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Renal segmental hypoplasia, Ask-Upmark kidney, in a patient with microalbuminuric hypertensive type 2 diabetes mellitus
diabetes research and clinical practice 80 (2008) e22–e24
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Letter to the Editor Renal segmental hypoplasia, Ask-Upmark kidney, in a patient with microalbuminuric hypertensive type 2 diabetes mellitus Diabetic nephropathy is one of the most frequent and clinically important complications of diabetes mellitus (DM), and a major cause of end-stage renal disease [1]. The diagnosis of diabetic nephropathy is almost always based on clinical grounds, not on renal biopsy findings, supported by long history of diabetes, evidence of target organ damage (e.g. diabetic retinopathy), and albuminuria/proteinuria preceding azotemia [1–3]. However, it is not necessarily diabetic nephropathy when renal disease occurs in diabetic patient, of whether type 1 or type 2. We encountered a patient with type 2 DM-associated renal dysfunction due to renal segmental hypoplasia, Ask-Upmark kidney [4]. A 46-year-old Japanese man with a 10-year history of type 2 DM was referred and admitted to our hospital because of poor diabetic control, hypertension, and the elevated serum creatinine levels. At age 36, after DM and hypertension were noted, he had been treated with oral anti-diabetic agents and antihypertensive agents including an angiotensin II receptor blocker; however, his DM and blood pressure control had deteriorated and his serum creatinine levels had gradually increased during the most recent year; thus, he was referred to our hospital. No urinary abnormalities (i.e. hematuria, or dip stick-positive proteinuria) had ever been detected. On admission, his height was 166 cm, weight 83.0 kg, and blood pressure 124/96 mmHg. Physical examination disclosed no remarkable findings, but laboratory examination revealed mild renal impairment and poor DM control: serum creatinine was 96.5 mmol/l (reference, 44.3– 97.46); 24-h creatinine clearance was 77.6 ml/min; urinary albumin excretion rate was 105.8 mg/min without any urine dip-stick/sediments abnormalities; and hemoglobin A1c was 11.8%. Neurological examination and ophthalmologic examination revealed no signs of diabetic neuropathy and retinopathy, respectively. Subcutaneous insulin injection twice a day was started. As he also complained of back pain during the hospitalization, abdominal ultrasonography was performed, which revealed bilateral small kidneys. Therefore, we further performed contrast-enhanced abdominal computed tomography (CT), which revealed a markedly small right kidney (5.7 cm 4.3 cm), segmental cortical thinning and dilated calices in the upper part of the left kidney, and no urinary tract abnormalities (Fig. 1A).
Renal scintigrams and renograms revealed markedly reduced accumulation or perfusion of technetium-99mdiethylenetriaminepentaacetic acid in the right kidney. Moreover, renal arteriography revealed uniformly small renal arteries from the aorta in the right kidney (Fig. 1B) and narrowed renal arteries with tiny renal arterial branches in the upper part of the left kidney (Fig. 1C), but no renal artery stenosis in either kidney. In the nephrographic phase, the normal parenchymal tissue remained segmentally only in the left kidney (Fig. 1D). The patient had no clinical or laboratory evidence of vasculitis or collagen diseases or history of frequent urinary tract infections. Because of his severe bilateral renal atrophy and because his blood pressure was controlled at around 120/70 mmHg with mild sodium restriction, we did not perform any surgical procedures or pathological examination, and we discharged him. Five months after discharge, his diabetic control remained good, but his systolic blood pressure was elevated to around 145–150 mmHg and renal function had deteriorated, with overt proteinuria (serum creatinine, 114.2 mmol/l; proteinuria, 0.77 g/day) (Table 1). Therefore, strict blood pressure control was initiated, and his renal function and proteinuria had improved by 1 year after the admission (Table 1). This present patient with a 10-year history of hypertensive type 2 DM showed mild renal dysfunction associated with microalbuminuria. We initially suspected diabetic nephropathy, but we incidentally found that he showed marked bilateral renal morphological abnormalities. No renal vascular lesions (i.e. atherosclerosis, or arteriosclerosis) were identified; thus, DM-related vascular lesions might not have contributed to the development of his morphological renal anomaly. Further, radiological examination revealed that the normal renal parenchymal tissue was separated from an atrophic lesion containing a thin cortex overlying dilated calices in the left kidney, which is consistent with the character of segmental renal hypoplasia, i.e., AskUpmark kidney [4–7]. The complex anomaly known as AskUpmark kidney was first described in 1929 by Erik AskUpmark [4]. This renal anomaly is frequently unilateral, but bilaterally asymmetrical hypoplasia has also been reported. The Ask-Upmark kidney, also known as renal segmental hypoplasia, was originally described as a congenital abnormality. However, recent clinical and experimental studies indicate that vesicoureteral reflux in utero or in infancy might play an important role in the development of
e23
diabetes research and clinical practice 80 (2008) e22–e24
Fig. 1 – Contrast-enhanced abdominal computed tomography revealed a markedly small right kidney (5.7 cm T 4.3 cm), segmental cortical thinning and dilated calices in the upper part of the left kidney (A). Renal arteriography revealed uniformly small renal arteries arising from the aorta in the right kidney (B), and the upper part of the left kidney (C), but no renal artery stenosis. Selective renal arteriography reveals minimal cortex in the upper part of the left kidney (D).
the renal defects [5]. Clinically, Ask-Upmark kidney usually presents with severe hypertension, or proteinuria, or renal dysfunction in pediatric or adolescent patients [6]. However, there is a case report describing hypertension and renal
dysfunction identified in a middle-aged adult with this segmental renal hypoplasia [7]. Although our patient showed no evidence of vesicoureteral reflux in adulthood, it has been argued that the absence of reflux at the time
Table 1 – The patient’s clinical course
Blood pressure (mmHg) Glucose (mmol/l)a Hemoglobin A1c (%)b Creatinine (mmol/l)c BUN (mmol/l) 24-h Ccr (ml/min) e-GFR (ml/(min 1.73 m2)) AER (mg/min) Proteinuria (g/day) Medication
Admission
5M
8M
10 M
12 M
120/70 12.06 11.8 96.5 5.71 77.6 60.6 105.8 0.23
145/95 13.78 7.1 114.2 8.93
130/90 17.39 9.2 100.0 5.71
120/88 8.39 6.2 105.31 7.50
47.6
54.3
0.77
0.45
125/88 8.67 12.4 115.0 6.07 72 47.2 121.7 0.52
51.4 0.28
Candesartan 4 mg Amlodipine 5 mg Salt restriction (6 g/day)
BUN: blood urea nitrogen (reference range: 2.86–7.14). 24-h Ccr: 24-h creatinine clearance. e-GFR: estimated glomerular filtration rate calculated using the MDRD study equation [13]. AER: albumin excretion ratio (reference range: 20–200). a Reference range: 4.17–6.11. b Reference range: 4.3–5.8. c Reference range: 44.3–97.46.
e24
diabetes research and clinical practice 80 (2008) e22–e24
diagnosis cannot rule it out as the initial cause of the atrophic kidney [6,7]. As observed in reflux nephropathy, renal parenchymal loss (nephron loss) might induce glomerular hypertension and hyperfiltration in the remnant glomeruli. This overload on remnant glomeruli might induce the morphological changes of glomerular hypertrophy, which progress to glomerulosclerosis resulting in microalbuminuria, overt proteinuria, and renal dysfunction [8]. It has also been reported that the threshold of progression of renal failure is associated with relatively mild clinical abnormalities, i.e., GFR of 70 ml/min and urinary protein excretion of 105 mg/day, in reflux nephropathy [9]. We believe that a similar mechanism might have contributed to the development of our patient’s renal manifestations; thus, strict blood control with an angiotensin II receptor blocker, which might decrease glomerular blood pressure, could improve proteinuria and renal dysfunction in our case. The correct diagnosis is essential for patient with DM associated with renal disease because prognosis and treatment vary according to the underlying cause. Previous reports describe that the major clinical characteristics suggesting non-diabetic renal diseases in DM patients include: (1) onset of overt proteinuria less than 5 years from the onset of diabetes; (2) prominent dysmorphic hematuria or red blood cell urinary casts; (3) abrupt onset or rapid progression of renal disease; (4) normal blood pressure with overt proteinuria and renal dysfunction; (5) absence of retinopathy or neuropathy [1–3,10–12]. These non-diabetic renal diseases have been reported to consist mainly of glomerular diseases (e.g. mesangial proliferative glomerulonephritis, minimal change nephropathy, and membranous nephropathy). However, morphological renal anomaly associated with DM resulting in renal dysfunction was not reported in these studies; thus, it is not known whether the 5 clinical criteria described above might also apply to the morphological renal anomaly in DM patients. Indeed, although our patient showed no diabetic retinopathy, he showed relatively long history of DM and hypertension, and he initially showed microalbuminuria without any remarkable urinary abnormalities, which might be easily misdiagnosed as typical diabetic nephropathy. This study indicates that renal morphological anomaly as seen in the present patient should be added to the list of diseases potentially associated with albuminuria/proteinuria, hypertension, and renal dysfunction in DM patients, and that renal morphological study should be performed when diabetic patients are seen.
Conflict of interest statement The authors state that they have no conflict of interest.
references
[1] H.-H. Parving, M. Mauer, E. Ritz, Diabetic nephropathy, in: B.M. Brenner (Ed.), Brenner & Recter’s Kidney, seventh ed., Saunders, Philadelphia, PA, 2004, pp. 1777–1818.
[2] G. Liu, H.-Y. Wang, A long story: from suspicion to identification of non-diabetic renal diseases in patients with diabetic mellitus, Nephrology 11 (2006) 531–532. [3] S. Olsen, Identification of non-diabetic glomerular disease in renal biopsies from diabetes; a dilemma, Nephrol. Dial. Transplant. 14 (1999) 1846–1849. [4] E. Ask-Upmark, Uber juvenile maligne Nephrosclerose und ihr Verhaltris zu Strunger in der Nierenentwiklung, Acta Path. Microbiol. Scand. 6 (1929) 383–442. [5] B.S. Arant, C. Sotelo-Avila, J. Bernstein, Segmental ‘‘hypoplasia’’ of the kidney (Ask-Upmark), J. Pediatr. 95 (1979) 931–939. [6] J. Babin, M. Sackett, C. Delage, M. Lebel, The Ask-Upmark kidney: a curable cause of hypertension in young patients, J. Hum. Hypertension 19 (2005) 315–316. [7] T. Sugimoto, Y. Tanaka, N. Nitta, T. Uzu, Y. Nishio, A. Kashiwagi, Renal segmental hypoplasia, Ask-Upmark kidney, in a patient with adult-onset hypertension, Intern. Med. 45 (2006) 1101–1102. [8] H. Matsuoka, Y. Nakashima, K. Oshima, Prognostic significance of the number of renal glomeruli in reflux nephropathy, BJU Int. 98 (2006) 172–176. [9] H. Matsuoka, K. Oshima, K. Sakamoto, T. Taguchi, S. Takebayashi, Renal pathology in patients with reflux nephropathy. The turning point in irreversible renal disease, Eur. Urol. 26 (1994) 153–159. [10] S. Olsen, C. Mogensen, How often is type II diabetes mellitus complicated with non-diabetic renal disease? Diabetologia 39 (1996) 1638–1645. [11] A. Tone, K. Shikata, M. Matsuda, H. Usui, S. Okada, D. Ogawa, et al., Clinical features of non-diabetic renal diseases in patients with type 2 diabetes, Diabetes Res. Clin. Pract. 69 (2005) 237–242. [12] S.S. Soni, S. Gowrishankar, A.G. Kishan, A. Ramam, Nondiabetic renal disease in type 2 diabetes mellitus, Nephrology 11 (2006) 533–537. [13] E. Imai, M. Horino, K. Nitta, K. Yamagata, K. Iseki, S. Hara, et al., Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease, Clin. Exp. Nephrol. 11 (2007) 41–50.
Tomoya Fuke Toshiro Sugimoto* Satoshi Ugi Yasushi Omura Yoshihiko Nishio Hiroshi Maegawa Atsunori Kashiwagi Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan *Corresponding author. Tel.: +81 77 548 2222; fax: +81 77 543 3858 E-mail address: [email protected] (T. Sugimoto) 9 March 2007 Published on line 21 February 2008 0168-8227/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2007.11.015
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Letter to the Editor Renal segmental hypoplasia, Ask-Upmark kidney, in a patient with microalbuminuric hypertensive type 2 diabetes mellitus Diabetic nephropathy is one of the most frequent and clinically important complications of diabetes mellitus (DM), and a major cause of end-stage renal disease [1]. The diagnosis of diabetic nephropathy is almost always based on clinical grounds, not on renal biopsy findings, supported by long history of diabetes, evidence of target organ damage (e.g. diabetic retinopathy), and albuminuria/proteinuria preceding azotemia [1–3]. However, it is not necessarily diabetic nephropathy when renal disease occurs in diabetic patient, of whether type 1 or type 2. We encountered a patient with type 2 DM-associated renal dysfunction due to renal segmental hypoplasia, Ask-Upmark kidney [4]. A 46-year-old Japanese man with a 10-year history of type 2 DM was referred and admitted to our hospital because of poor diabetic control, hypertension, and the elevated serum creatinine levels. At age 36, after DM and hypertension were noted, he had been treated with oral anti-diabetic agents and antihypertensive agents including an angiotensin II receptor blocker; however, his DM and blood pressure control had deteriorated and his serum creatinine levels had gradually increased during the most recent year; thus, he was referred to our hospital. No urinary abnormalities (i.e. hematuria, or dip stick-positive proteinuria) had ever been detected. On admission, his height was 166 cm, weight 83.0 kg, and blood pressure 124/96 mmHg. Physical examination disclosed no remarkable findings, but laboratory examination revealed mild renal impairment and poor DM control: serum creatinine was 96.5 mmol/l (reference, 44.3– 97.46); 24-h creatinine clearance was 77.6 ml/min; urinary albumin excretion rate was 105.8 mg/min without any urine dip-stick/sediments abnormalities; and hemoglobin A1c was 11.8%. Neurological examination and ophthalmologic examination revealed no signs of diabetic neuropathy and retinopathy, respectively. Subcutaneous insulin injection twice a day was started. As he also complained of back pain during the hospitalization, abdominal ultrasonography was performed, which revealed bilateral small kidneys. Therefore, we further performed contrast-enhanced abdominal computed tomography (CT), which revealed a markedly small right kidney (5.7 cm 4.3 cm), segmental cortical thinning and dilated calices in the upper part of the left kidney, and no urinary tract abnormalities (Fig. 1A).
Renal scintigrams and renograms revealed markedly reduced accumulation or perfusion of technetium-99mdiethylenetriaminepentaacetic acid in the right kidney. Moreover, renal arteriography revealed uniformly small renal arteries from the aorta in the right kidney (Fig. 1B) and narrowed renal arteries with tiny renal arterial branches in the upper part of the left kidney (Fig. 1C), but no renal artery stenosis in either kidney. In the nephrographic phase, the normal parenchymal tissue remained segmentally only in the left kidney (Fig. 1D). The patient had no clinical or laboratory evidence of vasculitis or collagen diseases or history of frequent urinary tract infections. Because of his severe bilateral renal atrophy and because his blood pressure was controlled at around 120/70 mmHg with mild sodium restriction, we did not perform any surgical procedures or pathological examination, and we discharged him. Five months after discharge, his diabetic control remained good, but his systolic blood pressure was elevated to around 145–150 mmHg and renal function had deteriorated, with overt proteinuria (serum creatinine, 114.2 mmol/l; proteinuria, 0.77 g/day) (Table 1). Therefore, strict blood pressure control was initiated, and his renal function and proteinuria had improved by 1 year after the admission (Table 1). This present patient with a 10-year history of hypertensive type 2 DM showed mild renal dysfunction associated with microalbuminuria. We initially suspected diabetic nephropathy, but we incidentally found that he showed marked bilateral renal morphological abnormalities. No renal vascular lesions (i.e. atherosclerosis, or arteriosclerosis) were identified; thus, DM-related vascular lesions might not have contributed to the development of his morphological renal anomaly. Further, radiological examination revealed that the normal renal parenchymal tissue was separated from an atrophic lesion containing a thin cortex overlying dilated calices in the left kidney, which is consistent with the character of segmental renal hypoplasia, i.e., AskUpmark kidney [4–7]. The complex anomaly known as AskUpmark kidney was first described in 1929 by Erik AskUpmark [4]. This renal anomaly is frequently unilateral, but bilaterally asymmetrical hypoplasia has also been reported. The Ask-Upmark kidney, also known as renal segmental hypoplasia, was originally described as a congenital abnormality. However, recent clinical and experimental studies indicate that vesicoureteral reflux in utero or in infancy might play an important role in the development of
e23
diabetes research and clinical practice 80 (2008) e22–e24
Fig. 1 – Contrast-enhanced abdominal computed tomography revealed a markedly small right kidney (5.7 cm T 4.3 cm), segmental cortical thinning and dilated calices in the upper part of the left kidney (A). Renal arteriography revealed uniformly small renal arteries arising from the aorta in the right kidney (B), and the upper part of the left kidney (C), but no renal artery stenosis. Selective renal arteriography reveals minimal cortex in the upper part of the left kidney (D).
the renal defects [5]. Clinically, Ask-Upmark kidney usually presents with severe hypertension, or proteinuria, or renal dysfunction in pediatric or adolescent patients [6]. However, there is a case report describing hypertension and renal
dysfunction identified in a middle-aged adult with this segmental renal hypoplasia [7]. Although our patient showed no evidence of vesicoureteral reflux in adulthood, it has been argued that the absence of reflux at the time
Table 1 – The patient’s clinical course
Blood pressure (mmHg) Glucose (mmol/l)a Hemoglobin A1c (%)b Creatinine (mmol/l)c BUN (mmol/l) 24-h Ccr (ml/min) e-GFR (ml/(min 1.73 m2)) AER (mg/min) Proteinuria (g/day) Medication
Admission
5M
8M
10 M
12 M
120/70 12.06 11.8 96.5 5.71 77.6 60.6 105.8 0.23
145/95 13.78 7.1 114.2 8.93
130/90 17.39 9.2 100.0 5.71
120/88 8.39 6.2 105.31 7.50
47.6
54.3
0.77
0.45
125/88 8.67 12.4 115.0 6.07 72 47.2 121.7 0.52
51.4 0.28
Candesartan 4 mg Amlodipine 5 mg Salt restriction (6 g/day)
BUN: blood urea nitrogen (reference range: 2.86–7.14). 24-h Ccr: 24-h creatinine clearance. e-GFR: estimated glomerular filtration rate calculated using the MDRD study equation [13]. AER: albumin excretion ratio (reference range: 20–200). a Reference range: 4.17–6.11. b Reference range: 4.3–5.8. c Reference range: 44.3–97.46.
e24
diabetes research and clinical practice 80 (2008) e22–e24
diagnosis cannot rule it out as the initial cause of the atrophic kidney [6,7]. As observed in reflux nephropathy, renal parenchymal loss (nephron loss) might induce glomerular hypertension and hyperfiltration in the remnant glomeruli. This overload on remnant glomeruli might induce the morphological changes of glomerular hypertrophy, which progress to glomerulosclerosis resulting in microalbuminuria, overt proteinuria, and renal dysfunction [8]. It has also been reported that the threshold of progression of renal failure is associated with relatively mild clinical abnormalities, i.e., GFR of 70 ml/min and urinary protein excretion of 105 mg/day, in reflux nephropathy [9]. We believe that a similar mechanism might have contributed to the development of our patient’s renal manifestations; thus, strict blood control with an angiotensin II receptor blocker, which might decrease glomerular blood pressure, could improve proteinuria and renal dysfunction in our case. The correct diagnosis is essential for patient with DM associated with renal disease because prognosis and treatment vary according to the underlying cause. Previous reports describe that the major clinical characteristics suggesting non-diabetic renal diseases in DM patients include: (1) onset of overt proteinuria less than 5 years from the onset of diabetes; (2) prominent dysmorphic hematuria or red blood cell urinary casts; (3) abrupt onset or rapid progression of renal disease; (4) normal blood pressure with overt proteinuria and renal dysfunction; (5) absence of retinopathy or neuropathy [1–3,10–12]. These non-diabetic renal diseases have been reported to consist mainly of glomerular diseases (e.g. mesangial proliferative glomerulonephritis, minimal change nephropathy, and membranous nephropathy). However, morphological renal anomaly associated with DM resulting in renal dysfunction was not reported in these studies; thus, it is not known whether the 5 clinical criteria described above might also apply to the morphological renal anomaly in DM patients. Indeed, although our patient showed no diabetic retinopathy, he showed relatively long history of DM and hypertension, and he initially showed microalbuminuria without any remarkable urinary abnormalities, which might be easily misdiagnosed as typical diabetic nephropathy. This study indicates that renal morphological anomaly as seen in the present patient should be added to the list of diseases potentially associated with albuminuria/proteinuria, hypertension, and renal dysfunction in DM patients, and that renal morphological study should be performed when diabetic patients are seen.
Conflict of interest statement The authors state that they have no conflict of interest.
references
[1] H.-H. Parving, M. Mauer, E. Ritz, Diabetic nephropathy, in: B.M. Brenner (Ed.), Brenner & Recter’s Kidney, seventh ed., Saunders, Philadelphia, PA, 2004, pp. 1777–1818.
[2] G. Liu, H.-Y. Wang, A long story: from suspicion to identification of non-diabetic renal diseases in patients with diabetic mellitus, Nephrology 11 (2006) 531–532. [3] S. Olsen, Identification of non-diabetic glomerular disease in renal biopsies from diabetes; a dilemma, Nephrol. Dial. Transplant. 14 (1999) 1846–1849. [4] E. Ask-Upmark, Uber juvenile maligne Nephrosclerose und ihr Verhaltris zu Strunger in der Nierenentwiklung, Acta Path. Microbiol. Scand. 6 (1929) 383–442. [5] B.S. Arant, C. Sotelo-Avila, J. Bernstein, Segmental ‘‘hypoplasia’’ of the kidney (Ask-Upmark), J. Pediatr. 95 (1979) 931–939. [6] J. Babin, M. Sackett, C. Delage, M. Lebel, The Ask-Upmark kidney: a curable cause of hypertension in young patients, J. Hum. Hypertension 19 (2005) 315–316. [7] T. Sugimoto, Y. Tanaka, N. Nitta, T. Uzu, Y. Nishio, A. Kashiwagi, Renal segmental hypoplasia, Ask-Upmark kidney, in a patient with adult-onset hypertension, Intern. Med. 45 (2006) 1101–1102. [8] H. Matsuoka, Y. Nakashima, K. Oshima, Prognostic significance of the number of renal glomeruli in reflux nephropathy, BJU Int. 98 (2006) 172–176. [9] H. Matsuoka, K. Oshima, K. Sakamoto, T. Taguchi, S. Takebayashi, Renal pathology in patients with reflux nephropathy. The turning point in irreversible renal disease, Eur. Urol. 26 (1994) 153–159. [10] S. Olsen, C. Mogensen, How often is type II diabetes mellitus complicated with non-diabetic renal disease? Diabetologia 39 (1996) 1638–1645. [11] A. Tone, K. Shikata, M. Matsuda, H. Usui, S. Okada, D. Ogawa, et al., Clinical features of non-diabetic renal diseases in patients with type 2 diabetes, Diabetes Res. Clin. Pract. 69 (2005) 237–242. [12] S.S. Soni, S. Gowrishankar, A.G. Kishan, A. Ramam, Nondiabetic renal disease in type 2 diabetes mellitus, Nephrology 11 (2006) 533–537. [13] E. Imai, M. Horino, K. Nitta, K. Yamagata, K. Iseki, S. Hara, et al., Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease, Clin. Exp. Nephrol. 11 (2007) 41–50.
Tomoya Fuke Toshiro Sugimoto* Satoshi Ugi Yasushi Omura Yoshihiko Nishio Hiroshi Maegawa Atsunori Kashiwagi Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan *Corresponding author. Tel.: +81 77 548 2222; fax: +81 77 543 3858 E-mail address: [email protected] (T. Sugimoto) 9 March 2007 Published on line 21 February 2008 0168-8227/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2007.11.015