1. Nephropathy and Diabetes Alasdair Mackie Consultant Physician Northern General Hospital

2. Topics to be covered Metformin use in renal impairment Microalbuminuria The importance of the CKD classification in Diabetes and Renal Disease

3. Prevalence of nephropathy in Diabetes Mellitus Type 1Type 2 Prevalence –Micro-alb (%) 16 (9-21)38 (15-60) –Overt proteinuria (%) 15 (18-22)15 (5-48) –At diagnosis (%) zero9 (5-20) Annual incidence –Overt proteinuria (%) 1.2 (0 – 3)1.5 (1 – 2) 25 yr incidence (%) 25 (18-34)28(25-47)

4. 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?

5. When would you stop Metformin? Serum Creatinine –100 μmol/L –130 –150 –180 –200 eGFR –Proteinuria and >60 –45 to 60 –30 to 45 –15 to 30 –15 or less

6. Current Clinical Practice Serum Creatinine –Around 130 to 150 μmol/L eGFR –Around 45 to 60 ml/min

7. 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

8. ManufacturersGDABNFNICE Howlett and Bailey [NEJM 1999] Renal Function CrCl <60 SCr >107 SCr >133 CrCl <90 Heart Failure √√√ns√ Tissue Hypoxia √√√ns√ Alcohol misuse √√nsns√ Severe liver disorders √√√ns√ Contra-indications to Metformin?

9. 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 patient- years exposure to Metformin.

10. 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]

11. 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]

12. 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

13. 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?

14. 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]

15. 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?

16. 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?

17. Screening for Micro-albuminuria ACR Proteinuria protocol 2+ ACR > 2.5(m) or 3.5(f) 2+ samples < 20 mg/mmol Retest in one year Incipient diabetic nephropathy Determine AER (? No. tests) > 20-200  g/min + No NDRD Pre-test for protein +ve -ve 2 more ACR +ve

18. Factors interfering with microalbumin screening IncreaseDecrease Poor glycaemic control ACE inhibitors FeverNSAIDs CCFMalnutrition UTI Exercise Haematuria

19. Classification of albumin excretion NormoalbuminMicroalbuminMacroalbumin AER (mg/24 hr) <30 30 - 300 >300 AER (μg/min) <20 20 - 200 >200 ACR (mg/mmol) Males<2.5 2.5 - 25 >25 Females<3.5 3.5 - 35 >35

20. 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

21. “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

22. 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]

23. 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

24. 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?

26. Why should we not screen for microalbuminuria? Many subjects with do not show progression –Microalbuminuria Adults –Regression26% –Progression19% Adolescents –Regression44% –Progression15% –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]

27. 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

28. 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

29. Diabetes and eGFR CaseClassificationCaveats What does it mean for patients? How to deal with in practice

30. 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.What is her CKD status? 2.What do you think about her renal function? 3.Are there any other tests you may wish to do? 4.What, if any, alteration[s] would you make to her treatment? 5.What else might you wish to do?

31. Classification of eGFR CKD 1*normal>90 ml/min CKD 2*mild60-90 CKD 3moderate30-59 CKD 4severe15-29 CKD 5end-stage or RRT<15 * Must have other evidence or renal disease, e.g proteinuria – haematuria - structural changes

32. Recent sub-classification CKD 3aeGFR of 45-59 CKD3beGFR 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] e.g. CKD 2p means an eGFR of 60 to 89 with proteinuria [PCR >100]

33. How do we estimate GFR? Modification of Diet in Renal Disease [MDRD] Formula: GFR{ml/min/1.73m 2 } = 175 x {SCr/88.4} -1.154 x {age} -0.203 x {0.742 if female} x {1.210 if AfroCaribbean}

34. 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

35. What does it mean for patients? I have another ‘disease’ Increased risk of death and/or cardio- vascular disease Aggressive risk factor management More frequent attendance and monitoring Referral to hospital Review of medication – Metformin Introduction of insulin

36. Clinical implications Risk of Cardiovascular Death in 30000 individuals followed up for 5 years CKD 319.5%2-3-fold ↑ risk CKD 424.3% CKD 545.7% Keith et al [2004] Arch Int Med

37. Cardiovascular Event Rate Age-standardised rate of cardiovascular events per 100-person years CKD Stage3a3b45 Go et al 2005 GFR ml/min/1.73m 2

38. 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 What is the point of knowing about patients with CKD?

39. 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

40. 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

41. 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.What further information would you like to know? 2.What further assessment[s] would you make? 3. How should she be managed? 4. What guidance would you offer her in relation to managing her diabetes and protein excretion?