General• AKI

• Causes• Investigation and management• Complications

• CKD• Causes• Investigation and management• Complications

• Nephrotic vs nephritic syndrome• Causes• Investigation and management• Complications

2

Renal Revision Summary

Specific• Glomerulonephritis

• Minimal change disease• FSGS• Membranous nephropathy• MPGN• IgA nephropathy• Post-streptococcal glomerulonephritis• Amyloidosis

• Polycystic kidney disease• Beware urology

• SLE (lupus)• ANCA-associated vasculitides• Anti-GBM disease

Mr Gangfløt – 50-year-old male

Mr Hukkelberg – 50-year-old male

Mr Mokkelbost – 50-year-old male

3

Layout for today’s session

1. No treatment

2. Dialysis

3. Kidney transplant

HistoryYou are a medical student on your elective in adeveloping country. Your next patient is MrGangfløt, a 50-year-old gentleman who visitsthe local doctor to complain about his swollenankles. He says that this has been botheringhim for many months.

Past medical history includes HTN and T2DM.

On examination, you note pitting oedema upto his knee level, as well as conjunctival pallor.

ObservationsHR 64, BP 174/102, RR 11, SpO2 98%, Temp37.3

4

Case-based discussion: 1

HistoryYou are a medical student on your elective in adeveloping country. Your next patient is MrGangfløt, a 50-year-old gentleman who visitsthe local doctor to complain about his swollenankles. He says that this has been botheringhim for many months.

Past medical history includes HTN and T2DM.

On examination, you note pitting oedema upto his knee level, as well as conjunctival pallor.

ObservationsHR 64, BP 174/102, RR 11, SpO2 98%, Temp37.3

5

Case-based discussion: 1

Peripheral oedemaCauses of bilateral:

• Heart• Heart failure

• Kidney• CKD• Nephrotic syndrome

• Liver• Liver failure

• Venous/lymphatic obstruction• Pelvic tumour• Not your first thought!

Clerking cont.• Serum pro-NT-BNP - normal• Serum liver function test

• Albumin – 36 (35-50)• Bilirubin – 4 (1-17)• ALT - 25 (<50)

• Serum urea and electrolytes• Urea - 6.9 (2-7)• Creatinine - 200 (50-120)

• Urine dipstick• Protein ++

• Glucose ++

6

Case-based discussion: 1

eGFR calculation[1]

Calculated using the MDRD (modification of diet in renal disease), which uses the following parameters:

1. Creatinine2. Age3. Gender4. Ethnicity

eGFR (ml/min/1.73 m2) =

175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

DefinitionProgressive deterioration in renal function

The KDIGO guidelines[2]:

• Present for >3 months• With implications for health• Abnormalities of kidney structure or function

1. This means ALL patients with an eGFR <60 or;2. ANY patient with markers of kidney damage:• Proteinuria• Haematuria • ACR >3 mg/mmol• Structural abnormalities (e.g. PKD)• Abnormalities on renal biopsy• History of renal transplant

7

Chronic Kidney Disease (CKD)

Epidemiology• It is estimated that 10% of the general

population are thought to have CKD• Risk factors:

• Age• Ethnicity: Afro-Caribbean• Co-morbidities: HTN, T2DM, renal disease• Medications• Congenital abnormalities• Urinary tract pathology

• CKD mortality is difficult to assess due tothe fact that patients with CKD will oftendie from linked cardiovascular diseaseprior to reaching end-stage renal failure.

8

Staging

CKD grade GFR range

G1 >90 ml/min, with some sign of kidney damage on other tests (if all the kidney tests are normal, there is no CKD)

G2 60-89 ml/min with some sign of kidney damage (if kidney tests are normal, there is no CKD)

G3a 45-59 ml/min with a mild-moderate reduction in kidney function

G3b 30-44 ml/min with a moderate reduction in kidney function

G4 15-29 ml/min with a severe reduction in kidney function

G5 <15 ml/min, established kidney failure - dialysis or a kidney transplant may be needed

9

Staging

Urinary albumin : creatinine ratio (ACR)In addition, CKD is staged by urinary ACR to measure how leaky the glomerulus is to protein

• A1 – ACR <3 (mg/mmol)• A2 – ACR 3-30 (mg/mmol)• A3 – ACR >30 (mg/mmol)

The higher the A grade in CKD, the poorer theprognosis, as proteinuria is considered a poorprognostic factor.

Aetiology

Diabetes mellitus

Hypertension Glomerulonephritis Other:• PKD• Renal artery

stenosis• SLE• Amyloidosis• RA• HIV

1 2 3

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Pathophysiology (Diabetes)

Mechanism of kidney damage:

1. Excessive glucose in the blood results in glycosylation of proteins

2. In particular, the efferent arteriolar surface proteins are prone to this

3. This leads to hyaline arteriole sclerosis, creating a stiff and narrow arteriole

4. This raises the pressure in the glomerulus and causes hyperfiltration and mesangial cell expansion

5. Over many years, this leads to reduced filtration and leakiness of the glomerulus

12

Pathophysiology (Hypertension)

Mechanism of kidney damage:1. In hypertensive states, the renal arteries

become stenosed

2. Reduced blood supply to the glomerular arterioles means the glomeruli undergo ischaemic injury

3. This results in deposition of macrophages

4. These release growth factors, which cause mesangial cell regression to mesangioblasts

5. These precursor cells produce excess extracellular matrix, causing glomerulosclerosis and lowered eGFR

13

Pathophysiology (Glomerulonephritis)

Definition:• Collective term for any condition that causes

inflammation of the glomerulus• Can present as AKI, CKD or nephrotic/nephritic

syndrome

Nephrotic • Minimal change• FSGS• Membranous

nephropathy

Nephritic• IgA nephropathy• Post-infectious GN• Anti-GBM disease• MPGN

[3]

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Pathophysiology (other causes)

Other:• PKD• SLE• RA• Amyloidosis• HIV• NSAIDs• Toxins• Etc.

Regardless of the aetiology, the end resultis glomerular scarring and resultant kidney failure

15

Clinical features

Symptoms SignsLethargy Hypertension

Pruritis Peripheral oedema

Nausea Pulmonary oedema

Anorexia Uraemic sallow: yellow/brown colour to skin

Frothy urine (secondary to proteinuria) Evidence of a specific underlying cause, e.g. butterfly rash in lupus

More features to come when we introduced dialysis and transplant*

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InvestigationsBloods• FBC • U&Es • HbA1c• Bone profile

Urine• Dipstick• ACR

Imaging• Renal US• CT KUB

Specialist tests• Renal biopsy• The “renal workup”

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ManagementLifestyle• Encourage regular exercise, achieve a healthy

weight and stop smoking• Offer dietary advice about potassium, phosphate,

calorie and salt intake (keep these low)• Low protein diets are NOT required

Pharmacological• ACE-inhibitor or ARB if:

• Diabetic + ACR of 3mg/mmol or more• Hypertensive + ACR of 3mg/mmol or more• An ACR of 7mg/mmol or more

• Offer statin and anti-platelet

Renal replacement therapy (RRT)• Dialysis – haemodialysis vs peritoneal dialysis• Kidney transplant

Why ACE-inhibitors?

“Stop them in AKI, start them in CKD”

1) They reduce the intraglomerular pressure and thus reduces hyperfiltration à less proteinuria

2) They reduce the blood pressure à a cause of CKD

3) Other – poorly studied, e.g. ATII causes renal injury

18

Complications

System Description

Cardiovascular Cardiovascular disease is the leading cause of death in CKD, e.g. IHD or heart failure

Musculoskeletal CKD-metabolic bone disease (CKD-MBD)

Endocrine Secondary hyperparathyroidism à Tertiary hyperparathyroidism

Haematological Anaemia (usually normocytic and normochromic). Caused by: 1) Low EPO production; 2) Reduced iron absorption; 3) Uraemia causing anorexia / reduced erythropoiesis

Metabolic Metabolic acidosis, hyperkalaemia, uraemic encephalopathy/pericarditis

[3]

DefinitionAlso known as renal osteodystrophy, this is a bone disorder that results in:• Bone and joint pain• Bone deformation• Bone fractures• Reduced mobility

19

CKD-MBD Mechanism1. Active vitamin D = 1,25-

dihydroxycholecalciferol

2. Reduced 1-alpha hydroxylase activity in CKD

3. Leads to reduced vitamin D activation

4. Less vitamin D means:

A. Reduced renal excretion of phosphate (rises)B. Reduced absorption of calcium in gutC. Reduced release of calcium from bone

5. Results in hypocalcaemia and hyperphosphataemia

6. Low calcium à raised PTH

Manage with phosphate binders & vitamin D analogues

Expected laboratory resultsSerum calcium ↓Serum phosphate ↑Serum vitamin D ↓Serum PTH ↑Alkaline phosphatase (ALP) ↑

20

RecapCKD is a progressive deterioration in renal function1. >3 months and;2. eGFR <60 or markers of kidney damage (e.g. haematuria,

ACR >3)

Staging:• G1 to G5 – based on eGFR• A1 to A3 – based on ACR

Management:• Lifestyle• ACE-inhibitors / ARBs• Renal replacement therapy (RRT) – when the time comes

Complications:• Cardiovascular disease• CKD-MBD• Hyperparathyroidism (2º or 3º)• Anaemia

HistoryMr Hukkelberg, a 50-year-old Afro-Caribbean male, is diagnosed with CKD in 2015 having presented with mild oedema.

Over the next 5 years, he undergoes regular monitoring, as well as management with lifestyle advice, ACE-inhibitors and sevelamer for known CKD-MBD.

Despite best efforts, by 2020 he has an eGFR of 19ml/min/1.73.

ObservationsHR 86, BP 145/82, SpO2 97%, temp 37.2

21

Case-based discussion: 2

22

ReferralNICE guidelines[5]:

People with CKD in the following groups should normally be referred for specialist assessment:

• GFR <30 ml/min/1.732

• Urinary ACR of 30 or more, with haematuria

• Urinary ACR of 70 or more (w/o diabetes)

• Sustained decrease in GFR of 15 ml/min/1.73 m2 or more within 12 months

• Hypertension that remains poorly controlled despite the use of at least 4 antihypertensive drugs at therapeutic doses

• Known or suspected rare cause of CKD

23

Dialysis

General:• Relies upon the principle of diffusion• Movement of solutes from an area of high

solute concentration to an area of low solute concentration…

• …through a semi-permeable membrane

1. Haemodialysis

2. Peritoneal dialysis

• In both of these renal replacement therapies (RRT), the patient’s blood is filtered by passing in close proximity to dialysate fluid and separated by a semi-permeable membrane

AV

24

Haemodialysis

Details:• Blood from the body is ran into an artificial kidney

(haemodialyser) ~3 times a week

Access:• Central line (jugular, femoral)• AV fistula

Dialysate includes:• Similar electrolytes to blood• Slightly raised bicarbonate

Complications:• Hypotension• Dialysis disequilibrium• AV fistula thrombosis / steal syndrome• SIRS

Hand

25

Peritoneal dialysis

Details• Dialysate is slowly infused into the peritoneal cavity via

a catheter.• The peritoneal membranes act as a natural filter for

dialysing the blood. • It can be used as a stop-gap to HD or for younger

people

Dialysate includes• Similar sodium/potassium to blood• Raised bicarbonate• 1.5%, 2.5% and 4.25% glucose – for ultrafiltration

Complications• Constipation can compress the catheter and

prevent fluid from returning to the dialysis machine

• Sclerosing peritonitis – rare, potentially fatal• Peritonitis – Staph epidermidis

26

OSCE Presentation: the dialysis patient

Signs of disease:• Peripheral oedema• Raised JVP• Neuropathy• Joint disease• Conjunctival pallor

Signs of dialysis• AV fistula – palpate, auscultate• Tunnelled line• Peritoneal dialysis catheter

27

Recap

CKD is a progressive deterioration in renal function1. >3 months and;2. eGFR <60 or markers of kidney damage (e.g. haematuria,

ACR >3)

Haemodialysis (HD):• Blood from the body is run into an artificial kidney

machine• Requires vascular access, e.g. central line / AV fistula• Patients have a lower mortality rate than for PD

Peritoneal dialysis (PD):• Dialysate fluid is introduced into peritoneal cavity with

peritoneal membrane acting as natural semi-permeable membrane

• Does not require vascular access• Patients have a higher mortality rate than for HD

HistoryMr Mokkelbost is a 50-year-old male who has been on haemodialysis for 5 years, whilst awaiting a kidney transplant.

Today, the patient received a call that they have reached the top of the list and must come in for a pre-operative assessment.

ObservationsHR 98, BP 139/84, SpO2 98%, Temp 37.2

28

Case-based discussion: 3

29

Kidney transplant

• Introduction of a donor kidney (deceased or live)• Given at the point of ESRD - 15ml/min/1.73m2

• Selecting an allograft donor: • Match ABO and HLA (A,B,C, DP, DR, DQ)

• Donor kidney is placed into the iliac fossa and “plumbed” into the host vasculature

• Usually the donor renal artery and renal vein are connected to the common iliac vessels

• “A third kidney”• Patients will have a J shaped (hockey) scar

30

Immunosuppression regimen

Must immunosuppress for life to avoid host rejection [6]

Initial induction:• KDIGO recommend starting a combination of

immunosuppressive medications, including biological (IL2-RA)

• E.g. basiliximab and tacrolimus

Maintenance therapy:• KDIGO recommend a combination of immunosuppressive

medications as maintenance therapy, including a CNI and an anti-proliferative agent (+/- steroids)

• E.g. ciclosporin/tacrolimus with MMF

Side effects:• Ciclosporin – gum hypertrophy / hyperlipidaemia• Tacrolimus – physiological tremor• Mycophenolate mofetil (MMF) – GI upset and marrow

suppression

31

Early complications

Delayed graft function • Requires dialysis• Risk factors include renal disease in donor, obese

recipients and prolonged ischaemic time

Infection• CMV is the most common viral infection of solid organ

transplant

Acute tubular necrosis of graft• Death of the graft for a number of reasons (not just

immune)

General surgical• Bleeding, infection, thrombosis

Acute rejection

32

RejectionHyperacute rejection• Type 2 hypersensitivity reaction• Pre-formed antibodies attack the allograft immediately• E.g. ABO incompatibility

Acute rejection• Weeks to months (~3)• Clinical features akin to infection (fever, tender graft, ↓GFR)

• 15-25% of patients will experience this• Requires a biopsy• Reversible with steroids • Living donor transplants get rejected less.

Chronic rejection• Months to years• Progressive occlusion or intimal hyperplasia of the

blood vessels• Less reversible

[6][7]

33

Late complications

Cardiovascular disease• Tacrolimus and ciclosporin can cause hypertension,

hyperlipidaemia and hyperglycaemia.• Dialysis à risk of IHD

Renal failure• Nephrotoxic effects of tacrolimus and ciclosporin• Chronic graft rejection• Recurrence of original disease in transplanted kidney

Malignancy• Skin cancer – all types• Educate patients about minimising sun exposure

Post-transplant lymphoproliferative disorder (PTLD)• One of the commonest malignancies following transplant• Seen most in those who are heavily immunosuppressed• Driven by EBV donated by the donor

34

OSCE Presentation: the transplant patient

Signs of disease• Peripheral oedema• Raised JVP• Neuropathy• Joint disease• Conjunctival pallor

Signs of transplant / immunosuppression• Defunctioned AV fistula – palpate, auscultate• Peritoneal dialysis catheter scars• Palpable abdominal mass in iliac fossa• J shaped (“hockey stick”) scar• Gum hypertrophy – ciclosporin• Tremor – tacrolimus• Bruising and skin malignancies –

steroids/immunosuppressants

35

Recap

CKD is a progressive deterioration in renal function1. >3 months and;2. eGFR <60 or markers of kidney damage (e.g. haematuria,

ACR >3)

Transplant• Donor allograft introduced into abdomen without removing

original kidneys• Requires lifelong immunosuppression

Early complications• Infection and bleeding• Delayed graft function• Rejection

Late complications• Skin cancer• Renal failure• CVD• PTLD

36

References

1. NIDDK. Estimating glomerular filtration rate. https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/kidney-disease/laboratory-evaluation/glomerular-filtration-rate/estimating#:~:text=The%20Modification%20of%20Diet%20in,patients%20age%2018%20and%20over.

2. KDIGO CKD guidelines - https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf3. KDIGO glomerulonephritis guidelines - https://kdigo.org/wp-content/uploads/2017/02/KDIGO-2012-GN-

Guideline-English.pdf4. BiteMedicine CKD textbook - https://app.bitemedicine.com/textbooks/chronic-kidney-disease5. NICE guidelines. Chronic Kidney Disease - https://www.nice.org.uk/guidance/cg182/chapter/1-

Recommendations6. KDIGO Kidney transplant guidelines - https://kdigo.org/wp-content/uploads/2017/02/KDIGO-2009-Transplant-

Recipient-Guideline-English.pdf7. Elizabeth Ingulli (2010). Paediatric nephrology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778785/

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