Diabetic Kidney Disease

Chapter: Diabetic Kidney Disease
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 L. 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 kidney disease (DKD) depends on the duration of diabetes mellitus (DM), severity of metabolic disturbances, coexisting hypertension, and genetic factors. DKD is present in up to 25% to 40% of patients with DM, and some of them develop end-stage kidney disease requiring renal replacement therapy. 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). Over time, this leads to glomerular hyalinosis, fibrosis of the interstitial tissue, and development of renal failure. Moreover, the presence of renal failure in patients with DM has been related to increases in cardiovascular risk and health-care costs.

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. Additionally, DKD is preferred over diabetic nephropathy because DM studies are often observational and lack biopsy data to prove involvement of lesions.

Major risk factors for the development of DKD include ethnicity, male sex, family history, gestational DM, hypertension, dyslipidemia, obesity, and insulin resistance, as well as elevated glycated hemoglobin (HbA1c) level, elevated systolic blood pressure, inflammation, hypovitaminosis D, proteinuria, and smoking.

The clinical classification of DKD 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 h 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 DM include recurrent urinary tract infections (neurogenic bladder is a risk factor), acute renal cortical necrosis, and tubulopathies.

DiagnosisTop

Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for >3 months with implications for health (Table 5.2-13). DKD is diagnosed when albuminuria, reduced estimated glomerular filtration rate (eGFR), or other manifestations of CKD are detected in patients with DM in the absence of other primary causes of renal failure.

Diagnostic Tests

All patients should have eGFR and albuminuria measurement for staging and to guide treatment decisions. In patients without overt proteinuria, the key screening test is the measurement of 24-hour urinary albumin excretion or its equivalent ACR (Table 5.2-14). 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. Serum creatinine should be used to calculate eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (see Chronic Kidney Disease).

Screening for kidney damage 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 urine concentration due to hydration. Some factors that may elevate the urinary ACR ratio (independently of kidney damage) include infection, marked hyperglycemia, congestive heart failure, exercise within 24 hours, fever, menstruation, and marked hypertension.

Perform the screening test for albuminuria and eGFR in patients with type 1 DM within 5 years of establishing the diagnosis, in all patients with type 2 DM at the time of diagnosis, and in all patients with comorbid hypertension. Repeat follow-up tests for albuminuria and serum creatinine measurements annually (or earlier if needed) to enable a timely diagnosis of CKD, monitor the progression of CKD, detect superimposed kidney diseases, assess the risk of CKD complications, dose drugs appropriately, and determine whether nephrology referral is needed. All patients with CKD stages 3 to 5 should undergo evaluation for renal failure complications.

Prevention and TreatmentTop

1. Careful individualized targets of glycemic control, medication prescription, patient education, therapeutic planning, and vigilance for hypoglycemia are all important in the management of patients with DKD. For both type 1 and type 2 DM optimize glucose levels to achieve and maintain DM 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 HbA1c are <7.0% (53 mmol/mol) for primary prevention, especially in patients with type 1 DM. Aim at an HbA1c <8.0% when eGFR is <60 mL/min/1.73m2 because of the increased risk of hypoglycemia with more intensive treatment. Doses of insulin and other injectable and oral glucose-lowering medications often need to be reduced or suspended at these eGFR levels. In the presence of established CKD, consider the use of a sodium-glucose cotransporter 2 (SGLT-2) inhibitor or glucagon-like peptide 1 (GLP-1) receptor agonist with proven efficacy in reducing the risk of CKD progression or cardiovascular events.

2. In patients with hypertension and albuminuria, overt proteinuria, and/or an eGFR <60 mL/min/1.73 m2, use an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB), aiming to maintain a target blood pressure level <140/90 mm HgEvidence 1 Strong 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). Lower blood pressure targets (<130/80 mm Hg) may be considered for patients based on individual anticipated benefits and risks, such as those with stroke or progressive kidney disease. In patients who tolerate these agents poorly, hypertension may be treated with other drugs, for example, nondihydropyridine calcium channel blockers or thiazide-type diuretics. Serum creatinine and potassium levels must be monitored periodically for the development of increased creatinine or hyperkalemia when ACEIs, ARBs, or diuretics are used.

3. Treat dyslipidemia using a statin. There are no specific target goals for low-density lipoprotein cholesterol (LDL-C). Consider measuring lipids to assess adherence to the drug 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. The use of antiplatelet and antithrombotic agents in patients with DKD for the prevention of CKD remains controversial.

4. For patients with non–dialysis-dependent DKD, 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/d. Reducing the amount of dietary protein below the recommended daily allowance of 0.8 g/kg/d 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 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 for the evaluation and management of potential complications of CKD. A suspicion of alternative or additional causes of nephropathy should also be the reason for referral. Other, more conservative criteria for referral and principles of CKD 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/1.73 m2, kidney enlargement (20%) and increase in renal plasma flow (10%-15%), no albuminuria or hypertension

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, mesangial proliferation, normal GFR, no albuminuria, no clinical symptoms

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/1.73 m2, ± HTN

Lesion progression may be stopped, sometimes reversible

10 (15)-25 years

4: Overt nephropathy

Persistent and irreversible proteinuria, GFR <60 mL/min/1.73 m2 and sustained HTN, edema, dyslipidemia

Lesion progression may be slowed and sometimes stopped

>15 years

5: Renal failure

End-stage kidney disease with GFR <15 mL/min/1.73 m2, HTN

Irreversible progression to end-stage renal failure

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

GFR, glomerular filtration rate; HTN, hypertension.

Table 5.2-13. CKD stages in diabetic nephropathy

Stage

eGFR (mL/min/1.73m2)

Evidence of kidney damage

No clinical evidence of CKD

≥60

 

1

≥90

+

 

2

60-89

+

 

3

30-59

+/−

 

4

15-29

+/−

 

5

<15

+/−

 

CKD stages 1-2 are defined by evidence of kidney damage (+), while CKD stages 3-5 are defined by reduced eGFR with or without evidence of kidney damage (+/−). Kidney damage is most often manifest as albuminuria (UACR >30 mg/g) but can also include glomerular hematuria, other abnormalities of urinary sediment, radiographic abnormalities, and other presentations. Focus on kidney-related care: diagnose the cause of kidney injury in stages 1-3, evaluate and treat risk factors for CKD progression in stages 1-4, evaluate and treat CKD complications in stages 3-5, and prepare for RRT in stages 4-5. At any stage of CKD, the degree of albuminuria, observed history of eGFR loss, and cause of kidney damage (including possible causes other than diabetes mellitus) may also be used to characterize CKD, evaluate prognosis, and guide treatment decisions.

Adapted from Diabetes Care. 2019;42(Suppl 1):S124-S138.

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy; UACR, urine albumin-to-creatinine ratio.

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.

We would love to hear from you

  • Do you have any comments?
  • Have you found a mistake?
  • Would you like to suggest a feature?

We use cookies to ensure you get the best browsing experience on our website. Refer to our Cookies Information and Privacy Policy for more details.