?
No, but Fire and forget strategy is employed because of the CV risk reduction
What are the issues with the usage of a statin in CKD?
Not well tested in your normal CKD population
What is a concern with statins in CKD?
rhabdomyolysis
For statin usage one might consider using general population doses for individuals with GFR category?
What benefit is their for low dose ASA? in CKD
- Low dose ASA (81 mg) has no role in primary
CV prevention in patients with CKD - Would be used in secondary prevention (post-
MI etc.)
What are the two renal replacement therapies discussed?
HD, PD, Kidney transplant
At what stage can complications of CKD be evidenct?
Stage G2
With respect to Na and water imbalance what occurs in CKD?
Progressive loss of ability of the kidneys to excrete excess
water and sodium.
Therefore weight gain, hypertension, peripheral and pulmonary ededma
When does sodium and water imbalance generally occur (Stage)
Stage 4 CKDW
What is the treatment of Sodium and water imabalance?
– Sodium and water restriction
* 90mmol sodium (<2g) and 1-2L of fluid per day
– Diuretics: Furosemide +/- metolazone
– Stage 5: Dialysis
What GFR are thiazide diuretics not effective
<30ml/min
Which diuretics are preferred for water loss?
Furosemide, but also become less effective as kindye funciton declines
Where does furosemide work?
Loop of Henle
Where does Metolazone work?
Distal convulated tubule
Why do we also treat with metolazone for add on therapy?
Synergistic diuresis with furosemide due to natriuretic
action at distal tubule
What can occur with furosemide?
We can sometimes see resistancd
What diuretic monitoring parameters are required?
Electrolytes (PotassiuM)
q1-2 weeks initially, every 3-6 months
What is metabolic acidosis?
Characterized by a ↓ in the pH of the blood (acidemia) and a
↓ in serum bicarbonate levels (<22 mmol/L)
How is metabolic acidosis exacerbated?
by hyperkalemia – further depresses NH3
production
When is metabolic acidosis most prominent?
Stages 4-5 of CKD
What is the treatment of metabolic acidosis?
Sodium bicarbonate tablets
* 325-500mg PO BID-TID (variable dose)
What are the benefits of treatment of metabolic acidosis?
Decreases CKD progression, imporved nutritional status
What is the concern with treating with sodium bicarbonate tablets?
Possibility of sodium loading
When can hyperkalemia occur in CKD?
Generally stages 4-5 of CKD
What is hyperkalemia generally caused by?
primarily due to decreased potassium excretion
What are some of the exacerbating factors of potassium?
– metabolic acidosis
– excessive potassium intake from diet
– potassium sparing diuretics
– ACE-i/ARBs
– prostaglandin inhibitors (NSAIDs)
What is considered mild hyperkalemia?
5.1-9 mmol/L
What is considered severe hyperkalemia?
> 7mmol/L
What does severe hyperkalemia cause?
Tachycardia, t wave peaking. just bad heart stuff
What is the treatment of hyperkalemia?
potassium binders (remove K+ in GI tract)
What is kayexalate?
– Cation exchange resin: Removes K+ ions by exchanging it
for Na2+ ions
– Not absorbed by the GI tract
What is CKD-MBD?
Abnormalities of calcium, phosphorus, PTH, or
vitamin D metabolism
Abnormalities in bone turnover, mineralization,
volume, linear growth, or strength
Vascular or other soft tissue calcification
What occurs in CKD-MBD?
Increased Serum phosphate
Decreased serum calcium
Decreased vitamin D
Increased Pth
What causes increase serum phsophate?
Increase kidney excretion, also calcium binds to excess phosphate in the blood
What causes decreased serum calcium?
Due to decreased GI absorption due to decreasted vitamin D
Why do we see decreased vitamin D in CKD-MBD?
Because the final synthesis step to active calcitriol occurs in the kidneys
What causes increase parathyroid hormone?
Negative feedback loop from increase calcium
When should CKD-MBD be monitored?
CKD G4-5
What does increasing serum concentrations of PO4 associate with?
CKD G3a-G5D, mortality
Is there benefit in treatment to prevent hyperphosphatemia?
No
What is considered increased with respect to phosphate? in ND-CKD
> 1.49mmol/L
What is considered increased with respect to phosphate? in HD/PD-CKD
> 1.78mmol/L
Why is the range threshold higher for HD/PD-CKD?
Because of how hard it is to regulate
What do low levels of calcium contribute to?
secondary hyperparathyroidism
and renal osteodystrophy, and prolong the QT interval
What do elevated serum concentrations of calcium associate with?
higher mortality and risk of CV events in CKD patients
What occurs in symptomatic hypocalcemia?
Numbness, tingling, myalgia
What is Ionized calcium?
This is the active calcium
What is the total calcium?
free (ionized) + calcium
bound to albumin
What is the corrected calcium
calcium adjusted for
albumin levels
What can albumin do with respect to calcium?
With variable concentrations of albumin we can see variable bound calcium/unbound
What is Severe HPT associated with?
calciphylaxis, CVD, neuromuscular disturbances, and
death in CKD stages 3-5D
When should PTH be treated?
– PTH should be progressively rising or persistently high in
order to initiate treatment
What are the three different types of renal osteodystrophy syndromes that may occur?
Hyperparathyroid bone disease
Adynamic bone disease
Osteomalacia
What is Hyperparathyroid bone disease?
(high bone turnover disease)
* ↑ bone turnover, ↑ PTH levels (secondary HPT)
What is adynamic bone disease?
(low bone turnover disease)
* ↓ bone turnover, normal or ↓ PTH levels
What is osteomalacia?
↓ vitamin D activity
What causes PTH increases (What pathways)
What does FGF-23 stand for?
fibroblast growth factor 23
What does FGF-23 do?
Initially maintain serum Ca & PO4 levels, at the expense of persistently high levels
How does FGF-23 work?
– Promotes PO4 excretion in kidneys
– Stimulates PTH to ↑ PO4 renal excretion
– Suppresses formation of calcitriol to ↓ PO4
absorption from GI tract
What does PTH do in the long run?
– ↑ Ca reabsorption and PO4 excretion in the kidneys
– ↑ Ca mobilization from bone
In advanced CKD the kidneys fail to respond to?
FGF-23 and PTH, therefore Ca and PO4 worsen
What does sustained Hyperparathyroid lead to?
Persistent calcium resorption form bone leading to high bone turnover
What occurs during high bone turnover (Osteitis fibrosis cystica)
- Bone pain and fragility
- Bone marrow fibrosis (can lead to EPO resistance)
- Also, refractory pruritis
What does Calciphylaxis lead to
Calcification and occlusion of small blood vessels
Ulceration, gangrene, secondary infection and high rates of mortality
How do we decrease phosphate in hyperparathyroid bone disease?
– Restrict dietary phosphate
– Phosphate binders
– Intensified dialysis schedules
How do we suppress PTH?
Vitamin D
Calcimimetics
parathyroidectomy
How do phosphate binders work?
All work by binding to dietary PO4 in the GI
tract → eliminated in feces
When do phosphate binders need to be taken?
Must be taken at the beginning of a meal
(within the first few bites)
– Patient counseling is important
What are calcium based binders used for?
As a phosphate binder and it can raise calcium
What is the typical dose of calcium based binders?
500mg of elemental calcium po TID with meals
What are the guidelines with respect to total recommended dose for calcium based bunders?
Not entirely known, needs to be monitored even in patients without hypercalcemia
What are the adverse effects of calcium?
Constipation, stomach cramps, potentially hyper calcemia if co-administered with calcitriol
What is calcitriol?
Vitamin D analogue that reverses low calcium
What/Why are aluminum or magnesium phosphate bunders/
OTC antacids and not recommended for chronic use because of the risk of accumulation and toxicity
What is sevelamer HCL?
Useful in patients with hypercalcemia or when
not controlled with Ca-based binders
What are the AE of sevelamer HCL?
GI Tolerability problems
What is lanthanum?
Similar to sevelamer, just a chewable form
Was is Sucroferric oxyhydroxide
Newest calcium-free binder that is iron based, but does not contribute ti iron intake.
Can cause black stools and nausea similar to AE
What does vitamin D therapy aid in?
Helps suppress PTH levels
How does vitamin D therapy suppress PTH levels?
– Stimulates absorption of Ca in the GI tract (neg.
feedback to ↓ PTH)
– Directly acts on parathyroid gland to suppress PTH
synthesis
What is the risk of vitamin D therapy?
↑ risk of hypercalcemia & hyperphosphatemia
– Causes an ↑ in FGF-23 levels
What is the uncertainties of vitamin D therapy?
Uncertain if it decreases fractures or mortality?
Should Vitamin D therapy be used in dialysis therapy?
No, Should not be routinely used in patients not on
dialysis – reserve for severe & progressive HPT
What are the Vitamin D analogues?
Calcitriol
Alfacalcidol
What are the AE of of Calcitriol and alfacalcidol?
Hypercalcemia, hyperphosphatemia
* Serum Ca and PO4 levels should be in range prior to initiating
therapy
What are calcimimetics?
– Increase sensitivity of the parathyroid gland to calcium
– Directly lowers PTH concentrations without increasing
serum Ca or PO4 (useful in hypercalcemia)
– Uncertain if ↓ fracture risk, cardiac events or mortality
What is the one calcimimetic available?
Cinacalcet
What is the issue with Cincacalcet?
Cost, Adverse effect of nausea vomiting diarrhea and HYPOcalcemia
What is antiresorptive treatment?
May ↑ BMD and ↓ fracture risk
What is prolia used for?
Hypercalcemia but can lead to hypocalcemia
What are the bisphosphonates used for?
– May induce/exacerbate low bone turnover
– Use with caution at CrCl <35 mL/min (rarely nephrotoxic)
What are the bisphosphonates used?
alendronate
What is prolia?
Poses risk of hypocalcemia but may increase BMD and decrease fracture risk.
Denosumab requires monitoring though
What is important with respect to hyperparathyroid bone disease treatment?
Monitoring, PTH levels tested monthly and drug interactions
What is a Parathyroidectomy?
Partial removal of parathyroid gland
Reserved for patients where PTH, calcium, phosphate abnormalities not medically correctable
“Hungry bone syndrome”
What is Adynamic bone disease
Decreased bone turnover, normal or decreased PTH levels
What is Osteomalacia?
Decreased vitamin D activity
What causes adynamic bonse disaese?
Lack of osteobalsts/osteoclasts stimulation (Leading to no bone remodeling)
What does adynamic bone disease result from?
Caclium and vitamin D supplementation and oversuppression of pTH (Possible an overtreatment of secondary hyperparathyroidiusm)
What is osteomalacia?
Softening of bone
What is the treatment of osteomalacia
Stopping aluminum containing phosphate binders
What is vascular calcification?
Vascular smooth muscle cells change into an osteoblast-
like cell
* Increased prevalence of cardiovascular calcification in
patients with CKD
Where is vascular calcification used for?
Seen in high and low bone turnover disease
What is reviewed in anemia related CKD? (4)
Hgb, reticulocyte count, transferrin saturation (TSAT), ferritin
What is the definition of anemia in CKD patients generally>
Normochromic, normocytic, – Anemia = Hgb < 130 g/L in males and < 120 g/L in females
What causes the anemia seen in ESRD/CKD?
Hypo-proliferative, decreased reticulocytes
Generally decreased because of a loss of erythropoeitin generation in the kidneys
What are some other causes of anemia in CKD/ESRD?
Decreasesd RBC half life in uremia, blood loses, bone marrow fibrosis or deficiencies in iron, folate, vit b12
Where is iron deficient anemia generally seen?
Stage 4-5 CKD dueu to decrease GI absorption inflammation, frequent blood tests and blood loss in Hemodialysis
Increase in iron demands with ESA therapy
What is absolute iron deficiency?
Decreased TSAT and decreased Ferritin
Total iron stores in the body are LOW
What is functional iron deficiency?
Decreased TSAT, normal or increased ferritin
Might be anemia of chronic disease and adding iron may not always help
What are the signs and symptoms of anemia?
– Weakness, lethargy, malaise
– Shortness of breath on exertion
– Impaired memory and concentration
– Feeling cold
Why should we treat anemia?
– Decreases patient quality of life
– Risk factor for adverse outcomes (e.g., LVH, CVD)
What are the pros of Erythropoiesis Stimulating Agents?
– Practically eliminated need for blood transfusions
– ↓ fatigue, symptoms of anemia (QofL)
What are the cons of Erythropoiesis Stimulating Agents (ESAs)
– Failed to improve CV outcomes
– Associated with increased risk of stroke and other
thromboembolic events
* Especially if treated to higher Hgb target values
What are the hemoglobin targets for treatment in anemia? why? (HGB)
100-110hgb. This is because their are more risks associated with higher targets and getting higher may not be possible
What are the hemoglobin targets for treatment in anemia?? (TSAT)
Maintain >20% and to avoid iron overload
What are the hemoglobin targets for treatment in anemia? why? (Serum ferritin)
> 100mcg/L (non-dialysis CKD and PD) and >200mcg/L (HD)
– Limit to avoid iron overload. Complicated b/c an acute phase
reactant – levels may be falsely elevated
What else should be maintained in anemia?
Normal serum Vitamin B12 and folic acid levels (also causes of anemia)
What are the ways we can treat anemia?
- Correct blood loss (e.g., treat GI bleeding)
- Replace vitamin, iron deficiencies
- Erythropoiesis-Stimulating Agent (ESA) Therapy
- Dialysis to correct uremia (as applicable)
- Blood transfusions if required
What should be avoided before all causes of anemia have been addressed?
ESA therapy
Most patients receiving ESA therapy will require ___
Iron supplementation
What may iron supplementation do?
Iron supplementation may further ↑ Hgb or allow a ↓ in the
ESA dose (even when TSAT and ferritin are already at target)
For CKD patients not on dialysis or using PD, select the
route of iron administration (PO/IV) based on:
– severity of iron deficiency (difference in bioavailability!)
– availability of venous access
– response to prior oral iron therapy
– side effects with prior oral or IV iron therapy
– patient compliance
– Cost
How long is an oral ion suggested to be used in patients not on dialysis or using PD?
1-3 months prior to initiating IV therapy
In HD patients and most/many PD patients IV route for iron administration is generally?
Requried
What are the oral formulations of iron/
FF,FS,FG, Feramax
Generally what amount of iron is required for individuals requiring iron dosing?
100mg-200mg elemental iron daily in 2-3 divides doses
What are the AE of Iron supplementation in iron?
stomach cramping, constipation, nausea, vomiting,
diarrhea, dark stools, heartburn, staining of teeth (liquid)
- Drug interactions – calcium, etc.
When is Iron supplementation delivered subcu utilized?
– Intolerant, unresponsive, non-compliant to oral iron
– Recommended 1st line in hemodialysis (HD) patients
What are the AE of IV iron?
– Hypersensitivity reactions → anaphylaxis, shock
* Primarily an issue with iron dextran
– Hypotension (can be minimized by decreasing the rate of infusion)
– Infection
What is Erythropoetin?
Hormone produced by kidney cells when they
sense decreased blood oxygenation
What does Erythropoeitin do?
Stimulates the development and maturation of
red blood cells
Increase Oxygen carrying capacity of the blood
Restore tissue oxygenation
What happens to erythropoeitin in CKD?
Generally decreases due to loss of function of kidney
What are the treatments available for Erythropoeitin therapy
Epoetin and Darbepoetin
What is Epoetin alfa?
– Resembles endogenous erythropoeitin
– Shorter half-life
What is Darbepoetin alfo?
– Second-generation molecule
– Longer half-life
What is the generally dosing of eprex?
50-100 units/kg IV or subcut 2-3 x weekly
What is the general dosing of Aranesp?
0.45 mcg/kg weekly IV or subcut weekly
What is the goal of therapy of Erythropoetin therapy/
– Reach Hgb target (~110 g/L) within 2 to 4 months, then maintain
– Gradual ↑ Hgb by ~10 g/L every month, to target
What dose adjustment management should be impolred if Hgb rise is inadequate?
<10 g/L) after 4 weeks ↑ dose by ~25%
What dose adjustment management should be implored if Hgb rise is excessive?
(>10g/L) in 2 weeks ↓ dose by ~25%
Why should you not adjust the dose of erythropoetin therapy more then every 1 to 2 months
Delays in changes in the Hgb levels as it takes 2-6 weeks
What parameters are monitored during Erythropoeitin Therapy?
– Serum iron, total iron binding capacity, iron
saturation, ferritin: every 1-3 months
– Hemoglobin: every 1-2 week initially, then monthly
What is the goal of Hgb levels for someone on Erythropoetin Therapy?
– Hgb > 100 g/L (non-HD) or > 110 g/L (HD) : hold or ↓
dose
What are the adverse effects of Erythropoeitin Therapy?
– Well-tolerate
– Hypertension (5-24%) – dose-dependent
– Flu-like symptoms (transient)
– Thrombosis – HD access site, VTE (5-10%)
– STROKE, MI, death → avoid Hgb >110g/L
– Pure Red Cell Aplasia (PRCA) (<1%)
What are the causes of erythropoietin “resistance”
– Iron deficiency
– Vitamin deficiency (e.g., B12, folate)
– Bleeding
- Inflammation/infection
– Aluminum toxicity
– Inadequate dialysis
What is the definition of Erythropoeitin resistance?
Incomplete or lack of response to ESA (Eprex >300U/kg/week or Aranesp 1.5 mcg/kg/wk
What is Hypoxia-inducible factor prolyl
hydroxylase inhibitors?
Inhibit enzyme that degrades hypoxia-
inducible factor = Improves iron mobilization
into serum, ↑ endogenous EPO production,
which ↑ Hgb (without causing a spike in EPO)
What can be used for the treatment of HIF PHIs?
Daprodustat (Jesduvroq®) approved by FDA in
2023, for treatment of anemia in patients
receiving dialysis
How is HIF-PHIs therapy administered/adverse effects?
- Dose: 1-24 mg po daily
- AE: possible risk of malignancy
What are the cardiovascular complications that may arise due to CKD?
- Hypertension
- Left Ventricular Hypertrophy (LVH)
- Heart Failure
- Hyperlipidemia
- Pericarditis
- Others:
– CAD, ACS, valvular heart disease, cardiomyopathy,
dysrhythmias, PVD
Hypertension is ___ and a ___ of CKD
Cause and consequence
How does hypertension progress in CKD?
General progression from stage 1-3
What percent of patients have hypertension once they have reached stage 5 CKD?
90%
What are the contributing factors of Hypertension in CKD?
- Salt and water retention
- Activation of RAAS
- Recombinant erythropoeitin therapy (ESA)
- Hyperparathyroidism
- Renal vascular disease
What are the therapies for hypertension/
Same as the prevention therapies (Ace/Arb therapy)
What is the most common structural cardiac abnormality in CKD patients?
LVH
What are the risk factors for LVH?
– Hypertension, fluid retention
– Anemia
– Diabetes
– Older age
– Abnormalities in calcium/phosphate homeostasis
– Uremia
Generally what does LVH lead to?
Leads to: Decreased diastolic compliance, ischemic heart
disease, HF
What is the treatment of LVH?
– Management of hypertension, fluid overload
– Treatment of anemia
– Manage calcium, phosphorus, PTH levels as per CKD-
MBD
In CKD patients heart failure can be precipitated by?
– Anemia
– LVH
– Hypertension, fluid overload
– CAD
How are the neurological complications of CKD addressed?
Generally occurs in ESRD
Dialysis or change dialysis prescription is generally implored
What are the treatments for pruritis?
Tx (with variable success): gabapentinoids,
capsaicin, sertraline, antihistamines, Uremol lotion
What specific agent can be used for the treatment of chronic pruritis?
Difelikefalin (Korsuva®):
* Peripheral kappa opioid receptor agonist
What is the definition of DIKD?
– Adverse functional or structural change to kidney after
administration of a drug, chemical or biological product
What is the diagnosis that generally leads to the DIKD diagnosis?
– Changes in SCr or urine output consistent with an AKI
– Kidney injury temporally associated with use of a
nephrotoxic drug
– Kidney injury due to a disease process ruled out
When discussing DIKD we are generally referring to individuals who had a?
Healthy kidney and not CKD
Does DIKD happen to people with CKD?
yes!
What are the many presentations of DIKD?
- Metabolic acidosis
- Changes to serum electrolytes
- Proteinuria
- Pyuria
- Hematuria
- Rise in SCr (or reduced eGFR)
- Decreased (or increased) urine output
- Symptoms: malaise, anorexia, nausea, vomiting, volume
overload (shortness of breath or edema)
What is the MOA of drug induced nephrotoxicity?
Indirect
Direct
Obstructive
Others
What are the indirect nephrotoxicities?
-Disruption of renal blood flow (pre-renal)
What are the direct kidney injury/damage types?
- Acute tubular necrosis
- Interstitial nephritis
- Glomerulonephritis
What are the obstructive uropathy damage types?
Bladder, Tubules??
What medications may affect the pre-renal blood flow?
ACE/ARB, SGLT2 inhibitors, NSAIDS, Calcineurin inhibitors
What changes occur to renal blood flow (pre-renal_
Acute decrease in GFR, Kidney recieves 25% of resting cardiac output
Who is at risk of Pre-renal blood flow complications?
– Heart failure, renal artery stenosis, volume depletion, CKD,
other nephrotoxins
What is the management for pre-renal blood flow issues?
Recongize and address, Start low and go slow, monitor SCr, BUN, Electrolytes, Watch for concurrent diuretics and hypotensive agents
Dose decrease of stop therapy as needed
What drugs may cause DKI/damage via intra-renal? (Tubular specific)
Aminoglycosides
Radiographic contrast media
Cisplatin
Amphotericin B
Calcineurin inhibitors (cyclosporine, tacrolimus)
Adefovir, cidofovir, tenofovir
Zoledronate
What is acute tubular necrosis?
- Ischemic or toxic cellular injury to renal tubules
- Generally dose-dependent
- Maintaining adequate hydration is an important
preventative measure for many drugs
Who are the at risk patients of Intra-renal injury?
Patients predisposed to renal injury
* Pre-existing CKD, older, multiple nephrotoxic drugs
What is the management for direct kindye injury/damage (Intra-renal)?
- Discontinue nephrotoxin
- Hydration may be necessary
- Monitor SCr, BUN, electrolytes
What medicaitons cause direct kidney injury/damage intrarenally, acute intersitial nephritis
Penicillins/Cephalosporins
Ciprofloxacin
NSAIDs
PPIs
Loop diuretics
Allopurinol
Phenytoin
What is acute intersitial nephritis?
Mainly immune related
What is the management of Acute Interstitial Nephritis>?
- Discontinue nephrotoxin, provide corticosteroids (maybe)
- Monitor SCr, BUN and symptoms of AIN for improvement
What is chronic interstitial nephritis?
Progressive (months to years) and irreversible
What causes chronic interstitial nephritis?
Lithium (↑ duration), calcineurin inhibitors
What can cause obstructive nephropathy?
Obstructive Nephropathy
Sulfonamides
Acyclovir
Methotrexate
Oral phosphate solution
Triamterene
Ciprofloxacin
What can cause blockages in obstructive nephropathy?
Precipitated drug crystals
myoglobin release may occur in obstructive nephropathy due to?
rhabdomyolysis
Uric acid release may occur in obstructive nephropathy due to?
Crystials with tumor lysis syndrome
RBC casts release may occur in obstructive nephropathy due to?
Glomerular hemorrhage
Generally obstructive nephropathy is?
Dose-dependent
Associated with inadequate hydration (causes
supersaturation and ↓ urine pH)
Solubility may be affected by either alkaline or
acidic urine
What is the management of Obstructive Nephrophathy?
– High urine volume
– Urinary alkalinization
Renal impairment can affect drug
ADME
Which changes in CKD have the most lcinical relevance?
Distribution and reduced elimination
Drug distribution is impacted by (CKD)
edema, ↓ protein binding,
uremia and metabolic acidosis
Drug elimination is impacted by
↓ filtration and alterations
in tubular secretion and reabsorption
