Kidney disease in people with diabetes Ian Gallen
Why is it important 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
Increased risk of renal replacement therapy for people with diabetes in Berkshire West (E+W average is 164%) CCG Excess over not diabetic Excess number of people Newbury 106% +7 Wokingham 247% +16 South Reading 198% +35 North and West Reading 181% +15
Key message Nephropathy in type Type 1 diabetes Nearly always due to hyperglycaemia Strong genetic predisposition Nephropathy in T2DM May be due to hyperglycaemia But often due to other causes particularly inflammation Frequently multi-factorial
Diabetic Nephropathy Diabetic kidney disease is defined by characteristic structural and functional changes. The predominant structural changes include mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis. The major clinical manifestations of diabetic nephropathy are albuminuria, hypertension and less often haematuria, and, in many patients, progressive chronic kidney disease, which can be slowed or prevented with optimal therapy. Diabetic nephropathy can occur in all forms of diabetes mellitus when the duration of diabetes is long-enough and level of glycaemia high enough to result in complications.
Pathology There are three major histologic changes in the glomeruli in diabetic nephropathy: mesangial expansion; glomerular basement membrane thickening; glomerular sclerosis (the Kimmelstiel-Wilson lesion) Other changes seen are hyaline deposits in the glomerular arterioles (infiltration of plasma proteins such as fibrin, albumin, immunoglobulins, and complement into the vascular wall) The mesangial expansion and glomerulosclerosis do not always develop in parallel, suggesting that they may have somewhat different underlying pathogenesis
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
Epidemiology in T1DM Approximately 20 to 30 percent will have microalbuminuria, after a mean duration of diabetes of 15 years Less than half of these patients will progress to overt nephropathy Microalbuminuria may regress or remain stable with good glycaemicand BP control with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). With intensive glycaemic control and the use of ACE inhibitors and ARBs to control BP, patients diagnosed with type 1 diabetes have lower rates of overt nephropathy and renal failure. The onset of overt nephropathy in type 1 diabetes is typically between 10 and 15 years after the onset of the disease. Those patients who have no proteinuria after 20 to 25 years have a low risk of developing overt renal disease.
Epidemiology int2dm The prevalence of progressive renal disease is lower in type 2 diabetes than in type 1 disease, but is higher in some ethnic groups. UKPDS data shows that at 10 years following diagnosis, the prevalence of moderately increased albuminuria, severely increased albuminuria, and either an elevated plasma creatinine concentration (defined as 175 micromol/l [2.0 mg/dl]) or requirement for renal replacement therapy was 25, 5, and 0.8 percent, respectively. The yearly rate of progression from diagnosis to moderately increased albuminuria, from moderately increased albuminuria to severely increased albuminuria, and from severely increased albuminuria to an elevated plasma creatinine concentration or renal replacement therapy was 2.0, 2.8, and 2.3 percent. Median time spent in each stage without progression to another nephropathy stage was 19, 11, and 10 years for those with no nephropathy, moderately increased albuminuria, and severely increased albuminuria, respectively. An creatinine >175 micromol/l]) required renal replacement therapy after a median period of only 2.5 years. This rate of progression is now slower with appropriate therapy (eg, angiotensin inhibition and rigorous blood pressure control)
Mechanism of diabetic kidney disease Glomerular hyperfiltration Hyperglycemia and Advanced Glycation products Hyperglycaemia may directly induce mesangial expansion and injury, perhaps in part via increased matrix production or glycation of matrix proteins Glycation of tissue proteins causes diabetic nephropathy and other microvascular complications by forming irreversible advanced glycation end products (AGEs). Activation of protein kinase C Activation of cytokines, profibrotic elements, inflammation, and vascular growth factors (vascular endothelial growth factor, VEGF)
Aetiolgy 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-κB), and release of inflammatory mediators, including, interleukin (IL) 1β 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.
Formation and effect of advanced glycation endproduct Normal Protein Function None Time
Genetic risk of diabetic nephropathy Genetic susceptibility is an important determinant of both the incidence and severity of diabetic nephropathy with markedly increased in patients with a diabetic sibling or parent who has diabetic nephropathy. The likelihood of the offspring developing overt proteinuria was 14 percent if neither parent had proteinuria, 23 percent if one parent had proteinuria, and 46 percent if both parents had proteinuria. Proposed genes are The angiotensin-converting enzyme (ACE) gene genotype as a potential genetic risk factor with conflicting data: In patients with type 2 diabetes, the DD polymorphism has been associated with an increased risk for the development of diabetic nephropathy. In type 1 diabetes there is strong correlation between genetic variation in the ACE gene and the development of nephropathy T The angiotensin-ii type 2 receptor gene (AT2) on the X-chromosome is associated in males. The aldose reductase gene, the rate-limiting enzyme for the polyol pathway. Variants of the PKCb1 gene have been associated with kidney disease in Chinese patients
Other risks for diabetic nephropathy Duration of diabetes Blood pressure Prospective studies have noted an association between the subsequent development of diabetic nephropathy and higher systemic pressures Poor glycaemic control Diabetic nephropathy is more likely to develop in patients with worse glycaemic control Ethnicity The incidence and severity of diabetic nephropathy are increased in African/Afro-carribean (3- to 6-fold compared to Caucasians), Mexican-Americans, and Pima Indians with type 2 diabetes. This observation in such genetically disparate populations suggests a primary role for socioeconomic factors, such as diet, poor control of hyperglycemia, hypertension, and obesity Obesity A high body mass index (BMI) has been associated with an increased risk of chronic kidney disease among patients with diabetes Smoking Smoking is associated with a variety of adverse effects in patients with diabetes Oral contraceptives
Key question in diagnosis 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 a guide and it is 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 risks of nephropathy, Patients without other microvascular complications can 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 likely
Albuminuria Microalbuminuria Hyperfiltration in very early disease (primarily in type 1 diabetes); moderately increased albuminuria, or "microalbuminuria" (defined as urinary albumin excretion between 30 and 300 mg/day or between 30 and 300 mg/g creatinine on a random urine sample) Macroalbuminuria Is increased albuminuria, (defined as urinary albumin excretion above 300 mg/day or above 300 mg/g creatinine on a random urine sample). Moderately increased albuminuria precedes the development of severely increased albuminuria and is considered to be a finding that predicts high risk for future nephropathy. The onset of severely increased albuminuria is followed by a slowly progressive decline in glomerular filtration rate (GFR) and, given enough time, end-stage renal disease Note some people with diabetes can have progressive kidney disease with little albuminuria
Work-up to confirm DN Urinalysis Persistent albuminuria (>300 mg/d or >200 μg/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.
Drug History 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.
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 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):1703-20. [Medline]. Lancet. Sep 12 1998;352(9131):837-53. [Medline].
Dipeptidyl peptidase inhibitors 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 2.5-5 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):1862-4. Expert Opin Drug Metab Toxicol. May 2013;9(5):529-50.
Sodium-glucose 2 (SGLT2) inhibitors 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.
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 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
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 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.
Dulaglutide protects against declining Renal function
Management of Hypertension 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.
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 (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
Therapeutic targets 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.
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
Treatment of End-Stage Renal Disease (ESRD) There are three primary treatment options for individuals who experience ESRD: 1. Hemodialysis 2. Peritoneal Dialysis 3. Kidney Transplantation
Procedure Hemodialysis 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
Hemodialysis (cont.) 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
Procedure Peritoneal Dialysis 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
Peritoneal Dialysis (cont.) Peritoneal Dialysis Diet Limit salt and fluid intake Consume more protein Some potassium restrictions Reduce caloric intake Complications Peritonitis
Kidney Transplant Procedure A cadaveric kidney or kidney from a related or nonrelated 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
Kidney Transplant (cont.) 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
References 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; 2003. 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; 2003. DeFronzo RA: Diabetic nephropathy: etiologic and therapeutic considerations. Diabetes Reviews 3:510-547, 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; 2003.