Diabetic Nephropathy

Chapter: Diabetic Nephropathy
McMaster Section Editor(s): Juan P. Brito, Victor M. Montori
Section Editor(s) in Interna Szczeklika: Barbara Jarząb, Ewa Płaczkiewicz-Jankowska
McMaster Author(s): René Rodríguez-Gutiérrez, Dania Quintanilla-Flores, Anally J. Soto-Garcia, Jose G. Gonzalez-Gonzalez
Author(s) in Interna Szczeklika: Jacek Sieradzki, Ewa Płaczkiewicz-Jankowska
Additional Information

Etiology, Pathogenesis, ClassificationTop

The development of diabetic nephropathy depends on the duration of diabetes mellitus, severity of metabolic disturbances, coexisting hypertension, and genetic factors. It is caused by changes in the basal membrane, which lead to a decrease in its negative charge and increase in the pore size. Concurrently, high blood glucose levels and blood pressure increase the intraglomerular pressure. As a result, albumin filtration is increased, initially in the form of albuminuria of 30 to 300 mg/24 hours or equivalent 30 to 300 mg/g creatinine in a random urine sample (albumin-to-creatinine ratio [ACR] 3-30 mg/mmol) and then overt proteinuria >300 mg/24 hours or >300 mg/g creatinine (ACR >30 mg/mmol); according to the current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, the use of the term “microalbuminuria,” corresponding to an ACR between 3 and 30 mg/g, has been discouraged. Over time, this leads to glomerular hyalinosis, fibrosis of the interstitial tissue, and development of renal failure. The clinical classification of diabetic nephropathy includes 4 key stages:

1) Asymptomatic nephropathy (corresponding to stages 1 and 2 of the Mogensen classification, also referred to as the classification of the natural history of diabetic nephropathy) (Table 5.2-12).

2) Albuminuria (30-300 mg/24 h; corresponding to stage 3 of the Mogensen classification).

3) Overt proteinuria (urinary albumin excretion >300 mg/24 hours or >300 mg/g creatinine in a random urine sample; corresponding to stage 4 of the Mogensen classification).

4) Renal failure (corresponding to stage 5 of the Mogensen classification). The dynamics of renal failure does not always correspond to the rate of worsening of proteinuria.

Other urinary system disorders that are more frequent in patients with diabetes include recurrent urinary tract infections (neurogenic bladder is a risk factor), acute renal cortical necrosis, and tubulopathies.

DiagnosisTop

Chronic kidney disease is defined as abnormalities of kidney structure or function present for >3 months with implications for health (Table 5.2-13).

Diagnostic Tests

In patients without overt albuminuria, the key screening test is the measurement of urinary albumin excretion (Table 5.2-14). Albuminuria is diagnosed if the results of at least 2 out of 3 measurements performed within 6 months are positive. Serum creatinine should be used to calculate the estimated glomerular filtration rate (eGFR).

Perform the screening test for albuminuria in patients with type 1 diabetes within 5 years of establishing the diagnosis and in patients with type 2 diabetes at the time of diagnosis. Repeat follow-up tests for albuminuria and serum creatinine measurements annually. Screening for kidney damage (albuminuria) can be most easily performed by measuring the urinary ACR using a random spot urine collection. Measurement of a spot urine sample for albumin alone without simultaneously measuring urine creatinine is less expensive but susceptible to false-negative and false-positive determinations as a result of variations in the urine concentration due to hydration. Two of 3 specimens used for the urinary ACR collected within 3 to 6 months should yield abnormal results before the patient is considered to have albuminuria.

Prevention and TreatmentTop

1. For both type 1 and type 2 diabetes, try to achieve and maintain diabetes control according to appropriate criteria (see Diabetes Mellitus); this is of key importance for reducing the risk and delaying the development of nephropathy and may even result in reversal of its early stages. Target levels of glycated hemoglobin (HbA1c) are <7.0% (53 mmol/mol) for primary prevention, especially in patients with type 1 diabetes. Aim at HbA1c <8.0% when the eGFR is <60 mL/min/1.73m2 due to the increased risk of hypoglycemia with more intensive treatment. Doses of insulin and other injectable and oral medications used to lower blood glucose levels often need to be reduced at that eGFR level.

2. In patients with albuminuria of 30 to 300 mg/24 hours, an ACR of 30 to 300 mg/g in a random urine sample, or overt proteinuria and blood pressure not meeting the target level (130/80 mm Hg), use an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blockerEvidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to indirectness and inconsistency. Wilmer WA, Hebert LA, Lewis EJ, et al. Remission of nephrotic syndrome in type 1 diabetes: long-term follow-up of patients in the Captopril Study. Am J Kidney Dis. 1999 Aug;34(2):308-14. PubMed PMID: 10430979. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Remission and regression in the nephropathy of type 1 diabetes when blood pressure is controlled aggressively. Kidney Int. 2001 Jul;60(1):277-83. PubMed PMID: 11422762. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9. PubMed PMID: 11565518. (do not combine these two drug classes). In patients who tolerate these agents poorly, hypertension may be treated with other drugs, for example, nondihydropyridine calcium channel blockers or thiazide-type diuretics.

3. Treat dyslipidemia using a statin. There are no specific target goals for low-density lipoprotein cholesterol. Consider measuring lipids to assess adherence to the medication regimen. A reduced statin dose is recommended in patients with an eGFR <60 mL/min/1.73 m2 (see Chronic Kidney Disease). The initiation of statin therapy has not been shown to be beneficial in patients undergoing chronic dialysis treatment.

4. For patients with non–dialysis-dependent diabetic kidney disease, the suggested dietary protein intake is the same as in the general population—approximately 0.8 g/kg of body weight per day (usual recommended daily allowance)—and sodium intake could be restricted to 50 to 100 mmol/day. Reducing the amount of dietary protein below the recommended daily allowance of 0.8 g/kg/day is not recommended because it does not alter glycemic control, cardiovascular risk, or glomerular filtration rate (GFR) decline.

Of note, considering some uncertainty regarding the effects of dietary protein intake, any restriction below the normal intake should be limited to highly motivated, well-nourished patients with access to a wide variety of foods and expert dietary supervision following a discussion of the uncertain effectiveness of this intervention.

5. Educate the patient about the need to avoid nephrotoxic substances, smoking cessation, and maintaining a recommended body weight.

6. When diagnosing renal failure (GFR <60 mL/min/1.73 m2), our pattern of practice is to refer the patient to a nephrologist. More conservative criteria for referral and principles of chronic kidney disease treatment: see Chronic Kidney Disease.

TablesTop

Table 5.2-12. Mogensen classification of diabetic nephropathy and its course

Diabetes duration

Stage

Clinical features

Prognosis

Since disease onset

1: Increased GFR, renal hypertrophy

GFR increased to 160 mL/min, kidney enlargement

Potentially reversible

2-5 years

2: Onset of histologic changes, altered structure and function of basement membrane

Thickening and altered electrical charge of basement membrane, enlarged mesangium, no albuminuria

May be partially reversible

5-10 (15) years

3: Early clinical nephropathy

Albuminuria 30-300 mg/24 h, GFR reduced from 160 to 130 mL/min, elevated blood pressure

Lesion progression may be stopped, sometimes reversible

10 (15)-25 years

4: Overt nephropathy

Persistent proteinuria (measured using standard methods), GFR decreased to 70 mL/min and later to 10 mL/min, sustained hypertension, edema, dyslipidemia

Lesion progression may be slowed and sometimes stopped

>15 years

5: Renal failure

Elevated serum creatinine, hypertension

Irreversible progression to end-stage renal failure

Based on Diabetes. 1983;32 Suppl 2:64-78.

GFR, glomerular filtration rate.

Table 5.2-13. Glomerular filtration rate (GFR) categories in chronic kidney disease

GFR category

GFR (mL/min/1.73m2)

Terms

1

≥90

Normal or high

 

2

60-89

Mildly decreased

 

3a

45-59

Mildly to moderately decreased

 

3b

30-44

Moderately to severely decreased

 

4

15-29

Severely decreased

 

5

<15

Kidney failure

 

Adapted from: Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter., Suppl. 2012; 2: 1–138.

Table 5.2-14. Albuminuria categories according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines

Parameter

Category

Normal to mildly increased

Moderately increased

Severely increaseda

Albumin-to-creatinine ratiob

mg/g

<30

30-300

>300

mg/mmol

<3

3-30

>30

Urinary albumin excretion rate (mg/24 h)c

<30

30-300

>300

Protein-to-creatinine ratiob

mg/g

<150

150-500

>500

mg/mmol

<15

15-50

>50

Urinary protein excretion rate (mg/24 h)c

<150

150-500

>500

Urine dipstick test for proteind

Negative or trace

Trace or +

+ or more

a Nephrotic proteinuria is diagnosed in patients with an albumin-to-creatinine ratio >2200 mg/g (>2200 mg/24 h) or a protein-to-creatinine ratio >3000 mg/g (>3000 mg/24 h).

b In the first morning urine sample or a random urine sample. The assumed average urinary creatinine excretion rate is 1 g/24 h or 10 mmol/24 h.

c In 24-hour urine.

d The results of the dipstick test depend on urine specific gravity.

Based on: Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Inter., Suppl. 2012; 2: 1-138.

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