Ian Gallen

 Over 40% of new cases of end-stage renal disease (ESRD) are attributed to diabetes.  In 2001, 41,312 people with diabetes began treatment for end-stage renal disease.  In 2001, it cost $22.8 billion in public and private funds to treat patients with kidney failure.  Minorities experience higher than average rates of nephropathy and kidney disease

Stage 1: Hyperfiltration, or an increase in glomerular filtration rate (GFR) occurs. Kidneys increase in size. Stage 2: Glomeruli begin to show damage and microalbuminurea occurs. Stage 3: Albumin excretion rate (AER) exceeds 200 micrograms/minute, and blood levels of creatinine and urea-nitrogen rise. Blood pressure may rise during this stage. Ian Gallen

Stage 4: GFR decreases to less than 75 ml/min, large amounts of protein pass into the urine, and high blood pressure almost always occurs. Levels of creatinine and urea-nitrogen in the blood rise further. Stage 5: Kidney failure, or end stage renal disease (ESRD). GFR is less than 10 ml/min. The average length of time to progress from Stage 1 to Stage 4 kidney disease is 17 years for a person with type 1 diabetes. The average length of time to progress to Stage 5, kidney failure, is 23 years. Ian Gallen

 Major cause of early death in DM  Major cause of amputation  RRT is arduous for the patient and expensive  Nephropathy is largely avoidable (or can be delayed)  Local performance is poor compared with national data Ian Gallen

 Diabetic nephropathy is a clinical syndrome characterized by the following:  Persistent albuminuria (>300 mg/d or >200 μ g/min) that is confirmed on at least 2 occasions 3-6 months apart  Progressive decline in the glomerular filtration rate (GFR)  Elevated arterial blood pressure Ian Gallen

 Nephropathy in type Type 1 diabetes Nearly always due to hyperglycaemia Strong genetic predisposition  Nephropathy in T2DM More common May be due to hyperglycaemia But often due to other causes particularly inflammation Frequently multi-factorial Ian Gallen

 Results from hyperglycemia, advanced glycosylation products, and activation of cytokines.  Inflammatory medium, resulting in activation of the innate immune system, which results in activation of the nuclear transcription factors-kappa B (NF- κ B), and release of inflammatory mediators, including, interleukin (IL)–1 β and tumor necrosis factor (TNF)– α.  Hyperglycemia also increases the expression of transforming growth factor- β (TGF- β ) in the glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF- β and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced collagen synthesis and may induce the vascular changes observed in persons with diabetic nephropathy.  Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes.  Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly African Americans, persons of Hispanic origin, and American Indians, may be particularly disposed to renal disease as a complication of diabetes.  Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. Ian Gallen

 Mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycosylation of matrix proteins.  Thickening of the glomerular basement membrane (GBM) occurs.  Glomerular sclerosis is caused by intraglomerular hypertension  The key change in diabetic glomerulopathy is augmentation of extracellular matrix. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the GBM and expansion of the mesangium due to accumulation of extracellular matrix. Ian Gallen

A and B Glomerulus showing only mild ischemic changes C, D Class II glomeruli with mild and moderate mesangial expansion, respectively. E and F Kimmelstiel–Wilson lesion. G is an example of glomerulosclerosis that does not reveal its cause Ian Gallen

 Light-Chain Deposition Disease  Multiple Myeloma  Nephritis, Interstitial  Nephrosclerosis  Nephrotic Syndrome  Renal Artery Stenosis  Renal Vein Thrombosis  Renovascular Hypertension Ian Gallen

 Urinalysis Persistent albuminuria (>300 mg/d or >200 μ g/min) that is confirmed on at least 2 occasions 3-6 months apart  Blood Tests Serum and Urinary Electrophoresis  Serum and urinary electrophoresis is performed mainly to help exclude multiple myeloma (in the appropriate setting) and to classify the proteinuria (which is predominantly glomerular in diabetic nephropathy).  Renal Ultrasonography Observe for kidney size, which is usually normal to increased in the initial stages and, later, decreased or shrunken with chronic renal disease. Rule out obstruction.  Renal Biopsy Renal biopsy is not routinely indicated in all cases of diabetic nephropathy, especially in persons with a typical history and a progression typical of the disease. It is indicated if the diagnosis is in doubt, if other kidney disease is suggested, or if atypical features are present.  Histologic Findings Mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycosylation of matrix proteins. Thickening of the glomerular basement membrane (GBM) occurs. Glomerular sclerosis. Ian Gallen

 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 Ian Gallen

 In persons with either type 1 or type 2 diabetes mellitus (DM), hyperglycemia 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 significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications. Kidney Int. Jun 1995;47(6): [Medline]. Lancet. Sep ;352(9131): [Medline]. Ian Gallen

 Sitagliptin-Approximately 80% of sitagliptin is cleared by the kidney; therefore, the standard dose of 100 mg daily should be reduced in patients with reduced glomerular filtration rates (GFRs). With an estimated GFR (eGFR) of 30 or greater to less than 50 mL/min/1.73 m 2, the recommended dose is 50 mg once daily, and with an eGFR less than 30 mL/min/1.73 m 2, a dose of 25 mg once daily is advised.  Saxagliptin is mg daily in patients with an eGFR greater than 50 mL/min, but dose adjustment is recommended in patients with an eGFR of 50 mL/min/1.73 m 2 or less to 2.5 mg daily.  Alogliptin also requires a dose reduction from 25 mg daily to 12.5 mg daily in patients with an eGFR of less than 60 mL/min/1.73 m 2 and to 6.25 mg daily if the eGFR is less than 30 mL/min/1.73 m 2.  Linagliptin-no dose adjustment is necessary in patients with a reduced GFR. [21]  Diabetes Care. Jul 2007;30(7):  Expert Opin Drug Metab Toxicol. May 2013;9(5): Ian Gallen

 Canagliflozin dose in patients with an eGFR of 45 to less than 60 mL/min/1.73 m 2 is 100 mg once daily and it is not recommended in patients with an eGFR of less than 45 mL/min/1.73 m 2.  Dapagliflozin not recommended in patients with an eGFR of less than 60 mL/min/1.73 m 2.  Empagliflozin eGFR of 45 to less than 60 mL/min/1.73 m 2 is 100 mg once daily and it is not recommended in patients with an eGFR of less than 45 mL/min/1.73 m 2. Ian Gallen

 Exenatide clearance is GFR dependent and is reduced at low GFRs.  GLP1 should be used with caution in patients with a GFR of 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 Br J Clin Pharmacol. Sep 2007;64(3): Endocr Pract. May-Jun 2011;17(3): Practical Diabetes 2013; 30(2): 71–76 Ian Gallen

 Progression of kidney disease is best achieved with a blood pressure control.  Long-term treatment with ACE inhibitors, usually combined with diuretics, reduces blood pressure and albuminuria and protects kidney function in patients with hypertension, type 1 DM, and nephropathy.  ACE inhibition has been shown to delay the development of diabetic nephropathy.  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).  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.  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.  In addition to beneficial cardiovascular effects, ACE inhibition has also been demonstrated to have a significant beneficial effect on the progression of diabetic retinopathy and on the development of proliferative retinopathy. Ian Gallen

 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 is availible.  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 hyperkalemia 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. Ian Gallen

 Endothelin antagonists have demonstrated antifibrotic, anti- inflammatory, and antiproteinuric effects in experimental studies.  Avosentan administered in addition to standard treatment with an ACE inhibitor or an ARB, reduced the mean relative urinary albumin excretion rate (-16.3% to -29.9%, relative to baseline). Ian Gallen

 Efforts should be made to modify and/or treat associated risk factors such as hyperlipidemia, smoking, and hypertension.  Specific goals for prevention include the following:  Optimal blood glucose control (hemoglobin A 1c [HbA 1c ] < 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 Ian Gallen

 Does the patient have any symptoms or do they feel completely well?  Diabetic nephropathy is commonly a completely asymptomatic condition until the patient has quite advanced renal impairment and it is therefore essential that annual screening by measuring Us and Es and performing urinalysis for microalbuminuria are undertaken.  How long has the patient had diabetes?  In general, the longer the patient has had diabetes the greater the risk of complications although this is is a very approximate guide and it is certainly possible to have had diabetes for only a few years and already developed complications (especially so for T2DM).  Conversely, some patients can have diabetes for many decades and develop few or any complications.  Does the patient have other microvascular complications?  The presence of other microvascular complications such as retinopathy and neuropathy increases the odds that the patient will also develop nephropathy, but this is only a rule of thumb and it certainly shouldn't be inferred that patients without other microvascular complications cannot, or will not develop nephropathy.  How good has the glycaemic control been over the years?  If there is a long history of poor glycaemic control with chronically high HbA1c then development of microvascular complications such as nephropathy is more likely than if control has generally been very good.  Has the patient been feeling non specifically unwell, experiencing pruritus, anorexia and weight loss?  These may be symptoms of uraemia, but the renal impairment should normally be picked up long before the patient develops these symptoms by the deterioration on the annual eGFR. Ian Gallen

 It is essential to ensure that a patient with deteriorating renal function is not on potentially nephrotoxic drugs such as non steroidal anti inflammatory agents.  If there has been a sudden step-wise deterioration in renal function check changes in medication or X-ray contrast invsetigations  eGFR is <30 ml/min, metformin therapy should be withdrawn. Ian Gallen

1American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004

 Hypertension Control - Goal: lower blood pressure to <130/80 mmHg Antihypertensive agents  Angiotensin-converting enzyme (ACE) inhibitors  captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, trandolapril, moexipril  Angiotensin receptor blocker (ARB) therapy  candesartan cilexetil, irbesartan, losartan potassium, telmisartan, valsartan, esprosartan  Beta-blockers Ian Gallen

Glycaemic targets Inidividualised 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. Ian Gallen

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, 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. Ian Gallen

 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 Ian Gallen

There are three primary treatment options for individuals who experience ESRD: 1. Hemodialysis 2. Peritoneal Dialysis 3. Kidney Transplantation Ian Gallen

 Procedure A fistula or graft is created to access the bloodstream Wastes, excess water, and salt are removed from blood using a dialyzer Hemodialysis required approx. 3 times per week, each treatment lasting 3-5 hrs Can be performed at a medical facility or at home with appropriate patient training Ian Gallen

 Hemodialysis Diet Monitor protein intake Limit potassium intake Limit fluid intake Avoid salt Limit phosphorus intake  Complications Infection at access site Clotting, poor blood flow Hypotension Ian Gallen

 Procedure Dialysis solution is transported into the abdomen through a permanent catheter where it draws wastes and excess water from peritoneal blood vessels. The solution is then drained from the abdomen. Three Types of Peritoneal Dialysis  Continuous Ambulatory Peritoneal Dialysis (CAPD)  Continuous Cycler-Assisted Peritoneal Dialysis (CCPD)  Combination CAPD and CCPD Ian Gallen

 Peritoneal Dialysis Diet Limit salt and fluid intake Consume more protein Some potassium restrictions Reduce caloric intake  Complications Peritonitis Ian Gallen

 Procedure A cadaveric kidney or kidney from a related or non-related living donor is surgically placed into the lower abdomen. Three factors must be taken into consideration to determine kidney/recipient match:  Blood type  Human leukocyte antigens (HLAs)  Cross-matching antigens Ian Gallen

 Kidney Transplant Diet Reduce caloric intake Reduce salt intake  Complications/Risk Factors Rejection Immunosuppressant side effects  Benefits No need for dialysis fewer dietary restrictions higher chance of living longer Ian Gallen

 Maintain blood pressure <130/80 mm/Hg  Maintain preprandial plasma glucose mg/dl  Maintain postprandial plasma glucose <180 mg/dl  Maintain A1C <7.0% Ian Gallen

American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004 National Kidney and Urologic Diseases Information Clearinghouse. Kidney Disease of Diabetes. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS; United States Renal Data System. USRDS 2003 Annual Data Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS; DeFronzo RA: Diabetic nephropathy: etiologic and therapeutic considerations. Diabetes Reviews 3: , 1995 National Kidney and Urologic Diseases Information Clearinghouse. Kidney Failure: Choosing a Treatment That’s Right For You. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), DHHS; Ian Gallen