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Donna Myers, M.D.
04-30-2010
- Diabetic nephropathy (DN) is one of the common long-term, microvascular complications of diabetes.
- Characterized initially by microalbuminuria (30-300 mg albumin/gram creatinine), then macroalbuminuria ("gross" or "clinical" protinuria) (>300 mg/gram creatinine), followed by elevated BUN and creatinine, and finally end-stage renal disease (ESRD).
- Pathologic changes in the kidney are classically nodular glomerulosclerosis, although histologic changes may include a number of other features.
- Occurs in any form of diabetes mellitus, with a similar prevalence rate of 25%.
- The predictive value of microalbuminuria for progression is strongest in type 1 diabetes
- Microalbuminuria within 10 years of onset of type 1 diabetes almost always progresses; after 16 years of diabetes, the onset of microalbuminuria is less predictive (30% progress).
- For type 2 diabetes the predictive value of microalbuminuria is weaker; 25% of type 2 patients have microalbuminuria at 10 years' duration, but only 20 - 40% will progress to macroalbuminuria.
- Although the outcome for diabetic nephropathy has improved due to improved blood pressure (BP) management and renin angiotensin aldosterone system (RAAS) blockade, despite advances in treatment, the increased prevalence of diabetes has increased the number of diabetic patients with ESRD.
- In type 1 diabetes, if both parents had HTN, there is an increased risk of developing chronic kidney disease (CKD).
- The majority of type 1 diabetes patients with macroalbuminuria have some sign of diabetic retinopathy, but only 47.5% of patients with type 2 diabetes and overt proteinuria have diabetic retinopathy.
- Chronic kidney disease (CKD) is classified by proteinuria and glomerular filtration rate (GFR) in ml/min/1.73 m2 as follows: Stage 1 = persistent proteinuria > 3 months, GFR > 90; Stage 2 = GFR 60 - 89; Stage 3 = GFR 30-59; Stage 4 = GFR 15-29; Stage 5 = GFR < 15.
- Glomerular hyperfiltration (GFR >120) occurs early in 25-50% of patients with diabetes; this triples the risk of developing diabetic nephropathy.
- Microalbuminuria or macroalbuminuria can be diagnosed based on a random urine sample collected for both albumin and creatinine, and confirmed on a different day. Random urine samples provide relatively good approximations of daily albumin excretion; 24 hour urine collections are not routinely used for diagnosis and may be less practical.
- Macroalbuminuria heralds a decline in glomerular filtration rate (GFR); the natural history is progression to end-stage renal disease (ESRD) within 3-5 years.
- Hypertension (HTN), or resting BP > 140/90 mmHg, virtually always occurs early in the course of DN; its absence puts the diagnosis of DN in question.
- Non-diabetic renal disease should be suspected if: < 5 yrs from the onset of diabetes; sudden onset of macroalbuminuria;reduced GFR in the absence of proteinuria; acute renal failure; active urinary sediment; and absence of diabetic retinopathy especially in type 1 diabetes.
- DN and stages 1-2 CKD generally have no symptoms, although HTN may be present.
- Nephrotic syndrome (> 3 grams albuminuria/day) causes renal sodium retention; frothy urine; weight gain with diffuse edema; progression to uncontrolled HTN and heart failure; and nocturia that may disrupt sleep.
- Imaging typically finds normal to large sized kidneys, even with advanced stages of CKD due to DN.
- Urine sediment is nephrotic (bland with lipiduria); microscopic hematuria may be present.
- Anemia, progressive metabolic acidosis, hyperphosphatemia with secondary hyperparathyroidism, and hyperkalemia may be present by stage 3 CKD.
- Late symptoms of uremia include anorexia, weight loss (often masked by fluid retention), early morning nausea, lack of energy and hypersomnolence; a metallic taste may be noted.
- With slowly progressive CKD, symptoms are indolent and the patient may be unaware of them.
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Dialysis generally indicated earlier with DN diabetes vs. other causes of ESRD, (i.e. when GFR is 10-15 ml/min vs. <10 ml/min) because of co-morbidities such as cardiovascular disease.
- Evaluate for diabetic retinopathy and other comorbidities (e.g. obesity, obstructive sleep apnea).
- Tighter blood glucose control early in the course of diabetes reduces hyperfiltration.
- In the early stages of DN (CKD 1-3) optimizing glycemic control may stabilize or even reverse renal disease; HbA1c of 6-7 % is advised.
- Educate patients about the relationship between poor diabetic control and the potential late complications of DN.
- With CKD stages 4-5, initially there is insulin resistance and worsening glycemic control; later, decreased renal degradation of insulin and hypoglycemia may ensue.
- When approaching ESRD, closely monitor for hypoglycemia and adjust; patients may come off insulin altogether.
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Metformin is contraindicated when GFR <60 or serum creatinine >1.5 mg/dl, because of an increased risk of lactic acidosis.
- Monitor blood pressure (BP) at each clinic visit and at home.
- Target BP <130/80 mmHg.
- Restrict dietary sodium restriction to 100 mM/day ( 2.3 grams), limit alcohol intake, promote weight loss (if needed) and exercise.
- Unilateral or bilateral renal artery stenosis (RAS) often coexists with DN; in CKD stages 1-2, RAS diagnosed with a gadolinium-enhanced Magnetic Resonance Angiography but in CKD stages 3-5, Doppler flow studies of the renal arteries or an unenhanced MRA useful.
- Most hypertensive diabetic patients will require multiple anti-HTN agents to achieve BP goals; thiazides or loop diuretics may be first-line therapy for many patients.
- RAAS blockade using angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARBs) is useful for both BP and proteinuria control and indicated for left ventricular systolic dysfunction; drug combinations of ACE-I and ARB may worsen renal outcome and if used, requires close renal monitoring. ACE-I and ARBs are contraindicated in women of child bearing age who are trying to become pregnant, patients prone to dehydration, patients with refractory hyperkalemia, or a rise in serum creatinine > 0.6 mg/dL with initiation of therapy.
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Beta-blockers are beneficial, especially in patients with a history of congestive heart failure but should be avoided in all patients with asthma.
- Calcium channel blockers (CCBs), both dihydropyridine (DHP) and non-DHPs, are useful; non-DHPs are more renoprotective but may depress myocardial function. CCBs may cause lower extremity edema and constipation.
- Simplify dosing schedules whenever possible to improve compliance.
- A spot urine albumin to creatinine ratio is recommended to screen for microalbuminuria.
- RAAS blockade should be initiated in type 1 diabetic patients with microalbuminuria with or without hypertension.
- With RAAS blockade, monitor closely to avoid hypotension and dehydration. Check serum potassium and creatinine levels at baseline and 7-10 days after initiation of therapy or an increase in dosage.
- Titrate RAAS blockade if microalbuminuria progresses, as blood pressure allows.
- Macroalbuminuria management is similar to that of microalbuminuria management; however, dietary sodium restriction is usually necessary at this stage, < 100 mM/day (< 2.3 grams).
- RAAS blockade in patients who have diabetes but no proteinuria is controversial; it may improve cardiovascular outcomes but actually worsen renal outcomes.
- Modest dietary protein reduction for CKD stages 4-5, 0.8 grams/kg but not in advanced CKD.
- At all stages of CKD, avoid high protein, weight reduction diets.
- High protein intake in CKD is associated with glomerular hyperfiltration, increased azotemia, metabolic acidosis and fatigue.
- Dietary counseling with reduction of processed foods and salt.
- Fluid retention is treated initially with dietary sodium restriction to < 2 grams/day.
- Diuretics should be used only if diet fails to manage edema.
- In early CKD (stages 1-2) thiazide diuretics are used; in CKD stages 3-5, loop diuretics (furosemide) preferred, and may require a twice daily dosing schedule .
- For comfort, avoid diuretics in the evening.
- Patients should elevate their legs (hip height) when sitting and after taking diuretics to reduce swollen legs.
- Support stockings during day and before getting out of bed in the morning may enhance diuretics and reduce risk of skin breakdown and infection.
- Serum electrolytes, creatinine and blood urea nitrogen should be monitored closely in all patients on diuretics.
- Mild pre-renal azotemia may be tolerated but severe pre-renal failure should be avoided.
- The National Kidney Foundation website is a resource for patient education (reference below).
- Early referral to nephrology lowers morbidity, promotes more timely placement of dialysis access, preemptive renal transplantation, lower overall costs, and improved survival.
- Late referral in general means by CKD stage 3.
- Check urine microalbumin annually beginning in type 1 diabetes after 5 years, and from the onset of type 2 diabetes; ; a positive finding requires confirmation.
- Check BP with each clinic visit; for orthostatic symptoms, check in supine, sitting and standing positions
- With known DN with CKD stages 1-2, monitor renal function at least every 6 months.
- With known DN with CKD stages 3-5 monitor every 3 months including serum electrolytes (sodium, potassium, chloride, CO2), bone-mineral balance (calcium, phosphorus, intact PTH), nutrition (serum albumin, urea nitrogen), anemia (Hgb, Hct, iron studies) along with an estimate of GFR (serum creatinine) and spot urine microalbumin.
- Stage 3 CKD requires referral to a nephrology consultant.
- In early DN (stages 1-2 CKD), goal is reversal of disease, achieved by tight glycemic control, BP management and RAAS blockade, especially in type 1 diabetes.
- With intermediate diabetic nephropathy (stages 3-4 CKD) goal is slowing progression by meticulous attention to known therapeutic interventions and avoidance of nephrotoxins.
- With late diabetic nephropathy (stage 5 CKD), goal is the avoidance of acute or chronic kidney disease (e.g. by contrast studies) and smoothing the transition to maintenance dialysis or transplantation in a timely manner.
- Referral to nephrology should be made by stage 3 CKD to evaluate for other causes of CKD, educate regarding management options for ESRD, arrange referral to vascular surgery for access planning, and plan for the possibility of preemptive renal transplantation.
- Potentially reversible comorbidities such as obstructive sleep apnea, cigarette smoking, morbid obesity, hyperlipidemia, RAS, bladder outlet obstruction with associated hydronephrosis and/or infection, and ongoing exposure to nephrotoxins (e.g. NSAIDs) should be addressed in all stages of DN.
- Patients considering pregnancy should be taken off RAAS blockade. Diabetic nephropathy may worsen during pregnancy, sometimes irreversibly.
- KDOQI;
KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.;
Am J Kidney Dis;
2007; Vol.
49; pp.
S12-154;
ISSN:
1523-6838;
PUBMED: 17276798
Rating:
Basis for recommendation
Comments:The Kidney Disease Outcomes Quality Initiative (K/DOQI) has published this comprehensive reference text for the clinician involved in managing diabetic patients with chronic kidney disease. Reviews national (USA) guidelines for management and the rationale for these therapies.
- Chobanian AV, Bakris GL, Black HR, et al.;
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.;
JAMA;
2003; Vol.
289; pp.
2560-72;
ISSN:
0098-7484;
PUBMED: 12748199
Rating:
Basis for recommendation
Comments:A landmark report outlining stricter guidelines for blood pressure control.
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