Approach

DKD is usually a clinical diagnosis in a patient with long-standing diabetes (>10 years) with albuminuria and/or reduced estimated glomerular filtration rate (eGFR) in the absence of signs or symptoms of other primary causes of kidney damage.[1] It is rare for people with type 1 diabetes to develop DKD without retinopathy, whereas signs of DKD may be present at diagnosis or without retinopathy in type 2 diabetes.[1] Reduced eGFR without albuminuria has become more common over time.[1][2]​​ Such patients usually have a better renal prognosis than those with overt albuminuria.

History

Patients inclined to develop DKD usually have poorly controlled diabetes and a family history of hypertension and/or kidney disease.[34]​ They also may have hypertension themselves, in particular nocturnal hypertension (non-dippers).[34][35]​

Patients may not develop symptoms until advanced stages of DKD.[36]​ In advanced stages, initial constitutional symptoms may include fatigue and anorexia. As patients become clinically uremic, encephalopathy, nausea and vomiting, dysgeusia (altered taste), bleeding, myoclonus, and pericarditis may be present.[37]​ 

Numbness in the legs (suggestive of peripheral neuropathy), poor vision (suggestive of retinopathy or cataracts), and pain in the legs (suggestive of neuropathy or peripheral vascular disease) are typical of advanced diabetes mellitus and should prompt further evaluation for DKD.

Physical exam

In the early stages of the disease, physical exam may be normal. It should assess for features of DKD, including hypertension and peripheral edema, as well as for other microvascular complications of diabetes mellitus, such as:

  • Retinopathy: decreased vision, retinal findings including dot and blot hemorrhages, microaneurysms (background retinopathy), and/or neovascularization (proliferative retinopathy)[38]

  • Neuropathy: decreased sensation in lower extremities in "stocking" pattern, foot ulcers, Charcot joints (peripheral neuropathy), and/or orthostatic hypotension without increase in heart rate (autonomic neuropathy).[39]

Physical examination should also assess for macrovascular complications including hypertension, vascular bruits, decreased pulses in extremities, and ischemic ulcers.

Other findings of long-standing and/or poorly controlled diabetes may also be evident, including:

  • Skin changes, such as xerosis (abnormal dryness of the skin), hyperpigmentation, necrobiosis lipoidica, and acanthosis nigricans[40]​

  • Costovertebral tenderness due to glycosuria and possible proclivity toward urinary tract infections[41]

  • Muscular atrophy[42]

  • Pallor, which may signify anemia.[43]

In overtly uremic patients, pericardial and/or pleuritic friction rubs, asterixis, and/or myoclonus may be evident.​ There may be platelet dysfunction, which manifests as bleeding tendency.[37] Metabolic acidosis, due to impaired ammoniagenesis and to accumulation of phosphates, sulfates, and hippurates, may be accompanied by Kussmaul respirations.[37][44]

Tests

Albuminuria and reduced eGFR are the most important predictors of progressive decline in kidney function.[45][46]​ Tests performed in the assessment of DKD include:

1. Urinalysis

  • This may show proteinuria. Increased specific gravity may point to prerenal causes of decreased eGFR.

  • Urinary leukocytes, bacteria, and nitrites indicate urinary tract infection.

  • After the initial screen, urinalysis is not needed unless there is a specific indication (e.g., unexpected rapid decline in renal function, symptoms of urinary tract infection).

2. Quantification of albuminuria

  • Albuminuria is an independent definition of chronic kidney disease (CKD) even if eGFR is ≥60 mL/minute/1.73 m². Detecting albuminuria is important because early intervention can prevent progression of CKD.[47]

  • Albuminuria may be quantified by the urinary albumin to creatinine ratio (ACR) in a spot sample, or, in a timed (e.g., 24-hour) urine collection, the albumin excretion rate (AER); however, timed collections are more burdensome and do not significantly improve accuracy.[1][47]

  • Use of the term "albuminuria" with subsequent quantification of the level or amount is now encouraged, such that an ACR of 30-299 mg/g or AER of 30-299 mg/24 hours is moderately increased albuminuria (previously known as microalbuminuria) and an ACR of ≥300 mg/g or AER of ≥300 mg/24 hours is severely increased albuminuria (previously known as macroalbuminuria).​[1][48]

  • To confirm moderately or severely increased albuminuria, at least 2 of 3 specimens collected within a 3- to 6-month period should be abnormal.[1]

  • ACR on a first-void spot urine specimen is the preferred test; a random spot urine specimen is an acceptable alternative.[49]

  • Exercise within 24 hours of specimen collection, infection, fever, congestive heart failure, significant hyperglycemia or hypertension, and menstruation may increase urinary ACR independently of kidney damage.[1]

3. Blood biochemistry

  • Serum creatinine should be measured and eGFR calculated.​[47]​​​ A 2021 Task Force convened by the National Kidney Foundation and the American Society of Nephrology recommended the adoption of the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (2021) that estimates kidney function using creatinine, age, and sex, but no race variable (eGFRcr).[50] EBMCalc: glomerular filtration rate estimation (eGFR) by CKD-EPI equation with creatinine, without race (2021) Opens in new window​​​ This replaces the original CKD-EPI equation, which was previously widely used to estimate kidney function and contained an adjustment for black race.[50]

  • Cystatin C is an alternative endogenous filtration marker biomarker that is increasingly being used to estimate renal function in clinical practice; it displays less variation due to muscle mass than creatinine and offers greater accuracy of GFR estimation, which improves the relationship between eGFR and subsequent risk of CKD-related outcomes, such as cardiovascular death and end-stage renal failure.[51]​ It is recommended for confirmatory testing of eGFR when more precise estimates are needed for clinical decision making; for example, to confirm the diagnosis of CKD when the creatinine-based eGFR is 45-60 mL/minute/1.73 m² and there are no other features of CKD (such as albuminuria or radiologic abnormalities), or when individuals have prominent non-GFR determinants of serum creatinine that make creatinine-based estimation of GFR less accurate, such as high muscle mass, low muscle mass, creatine supplements, high animal protein diet, vegetarian diet, liver disease, or extreme frailty.[50]​ National efforts are under way in the US to facilitate increased, routine, and timely use of cystatin C.[50] Like the 2021 CKD-EPI creatinine equation, the 2021 CKD-EPI creatinine-cystatin C equation was developed without a term for race. It uses both creatinine and cystatin C and is more accurate, more closely approximates measured GFR, and supports better clinical decisions than either marker alone.[50]

  • An eGFR persistently <60 mL/minute/1.73 m² is considered abnormal, although the threshold for diagnosis of DKD may vary in older patients.[1]

4. Imaging

  • Initial imaging should include ultrasound, which is useful to demonstrate kidney size and rule out differentials such as hydronephrosis, pyelonephritis, and stones.[37]​ Kidney size may initially be large if diabetes is uncontrolled, but is usually normal once DKD supervenes.[52]​ Doppler ultrasound may demonstrate renal artery stenosis.[37]

  • Computed tomography scan is useful to demonstrate kidney stones, hydronephrosis, and kidney size and may also help clarify a possible differential diagnosis. It is not routinely used in diagnosing DKD, but may be useful if ultrasound is of poor quality in patients with obesity or if follow-up imaging is required to clarify pathology seen on ultrasound.[37]

  • Magnetic resonance angiography is not routinely used in the diagnosis of DKD, but it may be useful in diagnosing renal artery stenosis or vasculopathies.[37] Previously, gadolinium was not given if the eGFR was <30 mL/minute/1.73 m²; however, newer gadolinium-based contrast agents (group II agents) are safe to use with low eGFR or in patients receiving maintenance dialysis.[53][54]

5. Kidney biopsy

  • The most sensitive and specific test for diagnosing DKD is a kidney biopsy that demonstrates mesangial expansion or nodular glomerulosclerosis. Although rarely necessary, it may be indicated under certain circumstances. Such circumstances include: people with type 1 diabetes who have had diabetes mellitus for a short period of time or who do not have retinopathy; a rapid decline in renal function associated with an active urine sediment; or evidence of another systemic disease.[36]

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