[15] Other typical lesions include hyalinosis of afferent and efferent arterioles, glomerular capsular drops, diffuse glomerular lesions with capillary wall thickening and mesangial matrix expansion (Case 1, Fig. 1). Renal histology in patients with T2DM is also markedly heterogeneous (Case 2, Fig. 2). A study of T2DM patients with normal eGFR and microalbuminuria by Fioretto et al. categorized renal biopsy findings into three patterns: 29% had normal or near normal

renal structure – Fioretto class 1 (C1). 29% had typical DN with predominant glomerular changes – Fioretto Class 2 (C2). 41% had atypical patterns with mild glomerular diabetic changes and disproportionately severe tubular, interstitial or vascular damage Fioretto Class 3 (C3).[16] The reasons for different kidney reactions to glycaemic injury are unclear, although potential factors include degree and duration of metabolic control, co-existing hypertension, interlobar renal Nutlin3a vascular changes and presence of diabetic retinopathy as a marker of microvascular PI3K inhibitor damage.[17] Recently, a new DKD phenotype has been described in diabetic patients with low GFR in the absence of microalbuminuria.[5] Approximately 25% of patients with T1DM or T2DM have been reported

to develop normoalbuminuric CKD.[18-20] Distinct sets of risk factors have been described for the development of low eGFR or increased AER, suggesting that eGFR and AER are complementary rather than obligatory markers of DKD.[5] Some studies that have attempted to document the natural history of normoalbuminuric DKD suggest a relatively benign course compared with albuminuric DKD, with lower rates of dialysis and mortality,[21, 22] whilst others have reported similar rates of decline in renal function.[20] Renal biopsies

of normoalbuminuric T1DM patients with preserved eGFR showed that greater width of the GBM predicted progression of DKD.[23] Moreover, normoalbuminuric T1DM patients with reduced eGFR had more advanced glomerular lesions compared with patients with preserved renal function.[24] Similarly, in T2DM, patients with normoalbuminuric CKD (eGFR <60 mL/min per 1.73 m2) were found to have more advanced glomerular, tubulointerstitial and learn more vascular lesions compared with patients with normoalbuminuria and preserved eGFR.[25] However, compared with patients with microalbuminuria or macroalbuminuria and CKD, the typical glomerular changes of DKD were less common in patients with normoalbuminuric CKD.[26] The above suggests that renal structural changes are more heterogeneous in normoalbuminuric than in albuminuric CKD (Fig. 3). In particular, for patients with T2DM and low eGFR, a recent biopsy study of 32 patients reported typical Fioretto C2 classification – typical DN changes for 22/23 microalbuminuric or macroalbuminuric patients with only 1/23 being classified as C3 – atypical patterns of renal injury.