Diabetes Renal Disease Management Dr Paul Laboi Dr Vijay Jayagopal York Hospital 0
Diabetic Nephropathy Diabetic nephropathy is a clinical syndrome characterised by the following: Persistent albuminuria (>300 mg/d or >200 μg/min) Progressive decline in the GFR Approximately 40% of people with diabetes will develop nephropathy. 1
Diabetic Nephropathy Is the leading cause of CKD in the UK Diabetes is responsible for 30-40% of all endstage renal disease (ESRD) Increases risk of CVD 3-5 fold and premature death 6 fold such that a significant number of patients do not survive long enough to receive RRT* *www.britishrenal.org 2
Recommendations for screening of nephropathy in patients with Type 2 diabetes Screening for diabetic nephropathy 1 Check all patients at diagnosis and annually for proteinuria Measure serum creatinine and calculate GFR annually Repeat if an abnormal test is obtained Urine test Normal Testing and classification of proteinuria 2 (Stage of nephropathy) Microalbuminuria Overt nephropathy (macroalbuminuria) Urine dipstick Negative Positive 0 Urinary Albumin Level 24-hour 30 mg/day 300 mg/day 1000 mg/day ACR (male) 2.0 mg/mmol 20.0 mg/mmol 66.7 mg/mmol ACR (female) 2.8 mg/mmol 28.0 mg/mmol 93.3 mg/mmol ACR: albumin:creatinine ratio; GFR: glomerular filtration rate. 1. National Institute for Health and Clinical Excellence. Type 2 Diabetes. The management of type 2 diabetes. CG 87, May 2009. Available at: http://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf Last accessed January 2013. 2. Canadian Diabetes Association. 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. September 2008. Available at: http://www.diabetes.ca/files/cpg2008/cpg-2008.pdf Last accessed January 2013.
The benefits of early tight control- UKPDS 10 year post-trial follow-up 1977 1991 Randomisation Intensive vs Conventional Treatment 1997 (20 years) Trial End 10-year Post-Trial Follow Up (Non-Interventional) 2007 (30 years) 12%* 16%** (NS) 9%* 15%* 25%* 24%* Any diabetes related endpoint Microvascular disease Myocardial infarction 4
YH Audit 2004-Overall mortality 21% 5
Mortality At the end of the 12 month period A fifth of all patients were dead 30% of patients with CKD 3 were dead Highest mortality was in patients over 45 and those with low GFR s No deaths in patients under 35 6
Is this expected? Cumberland Infirmary, Carlisle: 10 year data review of Joint DM Renal clinic (QJM, 2006) 130 patients seen; 41 (32%) died Mean survival from first visit to death 47.8 months Glasgow Royal Infirmary: DM-Renal clinic, 170 consecutively referred patients over 10 years (QJM; 2002) FU data available for up to 3 years in 62 32 of these were either dead or on dialysis 7
Key Staff: DSN Nephrologist Diabetologist Joint clinics York Model Additional Support: Dietician (diabetes/renal) Podiatry, pump team, renal psychologist, Dialysis nurses Not a recent development: Glasgow 1989 (initial data showed ESRD delayed by 2 years; QJM 1997) 8
Joint Clinic Audit Outcome Diabetes MDT clinic Total number of patients=97 Male=55(25-91). Mean age 66.6 yrs Female= 42( 35-87). Mean age 69.35 yrs Change in egfr= -1.9% Change in A1c HbA1c 2012= 70.12 ( 38-124) HbA1c 2013= 67.11 ( 36-118) Mortality 10 patients/97 (9.7%) Total number of patients=27 Male=20 (54-91) Mean age 72.7 yrs Female =7(51-89) Mean age 70.85 yrs Change in egfr= -11.5% Change in A1c HbA1c in 2012 = 68.12 ( 41-94) HbA1c in 2013= 69.12 ( 50-103) Mortality 5 patients/27 (18.3%) 9
Issues covered in clinic.. Glycaemic control Blood pressure control Urine MA reduction Cardiovascular prevention Nephrotoxic meds Anaemia, K Metabolic bone Acid/base status Fluid status Low-protein, salt diet 10
Considerations VJ - Diabetes medication review PL Review of BP control, Albuminuria, Metabolic parameters 11
Metformin Sensitises body tissues to insulin and reduces glucose production by the liver Advantages Disadvantages Well established Contraindicated in patients at increased risk of lactic acidosis Low risk of hypoglycaemia Gastrointestinal (GI) side effects, including diarrhoea No weight gain Many contraindications (e.g. renal failure or dysfunction, Appetite not increased severe infection, cardiac or respiratory failure, recent Beneficial effects on microvascular and myocardial infarction) macrovascular risk with evidence of improved Requires dose titration due to GI side effects (available in long-term cardiovascular outcomes modified-release formulations to mitigate this side effect) Can be used in combination with many classes of anti-diabetes drugs Relatively low cost Renal considerations Review metformin if egfr <45 Stop metformin if egfr <30 12
Sulphonylureas Act as insulin secretagogues by directly stimulating the β cells of the pancreas to secrete insulin Renal considerations SU s should be used with caution in patients with later stages of CKD, with education on the risk of hypoglycaemia, weight gain and self blood glucose monitoring 13
Thiazolidinediones Act as insulin sensitisers Renal considerations No need to reduce dose of pioglitazone in renal impairment. Fluid retention, weight gain, anaemia, bone density No information is available from dialysed patients 14
DPP-4 inhibitors (gliptins) Enhance insulin secretion in response to a meal by inhibiting the breakdown of the incretin hormones GLP-1 and GIP by the DPP-4 enzyme Renal considerations Linagliptin can be used for mild, moderate and severe renal impairment; no dose adjustment required Sitagliptin, saxagliptin and vildagliptin all require dose adjustment in moderate to severe renal impairment 15
GLP-1 receptor agonists Work by enhancing glucose-dependent insulin secretion from β-cells in the pancreas, suppressing excessive glucagon levels and delaying gastric emptying Renal considerations Unsuitable for patients with end-stage renal disease or severe renal impairment. Used now in stage 3 CKD, especially when weight loss is a desired outcome. Doses not altered. 16
Insulin Replace reduced or deficient insulin levels in patients with T2D and work in the same way as endogenous insulin Renal Considerations Half-life of insulin is prolonged in renal impairment due to lower levels of degradation. Risk of hypoglycaemia greater. Dose adjustment may be needed as renal function declines. Fluid retention, weight gain. Adjustments for patients on HD and PD 17
Licensed indications in Type 2 diabetes and renal impairment in the UK Drug Mild Moderate Severe Metformin x x Acarbose x Sulphonylureas Dose adjustment Nateglinide Dose adjustment Dose adjustment Repaglinide Use with caution DPP-4 inhibitors Sitagliptin Dose reduction Saxagliptin Dose reduction Vildagliptin Dose reduction British National Formulary July 2013 Available at: http://www.bnf.org Last accessed July 2013. Dose reduction Dose reduction Dose reduction Linagliptin Pioglitazone SGLT2 x x Liraglutide x GLP-1 analogue Insulin Exenatide Twice daily Once weekly Caution with dose escalation x x Lixisenatide Caution with dose escalation 18 x x
Primary composite endpoint* (%) Benefits of a multifactorial approach to type 2 diabetes management: Steno-2 80 60 40 (n=160) Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%) P=0.007 53% risk reduction (Intensive vs conventional therapy) P=0.01 Conventional therapy 50% relative risk reduction in the primary composite endpoint Sustained benefit on cardiovascular events in the intensive management group over an additional 5.5 years 2 Conventional treatment: 20 Intensive therapy In accordance with national guidelines Intensive treatment: 0 Number at risk Conventional therapy Intensive therapy 0 1 2 3 4 5 6 7 8 Time of follow-up (years) 80 72 70 63 59 50 44 41 13 80 78 74 71 66 63 61 59 19 Stepwise implementation of behaviour modification and pharmacological therapy that targeted hyperglycaemia, hypertension, dyslipidaemia and microalbuminuria, with secondary prevention of cardiovascular disease with aspirin *Death from cardiovascular causes, non-fatal myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, non-fatal stroke, amputation or surgery for peripheral atherosclerotic artery disease 1. Adapted from: Gaede P, et al. N Engl J Med 2003;348:383 93 2. Gaede P, et al. N Engl J Med 2008;358:580 91 19
Case study - 45 year old male taxi driver Newly diagnosed T2DM Raised fasting plasma glucose 7.8mmol/L BMI 29, conscious of his weight Lipids Tot Chol 6.0mmol/l LDL 2.5 mmol/l HDL 0.9 mmol/l Hypertensive BP= 152/92 mmhg No overt proteinuria dipstick negative 20
Case study - 45 year old male taxi driver Newly diagnosed T2DM Raised fasting plasma glucose 7.8mmol/L BMI 29, conscious of his weight Lipids Tot Chol 6.0mmol/l LDL 2.5 mmol/l HDL 0.9 mmol/l Hypertensive BP= 152/92 mmhg No overt proteinuria dipstick negative Q1. Dipstick is negative, would you consider this patient to have increased risk of declining renal function? 1. Yes 2. No 21
Case study - 45 year old male taxi driver Newly diagnosed T2DM Raised fasting plasma glucose 7.8mmol/L BMI 29, conscious of his weight Lipids Tot Chol 6.0mmol/l LDL 2.5 mmol/l HDL 0.9 mmol/l Hypertensive BP= 152/92 mmhg No overt proteinuria dipstick negative Q2. Which renal function test do you do? 1. egfr 2. Albuminuria 3. Both at same time 22
Case study - 45 year old male taxi driver Newly diagnosed T2DM Raised fasting plasma glucose 7.8mmol/L BMI 29, conscious of his weight Lipids Tot Chol 6.0mmol/l LDL 2.5 mmol/l HDL 0.9 mmol/l Hypertensive BP= 152/92 mmhg No overt proteinuria dipstick negative Q3. Which anti-diabetic drug would you initiate at this time? 1. Metformin 2. TZD 3. SU 4. DPP-4 inhibitor 5. SGLT2-I 6. GLP 7. Insulin 23
Case study - 45 year old male taxi driver Newly diagnosed T2DM Raised fasting plasma glucose 7.8mmol/l BMI 29, conscious of his weight Lipids Tot Chol 6.0mmol/l LDL 2.5 mmol/l HDL 0.9 mmol/l Hypertensive BP= 152/92 mmhg No overt proteinuria dipstick negative Q4. What other treatments should be initiated? 1. Antihypertensive medication 2. Statins 3. Both of the above 24
Diabetic CKD Your average Diabetic CKD 3/4 profile Age History of Diabetes for 7-10 yrs BMI BP Proteinuric Fluid overload Co-morbidities 2-3 BP meds 25
Diabetic kidney Pre-existing diabetes Persistent albuminuria/proteinuria Elevated Creatinine Diabetic retinopathy Normal or large kidneys on USS Non diabetes related kidney disease Other systemic disease Rapid increase in proteinuria, nephrotic syndrome Rapid rise in creatinine Refractory hypertension Active urinary sediment 26
CJASN October 07, 2013 vol. 8 no. 10 1718-1724 CJASN October 07, 2013 vol. 8 no. 10 1718-1724 CJASN October 07, 2013 vol. 8 no. 10 1718-1724 When is renal disease unlikely to be due to diabetes? Short duration of diabetes Accelerated worsening of proteinuria or creatinine Haematoproteinuria Biopsy findings FSGS 22% Hypertensive nephrosclerosis 18% ATN 17% IgA nephropathy 11% Membranous GN 8% Vasculitis 7% The Modern Spectrum of Renal Biopsy Findings in Patients with Diabetes, CJASN 2013, 8, 1718-24
ACEI & ARB combination therapy Esp useful in proteinuric patients Treating 1000 patients with combination therapy for a year would prevent 3 ESRDs and reduce proteinuria in 90 patients. But would result in 38 AKI s and 65 hyperkalemias Cost of AKI is $4886-7982 and cost of maintenance haemodialysis is $100,000/- Dual RAAS blockade for kidney failure: hope for the future. www.thelancet.com Vol 385 May 23, 2015. 43,256 from 150 RCTs Cost of CKD2 $1700/-, CKD3 $3500/- and CKD4 12,700/- 28
SBP 120-140 BP Either ACEi or ARB reduces progression by 16 to 30% Combination therapy in patients who have not responded to high dose single blockade? ONTARGET study did not show any benefit of 25,600 recruited patients, only 1200 had proteinuria Insufficient evidence but combination therapy is commonly prescribed in patients with refractory proteinuria >1gm Addition of Spironolactone Combination therapy ACEi + CCB / diuretic 29
Hyperkalemia When defined as >5.5, in patients with GFR < 60, average one episode per year. And more when treated with RAAS medications Drugs that increase potassium include ACEi, ARB, Aldosterone antagonists, potassium sparing diuretics and B blockers Management avoid Lo salt, use effective doses of thiazide and loop diuretics, manage acidosis, review drug combinations and reduce ACEi/ARB doses Patients on dialysis patients complain that arms and legs feel heavy & only way to remove potassium is by dialysis. 30
Acidosis Maintain venous bicarbonate >20-24 Starting dose of Sodium Bicarbonate is 500mgs three times a day Consider sodium loading and fluid overload Reduces potassium and ionised calcium Contraction alkalosis 31
Frusemide/Bumetanide Fluid balance Combinations loop plus Xipamide Loop plus spironolactone Drop in renal function, hyponatraemia, hypokalaemia, gout, cramps 32
Renal bone disease Secondary hyperparathyroidism low calcium, increasing phosphate and rising PTH Phosphate binders Calcium and non calcium based Calcium supplementation PTH suppression medically with alfa-calcidol and surgery 33
Symptom management Gout Prednisolone 10mgs for 5-7 days & Allopurinol 100mgs daily (cover with Pred at a lower dose) Restless legs & Cramps Gabapentin 100mgs daily or three times a week Neuropathic pain Gabapentin Chronic pain if small dose od Codeine or Tramadol does not work, consider Fentanyl patch starting at 6mcgs every 72 hrs Depression prevalence is 22%, 52% of patients with severe depression were prescribed antidepressants 34
Renal replacement therapy / dialysis Two options dependant on co-morbidities Palliative dialysis or aggressive dialysis as a means to transplantation(tb) Haemodialysis, chosen by 70-75% of patients, 12/150 dialyse at home Peritoneal dialysis and assisted form of PD glucose based solutions Transplantation Kidney pancreas tx or single organ tx 35
CKD and safety Antibiotic prescribing in CKD4 nitrofurantoin, aciclovir (shingles 400mgs stat followed by 200mgs BD) Severe hypoglycemia is 2.5 times more common in patients with proteinuria Non adherence linked with meds that have got to be taken more than twice a day and not related to number of medications Health supplements esp ginseng, fish oil. More so in the more educated and affluent population 36
The Elderly patient Creatinine is a function of muscle mass. Decreases in muscle mass might mask the association of reduced kidney function with decline in physical function. Fraility (slowness, weakness, energy, shrinking and physical activity) was twice as common in Cystatin diagnosed CKD3b, when serum creatinine was still normal 37
Which patients to refer to the joint clinic? Patients with egfr <30 or < 60 & progressively worsening renal function With persistent microalbuminuria, nephrotic syndrome, haemoproteinuria Those where egfr is falling despite control of proteinuria Those with anaemia or Ca<2.3 (and elevated PTH) or Phosphate>1.6 Raised K Uncontrolled hypertension/ fluid status 38