Urinary ACR (mg/g)
Normally to mildly increased
3.3 Renal Pathology in DKD
Renal tubules and interstitium may also undergo structural changes, particularly in the later stages of DKD. The thickening of the tubular basement membrane (Fig. 3.2) closely correlates with the thickening of the GBM. Tubulointerstitial fibrosis and tubular atrophy may be the best pathologic predictors of progressive loss of GFR, which are more universal in patients with type 2 diabetes. In fact, the renal pathologic change is heterogeneous in patients with type 2 diabetes; only a subset of patients with type 2 diabetes has typical diabetic glomerulopathy, whereas a considerable proportion has more advanced tubulointerstitial and vascular damage . Furthermore, the appearance of the kidney in some patients with type 2 diabetes is more suggestive of glomerular ischemia or tubulointerstitial disease.
3.4 Diagnosis of DKD
Diabetic retinopathy accompanied with microalbuminuria
Microalbuminuria in patients diagnosed with type 1 diabetes for more than 10 years
3.4.1 Measurement of Urinary ACR
Microalbuminuria is accepted as an independent risk factor associated with the progression of chronic kidney disease (CKD) and GFR loss. Measurement of microalbuminuria is currently widely available and easy to perform with relatively low cost. As the interpretation of results for albumin concentration alone may be unreliable due to variations in urinary concentration and timed collections are inconvenient, the ACR in a spot urine sample (preferably the first morning specimen) is recommended. Metabolic perturbation, hemodynamic factors, and presence of urinary tract infection may affect the appearance of albumin in the urine . Hence, the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend that elevated ACR be confirmed in the absence of marked hypertension, urinary tract infection, and cardiac failure with two additional tests during the next 3–6 months .
3.4.2 Measurement of Serum Creatinine Concentration and eGFR
In clinical practice, the serum creatinine concentration is the most frequently used index to evaluate renal function. However, it is not sensitive enough and may be highly misleading when patients have low muscle mass, especially in elderly patients with diabetes. Therefore, the KDOQI guidelines recommend that the GFR be estimated with the Modification of Diet in Renal Disease Study equation; however, the evidence shows that the usefulness of eGFR alone as a regular screening test for CKD in diabetes is less secure .
3.4.3 Ophthalmologic Examination
A study including a cohort of patients with type 1 diabetes and with type 2 diabetes revealed that a large proportion of patients with type 1 diabetes and macroalbuminuria also showed signs of diabetic retinopathy, whereas nearly half of the patients with hypertension and type 2 diabetes who had macroalbuminuria did not have concomitant retinopathy . Thus, the presence of retinopathy and macroalbuminuria in patients with type 1 diabetes strongly suggests DKD. In contrast, as for patients with type 2 diabetes, the accompanied presence of retinopathy is only partly useful in the discrimination of renal pathology, and the absence of retinopathy does not rule out the presence of DKD.
3.4.4 Indications for Renal Biopsy
eGFR rapidly declines, or renal dysfunction without significant proteinuria is observed.
The onset of proteinuria is sudden and progresses rapidly, particularly in patients with duration of type 1 diabetes <5 years. Alternatively, the evolution of proteinuria is atypical (e.g., nephrotic syndrome develops in the absence of persistent microalbuminuria).
The presence of macroscopic hematuria or active nephritic urinary sediment containing acanthocytes and red blood cell casts, which suggests glomerulonephritis, is detected.
3.5 Management of Patients with Diabetes and CKD
Management of patients with diabetes and CKD according to GFR
GFR (mL/min/1.73 m2)
All patients with diabetes
Screen for serum creatinine, ACR, eGFR, and serum potassium every 12 months
Consideration of dose adjustment of drugs in use
Screen for eGFR every 6 months
Screen for serum electrolyte (Ca, P included), acid alkali balance, hemoglobin, and parathyroid hormone
Evaluation of vitamin D
Consideration of test for bone mineral density
Referral to nephrologist when diabetes with non-DKD or the cause of CKD is unknown
Screen for eGFR every 3 months
Screen for serum electrolyte (Ca, P included), acid alkali balance, hemoglobin, parathyroid hormone, albumin, and weight
Consideration of dose adjustment of drugs in use
Referral to nephrologist
3.5.1 Treatment of DKD
Interventions deemed useful in preventing the progression of DKD include lifestyle improvement, strict glycemic and blood pressure (BP) control, control of dyslipidemia, and renin–angiotensin–aldosterone system (RAAS) blockade. Patients who develop ESRD may require renal replacement therapy (Fig. 3.4).
22.214.171.124 Lifestyle Improvement
The KDOQI guidelines recommend a dietary protein intake of 0.8 g/kg body weight per day for individuals with diabetes and stage 1–4 CKD . For patients with diabetes on hemodialysis (HD), 1.3 g/kg weight per day is suggested. Smoking should immediately be stopped upon the diagnosis of diabetes.
126.96.36.199 Glycemic Control
Hyperglycemia is the primary cause of DKD. Strict glycemic control through insulin or islet cell transplantation improves hyperfiltration, hyperperfusion, and glomerular capillary hypertension and decreases urinary albumin excretion in experimental diabetic animals. Moreover, strict glycemic control slows the development and progression of DKD in patients with diabetes.
In the Diabetes Control and Complications Trial (DCCT), patients with type 1 diabetes who received intensive therapy (average hemoglobin A1c [HbA1c] level of 7.2%) showed a 39% lower risk of developing microalbuminuria when compared to patients who received conventional therapy (average HbA1c level of 9.1%) at 6.5-year follow-up. Furthermore, patients receiving intensive therapy showed a 54% reduction in progression from microalbuminuria to macroalbuminuria . At the end of the DCCT, all patients in the previous two groups received intensive therapy, and nephropathy was evaluated based on urine specimens at 3 and 4 years after the original DCCT. The average HbA1c level was 8.2% in the previous conventional therapy group, and 7.9% in the previous intensive therapy arm. However, the intensive therapy group still has advantage over the former conventional therapy group with an 86% lower risk of new-onset albuminuria. More recently, data from the DCCT and Epidemiology of Diabetes Interventions and Complications (EDIC) study suggested a 50% reduction of the long-term risk of impaired GFR in patients undergoing intensive therapy as compared to their counterparts receiving conventional therapy .
A number of major studies have also reported a lower risk of DKD in patients with type 2 diabetes undergoing stricter glycemic control. As shown in the United Kingdom Prospective Diabetes Study (UKPDS), newly diagnosed patients with type 2 diabetes were randomly divided into intensive therapy (HbA1c level of 7.0%) treated with sulfonylurea or insulin and conventional therapy (HbA1c level of 7.9%) with diet alone . The reduction in the risk of developing microalbuminuria over 9 years and of progression from microalbuminuria to proteinuria was 24% and 42%, respectively, in the intensive therapy group. After study termination, patients were observed for another 10 years. Although the HbA1c level between the two groups was comparable within 1 year, lower risk of microvascular disease and myocardial infarction persisted. This phenomenon of prolonged beneficial effects on complications of diabetes achieved through strict glycemic control even being followed by less intensive glycemic control has been described as “metabolic memory” or “legacy effect.”