Diabetic Kidney Disease

How to Cite This Chapter: Parihar R, Pigeyre M, Rodríguez-Gutiérrez R, Quintanilla-Flores DL, Soto-Garcia AJ, Gonzalez-Gonzalez JG, Sieradzki J, Płaczkiewicz-Jankowska E. Diabetic Kidney Disease. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.13.4.1. Accessed October 20, 2021.
Last Updated: May 6, 2021
Last Reviewed: May 6, 2021
Chapter Information

Etiology, Pathogenesis, ClassificationTop

The development of diabetic kidney disease (DKD) depends on the duration of diabetes mellitus (DM), severity of metabolic or glycemic control disturbances, coexisting hypertension, and genetic factors. DKD is present in up to 20% to 40% of patients with DM and is characterized by slow and progressive decline, with some of the patients developing end-stage kidney disease requiring renal replacement therapy. It is caused by changes in the basal membrane that 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, leading to hyperfiltration. As a result, albumin filtration is increased, initially in the form of “microalbuminuria” of 30 to 300 mg/24 hours or 30 to 300 mg/g creatinine in a random urine sample (albumin to creatinine ratio [ACR], 2-20 mg/mmol), and then overt proteinuria >300 mg/24 hours (ACR >20 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, mortality, 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 2 and 20 mg/mmol, 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 (eg, African American), male sex, family history, gestational DM, hypertension, dyslipidemia, obesity, and insulin resistance, as well as elevated glycated hemoglobin (HbA1c) levels, elevated systolic blood pressure, inflammation, 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 6.2-1).

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 urine ACR >20 mg/mmol; 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 6.2-2). 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 calculated and albuminuria assessed 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 6.2-2). Two of 3 specimens used to determine 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 determining 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 falsely elevate the urinary ACR (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 calculate eGFR in patients with type 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, avoidance of nephrotoxins (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]), and vigilance for hypoglycemia are all important in the management of patients with DKD. For both type 1 and type 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. For most patients target levels of HbA1c are <7.0% (53 mmol/mol) for primary prevention. Aim for an individualized, higher HbA1c target when eGFR is <60 mL/min/1.73 m2 because of the increased risk of hypoglycemia with more intensive treatment. Doses of insulin and some other injectable and oral glucose-lowering medications often need to be reduced or suspended at these eGFR levels. In the presence of established CKD, the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors has been shown to reduce progression of nephropathy (if eGFR is between 30-60 mL/min/1.73 m2), with the strongest evidence for canagliflozin, followed by dapagliflozin and empagliflozin especially in the presence of albuminuria. The use of glucagon-like peptide-1 (GLP-1) receptor agonists in the glycemic regimen in patients with diabetes and CKD has proved to be efficacious in reducing cardiovascular events.Evidence 1High Quality of Evidence (high confidence that we know true effects of intervention). Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2021 Jan 13;372:m4573. doi: 10.1136/bmj.m4573. doi: 10.1016/s0272-6386(99)70360-4#PMID: 33441402; PMCID: PMC7804890.

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 <130/80 mm HgEvidence 2Strong 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. doi: 10.1016/s0272-6386(99)70360-4. 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. doi: 10.1046/j.1523-1755.2001.00797.x. PMID: 11422762. Brenner BM, Cooper ME, de Zeeuw D, et al; 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. doi: 10.1056/NEJMoa011161. PMID: 11565518.   Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-2229. doi: 10.1056/NEJMoa2025845. PMID: 33264825. Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2021 Jan 13;372:m4573. doi: 10.1136/bmj.m4573. PMID: 33441402; PMCID: PMC7804890. (do not combine these 2 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. Serum creatinine and potassium levels must be monitored periodically for the development of increased creatinine or hyperkalemia when ACEIs, ARBs, or diuretics are used. A recent randomized controlled trial showed that the addition of finerenone (nonsteroidal selective mineralocorticoid receptor antagonist) to ACEI/ARB therapy in patients with diabetic nephropathy was associated with lower risks of CKD progression and cardiovascular events compared with placebo; however, it has not been included in any guideline recommendations yet.

3. Treat dyslipidemia using a statin. Low-density lipoprotein cholesterol (LDL-C) should be controlled below the therapeutic target of 2.0 mmol/L. 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 showed lower benefit in reducing the rates of cardiovascular events and death in patients undergoing chronic dialysis treatment compared with the effects reported in the general population. 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. For patients on dialysis a higher dietary protein intake should be considered, since malnutrition is a major problem in some patients receiving dialysis. Of note, considering some uncertainty regarding the effects of dietary protein intake, any restriction below normal intake is not recommended and 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, cease smoking (including second-hand smoke exposure), and maintain a recommended body weight.

6. When diagnosing renal failure (eGFR <60 mL/min/1.73 m2, significant proteinuria, or both), consider referring the patient to a nephrologist for the evaluation and management of CKD and other potential causes of CKD especially if red flags are present, such as short duration of DM (<5 years), active urine sediment, no other known complications of DM, features of another systemic disease, sudden increase in albuminuria or rapid decline in eGFR, and a first-degree relative with CKD. Other, more conservative criteria for referral and principles of CKD treatment: see Chronic Kidney Disease.

TablesTop

Table 6.2-1. Mogensen classification of diabetic nephropathy and its course

Diabetes duration

Stage

Clinical features

Prognosis

Since disease onset

1: Increased eGFR, renal hypertrophy

eGFR 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 eGFR, no albuminuria, no clinical symptoms

May be partially reversible

5-10 (15) years

3: Early clinical nephropathy

Albuminuria 30-300 mg/24 h, eGFR 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, eGFR <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 eGFR <15 mL/min/1.73 m2, HTN

Irreversible progression to end-stage renal failure

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

eGFR, estimated glomerular filtration rate; HTN, hypertension.

Table 6.2-2. CKD stages in diabetic nephropathy

 

eGFR categories

(mL/min/1.73 m2)a

Albuminuria categories

(urine ACR/24 h)

A1 (normal):

<2 mg/mmol or

<30 mg/24 h

A2 (microalbuminuria):

2-20 mg/mmol or

30-300 mg/24 h

A3 (overt nephropathy):

>20 mg/mmol or >300 mg/24 h

G1b,d

Normal eGFR

(>90)

 

Treat

Treat

G2b,d

Mildly ↓ eGFR

(60-89)

 

Treat

Treat

G3ac,d

Moderately ↓ eGFR

(45-59)

Treat

Treat

Consider referral

G3bc,d

Moderately ↓ eGFR

(30-44)

Treat

Treat

Consider referral

G4c,d

Severely ↓ eGFR

(15-29)

Consider referral

Consider referral

Refer

G5c,d

End-stage renal failure

(<15)

Refer

Refer

Refer

Risk of CKD progression:

green, low risk; yellow, caution with close observation needed; orange, moderately increased risk; red, high risk, nephrology referral should be considered; dark red, very high risk, nephrology referral should be made.

a Focus on kidney-related care: Diagnose the cause of kidney injury in G1 to G3, evaluate and treat risk factors for CKD progression in G1 to G4, evaluate and treat CKD complications in G3 to G5, and prepare for renal replacement therapy in G4 and G5.

For any CKD stage the degree of albuminuria, observed history of eGFR decrease, and cause of kidney damage (including possible causes other than DM) may also be used to characterize CKD, evaluate prognosis, and guide treatment decisions.

b G1 and G2 are characterized by evidence of kidney damage.

c G3 to G5 are defined by reduced eGFR with or without evidence of kidney damage.

d Kidney damage most often manifests as albuminuria (urine ACR >30 mg/g), but it can also be associated with glomerular hematuria, other abnormalities of urinary sediment, radiographic abnormalities, and other presentations.

Adapted from Diabetes Care. 2020;43(suppl. 1):S135-S151 and Can J Diabetes. 2018;42:S201-S209.

↓, decreased; ACR, albumin to creatinine ratio, CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate.

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