AKI, CKD, Dialysis Flashcards
1
Q
Features of rhabdomyolysis
A
- Syndrome of muscle necrosis and release of intracellular muscle contents into circulation
- Reddish brown urine due to myoglobinuria in half of cases
- High CK, hyperkalaemia, hypocalcaemia, hyperphosphatemia, HAGMA
2
Q
Post-obstructive polyuria leads to impairment in:
A
UO > 200ml/hr for 2 hours or >3L/day
Impairment in:
- urine concentrating ability
- sodium reabsorption
- urinary acidification
- potassium secretion
3
Q
Acute Interstitial Nephritis
A
- Drug exposure accounts for > 70% of AIN
- Development of drug-induced AIN is not dose dependent and a recurrence/exacerbation of AIN can occur with second exposure to the same or related drug
- Triad of rash, fever, eosinophilia
Can also cause eosinophiluria
4
Q
How much protein should be eaten in patients with CKD to prevent progression
A
Reduced to 0.8g/kg/day
5
Q
Top 3 causes of CKD
A
Diabetes
Glomerulonephritis
HTN
6
Q
What is “fixable” and “unfixable” with dialysis
A
Fixable:
• Salt and water balance - fluid overload
• Clearance of “uraemic toxins” - uraemia
• Potassium homeostasis - hyperkalaemia
• Acid-base balance - metabolic acidosis
Unfixable
• Erythropoietin production - anaemia
• Vitamin D synthesis and phosphate - secondary hyperparathyroidism
7
Q
Effect of CKD on other organ systems
A
- Cardiovascular disease
- Hyperparathyroidism
- Uremic pruritus
- Malnutrition
- Uremic neuropathy
- Sexual dysfunction: Reversible factors (testosterone, prolactin, oestrogen), sildenafil, optimise dialysis if needed
8
Q
Definition of CKD
Stages of CKD
A
DEFINITION - eGFR < 60 present for 3 MONTHS (with or without other evidence of kidney damage) OR Presence of the following >3 months (irrespective of GFR) - Albuminuria - Glomerular haematuria - Structural abnormality (on imaging) - Pathological abnormality ( on biopsy)
Stage 1: GFR >90 Stage 2: GFR 60-89 Stage 3a: GFR 45-59 Stage 3b: GFR 30-44 Stage 4: GFR 15-29 Stage 5: <15 or dialysis
Stage 3A CKD with macroalbuminuria is normally due to diabetic kidney disease
Normal Urine ACR
- Male < 2.5, Female < 3.5
Microalbuminuria
Male Urine ACR: 2.5-25mg/mol
Female Urine ACR: 3.5-35mg/mmol
Macroalbuminuria
Urine ACR Male > 25mg/mmol
Urine ACR Female > 35mg/mmol
9
Q
eGFR
A
- Assumes steady state of creatinine generation and excretion
- Useful for monitoring patients in CKD
- Not appropriate in:
AKD/AKI
Children
Pregnancy
Extremes of body weight
Patients taking extra creatinine
10
Q
What is used to calculate eGFR
A
CKD-EPI?
The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) is currently used now
- More accurate at higher eGFR
– Validated across more populations
– Better prediction of adverse clinical outcomes cf. MDRD
11
Q
What is the most common cause of death in CKD and transplant
A
- CKD: Withdrawal is the most common cause of death followed by cardiovascular events
- Transplant: cancer and cardiovascular disease is the most common cause of death
12
Q
CV disease and CKD
A
Cardiovascular disease
– Principal cause of death at all stages of CKD
– Left ventricular hypertrophy
– Myocardial fibrosis
– Accelerated vascular disease (non-atherosclerotic)
– Widened pulse pressure
Antihypertensive agents (beta-blockers, RAS blockers) effective Lipid lowering agents not proven to be effective
13
Q
CKD and anaemia
A
- Common: less with ADPKD
- Proportional to CKD
Multifactorial
- Inflammation
- Higher blood loss
- Hyperparathyroidism
- Dysfunctional iron access
- Reduced EPO
Target Hb 110-120
Needs sufficient iron (T sats >20%, ferritin > 300)
Does not increase length life
Improves QOL
Reduces transfusions
14
Q
Causes of EPO resistant anaemia
A
- Iron deficiency (most common cause)
- Intercurrent infection
- Hyperparathyroidism
- Primary bone marrow pathology
- Folate/B12 deficiency
- Pure red cell aplasia
Production of antibodies against EPO related to exogeneous treatment.
Less common with newer diluents.
15
Q
Side effects of EPO
A
– Hypertension (commonest) - can be associated with
hypertensive encephalopathy
– Thrombosis of access
– Pure red cell aplasia
Adverse effects of higher Hb targets (death 45 – 48% increased risk, CVA, vascular access thrombosis) well
proven
16
Q
Causes of iron deficiency in HD patients
A
Most patients on HD are not physically able to absorb enough orally absorbed iron to prevent iron deficiency
– Loss of blood during dialysis (10-30mL)
– Increased mucosal loss (anticoagulation during dialysis)
– Clotted circuit – 200-500mL blood
– Low haem iron diet
– Increased hepcidin (reduces GI duodenal iron absorption by binding ferroportin and sequestering iron in the macrophages)
Hepcidin is a key regulator of iron homeostasis and plays a role in the pathogenesis of anaemia of chronic disease. Its levels are increased in patients with chronic kidney disease (CKD) due to diminished renal clearance and an inflammatory state.
17
Q
Iron management in HD
A
Target levels
– Ferritin > 300ug/mL
– Transferrin saturation > 20%
Intravenous iron required in majority
– Oral iron absorption poor and cannot replace average
daily iron loss
– Typically infused during HD treatment
– Maintenance protocols more effective than ‘reactive’ protocols
– Withhold during active infection
18
Q
How much renal function is substituted by dialysis?
A
15-20%
19
Q
Which patients are excluded from peritoneal dialysis
A
- Obese patients
- Abdominal surgery
- Poor vision
- Unstable home environment
- Not attentive to hygiene
- Patients without any residual renal function
If anuric or passing urine <500ml/day then they need to be transitioned to dialysis
RESIDUAL RENAL FUNCTION is required for a patient to undergo peritoneal dialysis
20
Q
PD vs HD
A
- PD catheter inserted 2-3 weeks before starting PD
Patients need RESIDUAL RENAL FUNCTION for PD - HD: fistula created 2-3 months prior
When to start dialysis
- eGFR 5-10ml/min
- Uraemic symptoms eg: itch, cognitive dysfunction, fatigue, SOB, muscle cramps, N+V
- Fluid overload that cannot be treated with
diuretics/fluid and salt restriction
- Hyperkalaemia that cannot be managed with dietary vigilance and potassium binders
- Pericarditis, uraemic encephalopathy
AEIOU Acidosis Electrolytes Ingestion of toxins Overload Uremia
21
Q
Haemodialysis access sites
A
- AV fistula
- AV grafts
- Tunnelled dialysis catheters
Descending in order for greater infection risk and less reliable
22
Q
Dialysis catheter related bacteremia and tx
A
• 40-80% gram positive
• S aureus CRB associated with 20-30% mortality
• ‘Around catheter’ contamination more common than ‘inside catheter’
• Higher in
– Patients with diabetes
– Non tunnelled lines
– Femoral>internal jugular>subclavian
• Always assume the catheter is source of infection in a febrile dialysis
patient until proven otherwise
• Cultures from catheter and peripheries
• Mandatory removal (send tip for culture) if
– Non tunnelled line
– Severe sepsis in tunnelled line
• Broad spectrum antibiotics
– Empiric vancomycin or linezolid if MRSA/ VRE colonised
– Include gram negative cover
– 14 days treatment for S aureus
• Evaluate for metastatic infection (endocarditis, osteomyelitis, epidural
abscess) if persistent fevers or bacteraemia
23
Q
Which of the following statements regarding haemodialysis (HD) and peritoneal dialysis (PD) is correct?
a. Patients on PD suffer greater fluctuations in their fluid state than patients on HD
b. Both HD and PD lose their effectiveness with time
c. Low serum urea levels are a reliable indicator of effective therapy
d. Weight gain in the absence of fluid overload commonly occurs in patients on PD
e. HD has a proven advantage over PD in preservation of residual kidney function.
A
d. Weight gain in the absence of fluid overload commonly occurs in patients on PD
24
Q
- Which of the following is true regarding mortality in HD patients?
a. Similar to the general population when high quality HD has been given
b. Commonest cause of fatality is infection
c. Fatality in HD patients is highest after a longer interdialytic break
d. Cardiovascular mortality is explained by traditional CV risk factors
e. Statin therapy for hyperlipidaemia has an established role in high risk patients on HD
A
c. Fatality in HD patients is highest after a longer interdialytic break
25
In PD, how do solute and water move across the peritoneal membrane?
3 transport processes occurring at the same time
1. DIFFUSION – where substances of high
concentration move towards areas of low
concentration.
2. CONVECTION – the difference in osmolality leads to movement of water and associated solutes across the
membrane.
3. ABSORPTION – the lymphatics constantly absorbs water and solutes.
Peritoneal Clearance is the net result of diffusion + convection – absorption.
26
Diffusion in PD
This is critical for removal of uraemic toxins in peritoneal dialysis.
Relies on –
• Concentration gradient
• Effective peritoneal surface area
• Intrinsic peritoneal membrane resistance
• Molecular weight of the solute concerned
27
(A) How can peritoneal clearance by increased?
| (B) How can fluid removal be increased by?
(A) Peritoneal CLEARANCE can be increased by:
1. Maximising time on PD
2. Maximising concentration gradient
• Increasing number of exchanges
• Increasing dwell volumes
3. Maximising effective peritoneal surface area
• Increasing dwell volumes
4. Maximising peritoneal fluid removal
(B) FLUID REMOVAL can be increased by:
1. Maximising the osmotic gradient
• Higher glucose concentration
• Increase number of exchanges
2. Use an osmotic agent that is not absorbed well
3. Increase urine output
- Increase in % of bags = increase amount of fluid removed
Different Bags: 1.5%, 2.5%, 4.25%, 7.5% (isodextrin)
- Increase in fill volume/number of cycles = increase solute clearance (eg: urea, K+)
28
What is the peritoneal equilibration test?
- Gives us an idea of the transport characteristics of an individual’s peritoneal membrane
- Assessed by using equilibration ratios between dialysate and plasma for urea (D/P urea), creatinine (D/P creatinine)
- By waiting for equilibration, this test measures the combined effect of diffusion and convection.
- UF volumes are inversely proportional to peritoneal transport characteristics for solutes
- High transporters rapidly absorb the osmotic agent into peritoneal capillaries, diminishing stimulus for ultrafiltration within a few hours of dwell, leading to reabsorption of fluid through rest of the dwell
- Low transporters have good ultrafiltration, because the osmotic gradient is maintained throughout the entire dwell
High Transporters:
- Benefit from APD modalities that use shorter dwell times (so they need more cycles for better solute clearance)
- Excellent solute clearance
- Poor ultrafiltrate
· High Transporters: require more cycles for better solute clearance, normally diabetics are high transporters
Low Transporter
- Benefit from longer dwell modalities such as CAPD
- Inadequate solute clearance
- Excellent ultrafiltration
- Patients with a so-called high transport status of the peritoneal membrane (i.e. a more permeable peritoneal membrane), characterized by a high dialysate to plasma (D/P) ratio of creatinine, have a low UF volume due to rapid dissipation of glucose from the PD fluid to the capillaries.
· Low Transporters: it would be ideal to start as a low transporter as most PD patients progress to being high transporters
○ The ideal would be to be a low transporter and non-diabetic
· Low Transporter --> High Transporter --> Membrane Failure
○ Membrane Failure: when dwell time of 4 hours, 4.25% bags, UF <400mL
When there is membrane failure, the patient will need to be transitioned from PD to HD
29
What are high transporter states
- Inherent high transporter
- Peritonitis: transient and reversible
- Acquired on long term PD, esp in patients with a greater cumulative dextrose load
30
Types of PD
2 main Types: APD (automated peritoneal dialysis) vs CAPD (continuous ambulatory peritoneal dialysis)
○ APD (automated): using a cycler, done at night, frees up the morning/afternoon, overnight using machine
○ CAPD (continous ambulatory): manual, done by the patient - 3 manual bags in the morning + afternoon and isodextrin bag at night 4-5 bags/day every day
§ Patients who are on CAPD are normally low transporters
31
Benefits of 7.5% icodextrin
- Relatively inert high molecular weight polymaltose
glucose polymer
- Less permeable than dextrose - ultrafiltration occurs for
a longer period of time.
- Equivalent UF volume as a 4.25% dextrose
- Best used in a long dwell
- Reduced carbohydrate load
- Potential advantage of reducing the long term metabolic complications associated with hypertonic dextrose
```
No impact on
– Residual renal function
– Urine output
– Incidence of peritonitis
– Peritoneal creatinine clearance
– Technique failure
– Patient survival
```
Icodextrin can lead to:
- Over estimation of Blood Glucose levels
with Glucometers based on glucose
dehydrogenase (Advantage, Acucheck)
- Under estimation of Serum amylase level
(false low)
32
Using low GDP (glucose degradation products) neutral pH solutions
Low GDP, neutral pH solutions on
other outcomes
```
• Preserved urine output
• Less inflow pain
• No effect on:
– Ultrafiltration
– Peritoneal clearances
– Peritonitis episodes
– Technique failure
– Mortality
```
33
Methods to preserve residual renal function with patients on PD
- Use of ACEi/ARBs for treatment of hypertension
- Low GDP, neutral pH PD solutions
Avoid
• Prolonged use of Aminoglycosides
• NSAIDS
• Contrast agents
GDP: glucose degradation products
34
What conditions favour PD vs HD
Favours PD
- BP control
- Lower EPO dose
- Quality of life as able to do at home
Favours HD
- CCF
- Hypoalbuminaemia
- Survival from critical illness in ICU
35
Indications for PD catheter removal
Indications for catheter removal include:
- refractory peritonitis (failure to respond to appropriate antibiotics within 5 days)
- relapsing peritonitis
- refractory exit-site and tunnel infection
- fungal peritonitis.
Also consider catheter removal if the patient is not responding to therapy, in infections caused by mycobacteria, or in polymicrobial infection with enteric pathogens.
If removed may require vascath for haemodialysis
36
Complications of PD
Infective
- Peritonitis
- Exit site infection
- Tunnel Infection
Pressure related: intra-abdominal pressure lowest when supine, greatest while sitting
- Hernias
- Dialysate leaks: pericatheter, abdominal, genitalia, pleural
```
Non-infective
- Access Related:
Catheter obstruction
Omental entrapment
Tip migration can occur due a mass or constipation
Cuff extrusion
- Ultrafiltration failure
- Technique failure
```
37
PD Peritonitis Features
- Clinical features consistent with peritonitis: abdominal pain, cloudy dialysate
- Dialysate WCC > 100, >50% polymorphs/neutrophils, positive gram stain
The most common pathogens are:
- Coagulase-negative staphylococci (eg Staphylococcus epidermidis)
- Staphylococcus aureus
- enteric Gram-negative bacilli
- Streptococcus and Enterococcus species.
- Infection with fungi is uncommon
Microbiology:
• 50% Gram positives = SKIN
- coagulase negative staph, staph aureus, enterococcus, streptococcus
• 15% Gram negatives = GUT
• 20% Culture negative = Don’t Know
• 4% Polymicrobial infection = Laparotomy/Remove Tenckhoff
• multiple Gram negatives or Gram positives and Gram negatives
• <2% Fungal infection = Panic and remove Tenckhoff
• 13% exit site infection
• 3% peritoneal fluid leak
• 31% hospitalization i.e. most treated in the community
Tx:
- IP Gentamicin 80mg daily (added to 1 bag of dialysis fluid) if level <0.6 for 2 weeks [dwell time 6 hours]
- IP Cephazolin 1.5g daily (added to 1 bag of dialysis fluid) [dwell time 6 hours]
o Replace cephazolin with vancomycin if history of MRSA, systemic symptoms or immediate hypersensitivity to penicillins - IP Vancomycin 2g daily if level <20 for 2 weeks
- IP Heparin 1000 units to be given with IP antibiotics or IP heparin 500 units/L of PD fluid (ie: 1000 units in a 2L bag of PD fluid)
- Antifungal Cover: PO Nilstat 1mL QID - to cover for fungal infections
- Gram Negative/enterococcus: can add PO ciprofloxacin 250mg BD, enterococcus does not respond to cephalosporins
Gram Positive: can add PO keflex
Recurrent peritonitis can result in sclerosing peritonitis which is fatal
38
Differential diagnosis of cloudy effluent
* Culture-positive infectious peritonitis
* Infectious peritonitis with sterile cultures
* Chemical peritonitis - Eosinophilia of the effluent
* Hemoperitoneum
* Malignancy (rare)
* Chylous effluent (rare)
* Specimen taken from “dry” abdomen
39
Risks for renal progression
Proteinuria
Hypertension
Proteinuria most important marker for progressive renal failure
• Reducing proteinuria key goal of renal preservation
• Hypertension reduction vital to delay CKD progression
• Aggressive BP targets i.e. 125/75 (<130/80) in patients with diabetic and nondiabetic
nephropathy with proteinuria.
• ACE-I or ARBs for proteinuric nephropathies, combination no longer
recommended.
• Tight glycaemic control essential in diabetics.
• Salt restriction and bicarbonate therapy appear beneficial
• All other renal protection methods e.g. protein restriction, statins not sufficient
evidence to ask questions about.
40
How doe proteinuria cause damage?
```
Damage via:
– Hyperfiltration
– Tubular toxicity from resorbing certain proteins
– Increased tubular work
– Mesangial toxicity
```
Proteinuria thought to be reduced by reducing intraglomerular pressure – hence ACEi
41
Risk factors of renal failure
```
GFR < 90
Diabetes
Age
Hypertension
Smoking
BMI
```
42
```
Which risk factor best predicts development of renal failure?
A. Age
B. Smoking
C. Hypertension
D. Obesity
E. GFR<90
```
E. GFR<90
43
A 60-year-old man with a five-year history of type 2 diabetes presents
for a routine check-up. The most appropriate screening test for diabetic
nephropathy is:
A. serum creatinine level.
B. spot urine albumin concentration.
C. 24 hour urine protein excretion.
D. spot urine albumin/creatinine ratio.
E. 12 hour urinary albumin excretion rate
D. spot urine albumin/creatinine ratio.
44
CKD and Hypertension
Aim BP < 120
Non Pharm
- Salt restriction (<2g/day) or <90mmol Na/24 hour
- Exercise: 150min/week
45
```
67 y.o. diabetic has significant renal impairment with the following results:
Creatinine 180mol/L (eGFR 34ml/min)
Hb 105 gm/L (115 - 135 gm/L)
Proteinuria 0.38 gm/day (<0.12 gm/day)
Blood pressure 150/90 mmHg and HbA1c 7.5%
Which of these is likely to have the greatest impact on slowing the
progression of CKD?
A. Blood pressure reduction.
B. Tight glycaemic control.
C. Erythropoietin therapy.
D. Control of serum phosphate.
E. Low protein diet.
```
A. Blood pressure reduction.
46
65 y.o. woman presents with vague symptoms of fatigue. The following biochemistry is noted:
Potassium 5.5 mmol/L [3.5-5.5]
Urea 48 mmol/L [<6.5]
Creatinine 1010 mol/L [<120]
Calcium 2.1 mmol/L [2.1-2.5]
Phosphate 2.3 mmol/L [0.8-1.4]
BP 165/95 mmHg, no oedema.
Apart from the fatigue she is asymptomatic, although some scratch marks are noted.
She has 8.8 cm kidneys without obstruction.
PHx of cholecystectomy and perforated appendix.
What is the most appropriate next step?
A. Urgent haemodialysis.
B. Urgent peritoneal dialysis.
C. Elective haemodialysis.
D. Elective peritoneal dialysis.
E. Urgent continuous venovenous haemodiafiltration
C. Elective haemodialysis.
47
Indications for URGENT dialyis s
```
• Hyperkalaemia
• Fluid overload
• Uraemic:
- Pericarditis
- Pleuritis
- Encephalopathy
- Bleeding
```
• Relative indication
- Urea >60 (creatinine level irrelevant)
48
```
In a patient requiring urgent dialysis which of the following parameters
would favour continuous renal replacement therapy (CRRT) rather than
intermittent haemodialysis (IHD)?
A. Active bleeding.
B. Coagulopathy.
C. Hyperkalaemia.
D. Hypotension.
E. Hypoxia.
```
D. Hypotension.
49
Pros and Cons of HD
Pros
• Efficient solute removal, reasonable fluid removal
• Intermittent – escape
Cons
• Intermittent –fluctuation in solute and fluid removal, BP
• Requires good cardiac function - weak hearts might suffer on HD
• Access can be difficult, especially in diabetics
• Heparin exposure
• Blood exposure to artificial circuit
• Strict attention required to fluid and solute intake
50
Pros and Cons of PD
```
Pros
• Smooth removal of solute and fluid
• Cardiac friendly
• No heparin. No blood contact with artificial products.
• Quick to learn -independence
```
```
Cons
• Peritonitis and Exit site infection
• Inefficient – reliance on residual renal function (protect)
• Respiratory embarrassment
• Requires dexterity +vision
```
51
67 y.o. diabetic on PD presents with abdominal pain, low grade fever and cloudy
dialysate. She has mild generalised abdominal tenderness and guarding but does
not appear particularly unwell. She is started on intra-peritoneal cephalexin. The
next day, her dialysate culture grows:
Enterococci, E-coli and Klebsiella species.
The most appropriate management step is:
A. exploratory laparotomy.
B. add intraperitoneal Ampicillin.
C. removal of the Tenckhoff catheter.
D. intraperitoneal gentamicin.
E. change to intravenous antibiotics.
A. exploratory laparotomy.
| This is because there is 3 enteric bugs and this may indicate a bowel perf somewhere
52
```
With regards to haemodialysis patients, survival is improved by?
A. Tight BP control
B. Tight weight control
C. Dialysis dose
D. Dialysis duration
E. Tight cholesterol control
```
D. Dialysis duration
53
Dialysis Adequacy
URR (urea removal ratio) = (pre-dialysis urea - post-dialysis urea)/ pre-dialysis urea
goal>70%
Kt/V
• where K’ is the dialyser clearance, ‘t’ is time, ‘V’ is the volume of body water
• Kt/V = clearance x time ÷a volume estimate of body water
• Kt/V thus represents the volume of body fluid completely cleared of urea -the
chosen marker - in a single dialysis
54
Complications of renal failure
* Cardiovascular disease
* Anaemia
* Renal bone disease
* Hypertension
* Hyperlipidaemia
55
A 71-year-old woman with hypertension and a remote smoking history of 20 pack years is found to have abnormal kidney
function on a routine blood test. Her current medication is enalapril 10 mg daily and amlodipine 10 mg daily and her last blood
pressure was 138/86 mmHg.
Her results are as follows: Normal values
Serum creatinine 168 mol/L [49–90]
Estimated glomerular filtration rate (eGFR) 31 mL/min/1.73 m2 [90–130]
Sodium (Na) 138 mmol/L [134–145]
Potassium (K) 4.7 mmol/L [3.5–5.0]
Haemoglobin (Hb) 116 g/L [120–160]
Calcium (Ca) 2.45 mmol/L [2.20–2.55]
Phosphate (PO4) 1.3 mmolL [0.78–1.43]
Urine albumin:creatinine ratio (ACR) 11 mg/g [< 3.5]
In addition to monitoring kidney function, what additional strategy should be the focus of her management?
A. Dietary potassium restriction.
B. Modification of cardiovascular risk.
C. Planning for dialysis access.
D. Reduction of proteinuria.
E. Repletion of haematinics.
B. Modification of cardiovascular risk.
56
Role of statins in CKD
* No clear benefits seen in dialysis patients
* Calcific disease rather than lipid-rich plaques
Calcium & Phosphate
• Treat the phosphate for the vessels as well as the bones
• Major cause of death is vascular disease (44% - cardiac, another
11% vascular)
• This isn’t necessarily rupture of lipid-rich plaques, much of it is stenotic disease.
57
```
65-y.o. on HD for 9/12, is on EPO 4,000u 2x/week. Previously Hb had been stable
(105 – 115 gm/L).
She now presents with a Hb of 89 gm/L. There have been no changes to her EPO
dose or other medications.
MCV 84 fL [78-98]
Serum iron 13 mol/l [13-35]
Iron saturation 18% [15-46]
Serum ferritin 630 g/l [20-300]
Retic count 30 x 109/L [12-100]
Which is the most likely cause for her EPO resistance?
A. Inflammation.
B. Pure red cell aplasia.
C. Vitamin B12 deficiency.
D. Iron deficiency.
E. Hyperparathyroidism.
```
A. Inflammation due to ferritin
58
Cardiovascular disease is the major cause of death in dialysis patients. Elevation
of which of the following clinical parameters carries the highest mortality risk?
A. Serum phosphate.
B. Serum cholesterol.
C. Serum homocysteine.
D. Serum parathyroid hormone.
E. Blood pressure.
A. Serum phosphate.
High phosphate = higher mortality
59
Treatment of hyperphosphatemia in CKD
Reduce PO4 - dialysis, binders
• Binders:
- calcium based –caltrate, cal-sup
- Magnesium -mylanta
- Aluminium -alutabs
- Non-Calcium based = lanthanum (Fosrenol), sevalamer (Renagel)
Prevent hyperparathyroidism as high PTH causes increased urinary phosphate excretion
- Replace vitamin D (1,25) to maintain normal calcium levels
- Use vitamin D as suppressive therapy
- If non-responsive consider calcimimetics (eg: cinacalcet) or PTHectomy (PTH>100)
• Avoid calcium based PO4 binders if calcium is high
60
```
Which of the following is most likely to increase serum phosphate in chronic renal
failure?
A. Calcium trisilicate.
B. Calcitriol.
C. Cinacalcet.
D. Calcitonin.
E. Alendronate.
```
B. Calcitriol
- Vit D increase Ca and Po4
- PTH just cares about Ca, increases Ca and decreases PO4
Vitamin D is about making bone
- Increased gut absorption of Ca nad Phosphate
- Reduced urinary losses of Ca and Phosphate
PTH is about maintaining serum Ca
- Reduced urinary loss of Ca
- Increased urinary loss of Phosphate
61
Cinalcacet
- Bind calcium sensing receptor and increase sensitivity to calcium (Cinacalcet/ Sensipar) useful for secondary hyperparathyroidism
- Reduced parathyroidectomy rate
- No evidence of improved mortality
with their use
- No longer on PBS for CKDMBD
62
Renal bone disease in CKD
* Hyperparathyroidism -osteitis fibrosa/ osteomalacia
* Low vitamin D (active form) –decreased bone mineralisation (osteopaenia)
* Adynamic bone disease/aluminium deposition – increased fracture risk
* Don’t say osteoporosis in written or long case
63
Features of calciphylaxis
```
• Subepidermal calcific obstruction of
small vessels
• May be precipitated by hypotension
• Central type associated with mortality
>50%
• Treatment difficult, includes hyperbaric
oxygen and reductions in calcium and
phosphate.
• Sodium thiosulphate (also a role as an antidote to cyanide poisoning, a nephroprotective agent and an antifungal drug)
```
64
Treatment of vascular calcification in CKD
• Vascular calcification is a big issue (beware questions on this) need to reduce
phosphate, PTH, calcium and CaxPO4 product
• most important REDUCE PHOSPHATE
65
Albumin in CKD
Marker of mortality
66
Definition of AKI
Acute Kidney Injury: defined as a sudden loss of renal failure with consecutive rise in creatinine and blood urea nitrogen.
As defined by the International Society of Nephrology (KDIGO)
- Urine Volume < 0.5mL/kg/hour for 6 consecutive hours (<400ml/day or <20ml/hr) OR
- Increase in serum creatinine by >26.5umol/L in 48 hours OR
- Increase in serum creatinine by 1.5x baseline within 7 days
67
When do you dose reduce apixaban?
Weight <60 kg, age >80 years, serum creatinine >133 micromol/L—use a lower dose for AF in the presence of at least 2 of these factors.
68
Pre-renal causes of AKI
Pre-Renal (renal hypoperfusion, 70%): consider shock, dehydration, vomiting, diarrhoea, cardiorenal syndrome, renal artery thrombus
- True volume depletion –gastrointestinal loss (vomiting, diarrhoea, bleeding);
renal losses (diuretics, glucose osmotic diuresis); skin or respiratory losses
(insensible losses, sweat, burns); third space sequestration (crush injury or
skeletal fracture);
- Hypotension – Severely decreased blood pressure can result from shock
(hypovolemic, myocardial, or septic)
- Drugs – that decrease afferent (pre glomerular dilatation) i.e. NSAIDs, Calcineurin inhibitors (cyclosporine, tacrolimus) OR decrease efferent (post glomerular) arteriolar constriction i.e. ACE-inhibitors or angiotensin II blockers OR cause volume depletion i.e. diuretics
- Oedematous states- decreased cardiac output in CCF and splanchnic venous
pooling and systemic vasodilation in cirrhosis causing reduced renal
perfusion(Hepatorenal syndrome)
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Renal causes of AKI
- Glomerular: Glomerulonephritis, thrombotic microangiopathy, vasculitis
Can have dysmorphic RBC and RBC casts
- Tubulo -interstitial: Acute tubular necrosis (ATN) and Acute interstitial nephritis (AIN)
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ATN
ATN- defined by histologic changes- necrosis of the tubular epithelium
and occlusion of the tubular lumen by casts and cell debris; 3 major
causes of ATN are:
- Renal ischemia: All causes of severe prerenal AKI particularly hypotension, shock and surgery
- Sepsis: Usually associated with hypotension
- Nephrotoxins- aminoglycosides, vancomycin, cisplatin, radiocontrast
material, cidofovir
Often cause BLAND URINE
- Usually caused by ischaemia - extension from pre-renal, usually secondary to pre-renal causes with continuing intravascular depletion, hypotension and renal ischaemia
Prolonged hypovolemia/shock
Thromboembolism
Thrombotic microangiopathy
Nephrotoxins (radiocontrast, myoglobin, radiation, drugs)
- Endotoxins: myoglobin (eg: rhabdomyolysis), casts (eg: MM)
- Exotoxin: aminoglycosides, IV contrast, chemotherapies
- Contrast induced nephropathy - to reduce the risk of this, should pre and post hydrate with isotonic NaCl
- Medications: aminoglycosides, cisplatin, anti Hep C medications (affecting proximal tubules)
- Pigment Nephropathy
□ Myoglobinuria due to rhabdomyolysis
□ Haemoglobinuria associated with haemolysis
- Acute uric acid nephropathy
- Medications: aminoglycosides, amphotericin B, IV contrast, chemotherapy
- Poisons: ethylene glycol, mercury, carbon tetrachloride
- Endogenous Substances: myoglobin, Bence Jones Protein, amyloid
- Occurs rapidly in 24 hours
Clinical Course
- Injury can predate changes to sCr
- sCr usually plateaus once parenchymal injury established
- Oliguria is a predictor of the need for KRT
- Polyuria usually heralds renal recovery and occurs prior to improvements in sCr
- Severe ATN can result in cortical necrosis
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AIN
Caused by inflammatory infiltrate in the renal interstitium (glomeruli normal)
Causes
- Drugs (NSAIDs, penicillins, cephalosporins, ciprofloxacin, PPIs,
diuretics etc.) : 70 to 75%
- Infections : Streptococcus, legionella, CMV 4-10%
-Tubulointerstitial nephritis and uveitis (TINU) syndrome –5-10%
- Systemic diseases: Sarcoidosis, Sjögren's syndrome, SLE and others: 10-20%
Presentation
- May present from few days to months after drug exposure
- Triad of rash, fever, eosinophilia
- Can also cause eosinophiluria
- White cell casts
Tx:
- Discontinuation of the potential causative agent is a mainstay of therapy
- 2-3 months course of prednisolone in those whose creatinine does not improve
within 7 days of stopping offending drugs
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Post renal causes of AKI
· Post-Renal (5%):
- PUJ
- Ureters: stones, cancer
- Bladder + Prostate: BPH, carcinoma of cervix, stones, cancer, neurogenic bladder
- Urethra: stones/cancer/benign prostatic hyperplasia/catheter blockage
- + Neurological
For post renal: should do renal US/CTKUB/bladder scan post void
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In a patient with AKI, what could a rash indicate?
Renal vasculitis or AIN
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AKI and urinary Na
Urine sodium concentration:
- Urine Na concentration is low in prerenal
disease (less than 20 mEq/L) in an attempt to conserve Na
- Urine Na concentration is high in ATN
(more than 40 to 50 mEq/L) due to impaired tubular function induced by the tubular injury
Fractional excretion of sodium: Better indicator than above
- FENa < 1% usually indicates prerenal AKI (indicative of sodium retention)
- FENa > 2% indicates (not always) ATN (damaged tubules unable to reabsorb Na)
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How is hypercalcemia vs cast nephropathy treated in myeloma AKI
- Hypercalcemia in myeloma causing AKI needs aggressive hydration
- Cast nephropathy in myeloma causing AKI needs urgent steroids/anti myeloma treatment
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Radiocontrast Nephropathy features and RF
| Pathogenesis and treatment
```
- Usually reversible, consequences
obviously dependent on intercurrent
patient issues
- Definition: >25% increase in SCr in 48
hours without another identifiable cause
```
RF:
- Pre-existing CKD or low renal perfusion (e.g. CCF, dehydration)
- Age >70
- Multiple myeloma
- Diabetes
- Volume and type of contrast media used
- Inpatients (?independent risk factor)
- Drugs like NSAIDs, ACE inhibitors and ARBs
Pathogenesis: both renal medullary hypoxia due to vasoconstriction and direct tubular injury lead to ATN
- Unlike other types of ATN, rapid recovery
- AKI usually within 24 - 48 hours of contrast administration and improvement within three to seven days
Treatment
- avoid nephrotoxins, pre and post IV hydration with 0.9% saline or NaHCO3
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Atheroembolic Renal Disease
- Cholesterol crystal embolization to the kidneys
- Usually after coronary angiography (commonest cause), renal angiography or
cardiovascular surgery
- AKI several weeks later (sometimes within 1-2 weeks)
- Urine bland, can have microscopic haematuria and minimal protein
- Cyanosis or discrete gangrenous lesions in the toes with intact peripheral pulses (blue toes), livedo reticularis and focal neurologic deficits, orange plaques in the retinal arterioles (Hollenhorst plaques)
- May be accompanied by-eosinophilia, eosinophiluria, and hypocomplementemia
Tx:
Supportive therapy and secondary prevention of CV disease with aggressive
lipid lowering therapy
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Where does gentamicin affect?
- Aminoglycosides freely filtered across glomerulus and partially taken up by
the proximal tubular cells
- Gentamicin levels inside PTC cells 100 to 1000 times serum levels……toxic to
the cells
- Non-oliguric AKI usually occurs 5 to 10 days after treatment with gentamicin
- Involvement of the distal tubular cells may lead to hypokalemia and
hypomagnesemia
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Heme Pigment Nephropathy (in
| rhabdomyolysis and hemolysis)
- Myoglobin and haemoglobin are filtered by the glomerulus into the urinary space
and degraded releasing heme
- Dipstick-positive haematuria in the absence of any RBC by microscopy may be the first clue along with pigmented granular casts
Heme can lead to AKI by three processes:
- Tubular obstruction, possibly in association with uric acid
- Direct proximal tubular cell injury
- Vasoconstriction leading to medullary hypoxia
- Also in rhabdomyolysis sequestration of large amounts of fluid in the injured
muscle can cause hypovolemia and pre renal AKI
- Treatment consists of fluid replacement and at times alkaline diuresis with
intravenous bicarbonate to reduce chances of tubular obstruction
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Hepatorenal Syndrome
- HRS is a reversible and functional renal failure that occurs in patients with
acute or chronic liver disease and portal hypertension
Diagnostic Criteria
- Diagnosis of cirrhosis and ascites
- Diagnosis of AKI
- No response after 2 consecutive days of diuretic withdrawal and volume expansion
- Absence of shock
- No current or recent treatment with nephrotoxic drugs
- No macroscopic signs of structural kidney injury defined as:
1. Absence of proteinuria (>500mg/day)
2. Absence of microhaematuria (>50RBC/hpf)
3. Normal findings on renal US
- Diagnosis of exclusion- rule out prerenal/renal//postrenal causes
- Incidence in cirrhotic patients with normal renal function is 18 and 39% at 1
and 5 years respectively
- Neither etiology of cirrhosis nor the Child Pugh score predicts HRS
- Caused by marked renal vasoconstriction causing low GFR in the face of vasodilatation of splanchnic vessels
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2 types of hepatorenal syndrome
1. Type 1 HRS
- Associated with doubling of serum creatinine > 2.5mg/dl (220
umol/l) or a 50% reduction in GFR to < 20ml/min in < 2 weeks. Median
survival without treatment is 2 weeks.
- Often multiorgan failure and hyponatremia
- Precipitating events: bacterial infections(specially SBP), gastrointestinal
bleeding, vigorous diuretic therapy, abdominal paracentesis or NSAIDs
2. Type 2 HRS
- Associated with a much less rapid decline in renal function and
mainly presents with refractory ascites.
- Median survival without treatment is
4-6 months
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Treatment of hepatorenal syndrome
Terlipressin with albumin
- Vasopressin analogue Terlipressin (IV 1 to 2 mg/ 4 to 6 hourly) and albumin
given for 2 days as IV bolus (1 g/kg per day) followed by 25 to 50 grams daily up
till 15 days
- Midodrine, octreotide, and albumin where terlipressin is not available
Midodrine (alpha-1 adrenergic agonist) orally at 7.5 mg tds and octreotide
(somatostatin analogue) at 100 mcg SC tds, increased as needed to 12.5 mg tds
and 200 mcg tds respectively
- Norepinephrine with albumin for ICU patient with hypotension
- Usually for ICU patient with hypotension
- Definitive HRS treatment is liver transplantation
83
Factors which may effect creatinine levels
* pregnancy
* muscle mass (e.g. amputees, body-builders)
* eating red meat 12 hours prior to the sample being taken
```
Serum creatinine may not provide an accurate estimate of renal function due to differences in muscle. For this reason, formulas were developed to help estimate the glomerular filtration rate (estimated GFR or eGFR). The most commonly used formula is the Modification of Diet in Renal Disease (MDRD) equation, which uses the following variables:
• serum creatinine
• age
• gender
• ethnicity
```
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Dialysis related amyloidosis
- Derived from beta2-microglobulin (beta2-m) which is normally cleared by kidney
- Beta2-m cleared poorly with low flux dialysis and PD
- Somewhat better but not adequate clearance with high flux dialysis as well
- Deposits particularly in bone, articular cartilage, synovium, muscle,
tendons, and ligaments
- Usual presentation with BL shoulder pain/carpal tunnel syndrome
- X-ray reveals bone cysts in involved bones
- Switch to highly biocompatible, high-flux membrane and do longer hours
dialysis
- Renal transplantation is the only definitive treatment
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How is phosphate homeostasis maintained?
- Proximal tubular reabsorption regulates serum P: 90% of P is reabsorbed in the proximal tubule at normal GFR
- With nephron loss, remaining nephrons must excrete more P per nephron to maintain P balance
e.g., at low GFR levels, if only 10% of P is
reabsorbed, serum P can remain normal
This adaptation is mediated by phosphaturic hormones:
- FGF-23 / Klotho
- PTH
- Reduction in 1,25-vitamin D to reduce active GI absorption
86
What are the features of parathyroid hyperplasia?
- Reduced 1,25-vitamin D
- Increased P
- Reduced Klotho and FGF23 activity
87
In late stage CKD what happens to FGF23?
- High Phosphate
- Maladaptive high FGF23
- High PTH
- Low 1,24 vitamin D
- Low klotho
KLOTHO
- Klotho is a putative ageing suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific
for FGF-23
- Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone– kidney–parathyroid control of phosphate and calcium.
- Klotho−/− mice display premature ageing and chronic kidney disease-associated mineral and bone disorder
(CKD-MBD)-like phenotypes mediated by hyperphosphataemia and remediated
by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor or NaPi-cotransporter).
- CKD can be seen as a state of hyperphosphataemia-induced accelerated ageing associated with klotho deficiency.
- Humans with CKD experience decreased klotho expression as early as stage 1 CKD; klotho continues to decline as CKD progresses, causing FGF-23 resistance and provoking large FGF-23 and parathyroid hormone increases, and hypovitaminosis.
88
Features of FGF23
- FGF 23 requires Klotho for binding to its receptor
- FGF 23 is a phosphaturic hormone that causes ventricular hypertrophy
- FGF 23 is a product of osteocytes and osteoblasts
89
ESKD and cortical bone
- Patients with ESKD have have early loss of cortical integrity and strength that contributes to fracture risk
- Cortical parameters derived from DXA images may be a useful diagnostic tool to aid in fracture prediction in patients with ESKD
90
1. Which of the following statements about FGF 23 is untrue?
a. FGF 23 decreases in chronic kidney disease stages 2 and 3
b. FGF 23 requires Klotho for binding to its receptor
c. FGF 23 is a phosphaturic hormone that causes ventricular hypertrophy
d. FGF 23 is a product of osteocytes and osteoblasts
a. FGF 23 decreases in chronic kidney disease stages 2 and 3
FGF23 INCREASES, KLOTHO DECREASES
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Which of the following occurs early in CKD?
a. An imbalance between phosphate intake and excretion
b. A decrease in urinary Klotho
c. A 10 to 100-fold rise in FGF-23
d. All of the above
d. All of the above
92
Regarding patients with chronic kidney disease-mineral and bone disorder, which of the following is / are true?
a. Levels of PTH are highly positively correlated to mortality
b. Stable CV mortality rates rise as patients enter CKD-stages 4 and 5
c. Traditional CV risk factors reduction improves mortality rates
d. Vascular calcification is positively associated with age, time on dialysis and mortality
d. Vascular calcification is positively associated with age, time on dialysis and mortality
93
A normally compliant 45 year old man with CKD misses a haemodialysis session and arrives in the casualty department with breathlessness. Biochemistry reveals elevation of the serum calcium (3.0 mmol/L) and phosphate (2.0 mmol/L). Which of the following statements is / are false?
a. Treatment with calcitriol increases absorption of dietary phosphate via activation of a NaPi cotransporter
b. Calcium-based phosphate binders rarely cause hypercalcaemia as gastrointestinal absorption is minimal
c. Calcimimetic drugs target the calcium-sensing receptor, shift the calcium set point to the left and require extracellular calcium for activity
d. For patients on dialysis, an elevated calcium phosphate product is associated with increased cardiovascular mortality
b. Calcium-based phosphate binders rarely cause hypercalcaemia as gastrointestinal absorption is minimal
94
PTH role
Parathyroid hormone maintains the concentration of ionised calcium. It is synthesised and released into the circulation in response to hypocalcaemia and hyperphosphataemia. Its synthesis is inhibited by vitamin D analogues and hypercalcaemia. Parathyroid hormone has multiple systemic effects including increased bone turnover by stimulation of both osteoblasts and osteoclasts. In the kidney it decreases excretion of calcium, increases excretion of phosphate and induces 1-a-hydroxylation of calcidiol. In normal physiology, an increase in parathyroid hormone has the net effect of increasing the concentration of calcium and decreasing the concentration of phosphate.
95
In addition to the raised calcium and phosphate levels, the patient is found to have an elevated PTH level of 80 pmol/L (normal range 1-7 pmol/L) and an ALP of 213 U/L. Which of the following statements is / are false?
a. Vascular smooth muscle cells can transdifferentiate into cells with an osteoblast phenotype and form bone islands within the blood vessel wall
b. Vascular calcification visible on plain X-ray of the patient’s abdomen and pelvis typically involves the media rather than the intima
c. The cause of the hypercalcemia is increased bone turnover with uncoupling of osteoblastic and osteoclastic activity
d. Sestamibi parathyroid scanning may show a parathyroid adenoma and is advisable before surgery
d. Sestamibi parathyroid scanning may show a parathyroid adenoma and is advisable before surgery
96
The patient has a kidney transplant and develops an acutely painful left hip 9 months post-transplant. He is on tacrolimus, prednisolone and mycophenolate mofetil for immunosuppression. Which of the following statements is/are true?
a. Treatment with glucocorticoids increases the risk of hip fracture by mechanisms that include inducing osteoblast and osteocyte apoptosis
b. Male transplant patients are unlikely to suffer osteoporosis or hip fracture unless they have glucocorticoid induced hypogonadism
c. This is likely to be the calcineurin induced pain syndrome (CIPS) because thatsyndrome is generally unilateral and involves weight-bearing joints
d. Prior secondary hyperparathyroidism is associated with an increased risk of osteonecrosis
a. Treatment with glucocorticoids increases the risk of hip fracture by mechanisms that include inducing osteoblast and osteocyte apoptosis
97
David is a 37 year old with chronic renal failure due to glomerulonephritis. He has been treated with haemodialysis for the past 14 months. He complains of pruritis and biochemistry reveals the serum calcium is 2.9 mmol/l and phosphate is 3.0 mmol/l.
Which of the following statements is / are incorrect?
a. He should be treated with calcitriol to suppress parathyroid hormone production
b. Compared to the general population his risk of cardiovascular disease is increased 10-20 times
c. High serum phosphate levels increase parathyroid hormone secretion
d. Serum phosphate levels can be reduced by increasing the hours spent on haemodialysis
a. He should be treated with calcitriol to suppress parathyroid hormone production
98
A 57 year old female dialysis patient has a hip fracture in a fall from a standing height. By DXA her bone density T-scores are -1 at the lumbar spine and -2.6 at the total hip and -3.7 at the forearm sites. Which of the following is / are false?
a. Assessment of fracture risk by DXA is less accurate in patients on dialysis than in the general population
b. The T-scores indicate greater loss of cortical than trabecular bone.
c. The T-scores suggest that hyperparathyroidism may be an underlying cause
d. An elevated P1NP and beta-CTx would confirm high bone turnover
e. Oral bisphosphonates do not impair renal function
d. An elevated P1NP and beta-CTx would confirm high bone turnover
99
Drug toxicity and action on glomerulus and tubules
Glomerular: GFR affected, albuminuria
Tubular: electrolyte and acid base disorders, water balance
100
72yo male with HTN treated with thiazide presents with hyponatremia. Which of the following is correct?
A. Thiazide diuretics block the ENaC in the collecting duct
B. 7-9% filtered sodium is reabsorbed in the distal convoluted tubule
C. Thiazide diuretics increase urine calcium excretion
D. Loop diuretics are more vasodilating than thiazide
E. Due to their action in the distal nephron, thiazides are more likely than loop diuretic to cause dilutional hyponatremia
E. Due to their action in the distal nephron, thiazides are more likely than loop diuretic to cause dilutional hyponatremia
101
Mechanism of nephrotoxicity of methotrexate, acyclovir, vit C
Methotrexate
Acyclovir
Vit C
Insoluble drug in urine - form crystals
102
How does vancomycin cause nephrotoxicity?
Drug-uromodulin interaction - cast formation
