Transcript Nephropathy and Diabetes

Nephropathy and Diabetes
Alasdair Mackie
Consultant Physician
Northern General Hospital
Topics to be covered
Metformin use in renal impairment
Microalbuminuria
The importance of the CKD classification
in Diabetes and Renal Disease
Prevalence of nephropathy in
Diabetes Mellitus
Type 1
Type 2
16 (9-21)
15 (18-22)
zero
38 (15-60)
15 (5-48)
9 (5-20)
– Overt proteinuria (%)
1.2 (0 – 3)
1.5 (1 – 2)
25 yr incidence (%)
25 (18-34)
28(25-47)
Prevalence
– Micro-alb (%)
– Overt proteinuria (%)
– At diagnosis (%)
Annual incidence
Case study 1
A 62 year-old lady with Type 2 DM for 12 years. Well controlled HbA1c of
7.2% on a combination of Gliclazide 80 mg bd and Metformin 1g bd.
Also suffers from Hypertension, IHD and ‘empty sella’ syndrome. On
Ramipril 10 mg, Bendro-fluomethazide 2.5 mg and Thyroxine 50 μg per day.
Renal function has been gradually deteriorating over two years with serum
creatinine now 142 μmol/L. eGFR 48.
You stop her Metformin and her HbA1c rises to 10.3% over the next six
months.
What would you do now?
When should we withdraw Metformin?
When would you stop Metformin?
Serum Creatinine
eGFR
– 100 μmol/L
– Proteinuria and >60
– 130
– 45 to 60
– 150
– 30 to 45
– 180
– 15 to 30
– 200
– 15 or less
Current Clinical Practice
Serum Creatinine
– Around 130 to 150 μmol/L
eGFR
– Around 45 to 60 ml/min
Remember
An 80 year old lady with a SCr of 100 has
an eGFR of 30
Whereas a
A 50 year old man with a SCr of 200 has an
eGFR of 45
Contra-indications to Metformin?
Manufacturers
GDA
BNF
NICE
Howlett and
Bailey
[NEJM 1999]
Renal
Function
CrCl <60
SCr >107
SCr >133
SCr >133
CrCl <90
Heart
Failure
√
√
√
ns
√
Tissue
Hypoxia
√
√
√
ns
√
Alcohol
misuse
√
√
ns
ns
√
Severe
liver
disorders
√
√
√
ns
√
MALA: the evidence
Most studies demonstrate no link between
Metformin and Lactate levels
– Freemantle Study exception 1.86 v 1.58 mmol/L
Case reports almost always where renal function
severely deranged for other cause[s]
DARTS-MEMO study: 1 case in 1847 patients
Swedish study 1977 to 1991: 2.4 cases of lactic
acidosis per 100 000 patient years
Cochrane database no cases with ~40 000 patientyears exposure to Metformin.
Lothian Study of Metformin and eGFR
Diabetes data-base holds 27 259 [3.5%] patients
19 924 Type 2 with a valid SCr measurement
11 297 currently taking Metformin
2880 [25.5%] are CKD 3 [GFR <60] or worse
No patients taking Metformin with CKD 4 or 5
Warren et al Diab Med [2007]
Lothian study
Local practice is to withdraw Metformin when SCr > 150
If eGFR threshold set at…..
≥36 would ‘allow’ similar number to remain on Metformin
and would permit use in SCr up to 180
– 263 [1.3%] with SCr <150 removed
– 241 with SCr >150 become eligible
40
– then 560 [~3%] would have to stop treatment with Metformin
– And 102 [0.5%] could start
All the newly ineligible individuals female.
Warren et al Diab Med [2007]
What should we do?
Database of all patients on Metformin
Annual test of SCr [and eGFR]
Continue metformin where ≥ 60 ml/min
Stop its use when eGFR ≤ 30 ml/min
Review cases where eGFR 30 to 60?
– Rate of decline
– Other co-morbidities
– More frequent monitoring
Consider re-starting where eGFR improves from
CKD 4
If you were 55….
And developed Type 2 Diabetes Mellitus. Fasting BS 7.6; HbA1c 8.3%.
Your blood pressure was measured at 168/84, urinalysis trace protein and
SCr 94 [eGFR 75]. Your serum cholesterol is 5.8 mmol/L and LDL 3.2. At
Eye Screening visual acuities were 6/6 and 6/9 {R and L}. Fundoscopy – N.
Would you screen your urine for albumin and if so how?
What would you do with the result?
Under what circumstances would you investigate for Non-diabetic Renal Disease?
If you were found to have micro-albumin how tightly would you control
(a)
Blood sugar?
(b)
Blood pressure?
(c)
And with what agent?
(d)
Cholesterol?
(e)
What additional advice would you offer?
How do we measure microalbuminuria?
‘albustix’ – exclude proteinuric subjects
– trace/intermittent positive
Micral-test strip
Albumin creatinine ratio: [first morning or random]
Albumin excretion rate
–
–
–
–
timed overnight collection
24-hour urine
timed ambulant collection
measured after water load
[Definition: 20 to 200g/min in 2 of 3 timed collections (~8 hours) over 3 months]
Who should be screened?
Exclude subjects with proteinuria
Type I
– DM developed pre-pubertally - from puberty
– DM developed after puberty - 5 years onwards
Type II
– from diagnosis – NICE recommends but ?
Annual testing?
What are the difficulties?
Which sample?
– Random sample
– First morning
How many in what timescale?
How do we manage the borderline samples?
Could it be a false positive
– Intercurrent illness
– Metabolic decompensation
Should we undertake timed collections?
If so in whom should we undertake?
Screening for Micro-albuminuria
Pre-test for protein
+ve
-ve
ACR
Proteinuria protocol
+ve
2 more ACR
-ve
2+ ACR > 2.5(m) or 3.5(f)
Retest in one year
Determine AER (? No. tests)
2+ samples < 20 mg/mmol
> 20-200g/min + No NDRD
Incipient diabetic nephropathy
Factors interfering with microalbumin
screening
Increase
Decrease
Poor glycaemic control
ACE inhibitors
Fever
NSAIDs
CCF
Malnutrition
UTI
Exercise
Haematuria
Classification of albumin excretion
Normoalbumin
Microalbumin
Macroalbumin
AER (mg/24 hr)
<30
30 - 300
>300
AER (μg/min)
<20
20 - 200
>200
Males
<2.5
2.5 - 25
>25
Females
<3.5
3.5 - 35
>35
ACR (mg/mmol)
To screen or not to screen?
Should lead to or be:
Identification of a high or higher risk group
Predictable prognosis for selected subjects
Intervention improves outcome
Reliable, accurate and valid measure
Cost effective
“To justify screening for microalbuminuria, there
should be evidence that identifying patients with
microalbuminuria provides a benefit in terms of
an enhanced response to therapeutic interventions
of improved glycaemic and BP control when
compared with treating the population of people
with diabetes as a whole, particularly those whose
urine albumin excretion is normal”
Newman et al [2005] Health Technology Assessment
Why do we measure Microalbumin?
NICE recommendations
Diabetes Guidelines
We get paid to do so or not….
Identifies a high risk clinical group e.g.
– Proliferative retinopathy
– Progression to Renal disease
– Vascular disease in Type 2 Diabetes
Other reason[s]
Microalbumin screening
Relationship of micro-albuminuria to outcome
– all cause mortality/CVS mortality and CVS events [Type 1 &2]
– development of proliferative retinopathy [Type 1]
– development of proteinuria and ESRD [Type 1 & 2]
Significant changes in microalbumin status
– Significant numbers of patients regress
Impact of intervention
– Glycaemic control
Type 1 :No evidence of benefit of improved glycaemic control
Type 2 :Limited evidence in slowing decline of GFR and progression to
proteinuria
– Blood pressure
Positive benefit in delaying progression to clinical proteinuria
No consistent treatment effect of ACEi in slowing decline of GFR
Areas of uncertainty
What is the benefit of screening and treatment
for those individuals who are normotensive?
What is the value of identifying those who
remain ma +ve despite achieving target BP?
Does regression of microalbuminuria reduce
the risk?
Algorithm for management of renal disease
in Type II Diabetes Mellitus
Measure urine ACR or [Alb]
Is micro-albuminuria or
proteinuria present?
and
No
Serum creatinine
> 150mol/l
Yes
Yes
Higher risk: ACE Inhibitor
A1c < 6.5 - 7.5%
BP < 135/75
A1c < 7%
BP < 140/80
Refer
Each visit: urine albumin & SCr
Aggressive cardiovascular RF Rx
Nice 2002
Why should we not screen for
microalbuminuria?
Many subjects with do not show progression
– Microalbuminuria
Adults
– Regression
– Progression
26%
19%
Adolescents
– Regression
– Progression
44%
15%
– Macroalbuminuria
Regression occurs but lower rates
What is the added benefit of identifying and treating
those with micro- as oppose to normo-alb?
Risk of under treating those without micro-alb
Health Technology Assessment - Newman et al. [2005]
A word about PCR
Protein:creatinine ratio
Units: mg protein/mmol creatinine
Measured by Clinical Chemistry
Measure where ‘dipstix’ positive
Random urine – universal container
What does it mean?
– PCR of 100 equivalent to 1g in 24 hours
– PCR of 50 equivalent to 500mgs in 24 hours
– PCR of >30 approximates to macroalbuminuria
Consider Non-Diabetic Renal Disease
In the absence of Diabetic Retinopathy
Advanced renal impairment with low AER
Rapid decline of eGFR
Rapid rise in protein excretion or Nephrotic Syndrome
Active urine sediment
– Vasculitides
Refractory hypertension
Symptoms +/or signs of other systemic disease
– Myeloma/amyloidosis
– SLE
– Vasculitides
Marked [>30%] reduction of GFR with introduction of
ACEi or ARB
Diabetes and eGFR
Case
Classification
Caveats
What does it mean for patients?
How to deal with in practice
Case scenario 3
An 78 year old lady attends your diabetes clinic. She
has had Type 2 diabetes for 4 years and is on Gliclazide
160 mg bd and Pioglitazone 15 mg. She takes Ramipril
5 mg and Amlodipine 10 mg to control her BP, together
with simvastatin 20 mg and aspirin 75 mg.
Her HbA1c is 8.2% and eGFR 42 ml/min. BP 154/76.
1.
2.
3.
4.
5.
What is her CKD status?
What do you think about her renal function?
Are there any other tests you may wish to do?
What, if any, alteration[s] would you make to her treatment?
What else might you wish to do?
Classification of eGFR
CKD 1*
CKD 2*
CKD 3
CKD 4
CKD 5
normal
mild
moderate
severe
end-stage or RRT
>90 ml/min
60-90
30-59
15-29
<15
* Must have other evidence or renal disease, e.g
proteinuria – haematuria - structural changes
Recent sub-classification
CKD
3a
eGFR of 45-59
CKD
3b
eGFR of 30-44
suffixed with p = associated with PCR >100
e.g. CKD 2p means an eGFR of 60 to 89 with
proteinuria [PCR >100]
How do we estimate GFR?
Modification of Diet in Renal Disease [MDRD] Formula:
GFR{ml/min/1.73m2} = 175 x {SCr/88.4}-1.154 x
{age}-0.203 x {0.742 if female} x {1.210 if AfroCaribbean}
Caveats
Less accurate at higher eGFR
Unrepresentative in Acute Renal Failure
Less accurate in those with muscle wasting
Not validated in certain groups
–
–
–
–
children
old age
pregnancy
certain racial groups
Requires ‘serial’ measurements at least > 3 months
to determine classification
Don’t forget the clock starts ticking at 40 – GFR declines 1 ml/min/annum
What does it mean for patients?
I have another ‘disease’
Increased risk of death and/or cardiovascular disease
Aggressive risk factor management
More frequent attendance and monitoring
Referral to hospital
Review of medication – Metformin
Introduction of insulin
Clinical implications
Risk of Cardiovascular Death in 30000
individuals followed up for 5 years
CKD 3
19.5%
CKD 4
24.3%
CKD 5
45.7%
2-3-fold ↑ risk
Keith et al [2004] Arch Int Med
Age-standardised rate of cardiovascular
events per 100-person years
Cardiovascular Event Rate
40
35
30
25
20
15
10
5
0
>60
CKD Stage
45-59
3a
30-44
15-29
3b
4
<15
GFR ml/min/1.73m2
5
Go et al 2005
What is the point of knowing about
patients with CKD?
Address cardiovascular risk to stop them
dying

Lifestyle , Diabetes, Hypertension, ACE inhibitors, Lipids
Slow progression of renal disease to delay
the need for dialysis
 Lifestyle , Diabetes, Hypertension, ACE inhibitors, Lipids
 (specific treatments)
Avoid harm and be prepared!
 Medicine management
 Ensure timely referral and access to pre-dialysis care
Conclusions
Be aware of eGFR in patients on Metformin
Stop Metformin when eGFR <30
Be alert to DM patients [usually Type 2] who may
have non-diabetic renal disease
Always check urine for protein
Consider the pros and cons of microalbumin testing
Know the eGFR of your DM patients and whether
declining
Be aware of the guidelines for referral to the Renal
Unit of your local hospital
Crude option appraisal:
Microalbumin screening in Type 2 DM
Option 1
Treat all with ACEi and no screening
Cost: £6629 per life year gained
Option 2
Screen all patients for microalbuminuria
Treat only those who are positive with ACEi
Cost: £15157 per life year gained
Option 3
Screen all not on BP therapy
Treat positives with ACEi
Cost: £5745 per life year gained
Supplementary Case
ZO is 16. She has had Diabetes for 4 years and until recently has had
good glycaemic control with HbA1c usually <8%. Over the last 12 to 18
months control has been less good with HbA1c of 12 to 14.5%. She has had
intermittent protein excretion. A recent random PCR was 131.2 with
two subsequent first morning levels >100. Her BP is 92/54.
1.
2.
3.
4.
What further information would you like to know?
What further assessment[s] would you make?
How should she be managed?
What guidance would you offer her in relation to managing her
diabetes and protein excretion?