Diabetic Nephropathy diagnosis & Treatment Dr. Firouzeh Moeinzadeh Assistant Professor of Nephrology Isfahan University of Medical Sciences

Definition of diabetic kidney disease Clinical course Diagnosis and Detection of Microalbuminuria Approach to cases Other consideration in treatmnt Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Definition of diabetic kidney disease Approximately 20% to 40% of patients with type 1 or type 2 diabetes mellitus develop diabetic kidney disease Persistent albuminuria (> 300 mg/24 h, or > 300 mg/g creatinine) confirmed in at least 2 of 3 samples, a relentless decline in glomerular filtration rate (GFR), raised arterial blood pressure, and enhanced cardiovascular morbidity and mortality. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Risk factors Poor glycaemic control Hyperlipidaemia Hypertension Genetic predisposition Ethnicity Long disease duration Smoking There are a number of risk factors that make people with diabetes more prone to renal disease, including those listed in the slide. Poor glycaemic control – there is plenty of evidence for this from the DCCT and UKPDS and their respective follow-up studies. People with hypertension or a family history of hypertension are more likely to develop renal disease than people without a family history of hypertension or renal disease. Some people at the onset of diabetes have increased glomerular filtration, known as hyper-filtration. It seems that these people are also more likely to develop renal disease. People of certain ethnicities are more likely to develop the disease, such as Afro-Caribbean people, Pacific Islanders and Pima Indians. Not surprisingly, the longer you have diabetes, the higher the risk of renal disease. Tobacco smoking damages the blood vessels and endothelial cells and induces hyperglycaemia, increasing the risk of renal disease. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Natural history of diabetic nephropathy Acute renal hypertrophy-hyperfunction Normoalbuminuria 10 to 15 years Microalbuminuria (incipient diabetic nephropathy) When we look at the natural history of diabetes, even at the onset a biopsy of the kidney shows some changes including thickening of the basement membrane. Kidney function reverts to normal and there is a period of normoalbuminuria. Microalbuminuria usually develops towards the end of the first decade (in type 1 diabetes). And if this is left untreated, overt diabetic nephropathy and subsequent renal failure will ensue. Proteinuria (clinical overt diabetic nephropathy) Chronic renal failure Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Clinical course The first clinical sign is moderately increased urine albumin excretion (microalbuminuria: 30–300 mg/24 h, or 30–300 mg/g creatinine; albuminuria grade A2). Untreated microalbuminuria will gradually worsen, reaching clinical proteinuria or severely increased albuminuria (albuminuria grade A3) over 5 to 15 years. GFR then begins to decline, and without treatment, end-stage renal failure is likely to result in 5 to 7 years Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Newly diagnosed, predominantly white, medically treated Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRD The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics) Newly diagnosed, predominantly white, medically treated No albuminruia 1.4% 2.0% C V D E A T H Microalbuminruia 3.0% 2.8% Macroalbuminruia 4.6% 2.3% Elevated Serum Creatinine 19% Diabetic nephropathy Dr. F. Moeinzadeh 10/21/1395

Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Mean reduction in GFR is between 2-20 ml/ min per 1.73 m2. In patients with microalbuminuria ,reductin in kidney function is variable. Mean reduction in GFR is between 2-20 ml/ min per 1.73 m2. Kiney involvement process is stage to stage and microalbuminuria is potentially reversible . but effective treatment targeting glycemia, control of blood pressure, RAS, reduction of blood cholesterol levels, and improving lifestyle factors can limit progression to 2 to 5 ml/min per 1.73 m2 per year, In diabetic patients, ,microalbuminuria is a risk marker for cardiovascular mortality and morbidity. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diagnosis and Detection of Microalbuminuria Establishing the diagnosis of microalbuminuria requires the demonstration of an elevation in albumin excretion in 2 of 3 spot urine samples that persists over a three- to six-month period. In this period, microalbuminuria should be positive in 2 or more than 2 tests . Urinary albumin excretion may be elevated independent of kidney disease by factors such as severe exercise within 24 hours, severe UTI, menstruation, fever, heart failure, and marked hyperglycemia. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diagnosis and Detection of Microalbuminuria 24-hour urine collection: the initial gold standard Screening can be more simply achieved by a timed urine collection or measurement of the urine albumin concentration on an early morning Complete collection is often difficult, and so this method is usually restricted to those with established diabetic kidney disease Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Urine albumin-to-creatinine ratio An untimed urinary sample The preferred screening strategy for microalbuminuria in all diabetics. Advantages: it gives a quantitative result that correlates with the 24-hour urine values over a wide range of protein excretion It is simple to perform and inexpensive, and repeat values can be easily obtained to ascertain that microalbuminuria, if present,is persistent. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Limitations of urine albumin to creatinin ratio -The optimal time to measure the urine albumin-to-creatinine ratio is uncertain. A slight preference for first morning void specimens. If this is inconvenient, specimens can be obtained at other times during the day. The timing of repeat measurements: preferable to obtain the samples at approximately the same time of day. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

24h albumin excretion rate Spot urinary microalbumin Alb/ Cr ratio Microalbuminuria 30-299 mg/24h 30-299 mg/L 30-299 mg/g Macroalbuminuria ˃ 300 mg/24h ˃ 300 mg/L ˃ 300 mg/g Diabetic nephropathy Dr. F. Moeinzadeh 10/21/1395

Screening for microalbuminuria in diabetes Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Case 1 A 52-year-old woman with T2DM diagnosed 1 year ago is referred to you for evaluation of proteinuria noted first 3 months ago. Family history is positive for diabetic nephropathy. Physical examination shows BP of 140/95 mm Hg and normal fundal examination findings and is otherwise unremarkable. Creatinine concentration of 0.9 mg/dL, and urinalysis shows protein (3+) with unremarkable sediment. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Which of the following statements is correct? a) The finding of proteinuria 6 months after the diagnosis of T2DM is strongly against the diagnosis of diabetic nephropathy. b) Normal fundal examination findings should strongly suggest an alternative diagnosis. c) The most likely diagnosis is diabetic nephropathy. d) Increases in BP in the majority of patients with diabetic nephropathy are seen only after decline in kidney function. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Natural history of microalbuminuria in diabetes mellitus The development of significant albuminuria before 5 years’ or after 25 years’ duration of T1DM decreases the likelihood of diabetic nephropathy. The onset of T2DM is generally unknown, one cannot as reliably use the natural history timeline to assist in diagnosis Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diabetic Nephropathy AND Diabetic Retinopathy 95% of patients with T1DM and diabetic nephropathy also have diabetic retinopathy, so the absence of retinopathy may imply a diagnosis other than diabetic nephropathy Diabetic retinopathy is concordant with diabetic nephropathy in only about 60% to 65% of cases; thus, its absence does not generate a high negative predictive value for the diagnosis of diabetic nephropathy. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diabetic retinopathy evaluation Seven-field fundus photos must be obtained to eliminate the presence of retinopathy and prompt kidney biopsy because a dilated ophthalmologic examination is insensitive. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Which of the following statements is correct? a) The finding of proteinuria 6 months after the diagnosis of T2DM is strongly against the diagnosis of diabetic nephropathy. b) Normal fundal examination findings should strongly suggest an alternative diagnosis. c) The most likely diagnosis is diabetic nephropathy. d) Increases in BP in the majority of patients with diabetic nephropathy are seen only after decline in kidney function. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Treatment of Diabetic Nephropathy Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: Cardiovascular risk reduction Glycemic control BP control Inhibition of the RAS Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Cardiovascular Risk Reduction Aggressive risk factor modification is undertaken, usually in partnership with the patient’s primary care physician. tobacco cessation lipid-lowering therapy Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Smoking cessation In both type 1 & 2 -It affects renal Hemodynamics, increases Catecholamines production. Patients With DM I & II who smoke have a greater risk of Urine albuminuria, and progression to ESRD is about twice as rapid than non-smokers. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Lipid lowering therapy Hypercholesterolaemia in progressive glomerular injury Reduction in cholesterol: reduce the rate of decline of GFR Reduction of AER in normotensive ,microalbuminuric type 2 diabetic patients has also observed on statin therapy. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Glycemic control A 48-year-old obese woman with T2DM presents to your office for follow-up. She is presently using metformin, 500 mg, twice daily and lisinopril, 20 mg, daily. BP is 130/74 mm Hg and physical examination findings: NL Potassium: 4.7 mEq/L, serum creatinine:0.9 mg/dL albumin-creatinine ratio, 400 mg/g , HbA1c: 9.1%. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Based on the evidence, what should the goal HbA1c concentration be for this patient? a) As close to 6% as possible. b) Around 7%. c) Between 8% and 9%. d) There is no relationship between HbA1c and microvascular outcome. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Last 3 trials established increased risk for hypoglycemic events related to intensive glycemic control to HbA1c concentrations of near 6.0%. Intensive glycemic control to an HbA1c concentration of 7.0% prevents microvascular (not macrovascular) complications (UKPDS). However, it is unclear whether any further HbA1c concentration reduction is of utility, particularly for preventing kidney disease outcomes. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Based on the evidence, what should the goal HbA1c concentration be for this patient? a) As close to 6% as possible. b) Around 7%. c) Between 8% and 9%. d) There is no relationship between HbA1c and microvascular outcome. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Case 3 A 52-year-old white man with T2DM complicated by retinopathy, neuropathy, and stage 3 CKD due to diabetic nephropathy comes in to your office for routine follow-up care. He is presently treated with insulin and Valsartan, 80 mg, daily. BP is 150/95 mm Hg and the rest of the examination: NL Potassium, 4.7 mEq/L; serum creatinine, 1.5 mg/dL; albumin-creatinine ratio, 800 mg/g; and HbA1c, 7.1%. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Based on the evidence, what should the goal BP be for this patient? a) Although lower BP decreases cardiovascular events, it has no impact on clinically meaningful renal outcomes. b) Less than 140/90 mm Hg. c) As low as tolerated, but > 110/70 mm Hg. d) It depends on the patient’s age, with a goal of <150/ 95 mm Hg in patients older than 65 years. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

BP control is of paramount importance Cardiovascular and kidney event rates are higher with increasing BP and are reduced progressively with therapy to lower BP. BP control is of paramount importance The current KDOQI guideline recommends a goal BP < 130/80 mm Hg, whereas the JNC 8 guidelines recommend a goal BP < 140/90 mm Hg for most patients with T2DM and diabetic nephropathy, but with individualization Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Based on the evidence, what should the goal BP be for this patient? a) Although lower BP decreases cardiovascular events, it has no impact on clinically meaningful renal outcomes b) Less than 140/90 mm Hg c) As low as tolerated, but > 110/70 mm Hg d) It depends on the patient’s age, with a goal of <150/ 95 mm Hg in patients older than 65 years Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Case 4 A 45-year-old has had T2DM for 7 years and it has been well controlled. Hypertension for the past 5 years, and it has been under good control. BP is 135/75 mm Hg. Physical examination notable for lower-extremity edema (1+) to the mid-shin. Findings are otherwise unremarkable. Drug history: metformin, 1,000 mg, twice daily and chlorthalidone, 25 mg, daily. Potassium, 4.1 mg/dL; serum creatinine, 1.3 mg/dL; albumin-creatinine ratio, 1,257 mg/g; and HbA1c, 6.9%. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

What should be added to his regimen to slow the progression of diabetic nephropathy? a) Add an ARB to the regimen with goal of decreasing proteinuria. b) His BP is well controlled, so continue on the same regimen. c) Switch chlorthalidone to furosemide, given the elevated creatinine concentration. d) Add both an ARB and an ACE inhibitor, with the goal of decreasing proteinuria to protein excretion < 300 mg/d. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

RAS blockade using various drugs, including ACE inhibitors, ARBs, direct renin inhibitors, and mineralocorticoid antagonists. RAS inhibition has proved to be the single most effective therapy for slowing the progression of diabetic nephropathy Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Efficacy of ACE inhibitors independent of BP control in slowing the progression of diabetic nephropathy in patients with T1DM and overt proteinuria. Although RAS blockade with more than 1 agent may be effective in reducing proteinuria, the adverse-event profile (hyperkalemia, acute kidney injury, and increased cardiovascular events) and no benefit in preventing end-stage kidney disease preclude its general use for the treatment of diabetic nephropathy. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

When I use ACEIs/ARBs in diabetic nephropathy? There is no evidence that ACE inhibitors or ARBs are effective for the primary prevention of microalbuminuria in patients with type 1 diabetes who are normoalbuminuric and normotensive. These patients should be screened yearly for microalbuminuria after five years and angiotensin inhibition initiated if persistent microalbuminuria is documented Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Studies in normoalbuminuric normotensive patients with type 2 diabetes are fewer but also show no benefit. For normoalbuminuric patients with type 2 diabetes and hypertension, or pre-existing CVD, use of ACE-Is with or without diuretics reduces the absolute risk of developing microalbuminuria by 2-4% over 4-5 years. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

We suggest using an ACE-I or an ARB in normotensive patients with diabetes and albuminuria levels >30 mg/g who are at high risk of DKD or its progression. (2C) Diabetic nephropathy Dr. F. Moeinzadeh 10/21/1395

What should be added to his regimen to slow the progression of diabetic nephropathy? a) Add an ARB to the regimen with goal of decreasing proteinuria. b) His BP is well controlled, so continue on the same regimen. c) Switch chlorthalidone to furosemide, given the elevated creatinine concentration. d) Add both an ARB and an angiotensin-converting enzyme (ACE) inhibitor, with the goal of decreasing proteinuria to protein excretion < 300 mg/d. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Other considerations Most sympathetic blockers and dihydropyridine CCB do not have significant antiproteinuric action despite effective blood pressure reduction, unlike nondihydropyridine CCB. Only diltiazem and verapamil appear to be as consistently effective as an ACE inhibitor or ARB in lowering protein excretion in diabetic patients Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Aldosterone antagonists appear to reduce proteinuria when used alone, and to have an additive effect on proteinuria when used in combination with an ACE inhibitor or an ARB in both type 1 and type 2 diabetes. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Glucagon-like peptide 1 receptor agonists GLP 1 receptor agonists are among the new glucose lowering agents with pleiotropic effects with a potential benefit on the kidney. Short-term studies demonstrated reduction in albuminuria up to up to 30 % with the glucagon-like peptide1 receptor agonist liraglutide. In addition to the glucose lowering effect, beneficial effects on blood pressure, body weight, inflammation and perhaps reduction in intraglomerular pressure, have been suggested as explanatory factors. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Sodium glucose transporter 2 inhibitors SGLT2 inhibitors have also been suggested to have favorable renal effects in addition to lowering of glucose. They lower blood pressure, albuminuria and body weight. Hyperfiltration was ameliorated with empagliflozin in type 1 diabetes and may be very important for the potential renoprotective effect of this class of agents . Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Reduction in protein intake Strong evidence indicates that high dietary protein intake increases risk of diabetic Nephropathy & its progression to ESRD. Lower intake of proteins has a lower incidence of albuminuria. It reduces Hyperfiltration & intraglomerular pressure. ADA recommends 0.8 gr/kg in diabetic nephropathy. Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Additional Therapeutic Considerations Insulin therapy: as kidney function decreases, insulin lasts longer, putting patients at risk for hypoglycemic episodes. Metformin in contraindicated in patients with eGFRs < 30 mL/min/1.73 m2 Consider dose adjustments for drugs. Increased risk for developing acute kidney injury from iodinated radiocontrast administration, volume depletion, or nonsteroidal anti-inflammatory drug use. Diabetes is also a known risk factor for arteriovenous fistula maturation failure. As with all patients with stage 4 CKD, dialysis access planning is vitally important Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397

Diabetic Nephropathy, Diagnosis & Treatment Dr. F. Moeinzadeh 09/08/1397