Renal Study Day Treating diabetic Nephropathy

Renal Study Day Treating diabetic Nephropathy

Ian Gallen

Royal Berkshire NHSFT

Copyright Ian Gallen 2019

What causes Diabetic Nephropathy?

• Persistent hyperglycaemia – Some people are more likely to get it than others

• But is it compounded by – Aging

– Hypertension both intra glomerular and systemic

– High salt intake

– Obesity

– Smoking

– Medications



American Journal of Kidney Diseases 2018 71, 884-895

(A) Diffuse mesangial matrix

expansion, increased mesangial hypercellularity, and prominent glomerular basement membranes in diabetic nephropathy.

(B) Diabetic nephropathy with (top)

diffuse mesangial expansion and arteriolar hyalinosis (red arrow) and (bottom) nodular mesangial expansion (Kimmelstiel-Wilson nodules) and concomitant hyalinosis of afferent and efferent arterioles

(C) Arteriolar hyalinosis: both

afferent and efferent arterioles, shown here at the vascular pole, are hyalinized in diabetic nephropathy. This insudation of plasma proteins is due to endothelial injury. In contrast to hypertensive lesions, for which only the afferent arteriole is affected, there is injury to both afferent and efferent arterioles in diabetic nephropathy.

Kidney biopsy images of diabetic nephropathy.


American Journal of Kidney Diseases 2018 71, 884-895


Albuminuria the hallmark of diabetic nephropathy predicts renal impairment

N Engl J Med 2015; 373:1720-1732

How dangerous is poor diabetic control with renal disease?

General Management

• Salt restriction

– Reducing dietary salt intake to less than 5-6 g/d and phosphorus and potassium restriction in advanced cases.

• Weight loss

• Bariatric surgery

• Smoking Cessation


Glycaemic control • In type 1 or 2 diabetes mellitus, hyperglycaemia has been

shown to be a major determinant of the progression of diabetic nephropathy.

• The evidence is best reported for type 1 DM. • Intensive therapy can partially reverse glomerular

hypertrophy and hyperfiltration, delay the development of microalbuminuria, and stabilize or even reverse microalbuminuria.

• Pancreatic transplant recipients in whom true euglycaemia is restored suggest that strict glycaemic and metabolic control may slow the progression rate of progressive renal.

• Intensive blood glucose control in patients with type 2 DM substantially reduced the cost of complications and increased the time free of complications.

Kidney Int. Jun 1995;47(6):1703-20. Lancet. Sep 12 1998;352(9131):837-53. Copyright Ian Gallen 2019

Renal-Biopsy Specimens before and after Pancreas Transplantation from a 33-Year-Old Woman with Type 1 Diabetes

of 17 Years' Duration at the Time of Transplantation

N Engl J Med 1998; 339:69-75 Copyright Ian Gallen 2019

Kidney International, VoL 47 (1995), pp. 1703—1 720

Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial


Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; HbA1c, hemoglobin A1c; Scr, serum creatinine; T1(2)DM, type 1 (2) diabetes mellitus; UPKDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

Tight glycaemic control is effective in T1, but less so in T2 DM


Sodium-glucose 2 (SGLT2) inhibitors

• Canagliflozin – dose in patients with an eGFR of 45 to less than 60

mL/min/1.73 m2 is 100 mg once daily and it is not recommended in patients with an eGFR of less than 45 mL/min/1.73 m2.

• Dapagliflozin – not recommended in patients with an eGFR of less than 60

mL/min/1.73 m2.

• Empagliflozin – eGFR of 45 to less than 60 mL/min/1.73 m2 is 100 mg once

daily and it is not recommended in patients with an eGFR of less than 45 mL/min/1.73 m2.




Empagliflozin and EGFR

N Engl J Med 2016; 375:323-334 Copyright Ian Gallen 2019

N Engl J Med 2016; 375:323-334

Empagliflozin and nephropathy




Canagliflozin in renal disease (CREDANCE)





Glucagonlike peptide-1 (GLP-1) agents

• Exenatide clearance is GFR dependent and is reduced at low GFRs.

• GLP1 should be used with caution in patients with a GFR of 30-50 mL/min and not be used at all if the eGFR is less than 30 mL/min.

• Liraglutide is not metabolized by the kidney, and no dose adjustment is necessary in patients with a decreased GFR, including ESRD, although data in this population are limited.

• ABCD audit shows Liraglutide safe and effective with eGFR>30 mL/min

• Dulaglutide recently shown to reduced decline in EGFrR in proteinuric T2DM (AWARD 7) Br J Clin Pharmacol. Sep 2007;64(3):317-27. Endocr Pract. May-Jun 2011;17(3):345-55. Practical Diabetes 2013; 30(2): 71–76



Dulaglutide vs Glargine in T2DM AWARD 7

• At week 26, eGFR – remained stable with dulaglutide – declined 1.9 mL/min/1.73 m2 with glargine

• The urine albumin-to-creatinine ratio declined in the 3 treatment groups over the 26 weeks – -26.7% for dulaglutide 0.75 mg – -27.7% for dulaglutide 1.5 mg – -16.4% for glargine

• Patients with urine albumin-to-creatinine ratio >300 mg/g had – less decline in eGFR with both doses of dulaglutide – greater reduction in the urine albumin-to-creatinine ratio with

dulaglutide 1.5 mg

Lancet Endo 2018 6, 8, 605-617 Copyright Ian Gallen 2019

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ALTITUDE, Aliskiren Trial in T2DM Using Cardio-Renal Endpoints; ARB, angiotensin receptor blocker; BP, blood pressure; CV, cardiovascular; DDT, doubling of serum creatinine, dialysis, or transplantation; ESRD, end-stage renal disease; IDNT, Irbesartan Diabetic Nephropathy Trial; IRMA-2, Effect of Irebesrtan in the Development of Diabetic Nephropathy in Patients With T2DM; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint; RENAAL, Reduction in End-Points in Non-Insulin Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention; SCr, serum creatinine; T1(2)DM, type 1(2) diabetes mellitus; VA-NEPHRON-D, Veterans Affairs Nephropathy in Diabetes.

Key BP Studies in Diabetic nephropathy


Management of Hypertension

1. Progression of kidney disease is best achieved with a blood pressure control.

2. Long-term treatment with ACE inhibitors, reduces blood pressure and albuminuria, type 1 DM

3. ACE inhibition has been shown to delay the development of diabetic nephropathy.

4. The beneficial effect of ACE inhibition on preventing progression from microalbuminuria to overt diabetic nephropathy is long-lasting (8 y) and is associated with the preservation of a normal glomerular filtration rate (GFR).

5. Treatment with an ACE inhibitor for 12 months has significantly reduced mean arterial blood pressure and the urinary albumin excretion rate in type 2 DM patients who have microalbuminuria.

6. ACE inhibitors are superior to beta-blockers, diuretics, and calcium channel blockers in reducing urinary albumin excretion in normotensive and hypertensive type 1 and type 2 DM patients.

7. ACE inhibition have a significant beneficial effect on the progression of diabetic retinopathy and on the development of proliferative retinopathy.


RAS in T2DM

• RENAALStudy and IDNT demonstrated that angiotensin II receptor blockers (ARBs) are superior to conventional therapy and amlodipine in slowing the progression of overt nephropathy.

• No head-to-head comparison of ACE inhibitors and ARBs . • MICRO-HOPE, ramipril reduced the risk for myocardial infarction, stroke, or

cardiovascular death by 26% after 2 years.

• Combined treatment with ACE inhibitors and ARBs significantly decreased blood pressure, proteinuria, and rate of change of reciprocal serum creatinine – however, higher cardiovascular death was reported among the olmesartan-treated patients

compared with placebo. Hyperkalemia was more frequent in the olmesartan–treated group than in the placebo group.

– Nephron-D trial, which evaluated the effect of adding losartan, an ARB, to the ACE inhibitor lisinopril on albumin-to-creatinine ratio in 1448 patients with type 2 diabetes was stopped early because of safety concerns.

– Combination therapy significantly increased the risk of hyperkalaemia and acute kidney injury.

– Thus, the combination should be avoided as a strategy to reduce proteinuria with the hope of slowing progression of diabetic nephropathy, and should be reserved for individual situations in which optimal control of blood pressure may require it.


New Engl J Med. 2001;345:851-860 Copyright Ian Gallen 2019

Kidney Int. 2016;90,164-71

Bariatric surgery and EGFR


Kidney Int. 2016;90,164-71 Copyright Ian Gallen 2019

Therapeutic targets

Glycaemic targets Individualized targets should be set with each patient. A target of 6.5% (48 mmol/mol) without experiencing unacceptably frequent hypoglycaemia is a

realistic aim. However, for a 75-year-old patient with a ten-year history of T2DM and an HbA1c of 9% (75 mmol/mol),

attempting reduction to 6.5% (48 mmol/mol) will probably confer no survival advantage and may even increase mortality rate as shown by the recent ADVANCE, ACCORD and VADT trials.

Caution in the elderly and those with frequent hypoglycaemia and hypoglycaemia unawareness and those who have had diabetes for many decades and have developed autonomic neuropathy, gastroparesis and other comorbidity that render coping with hypoglycaemia especially difficult.

Blood pressure targets Control of blood pressure has been shown to be an effective way of reducing the risk of nephropathy. Use ACE inhibitors or angiotensin receptor blockers (ARBs) first. NICE recommends BP<140/80 mm Hg for people. ACCORD-BP study that in patients with T2DM who are at increased cardiovascular risk, BP lowering to

target <120/80 conferred no survival benefit and some increased risk.


Measures for Prevention of Diabetic Nephropathy

• Efforts should be made to modify and/or treat associated risk factors such as hyperlipidemia, smoking, and hypertension.

• Optimal blood glucose control (heamoglobin A1c [HbA1c] < 7%)

• Control of hypertension (BP < 120/70 Hg)

• Avoidance of potentially nephrotoxic substances such as nonsteroidal anti-inflammatory medications and aminoglycosides

• Early detection and optimal management of diabetes, especially in the setting of family history of diabetes


Practice based investigations

Urine dipstick analysis Detect overt proteinuria, haematuria and infection. Haematuria is not a normal

feature of diabetic nephropathy and its presence should alert the physician to the possibility of an alternative diagnosis.

ACR Values of <3 are normal and >3, especially if persistent, may indicate early

nephropathy Renal ultrasound scan Assessing renal size and ruling out obstruction or other structural lesions are

important steps in making a diagnosis of diabetic nephropathy. What other investigations should be arranged? 1. Urinalysis to screen for haematuria and if haematuria is present (in the absence of

infection) then urinary microscopy should be performed to look for other features of active sediment such as casts. If these are present, they indicate a glomerular lesion such as glomerulonephritis.

2. Other blood tests such as protein strip, immunoglobulins, complement levels, CRP, ESR, calcium and auto-antibodies if there are clinical indications to do these.


Active management in practice

• Check your practice systems for all patients with DM and EgFR<45

• See if those patients are already known to renal team

• Review all medications

• Review investigations

• If not clear that it is diabetic nephropathy, refer

• For all, put care planning goals for glycaemic control, blood pressure, lipids, smoking and weight.

• Review peripheral pulses and refer if reduced





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Renal Study Day Treating diabetic Nephropathy