Chronic Kidney Disease

Question 1

What is chronic kidney disease (CKD)?

Answer 1

CKD is deteriorating kidney function and progressive impairment of any underlying cause for >3months

Question 2

What are the congenital and inherited causes of chronic kidney disease?

Answer 2

Polycystic kidney disease

Medullary cystic disease

Tuberous sclerosis

Congenital obstructive uropathy

Question 3

What are the primary and secondary glomerular disease causes of chronic kidney disease?

Answer 3

Primary glomerulonephritides
=> inc focal glomerulosclerosis

Secondary glomerular disease
=> systemic lupus
=> polyangiitis
=> granulomatosis with polyangiitis
=> amyloidosis
=> diabetic glomerulosclerosis 
=> thrombotic thrombocytopenia purpura
=> systemic sclerosis
=> sickle cell disease

Question 4

What are the vascular causes of chronic kidney disease?

Answer 4

Hypertensive nephrosclerosis (black african)

Renovascular disease

Small and medium sized vessel vasculitis

Question 5

What are the tubulointersitial causes of chronic kidney disease?

Answer 5

Tubulointersitial nephritis due to i.e. idiopathic, drugs, immunologically mediated

Reflux nephropathy

Tuberculosis

Schistosomiasis

Nephrocalcinosis

Multiple myeloma

Renal papillary necrosis i.e. diabetes, sickle cell disease + trait, analgesic nephropathy

Chinese herb neuropathy

Question 6

What are the most common causes of chronic kidney disease in the UK?

Answer 6

Diabetes

Glomerulonephritis

High BP / renovascular disease

Question 7

How is chronic kidney disease staged?

• pg 1393 kumar&clarks
• pg 302 ox handbook

Answer 7

Patients are staged according to

=> eGFR
=> Albuminuria

Both these parameters correlate with progressive renal impairment and cardiovascular risk

Question 8

Who does CKD affect?

Answer 8

Ethnic variation

End-stage kidney disease is much higher in:

i. Black African => hypertensive nephropathy more common in this group
ii. Asians => diabetes nephropathy more common in this group
iii. Middle eastern => schistosomiasis causing urinary tract obstruction most common in this group
iv. Elderly => CKD caused by atherosclerotic renal vascular disease
* >70% of CKD due to diabetes, hypertension and atherosclerosis

Question 9

Patients with chronic glomerular disease tend to deteriorate more quickly than those with chronic tubulointerstitial nephropathies.

What does the rate of decline to end-stage renal disease depend on in CKD?

Answer 9

Underlying nephropathy

Control on BP

Question 10

What is the underlying pathology as a result of CKD?

Answer 10

I. Each kidney has ~million nephrons. In CKD, many nephrons have scarred and failed => increased burden of filtration on a small number of nephrons

II. The small number of functioning nephrons undergo hyperfiltration (increased blood flow as flow hasn’t changed)

=> these nephrons adapt via glomerular hypertrophy and reduced arteriolar resistance

III. Increased flow, pressure and stress => raised intraglomerular capillary pressure => accelerates remnant nephron failure

IV. Increased flow/strain may be detected by new or increasing proteinuria

Question 11

What is the role of angiotensin II in CKD?

Answer 11

i. Ang II produced locally modulates intraglomerular capillary pressure and GFR
=> vasoconstriction of postglomerular arterioles + increasing the glomerular hydraulic pressure

ii. Ang II indirectly upregulates TGF-b (fibrogenic cytokine)
=> increases collagen synthesis

ii. Ang II indirectly upregulates plasminogen activator inhibitor-1
=> inhibits matrix proteolysis by plasmin
=> accumulation of excessive matrix
=> scarring in glomeruli and interstitium

Question 12

What does the prognosis of CKD depend on?

Answer 12

Reduced GFR and albuminuria independently assoc. with high risk of:

i. all cause mortality
ii. CVS mortality
iii. progressive kidney disease & kidney failure
iv. AKI

Question 13

What do you need to ask the patient if suspecting CKD?

Answer 13

Previous UTI, lower urinary tract symptoms

PMHx of hypertension, diabetes, ischaemic heart disease, systemic disorder, renal colic

Drug Hx

Family Hx inc. renal disease and subarachnoid haemorrhage

System review i.e. rare causes

Current state: symptomatic CKD if GFR <30
i. symptoms of fluid overload i.e. peripheral oedema, shortness of breath

ii. anorexia
iii. nausea & vomiting
iv. restless legs
v. fatigue & weakness
vi. pruiritis
vii. bone pain
viii. amenorrhoea
ix. impotence

Question 14

What peripheral signs might you notice on examination suggestive of CKD?

Answer 14

Periphery:

i. Peripheral oedema
ii. Signs of peripheral vascular disease or neuropathy
iii. Vasculitis rash
iv. Gout tophi
v. Joint disease
vi. Arteriovenous fistula
vii. Signs of immunosuppression i.e. bruising from steroids
viii. Uraemic flat / encephalopathy GFR <15

Question 15

What facial signs might you notice on examination suggestive of CKD?

Answer 15

Face:

i. Anaemia
ii. Xanthelasma
iii. Yellow tinge (uraemia)
iv. Jaundice (hepatorenal)
v. Gum hypertrophy (ciclosporin)
vi. Cushingoid (steroids)
vii. Periorbital oedema (nephrotic syndrom)
viii. Taut skin/telangiectasia (scleroderma)
ix. Facial lipidystrophy (glomerulonephritis)

Question 16

What neck signs might you notice on examination suggestive of CKD?

Answer 16

Neck:

i. JVP for fluid state
ii. scar from parathyroidectomy or lymphadenopathy

Question 17

What cardiovascular signs might you notice on examination suggestive of CKD?

Answer 17

CVS:

i. BP
ii. Sternotomy
iii. Cardiomegaly
iv. Stigmata of endocarditis
* if right sided heart failure or tricuspid regurgitation, JVP doesn’t reflect fluid state

Question 18

What respiratory signs might you notice on examination suggestive of CKD?

Answer 18

Pulmonary oedema or effusion

Question 19

What abdomen signs might you notice on examination suggestive of CKD?

Answer 19

Abdomen:

i. Peritoneal dialysis catheter or scars from previous ones
ii. Signs of previous transplant
iii. Ballotable polycystic kidneys ± palpable liver

Question 20

What general investigations are carried out for in CKD?

Answer 20

Bloods : 
=> U&E (compare with previous)
=> Hb (normochromic, normocytic anaemia)
=> Glucose 
=> Decreased Calcium ; increased phosphate & PTH (renal osteodystrophy)

=> Direct investigations of renal disease: ANA, ANCA, anti-phospholipid antibodies, paraprotein complement, cryoglobulin, anti-GBM (glomerular basement membrane)

Urine:
=> Dipstick (microscopy, culture and sensitivity),
=> Albumin/protein : creatinine ratio,
=> Bence jones

Ultrasound imaging

Histology

Question 21

What imaging is carried out in CKD?

Answer 21

Ultrasound for size, symmetry, anatomy, corticomedullary differentiation and to exclude obstruction

=> In CKD kidneys may be small except in diabetes, infiltrative disorders (amyloid, myeloma), adult polycystic kidney disease

=> If asymmetrical, consider renovascular disease

=> Scarring may be seen on ultrasound but isotope scans more sensitive

Question 22

When may a renal biopsy be needed in CKD?

Answer 22

Renal biopsy in progressive disease, nephrotic syndrome, systemic disease, AKI without recovery

Question 23

What are the risk factors for decline in CKD?

Answer 23

High BP

Diabetes

Metabolic disturbance

Volume depletion

Infection

NSAIDs

Smoking

*All CKD has increased risk of superimposed AKI => needs monitoring

Question 24

How often should CKD be monitored?

Answer 24

GFR & albuminuria should be monitored at least once a year or according to risk:

Very high risk : every 3-4 months

High risk : every 6 months

Question 25

RENOPROTECTION i) What are the goals of treatment? ii) What are the treatment measures? iii) What additional management is required?

Answer 25

i) Goal of treatment is to slow renal disease progression by maintaining => BP <130/80mmHg => Proteinuria <0.3g/24h ii) Treatment measures Patients with CKD and proteinuria >1g/24h => ACE-i or ARB => Addition of diuretic to prevent hyperkalaemia & help control BP or calcium channel blocker i.e. verapamil or diltiazem iii) Additional management => Statins to lower cholesterol <4.5mmol/L => Smoking cessation (3x higher deterioration risk in CKD) => Treatment of diabetes (HbA1c <53mmol/mol / 7%) => Normal protein diet

Question 26

Out of all the CKD patients, 50% have been transplanted, 42% are on haemodialysis and 8% are on peritoneal dialysis. Dialysis aims to mimic the excretory function of normal kidneys. What are the 4 main functions of the kidney?

Answer 26

1. Eliminating (nitrogenous & small molecular) wastes 2. Maintaining normal electrolyte concentrations 3. Preventing systemic acidosis 4. Maintaining normal extracellular volume

Question 27

When should dialysis be initiated?

Answer 27

eGFR ~10ml/min Long term dialysis is started when it's necessary to manage one or more symptoms of renal failure: => inability to control volume status inc. pulmonary oedema => inability to control BP => serositis => acid base or electrolyte abnormalities => pruriitis => nausea / vomiting / deterioration in nutritional state => cognitive impairment But should be according to individual patients needs, symptoms and life plans *Frail & patients with multiple co-morbidities choose to not undergo renal replacement therapy

Question 28

How does a haemodialysis work?

Answer 28

Anticoagulated blood from patient is pumped across a semi-permeable membrane - the dialyser, before being returned to the circulation. In the dailyser, ultrapure dialysate flows in the opposite direction and is in close contact with blood. Small solutes (not cells or larger molecular weight proteins) can cross the membrane and move by diffusion down a concentrate gradient. Transmembrane pressure allows controlled fluid removal by ultrafiltration. Over 4 hours session, 80L of blood is circulated through the dialyser. 3x/week or more

Question 29

Effective dialysis requires blood flow between 250 - 450ml/min. How is this achieved to allow access to dialysis?

Answer 29

Via a surgical fashioned arteriovenous fistula using radial or brachial artery and cephalic vein. In patients with poor quality arteries i.e. diabetes patients, synthetic arteriovenous grafts can be put in For many patients, a semi-permanent dual-lumen venous catheter is inserted into the jugular or femoral vein => although instant use, risk of bacteraemia, catheter malfunction, venous stenosis or occlusion

Question 30

What are the aims of haemodialysis?

Answer 30

1. Maintain euvolaemia 2. Maintain electrolyte balance => a low dialysate K+ allows control of hyperkalaemia => dialysate sodium controlled to prevent fluid shifts 3. Prevent acidosis => dialysate is buffered with bicarbonate => bicarbonate diffuses into blood to correct acidosis during treatment 4. Balancing frequency & duration of dialysis with quality of life => 3-5h of treatment 5x / week is adequate in maintaining volume and solute balance 5. Deliver enough dialysis => symptoms of under-dialysis are non-specific i.e. insomnia, itching and fatigue (despite correction of anaemia), restlesss legs and a peripheral sensory neuropathy

Question 31

What are haemodialysis specific complications?

Answer 31

1. Access (arteriovenous fistula or catheter) malfunction, thrombosis, stenosis or bleeding 2. Bloodstream infection => disseminate to soft tissue causing septic arthritis, endocarditis, vertebritis 3. Dialysis disequilibrium 4. Intra-dialytic hypotension due to rapid fluid removal from the extravascular spaces 5. Dialysis related amyloidosis => failure of clearing beta2-microglobulin leads to amyloid deposition.

Question 32

What is haemofiltration? What is haemodiafiltration?

Answer 32

1. Haemofiltration: => Plasma water with suspended solutes is removed by convection (+ve pressure) across a high flux semipermeable membrane. => Substitution fluid is infused to replace fluid losses. => Haemofiltration used in acute settings when patient not haemodynamically stable => Differs from haemodialysis as there is no dialysate 2. Haemodiafiltration: => Combination of dialysis and haemofiltration => Increase middle molecule clearance => Prevent long term dialysis complications i.e. dialysis related amyloidosis

Question 33

What is peritoneal dialysis? How is it carried out?

Answer 33

It uses peritoneal membrane as a semi-permeable membrane => avoiding the need for extracorporeal circulation of blood. => Simple, low tech but effective => Soft catheter is placed through the skin into the peritoneal cavity through the midline of the anterior abdominal wall => Dialysate runs into the peritoneal cavity under gravity => Urea, creatinine, phosphate and other uraemic toxins pass into the dialysate down their concentration gradients => Water is attracted into the peritoneal cavity by osmosis => More hypertonic solution improves fluid removal

Question 34

What are the complications specific to peritoneal dialysis?

Answer 34

1. Bacterial peritonitis - fever, abdo pain and cloudy peritoneal dialysate effluent => caused by staph. epidermidis, E.coli, pseudomonas, staph. aureus, mycobacterium 2. Constipation may impair flow of dialysate 3. Hernias caused by raised intra-abdominal pressure 4. Sclerosing peritonitis => long term patients develop progressive thickening of the peritoneal membrane

Question 35

Who should renal transplant be offered to? What are the benefits of renal transplant?

Answer 35

Every patient with or progressing towards stage G5 kidney disease => treatment of choice for end-stage kidney disease. Benefits: Successful renal transplantation provides complete rehabilitation in end-stage kidney disease. => Survival is better than dialysis => No dietary and fluid restrictions => Anaemia & infertility corrected

Question 36

What type of kidney donors do you get?

Answer 36

1) Diseased donor kidney => donor after brain death (heart beating donor) => donor after cardiac death (non-heart beating donor) - increased risk of delayed graft function 2) Living related or unrelated donor kidney => best graft function and survival especially if HLA matched

Question 37

80% of grafts survive 5-10 years and 50% survive 10-30 years. Which factors have improved patient and graft survival?

Answer 37

Appropriate patient selection Better donor-recipient compatibility (ABO & HLA) Improved surgical technique Efficient immunosuppressants

Question 38

What are the contraindications of renal transplant?

Answer 38

Absolute contraindication: i. Cancer with metastases Temporary contraindication: i. Active infection ii. HIV with viral replication iii. Unstable cardiovascular disease Relative contraindication: i. Congestive heart failure ii. Cardiovascular disease

Question 39

A combination of immunosuppression drugs are used at the minimal effective dose in CKD. What are the different types of monoclonal antibodies used for CKD? What is their mechanism of action?

Answer 39

1. Daclizuman or Basiliximab => selectively block activated T-cell via CD-25 2. Alemtuzumab => T & B cell depletion 3. Monoclonal antibodies used at the time of transplantation => reduces acute rejection & graft loss ; increases infection risk if non-selective

Question 40

A combination of immunosuppression drugs are used at the minimal effective dose in CKD. What is the mechanism of action of calcineurin inhibitors? What are some examples of calcineurin inhibitors? What are its side effects?

Answer 40

1. Tacrolimus ; cyclosporin 2. Calcineurin inhibitors inhibit T-cell activation and proliferation 3. High inter-individual variation and narrow therapeutic index => drug level monitoring required i) Clearance is dependent on cytochrome p450 => beware of drug interaction i.e. macrolide antibiotics & anti-fungal 4. Side effects: nephrotoxicity of the graft, high BP, cholesterol and new onset diabetes after transplantation (NODAT)

Question 41

A combination of immunosuppression drugs are used at the minimal effective dose in CKD. What are some examples of anti-metabolites? What are its side effects?

Answer 41

1. Mycophenolic acid ; azathioprine i) Mycophenolic acid (MPA) is used preferentially => better prevention of acute rejection and graft survival 2. Side effects: anaemia, leucopenia, GI toxicity and teratogenic *DO NOT use in pregnancy*

Question 42

A combination of immunosuppression drugs are used at the minimal effective dose in CKD. What is the mechanism of action of glucocorticoids? What are its side effects?

Answer 42

1. Reduces transcription of inflammatory cytokines => 1st choice treatment for acute rejection 2. Side effects: high BP, hyperlipidaemia, diabetes, impaired wound healing, osteoporosis, cataracts, skin fragility Sig. side effects => withdrawal of steroid use => steroid free immunosuppression preferred

Question 43

What are the complications of renal transplant?

Answer 43

1. Surgical i.e. bleeding, thrombosis, infection, urinary leaks, lymphocyte, hernia 2. Delayed graft function => common in donation after circulatory death (DCD) 3. Acute or chronic rejection 4. Infection : high risk of all infection esp hospital acquired or opportunistic infections within 6 months (prophylaxis for CMV and pneumocystis jirovecii given) ; community acquired after 6-12 months 5. Malignancy : 25x increased risk of cancer with immunosuppression esp. skin, gynaecological and post-transplant lymphoproliferative disorders. 6. CVD : 3.5x increased risk of premature CVD

Question 44

What happens in acute rejection? How do you treat acute rejection?

Answer 44

Acute rejection can be divided into: 1) Antibody mediated (rare unless known pre-sensitised recipient) 2) Cellular is the most common => causes low renal function diagnosed on graft biopsy 3) Treatment: high dose steroids and increase immunosuppression

Question 45

What happens in chronic rejection?

Answer 45

Chronic antibody mediated rejection causes progressive dysfunction of the graft *Most graft loss due to an immune response by donor-specific antibodies => causing damage to kidney microcirculation

Question 46

What is the prognosis of renal transplant?

Answer 46

Acute rejection <15% | Longer term graft loss = rare ~4%/year

Question 47

What are the factors contributing to graft loss?

Answer 47

1. Donor factors: age, comorbidity, living/deceased, (donation brain death [DBD] / donation circulatory death [DCD] 2. Rejection 3. Infection 4. BP/CVD 5. Recurrent renal disease in graft * Most common = death with a functioning graft => graft outlives the patient

Question 48

What are the CKD related Complications?

Answer 48

Anaemia Acidosis Oedema CKD-MBD (mineral bone disorders) Restless legs/cramps Cardiovascular disease Skin disease i.e. pruritus Metabolic abnormalities i.e. gout, insulin & lipid metabolism

Question 49

CKD renal complications i) What is the pathology underlying anaemia in CKD? ii) How do you manage anaemia in CKD?

Answer 49

Normochromic, normocytic anaemia due to: => Erythropoietin deficiency => Increased blood loss (during haemodialysis, occult GI bleed, platelet dysfunction) => Iron, folate, B12 deficiency => Increased haemolysis (shortened RBC lifespan in uraemia ; haemodialysis) => ACE inhibitors => Bone marrow toxins Management: Synthetic erythropoiesis-stimulating agents (ESAs) IV or subcutaneously Monitor Hb every 2 weeks Hypertension major side effect of ESA => BP monitoring

Question 50

CKD renal complications Most patients with CKD have mixed bone disease by late stage 3 CKD i) i) What is the pathology underlying mineral bone disorders in CKD? ii) How do you manage mineral bone disorders in CKD?

Answer 50

Mineral bone disorder changes: 1. High serum phosphate 2. Reduced hydroxylation of Vit. D 3. Secondary hyperparathyroidism => reduced activation of vitamin D in parathyroid gland => increase release of PTH 4. PTH promotes reabsorption of calcium from bone to reverse hypocalcaemia caused by 1,25 dihydroxycalciferol deficiency and phosphate retention => increase in osteoclastic activity = cyst formation and bone marrow fibrosis => osteomalacia, osteoporosis, osteosclerosis, adynamic bone disease * Biochemical findings: hypocalcaemia, hyperphosphataemia, high PTH, high ALP (increased bone turnover) 5. Longstanding 2nd hyperparathyroidism => tertiary hyperparathyroidism - hyperplasia of the glands and PTH release independent of calcium or 1,25 dihydroxycalciferol => high bone turnover leads to hypercalcaemia Management: 1. Treat if phosphate >1.5mmol/L with dietary restriction ± phosphate binders 2. Vitamin D supplements i.e. cholecalciferol, if high PTH persists give Vit D analogues i.e. alphacalcidiol

Question 51

CKD renal complications i) How do you manage oedema in CKD?

Answer 51

Restrict fluid/sodium intake High dose of loop diuretics Loop and thiazide (inhibits distal tubule sodium excretion) diuretics combination

Question 52

CKD renal complications i) How do you manage acidosis in CKD?

Answer 52

Sodium bicarbonate supplements for patients with eGFR <30 and low serum bicarbonate

Question 53

CKD renal complications i) How do you manage restless legs/cramps in CKD?

Answer 53

Exclude iron deficiency as cause Sleep hygiene advice Severe cases : gabapentin / pregabalin

Question 54

CKD other complications i) What is the pathology underlying cardiovascular disease risk in CKD? ii) How do you manage this?

Answer 54

CKD increases risk of CVD x16 due to: => high BP => vascular stiffness (due to uraemia + raised calcium, PTH & phosphate increases calcification) => inflammation => oxidative stress => abnormal endothelial function Manage by: i) Low dose anti-platelets i.e. aspirin ii) Atorvastatin