Diabetic Kidney Disease: General management

Does this patient have diabetic kidney disease?

History, signs and symptoms

The two chief signs of diabetic kidney disease (DKD) are increased urinary albumin excretion and reduced kidney function, as measured by estimated glomerular filtration rate (eGFR) based on serum creatinine.

Urine albumin excretion: Higher levels of urine albumin excretion are continuously correlated with severity of kidney disease, but thresholds are commonly used to categorize DKD (See Figure 1). Microalbuminuria, more recently termed moderately increased albuminuria and defined as an albumin-to-creatinine ratio (ACR) of 30-300 mg/g, occurs in 20-30% of diabetics after 5-15 years of disease. Macroalbuminuria, recently termed severely increased albuminuria and defined as an ACR >300 mg/g, is usually seen after approximately 10 years of disease and can increase with time.

Classification of urine albumin excretion

Glomerular filtration rate: GFR is estimated from serum creatinine concentration (eGFR). Reduced GFR, usually defined as eGFR < 60 m/min/1.73m², represents a measure of kidney damage that is complementary to albuminuria. While it was previously thought that DKD generally manifested first with abnormal urine albumin excretion rate, it is now shown that it presents by a reduction in GFR in setting of normal urine albumin excretion in a sizable minority of people with type 1 or type 2 diabetes.

Hypertension: In people with type 1 diabetes, increase in urine albumin excretion is closely correlated with the onset of hypertension. The blood pressure begins to rise around the time microalbuminuria develops and continues to rise with worsening kidney function. In comparison, approximately 40% of people with type 2 diabetes are hypertensive at diagnosis of diabetes and in nearly half of these patients, hypertension predates microalbuminuria. Furthermore, among people with type 2 diabetes, hypertension is strongly associated with obesity. For more details on signs and symptoms, please see section below, “Does the patient have diabetic kidney disease?”

Other kidney diseases in differential

Differential diagnoses of proteinuric kidney disease in diabetic patients includes other proteinuric glomerular diseases, such as focal segmental glomerulosclerosis, IgA nephropathy, membranous glomerulonephritis, minimal change disease, amyloid kidney disease, lupus nephritis, HIV nephropathy, HCV/HBV-associated kidney disease, etc.

Differential diagnosis for non-proteinuric kidney disease falls along pre-renal, renal and post-renal categories, as detailed in the section on diagnosis of acute kidney injury. However, a few conditions that are frequently responsible for acute increases in serum creatinine in people with diabetes include volume depletion (e.g., due to diuretics), particularly in the setting of RAAS blockade; urinary obstruction; and adverse effects of medications (e.g., NSAIDs, medications causing allergic interstitial nephritis).

Red flags suggesting non-DKD etiologies for kidney disease in people with diabetes

Albuminuria <5 yrs after the onset of type 1 diabetes
Nephrotic-range proteinuria (albumin-creatinine ratio [ACR] > 3g/g or albumin excretion rate [AER] >3g/24hr)
Acute drop in GFR or rise in urine albumin excretion
Refractory hypertension
Hematuria or otherwise active urine sediment e.g., dysmorphic red blood cells [RBCs] and cellular casts
Absence of diabetic retinopathy (DR) in people with type 1 diabetes (DKD is seen in absence of DR in as many as half of people with type 2 diabetes in small series)
>30% GFR drop in 2-3 months after renin-angiotensin-aldosterone system (RAAS) blockade
Signs/symptoms of other systemic disease

Other microvascular complications (retinopathy, neuropathy): Most people with type 1 diabetes and DKD have DR, which usually precedes kidney disease. Notably, reverse is not the case, i.e., most DR patients do not have DKD. Association between DR and DKD is less predictable in type 2 diabetes. In small biopsy series, there appears to be a close association between DR and presence of Kimmelstiel-Wilson nodules on kidney biopsy. People with type 2 diabetes with DR and proteinuria are most likely to have DKD, while ~30% of type 2 diabetics without DR may have kidney disease due to other etiology.

Pathology

The Research Committee of the Renal Pathology Society has described four classes of glomerular lesions:

Class I- GBM thickening. No mesangial expansion, increased mesangial matrix or global glomerulosclerosis in >50% of glomeruli
Class II- Mild (IIa) or severe (IIb) mesangial expansion
Class III- >1 Kimmelstiel-Wilson lesion (nodular intercapillary glomerulosclerosis), but less than 50% glomerulosclerosis
Class IV- advanced sclerosis. >50% glomerulosclerosis attributable to DKD.

Severity of interstitial and vascular lesions are also scored as below:

Score of 0: No interstitial fibrosis or tubular atrophy (IFTA), no lymphocyte/macrophage infiltrates and no arterial hyalinosis.
Score of 1: IFTA in <25% of tissue, lymphocyte/macrophage infiltrates around atrophic tubules only or one arteriole with hyalinosis.
Score of 2: IFTA in 25-50% of tissue, diffuse lymphocyte/macrophage infiltrates, >1 arteriole with hyalinosis.
Score of 3: IFTA in >50% of tissue, diffuse lymphocyte/macrophage infiltrates, or >1 arteriole with hyalinosis.

What tests to perform?

Urine albumin excretion

Urine albumin excretion should be measured annually in all people with diabetes, starting at diagnosis in type 2 diabetes and 5 years after diabetes onset in type 1 diabetes. Urine albumin excretion should be measured using an albumin-to-creatinine ratio (ACR) in a random urine sample. Urine dipstick is not an appropriate test because it only detects urine albumin excretion exceeding 300-500 mg/L and is susceptible to error due to urine volume and dilution.

ACR indexes urine albumin to urine creatinine concentration, which corrects for changes in urine dilution. ACR is also preferable to albumin excretion rate as the latter requires a timed urine collection, which is cumbersome and error-prone. ACR can be transiently increased in setting of fever, exercise, poor glycemic control, uncontrolled hypertension, decompensated congestive heart failure, high dietary protein intake and in presence of urinary tract infections. Therefore, an abnormal urine albumin excretion should be confirmed in 2 of 3 repeat ACRs over the 3-6 months.

Please refer to section above, ” Does the patient have diabetic kidney disease? ” for limitations of the above recommendations.

Glomerular filtration rate

Serum creatinine should be measured yearly starting at diagnosis of type 2 diabetes and 5 years after diabetes onset of type 1 diabetes, with changes to medications known to affect or be affected by kidney disease, and with acute illness. Serum creatinine should be used to estimate GFR using validated estimating equations (Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]), which also incorporate patient age, sex, and race. Estimated GFR <90 mL/min/1.73 m² is abnormal and is used to grade severity of DKD.

The MDRD-estimated GFR is imprecise and less useful in the GFR range ≥ 60 mL/min/1.73 m². Approaches using serum cystatin C have been suggested as a more precise alternative to estimating GFR in this range. Estimated GFR calculated from a formula based on serum cystatin C may be more strongly associated with progression to kidney failure and death than the one based on serum creatinine. However, this modest incremental increase in accuracy is not shown to merit the associated increase in cost in clinical practice. Furthermore, there is concern that cystatin C may be reflecting non-GFR contributions to these outcomes because it is increased with risk factors which predispose to these outcomes. Currently, cystatin C is not routinely available in clinical laboratories.

Urinalysis

Urinalysis is an informative, non-invasive and inexpensive test and should be performed in all patients with kidney disease (albuminuria or reduced eGFR). Relevant information gleaned from urinalysis includes presence of hematuria (red urinary pellet, RBC in microscopy), urinary tract infections (white blood cell count (WBC), bacteria, leukocyte esterase, etc), crystals and an active urine sediment (cellular casts, dysmorphic red blood cells).

Kidney imaging

Renal ultrasound is advisable if rise in serum creatinine is suspected to be due to urinary tract obstruction. It is also helpful for evaluation of baseline kidney size and disease chronicity. For example, small echogenic kidneys with high resistive indices suggest chronic, irreversible disease. Ultrasound with Doppler is used to evaluate renal vascular flow, for example if deterioration of renal function is suspected to be due to renal arterial stenosis (e.g., rapid rise in serum creatinine with RAAS blockade).

Retinopathy evaluation

In type 1 diabetes, diabetic retinopathy occurs in vast majority of people with DKD and prevalence of retinopathy correlates with the presence of albuminuria. In type 2 diabetes, the two are less tightly correlated. In small studies, roughly half of people with type 2 diabetes, proteinuria and diabetic glomerulopathy on biopsy have DR, which means that in about half of people with type 2 diabetes, diabetic glomerulopathy can exist in absence of retinopathy. On the other hand, retinopathy is much more prevalent in people with diabetic glomerulopathy than those with non-diabetic kidney disease on biopsy, so presence of retinopathy does increase likelihood that kidney disease is due to diabetes. However, the absence of retinopathy does not rule out kidney disease due to diabetes. As such, concomitant retinopathy evaluation is prudent in both type 1 and type 2 diabetic patients.

Referral to nephrologist

Per K/DOQI guidelines, patients should be referred to a nephrologist if their clinical course is not consistent with DKD or if they display signs of other causes of kidney disease (see red flags in section above, “Does the patient have diabetic kidney disease?”). Furthermore, patients with eGFR below 30 ml/min should be referred to a nephrologist for education and planning for renal replacement therapy and close management of chronic kidney disease complications even if the clinical course is consistent with DKD.

Kidney biopsy: Kidney biopsy is not commonly performed in diabetic patients with kidney disease unless their clinical course is not consistent with DKD (e.g., acute loss of kidney function or rise in proteinuria) or if they display signs of other causes of kidney disease (e.g., hematuria, an active urinary sediment). As discussed above, absence of diabetic retinopathy, particularly in people with type 1 diabetes and kidney disease may be an indication for a biopsy to confirm the etiology of kidney disease. Some of the relative contraindications for kidney biopsy are small hyperechoic kidneys (<9cm) which suggest chronic irreversible disease (and likely fibrosed and pathologically uninformative tissue), solitary native kidney, severe hypertension and uncorrectable bleeding diatheses.

Limitations:

The ideal time for measuring albumin-to-creatinine ratio is not certain. As such and in light of clinical convenience, ACR measurement is recommended in random voided urine samples.

Accurate conversion of ACR to absolute daily albumin excretion depends on the assumption of daily creatinine excretion of ~1g. Therefore, extreme departures from the 1g daily creatinine excretion tends to over- or under-estimate daily albumin excretion in individuals with much lower or higher daily creatinine excretion, respectively (e.g., a cachectic older woman vs. a heavily muscular young man).

There are also racial/ethnic- and gender-based differences in albumin and creatinine excretion. Daily creatinine excretion in higher in men compared to women and in African Americans and Mexicans compared to non-hispanic whites. However, these differences are less important in clinical practice where relative change in individual patients over time affects management more than small differences in absolute albumin excretion at a given time.

How should patients with diabetic kidney disease be managed?

Blood pressure control (see chapter on diabetes and blood pressure management for more details)

Blood pressure is one of the most important factors influencing progression of diabetic kidney disease and therefore should be aggressively controlled. The SPRINT trial showed reduced mortality in people with non-diabetic CKD with lower blood pressure targets (<120/80). In patients with diabetes or kidney disease, KDIGO recommends treating patients to a blood pressure of <140/90 in absence of proteinuria and <130/80mm Hg in presence of proteinuria. The first-line agents for treatment of hypertension in people with diabetes are ACE-Inhibitors (type 1 diabetes) or Angiotensin Receptor Antagonists (ARB) (type 1 or 2 diabetes).

Using multiple agents/Combination Therapy

The majority of hypertensive patients with diabetes require more than one agent to control blood pressure to the recommended target level. Diuretics or/and calcium channel blockers may be added to ACE-Inhibitors or Angiotensin Receptor Antagonists. Thiazide diuretics, such as chlorthalidone, are similarly effective in reducing coronary heart disease. However, their use in diabetes is less optimal given their metabolic adverse effects, such as hyperglycemia. More detailed information on specific classes of antihypertensive agents is given below.

Inhibition of the renin-angiotensin system

The RAAS plays a central role in the pathogenesis and progression of diabetic kidney disease. Therefore inhibition of this system with ACE-Inhibitors or ARBs is one of the most important steps in the treatment of DKD.

All hypertensive patients with diabetes should be treated with an ACE-Inhibitor or ARB.
Normotensive patients with microalbuminuria or macroalbuminuria may benefit from treatment with an ACE-Inhibitors or Angiotensin Receptor Antagonists. From a kidney perspective there is no data to support treatment of normotensive, normoalbuminuric patients with ACE-I or ARBs, although there may be some benefit for retinopathy.
Patients who are intolerant to ACE inhibitors due to cough usually tolerate an ARB. While angioedema has also been reported with ARBs, it is a rarely seen side effect and much less common that with ACE-Inhibitors.
Aldosterone antagonists (spironolactone, epleronone) and direct renin inhibitors (aliskerin) reduce proteinuria in short-term studies but have not been demonstrated to prevent the development or progression of DKD or cardiovascular disease.
Dual RAAS blockade is not recommended (see section on Antihypertensive agents, below)

Blood glucose control (see chapter on glycemic control for more details)

Blood glucose control plays an important role in the prevention and progression of DKD and other microvascular diabetes complications. Therefore, good glycemic control is critical for the management of kidney disease and other diabetic complications in these patients. In general, the ADA recommends a HbA1C goal of <7%. However, many patients with CKD are at increased risk of hypoglycemia, particularly the older patients with many cormorbidities, and should be considered for higher glycemic targets.

HbA1c in DKD

Chronic kidney disease, end stage kidney disease (ESRD) and treatment with erythropoiesis stimulating agents (ESAs) have been shown to be associated with decreased red blood cell survival or an increase in red blood cell production/turnover, thereby causing artificially low HbA1C levels in some of these patients. Other reports have shown an increase of HbA1C in CKD through possibly carbamylation of hemoglobin or acidosis. As a result HbA1C levels may not be as accurate in assessing glycemic control in patients with CKD or ESRD.

Effects of DKD on glucose control. With advanced GFR loss, typically <20 mL/min/1.73m² or ESRD, insulin catabolism is diminished and gluconeogenic capacity by the kidney is impaired. Therefore glucose-lowering therapy often requires reduction to avoid hypoglycemia.

Sodium-glucose co-transporter 2 (SGLT2) Inhibitors for the treatment of patients with type 2 DM

SGLT2 inhibitors have emerged as a novel class of medications for the treatment of type 2 DM and have been demonstrated to have beneficial effects beyond their glucose lowering abilities both for cardiovascular and renal endpoints. Empagliflozin has been demonstrated to reduce worsening DKD (defined as progression to macroalbuminuria, doubling of serum creatinine or initiation of renal replacement therapy). The mechanism for this is thought to relate to renovascular effects of the medication. Canagliflozin has been found to reduce the incidence of worsening albuminuria, reduction in GFR and need for renal replacement therapy. SGLT2 inhibitors are, however, not indicated for patients with reduced GFR (eGFR<60 ml/min for Dapagliflozin and eGFR<45/min for Canagliflozin and Empagliflozin).

Lipid control

Hyperlipidemia is common in diabetic patients with renal disease. Treatment with a statin does not affect progression of kidney disease, but reduces cardiovascular disease risk in people with diabetes and chronic kidney disease. Therapy with a Statin should be considered if the LDL cholesterol is >100 mg/dl with an LDL treatment goal of <100 mg/dl. An LDL treatment goal of <70 mg/dl is optional.

Dietary considerations

For diabetics with chronic kidney disease, a moderate protein restriction of 0.8 g/kg body weight per day has been shown to reduce the risk of progression of albuminuria/proteinuria and loss of GFR. Recent data also suggest that ‘Mediterranean’ diets with more fruits and vegetables, fiber, legume and nuts and lower intake of salt, refined sugar and meat -particularly red meat- may slow progression of kidney disease. For other dietary interventions in patients with chronic kidney disease please see the chapter on chronic kidney disease.

Lifestyle Changes

Smoking has been demonstrated to contribute to the rapidity of GFR loss in diabetic patients with kidney disease. Therefore smoking cessation should be strongly considered for any diabetic patient. Regular exercise can lead to weight loss, reduction in creatinine and albuminuria and should be encouraged. Normalization of the BMI (18.5-14.9) should be a treatment goal.

Antihypertensive agents

Consider adding an antihypertensive agent to ACE inhibitors or ARBs for treatment of hypertension among patients with diabetes:

Dihydropyridine calcium channel blockers (CCBs). Dihydropyridine CCBs (e.g., amlodipine, felodipine) as a sole agent have been shown to increase proteinuria in the IDNT study but are thought to be safe if used in combination with an ACE-Inhibitor or ARB. In fact, the ACCOMPLISH study has demonstrated superiority with regards to progression of chronic kidney disease of the combination of an ACE-Inhibitor with a dihydropyridine CCB as compared to the ACE-Inhibitor combined with hydrochlorothiazide.
Diuretics. Diuretics and RAAS inhibitors are synergistic in terms of effect on BP, ie, the combined effect of agents from these classes on BP is equal to or greater than the sum of individual effects of each medication. Patients with diabetes and normal or near-normal GFR usually respond to thiazide-type diuretics. In the diabetic subgroup of ALLHAT, chlorthalidone reduced the primary endpoint of fatal coronary heart disease and myocardial infarction to the same degree as lisinopril or amlodipine and was superior for prevention of heart failure.
Non-dihydropyridine calcium channel blockers (CCBs). Non-dihydropyridine CCBs (e.g., diltiazem, verapamil) reduce proteinuria in short-term studies but have not been demonstrated to prevent the development or progression of DKD or cardiovascular disease. Non-dihydropyridine CCBs tend to have less potent effects on BP than dihydropyridine CCBs.
Beta blockers. Beta blockers have proven benefit for comorbidities that often accompany diabetes, including coronary artery disease, stroke, and congestive heart failure, and are often indicated for these conditions. In the absence of these conditions, the utility of beta blockers for BP control in diabetes is not clear. Beta blockers and RAAS inhibitors are not synergistic in terms of effect on BP, ie, the combined effect of agents from these classes on BP is often less than the sum of individual effects of each medication.

What happens to patients with diabetic kidney disease?

Progression of albuminuria

DKD is traditionally characterized by progressively rising urine albumin excretion. Higher levels of urine albumin excretion, particularly above 300 mg/g creatinine or 300 mg/d (“macroalbuminuria”), usually represent progressive parenchymal kidney damage and identify individuals at high risk of GFR loss. Modifiable risk factors for worsening albuminuria include poor glycemic control, high blood pressure, obesity, and smoking. Intensive glycemic control and RAAS antagonists have been proven in clinical trials to reduce the risk of albuminuria progression in types 1 and 2 diabetes.

Regression of albuminuria

Not all patients with DKD progress, and many patients with “microalbuminuria” (30-299 mg/g creatinine or 30-299 mg/d), even if persistent, will subsequently “regress” to normal urine albumin excretion (< 30 mg/g creatinine or 30 mg/d). Regression may occur in up to half of patients with type 1 diabetes and microalbuminuria, while rates in type 2 diabetes are less clear. Regression may occur spontaneously or as a result of medications, e.g., RAAS inhibitors.

Regression is more common with better glycemic control, lower blood pressure, and more favorable circulating cholesterol levels. In kidney biopsies of persons with type 1 diabetes, lesions of diabetic glomerulopathy have been demonstrated to regress with normalization of glycemia via pancreas transplantation.

GFR loss

Rate of GFR loss is closely tied to level of albuminuria. GFR loss occurs with normal urine albumin excretion and microalbuminuria, though rate of loss tends to be relatively slow (usually <3-5 mL/min/1.73 m²/yr) and this can be difficult to detect in the “normal” range of GFR (≥ 60 mL/min/1.73 m²). GFR loss with “macroalbuminuria” averages up to 5-10 mL/min/1.73 m²/yr and can exceed this range in some cases. GFR loss leads to metabolic complications of chronic kidney disease and ESRD.

End stage renal disease

ESRD requiring renal replacement therapy is a severe complication of diabetes. Most patients with DKD will not progress to ESRD within their lifetime, but those who do progress experience substantial personal hardship. Renal replacement therapies are time- and resource-intensive and are associated with adverse effects and complications. 5-year survival after reaching ESRD is < 40%.

Cardiovascular disease

Patients with DKD are at particularly high risk of cardiovascular disease. Among patients with diabetes, the presence of albuminuria and low GFR (<60 mL/min/1.73 m²) each increase risks of cardiovascular events and death. Patients with DKD are up to 11 times more likely to die, often of cardiovascular disease, than to progress to ESRD. Therefore, prevention and treatment of cardiovascular disease should be a major focus for all patients with DKD.

How to utilize team care?

Care of the diabetic patient can be complex and challenging and may require the involvement of a whole team of healthcare providers. Team composition will vary according to patient needs, patient load, clinical setting and professional skills. In general team care requires at least a “core” team, which involves a physician, nurse and dietician, at least one of whom is a certified diabetes educator.

Many other healthcare professionals can and need to be team members or collaborative consultants if needed. The team can minimize the patient’s health risk by assessment, intervention and surveillance to prevent and identify problems early and start treatment.

Registered Nurses play a central role in the “core team” and can lead the administration of protocol based care. With medical direction a nurse can make management decision about glucose, lipid, anemia and hypertension management and can also provide valuable education for the patient.
Registered Dieticians can provide medical nutrition therapy that has been shown to improve outcomes and save money in the care of diabetic patients. For the patient with diabetic kidney disease dieticians are invaluable in guiding salt, phosphorus, protein, potassium and caloric restriction as deemed appropriate by the physician.
Clinical Pharmacists can provide important medication counseling, diabetes education, insulin initiation and adjustment, help with insulin pumps and glucose sensors and also help with blood pressure treatment and adjustment of antihypertensive management.
Important other team members or consultants include nephrologists, endocrinologists, ophthalmologists, podiatrists, psychologists, social workers, vascular surgeons, cardiologists, neurologists, physical therapists, and obstetricians.

Are there clinical practice guidelines to inform decision making?

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 49:S12-S154, 2007.
KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 39:S1-266, 2002

Other considerations

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