'Primary' nephrosclerosis in a type 1 diabetic patient

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End-stage renal disease is a well known long-term complication of type 1 diabetes. Its diagnosis in typical cases is obvious, and, in non-typical cases, i.e. those lacking the classic hallmark of proteinuria or showing discrepancies between end-organ damage (in particular between nephropathy and retinopathy), a renal biopsy is usually indicated [1]. However, the work-up protocol is tailored for patients referred early to nephrologists. The clinical choice may be less clear, however, in the case of late referral, when the renal disease is advanced and a renal biopsy (displaying the presence of a non-diabetic nephropathy) is probably of minor therapeutic relevance. The present case report is that of a patient referred late to the nephrologist, who performed a renal biopsy because of an atypical course, during the work-up of the patient for a pancreas–kidney transplantation. The diagnosis of renal damage, which was that of nephrosclerosis in a patient who was not hypertensive at the time of diagnosis, offers the opportunity to discuss this diagnostic entity, which has been considered with alternative fortunes in the medical literature and has recently been ‘rediscovered’ as an underestimated cause of chronic kidney disease [2–5]. This disease, which is a potential cause of end-stage kidney failure, and is considered to be a pre-hypertensive lesion, and not just the result of long-standing hypertension, is interesting because of the predisposing factors associated with it, Including: genetic aspects, subtle alterations in blood coagulation, cigarette smoking, dyslipidaemia, hyperinsulinism and obesity [2–5]. According to a detailed, expansive search strategy on MEDLINE (1966–August 2004) and EMBASE (1988–August 2004), that we performed combining the MESH-Emtree and free terms related to diabetes with those related to nephrosclerosis/nephroangiosclerosis, our present report is the first on an association between diabetes mellitus and non-hypertensive nephrosclerosis. A 27-year-old woman who had type 1 diabetes since the age of 4 was admitted to our nephrology ward in 1999. She was an employee of a hospital cleaning agency. Her family history was positive for juvenile hypertension and negative for diabetes mellitus, nephropathies, cardio-vasculopathies and neoplasia. Because of her poor compliance, her diabetic control was irregular. Her weight was 54 kg (body mass index = 19 kg/m2). She had smoked 20–25 cigarettes per day since she was 13 years old. She had had one regular pregnancy at age 18, one voluntary abortion, and two spontaneous abortions, the latter at 20 and 26 years of age (in the first trimester). In 1997, she was hospitalized in a diabetology ward in a different city. During that admission, non-proteinuric chronic kidney failure (serum creatinine: 2.7 mg/dl) was detected in the absence of significant diabetic retinopathy; hyperthyroidism was also diagnosed, and treated with methimazole. In 1998, she moved to Turin and started an irregular follow-up in our Diabetic Outpatient Care Unit. Her diagnostic work-up revealed normal blood pressure (110–130/70–85 mmHg) and pre-proliferative diabetic retinopathy, in the absence of autonomic neuropathy, dyslipidaemia and cardio-vasculopathy; in addition, severe kidney failure was confirmed. She did not have a history of hypertension, and was normotensive at all the clinical visits, which were, however, somewhat irregular, which had been performed in diabetology, during pregnancy and during hospitalizations. She was hospitalized in the Nephrology ward for a diagnostic evaluation and the initiation of work- up for a pancreas–kidney graft. On admission, her serum creatinine was 4.5 mg/dl, creatinine clearance 16 ml/min, proteinuria 0.8 g/24 h, cholesterol 204 mg/dl (high-density lipoprotein = 48 mg/dl) and triglycerides 113 mg/dl. Renal ultrasound and Doppler ultrasonography showed kidneys of normal size, with sinusal sclerolipomatosis and bright thin cortices (longitudinal diameter: left, 10 cm; right, 11 cm), without signs of arterial stenosis, but with a bilateral increase of the arterial resistance index. A renal scintiscan showed symmetrically reduced parenchymal phases without signs of obstruction. Proteinuria was non-selective, and microscopic urinalysis showed 3–5 red blood cells per high power field (400×), with rare hyaline casts. A renal biopsy was performed in view of the patient's atypical course and the preserved kidney size. On light microscopy, 20 glomeruli were seen, 11 of which had global ischaemic glomerulosclerosis (the other nine had diffuse collapsing of the basal membranes), with tubular atrophy, interstitial fibrosis and myo-intimal hyperplasia (Figure 1). We made the diagnosis of nephrosclerosis without evidence of diabetic nephropathy. Light microscopy shows global ischaemic glomerulosclerosis in some glomeruli, with diffuse tubular atrophy and interstitial fibrosis. The other glomeruli shows a slight thickening and a diffuse collapsing of basal membranes. In the arteries, myo-intimal hyperplasia is detectable. The patient was discharged on low doses of angiotensin-converting enzyme (ACE) inhibitors (enalapril 5 mg), acetylsalicylate and a low protein, vegetarian diet (0.6 g/kg/day) supplemented with α-ketoanalogues. In March 2001, she received a pre-emptive pancreas–kidney graft (with her adjunct immunosuppressive treatment consisting of steroids, tacrolimus and mycophenolate mofetil). She is presently well, with normal renal function (serum creatinine 0.9 mg/dl), proteinuria <0.4 g/day and full glyco-metabolic control. Performing a renal biopsy in a pre-dialysis patient is not beyond criticism, because of the increased risk of complications and its limited therapeutic impact [6]. In the case of this patient who had a pre-emptive kidney–pancreas transplantation in our centre, the decision to perform a biopsy was made to also rule out the possibility of a glomerular disease that potentially could recur in the graft—an ancillary element of modulating immunosuppressive therapy. The finding of nephrosclerosis was unexpected in this young, non-hypertensive woman. It may support the idea, suggested by Meyrier and Simon, that this condition may be underdiagnosed, due to the habit of reserving the renal biopsy procedure for patients whose clinical and urinary picture (proteinuria, ‘active’ urinary sediment, haematuria) is suggestive of a glomerular disease potentially amenable to some kind of therapy [2]. Indeed, while relatively rare situations (such as isolated nocturnal hypertension) could not be ruled out completely in her case, since 24 h blood pressure monitoring was not performed, she was always normotensive at her out-patient visits and during her hospitalizations, a pattern that is in disagreement with the usual history of patients with ‘hypertensive nephrosclerosis‘, which is dominated by high blood pressure levels, over years or decades. While the typical lesions of nephrosclerosis may actually precede the development of hypertension, at least in some high risk ethic subgroups, as they do in animal models [7], cigarette smoking was the only putative risk factor, beside diabetes, that was present in this young woman. Smoking has been implicated in the development and progression of chronic kidney disease, particularly with regard to its detrimental effect on renal vasculature. The link with ‘primary’ nephrosclerosis is putative. It was originally postulated by Meyrier and Simon in a pivotal paper on this topic [2], and it recently was widely discussed, with somwhat conflicting results. While some studies suggest that the renal damage caused by smoking is mainly confined to the small interlobular arteries, its effect on the vasculature throughout the body appears to be enhanced by diabetes. The combination of the two is so noxious as to render the prognosis of diabetics who smoke ‘abysmal’ [8,9]. Conversely, smoking is considered a potent risk factor in the development of nodul

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