T. Rott1, A. Hvala1, M. Koselj2, M Koselj-Kajtna3, A Kandus3
1Institute of Pathology, Faculty of Medicine, 2Department of Endocrinology and Diabetes, 3Department of Nephrology, University Medical Centre, Ljubljana, Slovenia
Background. Post-transplant diabetes mellitus (PTDM) is one of the major metabolic complications of solid organ transplantations. As in patients with pre-existent diabetes mellitus (DM) type 1 and type 2, patients with PTDM are at increased risk for the development of the micro-vascular complications, including retinopathy, nephropathy and neuropathy (1,2). Up until now, there was only a small number of reported studies of de novo diabetic nephropathy (DN) on renal graft in patients with PTDM, from the first report by Gimenez et al., to the recent report by Bhalla et al. (3,4). Therefore, the aim of our study was to identify de novo DN in our group of patients with PTDM.
Methods. Clinical criteria for assigning patients as having PTDM, included pre-transplant non-diabetic nephropathy with end-stage renal failure, no evidence of DM prior to transplantation, and the definition of PTDM according WHO criteria of DM. In our group of patients with kidney transplantation in the period 1986-2001, the incidence of PTDM was 8% (34 patients) (5). These 34 patients were reviewed retrospectively. Patients' age, sex, native renal disease, type of graft (cadaveric or from living donor), immunosuppressive regimen, transplant and PTDM duration, proteinuria and s-creatinine were analyzed. Indication for allograft biopsy was the increase in s-creatinine. Twenty-one out of 34 patients with PTDM had graft biopsy. Light microscopy, immune-fluorescence (IF) and electron microscopy (EM) were performed in 10 selected patients with linear IgG and/or albumin staining of basement membranes (BM).
Results. Early signs of de novo DN was found in 5 patients, 4 females, 1 male, with mean age 47.4 years (29-56), 4 with cadaveric graft. Their native renal diseases were: polycystic kidney disease (2), analgesic (2), and Balkan endemic nephropathy (1). Three patients were slightly proteinuric (0.3-0.5 gr/L), 2 patients had no proteinuria. Mean s-creatinine was 211.4 μmol/L (140-294). All patients received steroids and cyclosporine, micophenolate mofetil was added in 1. Two patients with PTDM were treated with insulin, 2 with oral hypoglycemic agents, and 1 with diet alone. PTDM was diagnosed on average 2.4 months after transplantation (1-6). Histologic diagnosis of de novo DN was made, on average, 52.6 months after transplantation (8-115) and 50.2 months (2-114) after PTDM. A diagnosis of de novo DN was based on light, IF and EM changes. Mild mesangial matrix expansion was found in all patients, mild/moderate mesangiocellular proliferation in 3 cases, but early nodular intercapillary hyalinosis in only one case. Moderate/severe arteriolar hyalinosis was found in all 5 patients, afferent and efferent arteriolar hyalinosis in 2, with moderate/intense granular arteriolar deposits of C3 in all 5 patients, and additional IgM deposits in 3 of them. Linear albumin, IgG and IgA staining of glomerular and/or tubular, and Bowman's capsular BM was found in 5, 4 and in 1 case, respectively. Segmental thickening of glomerular capillaries' BM, from 770 up to 1200 nm, was found in 3 patients, with also thickened peritubular capillaries' BM in one of them. DN with glomerular capillaries' BM thickening of lamina densa, was accompanied with early stages of transplant glomerulopathy in all cases displaying segmental subendothelial lucent zones.
Conclusions. PTDM is recognized as an adverse event associated with the use of corticosteroids, cyclosporine, or tacrolimus. The frequency of PTDM ranges from 2 to 50% (6). According to our findings, one could conclude, that de novo DN could be relatively frequent complication of PTDM, also occurring earlier than predicted (2). Afferent and efferent arteriolar hyalinosis, most probably pathognomonic for DN, together with linear IgG and albumin deposition on glomerular BM in two our patients, without obvious glomerular BM’s thickening, supports the findings of Hariharan et al. that arteriolar hyalinosis is probably the earliest lesion in DN. Linear IgA deposition in glomerular BM is unusual, but not rare event (7). Besides glomerular BM thickening, thickened BM of peritubular capillaries seems to represent characteristic change in DN (8).