Chronic Kidney Disease. particularly Diabetic Kidney Disease

A practical approach to

Chronic Kidney Disease

.

particularly Diabetic Kidney Disease

Project Inspire Lectures December 2020 Nigel Fong

Outline

1. Diagnose DKD & distinguish from other causes of renal

impairment.

2. Be able to manage a patient with DKD.

This is a typical CKD patient’s chronic medication list.

By the end of the session… you should understand the reason for each of these.

1. Aqueous cream 1 application BD 2. Aspirin 100mg OM 3. Atorvastatin 20mg ON 4. Bisoprolol 5mg OM 5. Calcium Carbonate 2 tab TDS with meals 6. Escitalopram 10mg ON 7. Furosemide 20mg OM 8. Insulin Glargine 12U ON 9. Lactulose 10ml TDS PRN constipation 10. Losartan 100mg OM 11. Metformin 850mg BD 12. Nifedipine 30mg BD 13. Omeprazole 20mg OM 14. One alpha calcidol 0.25mcg 3x / week 15. Paracetamol 1g TDS PRN pain 16. Sangobion 1 tab OM 17. Senna Tab 2 tab ON PRN constipation 18. Sodium bicarbonate 500mg TDS 19. Tears Naturale 1 drop to both eyes QDS

Definition of Diabetic Kidney Disease (DKD)

Traditional definition:

• Diabetic Nephropathy = Albuminuria+ Retinopathy+ Diabetes

• Based on early pathological studies & observed clinical history in T1DM

Broader definition:

• DKD = Diabetes + ↓ GFR AND/OR Albuminuria. • Absence of retinopathy does not rule out DKD. • Patients with DKD can have normal GFR.

Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk.

Management Goals Plan for RRT Health Promotion & Manage Comorbids Manage Complications Screen & Diagnose Retard DKD Progression DM _ESRF Transplant Palliative Early DKD Advanced DKD Albuminuria ………. GFR >90 >60 45 30 15 Dialysis RRT or Palliate

Who to Screen

•

Early diagnosis = Early treatment = Delay ESRF.

•

All patients with DM should be screened annually

• T1DM: Begin 5 years after diagnosis • T2DM: Begin at diagnosis (time of disease onset unknown) • Except patients with limited life expectancy who will not benefit from treatment. Screen & Diagnose

•

Remember DKD =

Diabetes

+

↓ GFR

AND/OR

Albuminuria

Estimate from Serum Cr Creatinine Clearance measurement 24h urine collection Preferred _{Spot urine albumin/Cr ratio} 24h urine albumin collection 2 tests, 3 months apart Don’t use urine dipstick!

How to Screen

Screen & Diagnose Microalbuminuria Macroalbuminuria

Q1

The following patients with DM are found to have raised serum Cr. Which of the proposed further investigation / management is INCORRECT?

Patient Further Investigation

a) 31-year-old with T1DM since 14 years old. He is otherwise

well. No further tests apartfrom history & exam.

b) 40-year-old with T2DM diagnosed 2 years ago. eGFR is 33 ml/min this year, from 41 ml/min 12 months ago, and 53 ml/min 24 months ago. No further tests apartfrom history & exam. c) 45-year-old with longstanding DM and raised serum Cr. He recently complains of persistent sinusitis, difficult-to-control asthma, lower limb rash, and numbness over his right thigh. Renal biopsy. d) 60-year-old with DM who now complains of abdominal pain

Exclusion of other causes of CKD

•

Majority of diabetics with renal

impairment have DKD, particularly in

longstanding & poorly controlled DM.

•

Renal biopsy is not routine.

•

However, be alert for other causes of

CKD – particularly:

• Any cause that is reversible • Any cause with systemic complications that must be treated. Can J Diabetes.2018 Apr;42 Suppl 1:S201-S209 Screen & Diagnose

Red Flag Suspicion Further tests Rapid progression (eGFR ↓ >5 ml/min/1.73m² per year) Renal biopsy Persistent hematuria or active urinary sediment GN Renal biopsy Autoantibody testing. Viral screening. Frank nephrotic or nephritic syndrome GN Signs or symptoms of systemic disease e.g. SLE GN – secondary Anaemia and hypercalcaemia out of proportion

to kidney impairment Myeloma Serum & urine protein electrophoresis Resistant hypertension or eGFR decline >30%

after starting angiotensin inhibition Renal artery stenosis Renal artery dopplerultrasound Strong family history of congenital renal disease Congenital e.g.

ADPKD As per suspected cause

Exclusion of other causes of CKD

A1

The following patients with DM are found to have raised serum Cr. Which of the proposed further investigation / management is INCORRECT?

Patient Further Investigation

a) 31-year-old with T1DM since 14 years old. He is otherwise

well. No further tests apartfrom history & exam.

b) 40-year-old with longstanding T2DM and presumed DKD. eGFR is 33 ml/min this year, from 41 ml/min 12 months ago, and 53 ml/min 24 months ago. No further tests apartfrom history & exam. c) 45-year-old with longstanding DM and raised serum Cr. He recently complains of persistent sinusitis, difficult-to-control asthma, lower limb rash, and numbness over his right thigh. Renal biopsy. d) 60-year-old with DM who now complains of abdominal pain

Outline

1. Diagnose DKD & distinguish from other causes of renal impairment.

2. Be able to manage a patient with DKD.

Management Goals Plan for RRT Health Promotion & Manage Comorbids Manage Complications Screen & Diagnose Retard DKD Progression DM _ESRF Transplant Palliative Early DKD Advanced DKD Albuminuria ………. GFR >90 >60 45 30 15 Dialysis RRT or Palliate

Medical Therapy for DKD

1. Glycemic Control aiming HbA1c ~7%

2. BP Control, aiming BP <130/80 mmHg

3. RAS blockade

4. SGLT-2 inhibition

5. Avoid further renal insult

Retard DKD Progression

Medical Therapy for DKD

1. Glycemic Control

• Aim HbA1c ~7.0% in general • Individualize HbA1c target • HbA1c may be erroneous in CKD • Falsely high: decreased erythropoiesis • Falsely low: reduced RBC survival, treatment with erythropoietin. • As GFR falls, renal excretion of insulin & OHGAs fall – danger of overly tight DM control & hypoglycemic events. Retard DKD Progression Singapore ACE guideline 2017

Medical Therapy for DKD

2. BP Control

• Guidelines - KDIGO: <130/80 mmHg, JNC8: <140/90 mmHg • Targets being challenged by new evidence (e.g. SPRINT trial). • Remains an area of debate Retard DKD Progression

Q2

A 50-year-old lady sees you for routine follow up of T2DM. Her blood pressure today is 148/91 mmHg with similar readings in her home BP diary. Her comorbids include asthma and hyperlipidemia. Serum Cr: 106 µmol/L eGFR: 48 ml/min/1.73m2 Urine ACR: 40 mg/mmol HbA1c: 7.2% Her current medicines are: • _{Metformin 850mg TDS} • Glipizide 10mg BD • _{Amlodipine 5mg OM} • Atorvastatin 10mg ON Which of the following is MOST appropriate? a) ↑ amlodipine to 10mg OM b) Add bisoprolol 2.5mg OM. c) Add enalapril 5mg OM d) Add dapagliflozin 10mg OM e) Make no changes

Medical Therapy for DKD

3. Renin-Angiotensin System (RAS) Blockade

Retard DKD Progression

Wolf & Sharma. In Comprehensive Clinical Nephrology, 5e.

RAS blockade reverses glomerular hypertension, which is a key mechanism leading to proteinuria & glomerular damage.

Medical Therapy for DKD

3. Renin-Angiotensin System (RAS) Blockade

Retard DKD Progression

Fong JMN, Tsang LPM, Kwek JL, Guo WW. SMJ 2020.

Diabetic patient subgroup Recommendation Landmark studies

Reduced eGFR (< 60 ml/min/1.73m²) ACE-I/ARB of definite benefit in reducing albuminuria & slowing GFR decline. Captopril Trial (1993), RENAAL (2001), IDNT (2001). Preserved GFR + macroalbuminuria Preserved GFR + microalbuminuria IRMA-2 (2001), DETAIL (2004), INNOVATION (2007). Preserved GFR, no albuminuria, and hypertension (systolic BP >130mmHg) ACE-I/ARB delays the onset of microalbuminuria. BENEDICT (2004), ROADMAP (2011). Preserved GFR, no albuminuria, and

normal BP No evidence of benefit with ACE-I/ARB

A2

A 50-year-old lady sees you for routine follow up of T2DM. Her blood pressure today is 148/91 mmHg with similar readings in her home BP diary. Her comorbids include asthma and hyperlipidemia. Serum Cr: 106 µmol/L eGFR: 48 ml/min/1.73m2 Urine ACR: 40 mg/mmol HbA1c: 7.2% Her current medicines are: • _{Metformin 850mg TDS} • Glipizide 10mg BD • _{Amlodipine 5mg OM} • Atorvastatin 10mg ON Which of the following is MOST appropriate? a) ↑ amlodipine to 10mg OM b) Add bisoprolol 2.5mg OM. c) Add enalapril 5mg OM d) Add dapagliflozin 10mg OM e) Make no changes

Q3

A 50-year-old lady sees you for routine follow up of T2DM. BP: 148/91 mmHg Serum Cr: 106 µmol/L Serum K: 4.9 mmol/L She is on amlodipine 5mg OM. You add enalapril 5mg OM. 2 weeks later, she complains of cough. BP: 143/88 mmHg Serum Cr: 121 µmol/L Serum K: 5.3 mmol/L What is the next course of action? 1. Stop enalapril 2. Switch enalapril to losartan 3. Continue enalapril & give cough mixture 4. Refer for evaluation of possible renal artery stenosis 5. Counsel on low potassium diet Options: a) 1, 4, and 5 b) 2, 4, and 5 c) 2 and 5 d) 3 and 5 e) 3 only.

Medical Therapy for DKD

3. Renin-Angiotensin System (RAS) Blockade

• Practical tips on use of ACE-I / ARB • Start low & titrate upwards until (i) max dose, (ii) normal BP & albuminuria, or (ii) further increases not tolerated. • If ACE-I cause cough, change to ARB.

• Recheck K & Cr 2 weeks after starting or dose increase. ↑ Cr 20-30% expected but if ↑ >30%, consider renal artery stenosis.

• Reduced GFR is not a contraindication – these patients benefit most.

• Manage hyperkalaemia with low K diet +/- diuretics before stopping ACE/ARB. • Do not combine ACE-I & ARB.

• ACE-I / ARB contraindicated in pregnancy, ACE/ARB-triggered angioedema.

Retard DKD Progression

A3

A 50-year-old lady sees you for routine follow up of T2DM. BP: 148/91 mmHg Serum Cr: 106 µmol/L Serum K: 4.9 mmol/L She is on amlodipine 5mg OM. You add enalapril 5mg OM. 2 weeks later, she complains of cough. BP: 143/88 mmHg Serum Cr: 121 µmol/L Serum K: 5.3 mmol/L What is the next course of action? 1. Stop enalapril 2. Switch enalapril to losartan 3. Continue enalapril & give cough mixture 4. Refer for evaluation of possible renal artery stenosis 5. Counsel on low potassium diet Options: a) 1, 4, and 5 b) 2, 4, and 5 c) 2 and 5 d) 3 and 5 e) 3 only.

Medical Therapy for DKD

4. SGLT-2 inhibition

Retard DKD Progression Cherney et al. Circulation. 2014 Feb 4;129(5):587-97.

Q4

You see four 52-year-old men with longstanding T2DM and hyperlipidemia.

Who will benefit from the addition of a SGLT2-inhibitor at this visit?

BP

mmHg eGFRml/min/1.73m2 UACR_mg/g HbA1c Other issues Existing meds

A 142/88 58 234 8.4% NSTEMI 3/12 ago Atorvastatin, Aspirin, Bisoprolol, Metformin.

B 142/88 58 234 8.4% TIA 3/12 ago Atorvastatin, Metformin, Losartan C 142/88 58 234 8.4% E coli pyelonephritis

3/12 ago Amlodipine, Atorvastatin, Metformin,Insulin (Novomix), Losartan D 142/88 28 234 8.4% Atrial fibrillation Amlodipine, Atorvastatin, Metformin, Insulin (Novomix), Losartan, Warfarin

Zelniker T, Wiviott S, Raz I, Im K, Goodrich E, Bonaca M et al. The Lancet. 2019;393(10166):31-39 Meta-analysis of SGLT2i trials on the composite of worsening of renal function, end-stage renal disease, or renal death Conclusion: ↓ major adverse cardiovascular events in patients with atherosclerotic cardiovascular dx ↓ risk of cardiovascular death or hospitalisationfor heart failure ↓ risk of progression of renal disease

Medical Therapy for DKD

4. SGLT-2 inhibition

• Guidelines are evolving - not 1st _{line yet.}

• Strong indication for:

• DKD with persistent albuminuria despite optimal ACE-I/ARB

• DKD with suboptimal HbA1c despite metformin, lifestyle & diet changes. • Contraindications:

• eGFR <45 ml/min/1.73m2 _{(perhaps 30 ml/min/1.73m}2 _{for canagliflozin)}

• DKA – risk of euglycemic DKA • Type 1 DM

• Frequent / severe urogenital infections

• Lower limb amputation or peripheral vascular disease (debated) • Watch for hypoglycemia & dehydration.

A4

You see four 52-year-old men with longstanding T2DM and hyperlipidemia.

Who will benefit from the addition of a SGLT2-inhibitor at this visit?

BP

mmHg eGFRml/min/1.73m2 UACR_mg/g HbA1c Other issues Existing meds

A 142/88 58 234 8.4% NSTEMI 3/12 ago Atorvastatin, Aspirin, Bisoprolol, Metformin. Start ACE-I / ARB first

B 142/88 58 234 8.4% TIA 3/12 ago Atorvastatin, Metformin, Losartan

C 142/88 58 234 8.4% E coli pyelonephritis

3/12 ago Amlodipine, Atorvastatin, Metformin,Insulin (Novomix), Losartan D 142/88 28 234 8.4% Atrial fibrillation Amlodipine, Atorvastatin, Metformin, Insulin (Novomix), Losartan, Warfarin

X

Medical Therapy for DKD

5. Avoid further renal insult

• Episodes of AoCKD accelerate CKD progression • Beware: • Nephrotoxic drugs e.g. NSAIDs. • Nephrotoxic supplements / traditional medicine • Drug dosing – e.g. dose reduction for metformin. • Dehydration (diuretics, SGLT-2 inhibitors). Retard DKD Progression

Medical Therapy for DKD

1. Glycemic Control aiming HbA1c ~7%

2. BP Control, aiming BP <130/80 mmHg

3. RAS blockade

4. SGLT-2 inhibition

5. Avoid further renal insult

Retard DKD Progression

Management Goals Plan for RRT Health Promotion & Manage Comorbids Manage Complications Screen & Diagnose Retard DKD Progression DM _ESRF Transplant Palliative Early DKD Advanced DKD Albuminuria ………. GFR >90 >60 45 30 15 Dialysis RRT or Palliate

Comorbids & Counselling

Cardiovascular death is #1 cause of death in CKD / ESRF • Guideline-directed medical therapy - antiplatelets, beta-blocker, lipid control etc. Non-pharmacological aspects • Dietary advice – low K, fluid restrict if necessary, DM diet • Weight management • Avoidance of nephrotoxic drugs & supplements • Smoking cessation • Vaccination Health Promotion & Manage Comorbids

Management Goals Plan for RRT Health Promotion & Manage Comorbids Manage Complications Screen & Diagnose Retard DKD Progression DM _ESRF Transplant Palliative Early DKD Advanced DKD Albuminuria ………. GFR >90 >60 45 30 15 Dialysis RRT or Palliate

Complications in advanced CKD

Common to both DKD & other causes of CKD

A

naemia

B

lood pressure

C

alcium, Phosphate

Vitamin

D

, PTH, and Renal Bone Disease

E

lectrolytes – hyperkalaemia, acidosis

F

luid overload

Manage Complications What you should know as a HO (& for exams): • Understand your patient’s complicated drug list. • Be able to manage acute inpatient issues.

Fluid overload in CKD

•

_{Fluid restrict}

•

_Diuretics

• Thiazide diuretics lose effectiveness < eGFR 30ml/min/1.73m2_{, use loop diuretics.} • _{Often need relatively high doses of diuretics.}

•

_{Acute fluid overload}

• Assess if dialysis is necessary (e.g. desaturation, no longer has urine output) • _{IV furosemide (IV dose = at least 1x – 2x daily PO dose if significant overload).} • If furosemide does not work, options are: • _{Add metolazone} • Give furosemide as infusion • _{Give IV albumin with furosemide} • Dialysis Manage Complications

Acidosis in CKD

•

_{Chronic acidosis is common and is associated with mortality}

• Usually a NAGMA initially, then NAGMA + HAGMA as uremia sets in

•

Give sodium bicarbonate tabs

•

Aim HCO

3-

_{> 22mmol/L}

Manage Complications

Q5

A 52-year-old man is on follow up for T2DM with DKD. Latest eGFR is 35ml/min/1.73m2_. Hb: 9.2 g/dL Ferritin: 106 ng/mL Transferrin Saturation: 24% B12 / Folate: Normal What is the next course of action? 1. Take a dietary history 2. Refer for colonoscopy 3. Iron supplementation 4. Erythropoiesis stimulating agent Options: a) 1 and 3. b) 1 and 4. c) 1, 2, 3. d) 1, 2, 4. e) 1, 2, 3, 4.

Anaemia in CKD

•

Anaemia develops in late CKD due to ↓ erythropoietin production.

•

Look for other causes of anaemia particularly GI malignancy.

•

Management

• Ensure adequate iron store – aim Ferritin >500 ng/mL, transferrin saturation >30% • If still anaemia & iron replete, prescribe erythropoietin stimulating agent. • Target Hb 10 – 11.5 g/dL

Fong JMN, Tsang LPM, Kwek JL, Guo WW. SMJ 2020. Manage Complications

A5

A 52-year-old man is on follow up for T2DM with DKD. Latest eGFR is 21ml/min/1.73m2_. Hb: 9.2 g/dL Ferritin: 106 ng/mL Transferrin Saturation: 24% B12 / Folate: Normal What is the next course of action? 1. Take a dietary history 2. Refer for colonoscopy 3. Iron supplementation 4. Erythropoiesis stimulating agent Options: a) 1 and 3. b) 1 and 4. c) 1, 2, 3. d) 1, 2, 4. e) 1, 2, 3, 4.

Calcium, Phosphate & Renal Bone Disease

Calcium, Phosphate & Renal Bone Disease

Q6

A 52-year-old man is on follow up for DKD. Latest eGFR is 14ml/min/1.73m2_. He has vascular access created but has yet to start dialysis. Ca2+_{: 1.8 mmol/L (2.1-2.4)} PO₄3-_{: 2.4 ng/mL (0.8-1.6)}

Vitamin D: 40 nmol/L (normal) Intact PTH: 90 pg/ml (10-65) What is the next course of action? a) Start calcium carbonate 1250mg TDS with meals. b) Start calcium carbonate 1250mg TDS, taken 2h after meals. c) Start lanthanum carbonate 500mg TDS with meals. d) Start ergocalciferol (vitamin D2) 50,000 U / week x 8 weeks e) Start one alpha calcidol (activated vitamin D) 0.25mcg 3x / week

Calcium, Phosphate & Renal Bone Disease

Manage Complications

CKD with ↓ Ca

2+

_{(2° hyperparathyroidism)}

1. Lower PO₄3- _{with Ca}2+_{-based phosphate binder}

2. When PO₄3- _{controlled, give vitamin D to ↑ Ca}2+_{, ↑ vit D, and ↓ PTH}

• Give activated vitamin D in CKD 4-5

• Ensure PO₄3- _{controlled before giving (vit D will ↑ PO} 43-)

• Aim to keep Vit D > 30 ng/mol, iPTH normal range (2-9x normal if on dialysis)

CKD with ↑ Ca

2+

_{(3° hyperparathyroidism)}

1. Use non-calcium-based phosphate binder (Lanthanum, Sevelamer), hold vitamin D 2. Options for ↑ Ca2+

• Cinacalcet (calcimimetic) • Parathyroidectomy

A6

A 52-year-old man is on follow up for DKD. Latest eGFR is 14ml/min/1.73m2_. He has vascular access created but has yet to start dialysis. Ca2+_{: 1.8 mmol/L (2.1-2.4)} PO₄3-_{: 2.4 ng/mL (0.8-1.6)}

Vitamin D: 40 nmol/L (normal) Intact PTH: 90 pg/ml (10-65)

What is the next course of action?

a) Start calcium carbonate 1250mg TDS with meals – PO4 binder

b) Start calcium carbonate 1250mg TDS, taken 2h after meals – Ca supplement

c) Start lanthanum carbonate 500mg TDS with meals. d) Start ergocalciferol (vitamin D2) 50,000 U / week x 8 weeks e) Start one alpha calcidol (activated vitamin D) 0.25mcg 3x / week

Complications in advanced CKD

Common to both DKD & other causes of CKD

A

naemia

B

lood pressure

C

alcium, Phosphate

Vitamin

D

, PTH, and Renal Bone Disease

E

lectrolytes – hyperkalaemia, acidosis

F

luid overload

Manage Complications What you should know as a HO / F1 (& for exams): • Understand your patient’s complicated drug list. • Be able to manage acute inpatient issues.

Management Goals Plan for RRT Health Promotion & Manage Comorbids Manage Complications Screen & Diagnose Retard DKD Progression DM _ESRF Transplant Palliative Early DKD Advanced DKD Albuminuria ………. GFR >90 >60 45 30 15 Dialysis RRT or Palliate

A typical CKD patient’s medication list

1. Aqueous cream 1 application BD 2. Aspirin 100mg OM 3. Atorvastatin 20mg ON 4. Bisoprolol 5mg OM 5. Calcium Carbonate 2 tab TDS with meals 6. Escitalopram 10mg ON 7. Furosemide 20mg OM 8. Insulin Glargine 12U ON 9. Lactulose 10ml TDS PRN constipation 10. Losartan 100mg OM 11. Metformin 850mg BD 12. Nifedipine 30mg BD 13. Omeprazole 20mg OM 14. One alpha calcidol 0.25mcg 3x / week 15. Paracetamol 1g TDS PRN pain 16. Sangobion 1 tab OM 17. Senna Tab 2 tab ON PRN constipation 18. Sodium bicarbonate 500mg TDS 19. Tears Naturale 1 drop to both eyes QDS Manage Complications

THANK YOU

nigelfong@gmail.com

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