diabetic kidney disease. Tubulointerstitial changes in diabetic kidney disease. (A) Normal renal cortex. (B) Thickened tubular basement membranes and interstitial widening. (C) Arteriole with an intimal accumulation of hyaline material with significant luminal compromise. (D) Renal tubules and interstitium in advancing diabetic kidney disease, with thickening andwrinkledtubular basement membranes (solid arrows), atrophictubules(dashed arrow), some containing casts, andinterstitial widening with fibrosis and inflammatory cells (dotted arrow). All sections were stained with period acid–Schiff stain. Original magnification, 3200. Table 2. International pathologic classification of glomerular changes in diabetic kidney disease Class Description Inclusion Criteria 1 Mild or nonspecific light microscopy changes and electron microscopy– proven GBM thickening GBM.395 nmin women and.430 nminmen 9 yr of age and older; biopsy does not meet any of the criteria mentioned below for classes 2–4 2a Mesangial expansion, mild Mild mesangial expansion in .25% of the observed mesangium; biopsy does not meet criteria for class 3 or 4 2b Mesangial expansion, severe Severe mesangial expansion in .25% of the observed mesangium; biopsy does not meet criteria for class 3 or 4 3 Nodular sclerosis (Kimmelstiel–Wilson lesion) At least one convincing Kimmelstiel–Wilson lesion; biopsy does not meet criteria for class 4 4 Advanced diabetic glomerulosclerosis Global glomerular sclerosisin .50% of glomeruli; lesions from classes 1–3 Degree of mesangial expansion: mild mesangial expansion occupies an area smaller than the area of the capillary lumen. Severe mesangial expansion occupies an area greater than the area of the capillary lumen (33). GBM, glomerular basement membrane. 2036 Clinical Journal of the American Society of Nephrology (44–47) (Figure 6). In DM2, systemic hypertension and obesity also contribute to glomerular hyperfiltration via mechanisms, such as high transmitted systemic BP and glomerular enlargement (47). Glomerular hyperfiltration is a well characterized consequence of early diabetes. Overall, it is observed in 10%–40% or up to 75% of patients with DM1 and up to 40% of patients with DM2 (48). Mechanisms underlying glomerular hyperfiltration in diabetes are incompletely understood (48); however, one plausible mechanism is increased proximal tubular reabsorption of glucose via sodium–glucose cotransporter 2, which decreases distal delivery of solutes, particularly sodium chloride, to the macula densa (49,50). The resulting decrease in tubuloglomerular feedback may dilate the afferent arteriole to increase glomerular perfusion, while concurrently, high local production of angiotensin II at the efferent arteriole produces vasoconstriction. The overall effect is high intraglomerular pressure and glomerular hyperfiltration (47,49) (Figure 7). Diagnosis of DKD The clinical diagnosis of DKD is on the basis of measurement of eGFR and albuminuria along with clinical features, such as diabetes duration and presence of diabetic retinopathy (51,52). DKD is identified clinically by persistently high urinary albumin-to-creatinine ratio $30 mg/g and/or sustained reduction in eGFR below 60 ml/min per 1.73 m2 (53). Screening for DKD should be performed annually for patients with DM1 beginning 5 years after diagnosis and annually for all patients with DM2 beginning at the time of diagnosis. In patients with albuminuria, the presence of diabetic retinopathy is strongly suggestive of DKD. The preferred test for albuminuria is a urinary albumin-to-creatinine ratio performed on a spot sample, preferably in the morning (51,52). The eGFR is calculated from the serum creatinine concentration. Although the Chronic Kidney Disease-Epidemiologic Prognosis Initiative equation is more accurate, particularly at eGFR levels in the normal or near-normal range, the Modification of Diet in Renal Disease equation is typically reported by clinical laboratories (52). Confirmation of albuminuria or low eGFR requires two abnormal measurements at least 3 months apart. If features atypical of DKD are present, then other causes of kidney disease should be considered. Atypical features include sudden onset of low eGFR or rapidly decreasing eGFR, abrupt increase in albuminuria or development of nephrotic or nephritic syndrome, refractory hypertension, signs or symptoms of another systemic disease, and .30% eGFR decline within 2–3 months of initiation of a renin-angiotensin system inhibitor (53). Treatment of DKD Prevention of diabetic complications, particularly DKD, by long-term intensive glycemic control from early in the course of diabetes is well established for DM1 and DM2 Table 3. International classification of interstitial and vascular lesions in diabetic kidney disease Type of Lesion and Criteria Score IFTA, % Absent 0 ,25 1 25–50 2 .50 3 Interstitial inflammation Absent 0 Infiltration only in relation to IFTA 1 Infiltration in areas without IFTA 2 Vascular lesions arteriolar hyalinosis Absent 0 At least one area of arteriolar hyalinosis 1 More than one area of arteriolar hyalinosis 2 Presence of large vessels arteriosclerosis No intimal thickening 0 Intimal thickening less than thickness of media 1 Intimal thickening greater that thickness of media 2 IFTA, interstitial fibrosis and tubular atrophy. Figure 5. | Conceptual model of the natural history of