My Nephrology Registrar Seminar Talk from September 2013 Topics Covered Pathogenesis of Diabetic Nephropathy Other Renal Disease in Diabetes Treatment of Diabetic Kidney Disease + The Joint Renal Diabetic Clinic

1. Diabetic Kidney
Disease
Dr Richard McCrory

2. 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

3. A few questions to
ponder…
(Answers will come later!)

4. 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

5. SCE Sample Question
A 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

6. 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/24hr
USS kidneys normal appearances, left kidney 12.9cm, right kidney 13.3cm

7. 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/L
Urinary ACR 220mg/mmol

8. The Prevalence and
Impact of Diabetic
Kidney Disease

9. Worldwide Prevalence of Diabetes

10. 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

11. 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

12. 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

13. 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

14. UK Renal Registry 15th Annual Report
Survival at 1 year after 90 days for incident diabetic and
non-diabetic patients by age group for patients starting RRT in 2010

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

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

17. USRDS Atlas 2011
http://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

18. 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

19. Pathogenesis

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

21. The Glomerular Filtration Barrier

22. Jefferson et al KI 2008

23. 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

24. Natural History of Diabetic
Nephropathy
NDT, 1991

25. Stage 1 Stage 5
Chronic renal
failure
Stage 2 Stage 4
Overt
nephropathy
Stage 3
Incipient
nephropathy
Adapted from Mogensen et al, Diabetologia 1979; 17: 71-76
Natural history of diabetic nephropathy
Pre-nephropathy
Normoalbuminuria

27. 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

28. Which of the following is not associated with
nodular glomerulosclerosis?
• Diabetic nephropathy
• Fibrillary glomerulonephritis
• Membranous nephropathy
• Amyloidosis
• Chronic Type 1 MPGN

29. 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 polyclonal
Monoclonal IF:- MPGN, or paraprotein related disease such as
LCDD or amyloidosis
Polyclonal IF:- Immunotactoid, Fibrillary GN, Cryoglobulinaemia

30. SCE Sample Question
A 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

31. 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/24hr
Ultrasound scan of kidneys normal appearances, left kidney 12.9cm,
right kidney 13.3cm
ANSWER - B

32. 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/L
Urinary ACR 220mg/mmol ANSWER – A!

33. 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

34. When does a Diabetic not need a biopsy?
• Is there a consistent history?
• Negative Immunology
• Bland Sediment
• Retinopathy
• Is renovascular disease contributing to
deterioration?

35. 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.

36. Retinopathy and Nephropathy
1. Patients with T1DM and nephropathy
almost always have retinopathy
2. Patients with T1DM and retinopathy almost
always have nephropathy
3. In patients with T2DM with DN, retinopathy
will be present in 30 %
4. In T2DM, severe retinopathy is associated
with Kimmelstiel-Wilson nodules

37. Retinopathy and Nephropathy.
1. Patients with T1DM and nephropathy
almost always have retinopathy - TRUE
2. Patients with T1DM and retinopathy almost
always have nephropathy - FALSE
3. 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

38. Treatment
Strategies

39. Treatment Strategies
1. Glycaemic control
2. Blood pressure control
3. RAAS control
4. Proteinuria control
5. Cholesterol control

40. 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

41. 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.

42. UK Prospective Diabetes Study
Intensive glucose control
HbA1c7.0 % (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

43. 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

44. 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 changes
Aspirin and ACE inhibitor)

45. 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-effective
AND NNT = 5…

46. Joint Diabetes Renal Clinic – Realities
Joss et al. 2002
n = 107 over 29 months (50% Cre >200)
– Absolute ΔSBP 13mmHg
– Absolute ΔDBP 12mmHg
– ΔCholesterol 1.4 (1.8, 1.0)
– ACR 268 → 131

47. Joint Diabetic Renal Clinic – Realities
Jayapaul et al. 2006
130 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)

48. Joint Diabetic Renal Clinic – Realities
Slade et al. 2011 (New Zealand)
44 DN patients @ high risk of progression
No change in weight / HbA1c / Proteinuria
– At time of referral - 7.97 ml/min/yr
– Following clinic intervention - 3.17 ml/min/yr

49. 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