Diabetic Kidney Disease

Dr Richard McCrory

What we will cover• Prevalence and Impact of Diabetic

Kidney Disease• Pathogenesis of Diabetic Nephropathy• Other Renal Disease in Diabetes• Treatment Issues

– The Integrated Approach

A few questions to ponder…

(Answers will come later!)

For the next three cases, what is the most likely diagnosis?

• Diabetic nephropathy• Focal and segmental glomerulosclerosis• Hypertensive nephropathy• Pauci-immune glomerulonephritis• Idiopathic membranous nephropathy

SCE Sample QuestionA 53-year-old man presented to his GP with a right inguinal hernia. He

had a 6-year history of hypertension that had been initially treated with atenolol but he had neither visited a doctor nor taken any medication for 3 years. There was no other significant medical history. He smoked 30 cigarettes per day.

On examination, his blood pressure was 176/96 mmHg, his heart sounds were normal and his chest was clear. Fundoscopy revealed bilateral dot haemorrhages, microaneurysms and hard exudates. Urinalysis showed protein 4+, blood 2+.

Investigations Serum creatinine 176 μmol/L (60–110)

Fasting plasma glucose 16.7 mmol/L (3.0–6.0) Urinary albumin:creatinine ratio 287 mg/mmol (<2.5)

USS of kidneys normal appearances, left kidney 10.4 cm, right kidney 11.2 cm

A Non-SCE Question!A 26 year old male with Prader-Willi Syndrome is referred to nephrology clinic with a 4 month history of lower leg swelling. He was diagnosed with Type 2 Diabetes in 2007. He smokes 40 cigarettes per day.

On examination, his BMI was 32 kg/m2, blood pressure was 120/82 mmHg, his heart sounds were normal and his chest was clear. The abdomen was normal. He had oedema to tibial tuberosities. Fundoscopy was normal. Urinalysis showed protein 3+, blood +

Investigations:Serum Creatinine 33 µmol/L, Albumin 37 g/L, HbA1c 10.4%

24 hour urine protein output 3.03g/24hrUSS kidneys normal appearances, left kidney 12.9cm, right kidney 13.3cm

A further Non-SCE Question!A 28 year old lady is referred to outpatient clinic with a 6 month history of night sweats and joint swelling . She was diagnosed with Type 1 Diabetes at the age of 11 and had stopped her ACE inhibitor 18 months ago in an attempt to conceive despite having documented proteinuria with an ACR of 50mg/mmol .

On examination, there was bilateral synovial swelling of both hands and knees. She had ankle oedema to tibial tuberosities. BP 125/87mmHg. Fundoscopy demonstrated evidence of photocoagulation burns. Urinalysis demonstrated 3+ protein and a trace of blood

Investigations:Creatinine 167 umol/L, Haemoglobin 79 g/L

C-Reactive Protein 230 mg/L, pANCA 160, MPO 5.1 IU/LUrinary ACR 220mg/mmol

The Prevalence and Impact of Diabetic

Kidney Disease

Worldwide Prevalence of Diabetes

Diabetes Statistics

310 million diagnosed with Diabetes in 2011

USA spent $201 billion of its healthcare dollars on diabetes or 43% of global healthcare expenditure due to diabetes

The Spectrum of CKD in Patients with Diabetes

Diabetes No Diabetes

Other Kidney Disease

Diabetic Nephropathy

Hypertension

Renovascular Disease

Source: Canadian Journal of Diabetes 2013; 37:S129-S136

Acute Kidney Injury + Diabetes• Cumulative Risk and independent of other major risk

factors of progression.

• 3679 diabetic patients (Jan 1999- Dec 2008)• Mean age = 61.7 years• Mean baseline Creatinine = 90 µmol/L

• 1822 hospitalized– 530 experienced one AKI episode, 157/530 ≥2 AKI episodes.

• Risk of Stage 4 CKD– AKI versus no AKI HR 3.56 [95% CI 2.76, 4.61)

Thakar et al. CJASN Sept 2011

Percentage distribution of primary renal diagnosis by age in RRT Incident cohort (2011)

In 2011, 201 patients in NI started RRT 26% had Diabetes as Prim. Diagnosis

UK Renal Registry 15th Annual Report

Survival at 1 year after 90 days for incident diabetic andnon-diabetic patients by age group for patients starting RRT in 2010

Median life expectancy on RRT by age group,incident patients starting RRT from 2000–2008 cohort

Median life expectancy on RRT by age group,incident diabetic patients starting RRT from 2000–2008 cohort

USRDS Atlas 2011http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm

Diabetes is the most important cause of ESRD

but very few diabetics are on renal replacement

Diagnosis

Hyperfiltration

Micro-albuminuria

Macro-albuminuria

Renal failure

Perkins BA, Et al. N Engl J Med 2003;348:2285-93.

When does Nephrology get involved?Type 1 DM

Type 2 DM

Pathogenesis

Forbes and Cooper Physiol Rev 2013;93:137-188

The Glomerular Filtration Barrier

Jefferson et al KI 2008

What’s happening in the Nephron?Earliest change: • Glomerular enlargement • GBM widening

Early lesions: • Mesangial expansion• Mesangiolysis

Established lesions • Nodular sclerosis • Marked mesangial expansion • Afferent,efferent arteriolar hyaline • Microaneurysms

Natural History of Diabetic Nephropathy

NDT, 1991

Stage 1 Stage 5Chronic renal

failure

Stage 2 Stage 4Overt

nephropathy

Stage 3Incipient

nephropathy

Adapted from Mogensen et al, Diabetologia 1979; 17: 71-76

Natural history of diabetic nephropathy

Pre-nephropathyNormoalbuminuria

Biopsy Question

• A 65 year old man underwent a renal biopsy for investigation of impaired GFR and proteinuria

• The biopsy was reported as showing nodular glomerulosclerosis

Which of the following is not associated with nodular glomerulosclerosis?

• Diabetic nephropathy

• Fibrillary glomerulonephritis

• Membranous nephropathy

• Amyloidosis

• Chronic Type 1 MPGN

Differential for Nodular Glomerulosclerosis on Kidney Biopsy

If Immuno is negative( more common): – Diabetic Nephropathy– Chronic Thrombotic Microangiopathy– Chronic ischemic disease or hypoxia– Smoking associated nodular sclerosis – Nasr et al. JASN 2006

If Immuno is positive, either monoclonal or polyclonalMonoclonal IF:- MPGN, or paraprotein related disease such as

LCDD or amyloidosisPolyclonal IF:- Immunotactoid, Fibrillary GN, Cryoglobulinaemia

SCE Sample QuestionA 53-year-old man presented to his GP with a right inguinal hernia.

He had a 6-year history of hypertension that had been initially treated with atenolol but he had neither visited a doctor nor taken any medication for 3 years. There was no other significant medical history. He smoked 30 cigarettes per day.

On examination, his blood pressure was 176/96 mmHg, his heart sounds were normal and his chest was clear. Fundoscopy revealed bilateral dot haemorrhages, microaneurysms and hard exudates. Urinalysis showed protein 4+, blood 2+.

• Investigations – Serum creatinine 176 μmol/L (60–110) – Fasting plasma glucose 16.7 mmol/L (3.0–6.0) – Urinary albumin:creatinine ratio 287 mg/mmol (<2.5) – Ultrasound scan of kidneys normal appearances, left kidney 10.4

cm, right kidney 11.2 cm

ANSWER - A

A Non-SCE Question!A 26 year old male with Prader-Willi Syndrome is referred to nephrology clinic with a 4 month history of lower leg swelling. He was diagnosed with Type 2 Diabetes in 2007. He smokes 40 cigarettes per day.

On examination, his BMI was 32 kg/m2, blood pressure was 120/82 mmHg, his heart sounds were normal and his chest was clear. The abdomen was normal. He had oedema to tibial tuberosities. Fundoscopy was normal. Urinalysis showed protein 3+, blood +

Investigations:Serum Creatinine 33 µmol/L, Albumin 37 g/L, HbA1c 10.4%24 hour urine protein output 3.03g/24hrUltrasound scan of kidneys normal appearances, left kidney 12.9cm, right kidney 13.3cm

ANSWER - B

A further Non-SCE Question!A 28 year old lady is referred to outpatient clinic with a 6 month history of night sweats and joint swelling . She was diagnosed with Type 1 Diabetes at the age of 11 and had stopped her ACE inhibitor 18 months ago in an attempt to conceive despite having documented proteinuria with an ACR of 50mg/mmol .

On examination, there was bilateral synovial swelling of both hands and knees. She had ankle oedema to tibial tuberosities. BP 125/87mmHg. Fundoscopy demonstrated evidence of photocoagulation burns. Urinalysis demonstrated 3+ protein and a trace of blood

Investigations:Creatinine 167 umol/L, Haemoglobin 79 g/LC-Reactive Protein 230 mg/L, pANCA 160, MPO 5.1 IU/LUrinary ACR 220mg/mmol

ANSWER – A!

Suspicious for non-diabetic nephropathy

• Onset within 5 years of dx of diabetes• Acute onset• Active sediment• Unusual review of systems• Serologies

ANA, Hep B, Hep C

• Absence of retinopathy or neuropathy

When does a Diabetic not need a biopsy?

• Is there a consistent history?• Negative Immunology• Bland Sediment• Retinopathy

• Is renovascular disease contributing to deterioration?

What may you expect to find on the renal biopsy of a diabetic patient?

Columbia University Medical Center 2011

620 kidney biospies from patients with diabetes.– 37% of patients had DN alone– 36% had NDRD alone– 27% had DN plus NDRD

Longer duration of DM was associated with a greater likelihood of DN and a lower likelihood of NDRD

DM duration ≥12 years was the best predictor (58% sensitivity, 73% specificity) of DN alone.

Retinopathy and Nephropathy1. Patients with T1DM and nephropathy

almost always have retinopathy2. Patients with T1DM and retinopathy almost

always have nephropathy3. In patients with T2DM with DN, retinopathy

will be present in 30 %4. In T2DM, severe retinopathy is associated

with Kimmelstiel-Wilson nodules

Retinopathy and Nephropathy.1. Patients with T1DM and nephropathy

almost always have retinopathy - TRUE2. Patients with T1DM and retinopathy almost

always have nephropathy - FALSE3. In patients with T2DM with DN, retinopathy

will be present in 30 %– FALSE (60%)4. In T2DM, severe retinopathy is associated

with Kimmelstiel-Wilson nodules - TRUE

Treatment Strategies

Treatment Strategies1. Glycaemic control2. Blood pressure control3. RAAS control4. Proteinuria control5. Cholesterol control

What about control of diabetes?

Type 1 Diabetes• DCCT trial

– Basal-bolus/insulin pump versus BD insulin

– Reduction in incidence and progression of albuminuria

– Followed up for 22 years – 50% reduction in incidence of impaired GFR

Type 2 Diabetes• UKPDS/ACCORD/ADVANCE• Intensive v standard

glycaemic control• Probably some benefit in

reduction in DN but less impressive than for T1DM

NICE Guidance on Diabetes and CKD

1. Achievement of HbA1c targets of 6.5–7.5% -

2. Prescription of ACE inhibitors titrated to full dose.

3. Control of hypertension to below 130/80 mmHg

4. Timely referral to a nephrologist.

UK Prospective Diabetes StudyIntensive glucose controlHbA1c 7.0 % (T) vs 7.9 % (C) reduced risk of:

– any diabetes-related endpoints 12% – microvascular endpoints 25%– myocardial infarction 16%

Blood pressure control policy 144/82 (T) vs 154/87 (C) mmHg reduces risk of:

– any diabetes-related endpoint 24%– microvascular endpoint 37%– stroke 44%

The benefit from tight glycaemic control is less than the benefit

from less-than-good blood pressure control

RENAAL / IDNT – The DIAMETRIC Database (2011)

• For every 5mmHg reduction in SBP– ~2% risk reduction in CV risk

• For every Logarithmic reduction in albuminuria– ~12% reduction in CV risk

• 35% of subjects had either a reduction in BP and no change in albuminuria or vice versa

• Discordance existed between effects of ARB’s on BP and albuminuria

The Steno-2 Study – An Integrated Approach (Gaede, 2003)

80 patients randomly assigned to conventional Tx or intensified multifactorial intervention

Targets– Hyperglycaemia– Hypertension– Dyslipidaemia– Uprot– Secondary prevention CV disease (Smoking

cessation, Exercise, Dietary changesAspirin and ACE inhibitor)

Steno-2 Results

• Intensified Treatment- Lower risk of– CV disease 0.47 (0.27-0.73)– Nephropathy 0.39 (0.17-0.87)– Retinopathy 0.42 (0.21-0.86)– Autonomic neuropathy 0.37 (0.81-0.79)

AND Cost-effectiveAND NNT = 5…

Joint Diabetes Renal Clinic – Realities

Joss et al. 2002n = 107 over 29 months (50% Cre >200)

– Absolute ΔSBP 13mmHg– Absolute ΔDBP 12mmHg– ΔCholesterol 1.4 (1.8, 1.0)– ACR 268 → 131

Joint Diabetic Renal Clinic – Realities

Jayapaul et al. 2006130 patients• Slope of creatinine clearance vs. time

– 1.09±1.34 ml/min/month in 1st year to 0.39±0.73 ml/min/month in 3rd year

(p < 0.004)• HbA1c unchanged• Significant improvement in SBP + DBP

(41% achieved <140/<80mmHg)

Joint Diabetic Renal Clinic – Realities

Slade et al. 2011 (New Zealand)44 DN patients @ high risk of progressionNo change in weight / HbA1c / Proteinuria

– At time of referral - 7.97 ml/min/yr– Following clinic intervention - 3.17 ml/min/yr

Summary• Diabetes (especially Type 2) placing heavy

CVD and Renal Burden on health services• In Diabetic Nephropathy

– Margins gained with Blood Pressure + Proteinuria control over glycaemic control

– Recognise the intensity of resource investment + dedicated time needed to achieve this

• Joint Diabetes Renal Clinics– Needs enthusiastic members of endocrine and

renal team!– Providing evidence to directorates that they make

a difference is tricky