- Email: [email protected]
Does peripheral neuropathy invariably accompany nephropathy in type 1 diabetes mellitus?
Diabetes Research and Clinical Practice 39 (1998) 55 – 61
Does peripheral neuropathy invariably accompany nephropathy in type 1 diabetes mellitus? J.E. Shaw a,*, R. Gokal b, S. Hollis c, A.J.M. Boulton a b
a Department of Medicine, Manchester Royal Infirmary, Manchester, UK Department of Renal Medicine, Manchester Royal Infirmary, Manchester, UK c Medical Statistics Unit, Lancaster Uni6ersity, Lancaster, UK
Received 12 November 1997; received in revised form 12 November 1997; accepted 25 November 1997
Abstract In patients with Type 1 diabetes mellitus complicated by diabetic nephropathy and retinopathy, it is usually believed that significant neuropathy is almost universal, but few studies have directly addressed this. This study assessed neuropathy in 91 such subjects, using vibration perception thresholds (VPT) and the neuropathy disability score (NDS). A total of 34% of subjects had no neuropathy on age adjusted VPT (z score) and 26% had no neuropathy on NDS. The severity of neuropathy as measured by VPT z score was related to increasing glycated haemoglobin (P =0.02) and male sex (P= 0.03), and NDS was independently associated with age (P B 0.0001) and HbA1c (P=0.003). These factors together accounted for only 12 and 31% of the total variance in VPT z score and NDS, respectively. In conclusion, the study has shown that a significant proportion of patients with diabetic nephropathy are free of neuropathy, but the full explanation for their protection from neuropathy is unclear. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Diabetic neuropathy; Diabetic nephropathy; Diabetes mellitus; Renal transplantation
1. Introduction Peripheral neuropathy is a common diabetic complication and since, like retinopathy and * Corresponding author. Present address: International Diabetes Institute, 260 Kooyong Road, Caulfield 3162, Victoria, Australia. Tel.: + 61 3 92585050; fax: +61 3 92585090; e-mail: [email protected]
nephropathy, it is related to age, diabetes duration and glycaemic control, it is often assumed that in the presence of significant nephropathy and retinopathy, neuropathy is inevitable [1,2]. Studies of neuropathy in this population, however, are limited. Fernando et al. demonstrated that mean vibration perception threshold (VPT) and nerve conduction velocity are abnormal in patients with microalbuminuria and more so in
0168-8227/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 1 6 8 - 8 2 2 7 ( 9 7 ) 0 0 1 2 2 - 8
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J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61
those with overt nephropathy [3]. Pugh et al. examined the case notes of patients starting renal replacement therapy and found a diagnosis of neuropathy recorded in 84% of patients with Type 1 diabetes and 60% of those with Type 2 diabetes [4] and all of the 48 patients assessed prior to renal transplantation [5], were reported to have neuropathy. That the group as a whole has, on average, worse neurological function than nonnephropathic patients is clear even from this small number of studies, but data on the full spectrum of neurological function in patients with nephropathy has not previously been reported. Such information would, however, be valuable not only for quantifying the risk of foot problems (ulceration and lower limb amputation), but also for understanding the links between the different diabetic complications. In particular, the authors suspected that there existed a group of patients with significant nephropathy, but minimal neuropathy. Such a group would be interesting, as it may provide insights into the pathogenesis of and susceptibilities to the different complications. The study’s aim was therefore to describe the range of neuropathy in patients with Type 1 diabetes, complicated by nephropathy and to test the hypothesis that patients with nephropathy can be free of significant neuropathy.
2. Methods All patients with Type 1 diabetes attending a special diabetic nephropathy clinic within an 18month period were included in the study. Type 1 diabetes was defined as onset before age 40 and commencement of insulin within 2 years of diagnosis. Nephropathy was judged to be present if proteinuria was greater than 0.20 g/24 h and attributed to diabetes if the patient had retinopathy and there were no clinical signs suggestive of an alternative cause. Neuropathy was assessed by measuring the VPT at the great toe of the dominant foot, using a biothesiometer (Arnold Horwell, London, UK). The mean of three trials was used and a z score was derived after logarithmic transformation and correction for age, height and sex [6]. A z score of ‘0’ represents the 50th percen-
tile of the non-diabetic reference population and a score of ‘2’ represents the 97.5th percentile. Neuropathy was classified as absent (zB 2.0), mild (z= 2.0–3.0), moderate (z= 3.0–4.0) and severe (z\ 4.0). The raw VPT data were also used, as categorisation of severity, according to risk of ulceration, has been previously reported [7]. Based on this, neuropathy was classified as absent (0– 15V), mild (16–24V), moderate (25–39V) and severe (\ 39V). A clinical assessment of neuropathy was carried out using the modified neuropathy disability score (NDS), encompassing ankle reflexes, vibration, pain and temperature sensation [8]. Neuropathy was classified as absent (0– 2), mild (3–5), moderate (6–8) and severe (9–10). Serum creatinine, HbA1c and 24 h urinary protein was also measured.
2.1. Statistical methods Data were presented as means9 S.D. Logarithmic transformation was applied to creatinine and urinary protein (after replacing zeros by 0.1) and these data presented as geometric mean× /} anti-logged S.D. In order to identify associations with neuropathy, VPT (raw and z score) and NDS were treated as continuous variables and correlated with other factors using Spearman’s rank correlation. The most significant associations were determined by stepwise regression. Transplant patients were excluded from calculations for creatinine and 24-h urinary protein, as their current renal status does not reflect their past history.
3. Results A total of 91 subjects with Type 1 diabetes and nephropathy were studied. A total of 21 patients had previously undergone renal transplantation. Of these, 20 subjects were on cyclosporin, 15 on prednisolone, two on azathioprine and one on FK506. Background data on the subjects are shown in Table 1. For the whole group of 91 patients, the mean values for VPT, z score and NDS were 25V, 2.74 and 5.3, respectively, indicating high levels of neuropathy. Table 2 shows the percentage of subjects classified into each category
439 10 42 9 10 449 11
91 21 70
Age (year)
53
57 71
16 9 9 14 9 8 16 9 10
27 99
Age at onset (year)
27 9 8 28 9 6
% Male Diabetes duration (year)
182×/} 1.8
178×/}1.7 166×/} 1.4
Creatinine (mmol/l)
Data shown are the mean 9S.D. Creatinine and urinary protein are shown as geometric mean×/} anti-logged S.D. * P= 0.002 transplant versus non-transplant.
Whole group Transplants only Non-transplants
n
Table 1 Background data of all subjects
1.7×/} 2.5*
1.3×/}3.0 0.4×/}2.6*
24 h urine protein (g)
9.891.7
9.6 91.7 9.2 9 1.5
HbA1c
2.70 91.47
2.749 1.48 2.87 9 1.52
VPT z score
24 9 15
259 16 25 9 16
Raw VPT (V)
5.59 3.2
5.39 3.3 4.8 9 3.6
NDS
J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61 57
J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61
58
Table 2 The percentage of subjects in each category of neuropathy Neuropathy category
VPT z score
Raw VPT
NDS
Absent Mild Moderate Severe
34 19 26 22
40 22 12 26
26 27 24 24
the proportion of subjects free of neuropathy differed between those with background and proliferative retinopathy. Correlations between factors potentially associated with neuropathy and each of NDS and VPT z score are shown in Table 4. Using stepwise regression analysis and entering HbA1c first, HbA1c (P=0.02) and sex (P= 0.03) were independently associated with z score and together accounted for 12% of the variance in z score. Entering age first, age (PB 0.0001) and HbA1c (P=0.003) were independently associated with NDS and together accounted for 31% of the variance.
Data given as percentage values. Not all the columns add up to exactly 100%, as figures have been rounded.
of neuropathy by the three measurements and demonstrates that a substantial number of subjects are free of neuropathy. Of the subjects, 15% had no neuropathy as judged by both a normal NDS (B 3) and normal VPT z score (B 2.0) and 20% had a normal NDS and normal raw VPT (B 15V). Table 3 shows how a number of factors vary according to neuropathy classified by z score. Males had a higher mean ( +6 S.D.) z score than females (3.03 +6 1.48 versus 2.34 +6 1.40, P= 0.03), but there was no significant sex difference in NDS (5.53 versus 5.08, P \0.1). Transplant patients were evenly distributed between the neuropathy groups and had similar mean neuropathy scores to non-transplant patients (Table 1). The proportion of transplant patients free of neuropathy was 24% when considering either NDS and z score, or NDS and raw VPT. All 91 subjects had retinopathy and in only nine (five male, one transplant) was this background retinopathy. Neither the mean scores of the neuropathy measurements, nor
4. Discussion The data presented in this study confirm that although neuropathy is common and often severe in patients with nephropathy, up to one third appear to be free of neuropathy. This is quite different from earlier results from patients awaiting renal transplantation [5], in whom neuropathy was reported to affect all 48 patients studied. However, the diagnostic criteria were unclear in that study. In a large group of IDDM patients assessed prior to pancreatic transplantation (290 patients, of whom 139 also underwent kidney transplantation) Kennedy et al. found that only 7–13% had no neuropathy [9]. Whilst our study used simple clinical and quantitative sensory methods, which have been shown to correlate with foot ulceration and amputation [7,10],
Table 4 Correlations between neuropathy and other parameters VPT z score
Age Diabetes duration Age at onset HbA1c Creatinine 24 h urine protein
NDS
Correlation coefficient
P value
Correlation coefficient
P value
0.224 0.151 0.114 0.215 0.218 0.144
0.02 0.08 0.14 0.02 0.04 0.13
0.432 0.228 0.233 0.279 0.161 −0.135
0.00001 0.02 0.01 0.005 0.10 0.15
Spearman’s rank correlation used. Data on creatinine and 24 h urine protein exclude transplant patients.
48 41 71 74
B2.0 2.0–3.0 3.0–4.0 \4.0 23 18 25 26
% Transplants
41 9 10 39 9 9 46 912 46 9 8
Age (year) 27 98 23 99 29 98 29 97
Diabetes duration (year)
Values are given as percentages and mean 9S.D. Creatinine and urinary protein are shown as geometric mean×/}anti-logged S.D. Data on creatinine and 24 h urine protein exclude transplant patients.
% Male
VPT z score
Table 3 Associations with neuropathy as categorised by VPT z score
1498 16 911 18 9 10 16 98
Age at onset (year)
163×/} 1.7 158×/} 1.5 179×/} 2.0 256×/}2.0
Creatinine (mmol/l)
1.5×/}2.4 1.7×/}2.8 1.9×/}2.4 1.8×/} 3.0
24 h urine protein (g)
9.0 9 1.3 10.0 9 1.8 9.6 9 1.7 10.39 1.8
HbA1c
J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61 59
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J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61
Kennedy used an array of electrophysiological measurements and the relevance of subtle abnormalities in these parameters is not always clear in patients with longstanding diabetes. Furthermore, in an earlier report from Minneapolis, Navarro et al. reported that using less detailed electrophysiological investigations, 28% of patients being evaluated for pancreatic transplantation had no neuropathy [11]. As in other populations, better glycaemic control and younger age was associated with lesser degrees of neuropathy [12,13]. Age remained a significant association even when VPT was age corrected by the z score. Diabetes duration showed a less clear association than age, perhaps indicating that age is more important than duration in the development of neuropathy. HbA1c maintained its association when transplant patients, who may have improved their control posttransplant, were excluded. Amongst this group of patients in whom renal damage has arisen mainly from a combination of chronically poor glycaemic control and a long disease duration, it is surprising that age and HbA1c retain their usual association with neuropathy. Although conclusions are limited by the cross-sectional nature of the study, this seems to show the absence of a plateau effect between HbA1c and neuropathy and that neuropathy continues to become more severe and prevalent across a wide range of worsening glycaemic control. There was a strong association between male sex and neuropathy. This finding has not appeared in other studies [8,13 – 15] which have shown the prevalence of neuropathy to be unaffected by sex. Transplant patients had a similar pattern of neuropathy to non-transplant patients, although it might have been expected that as the study has shown a weak correlation of neuropathy and creatinine and that transplant patients have the most severe renal disease, they would also have very severe neuropathy. Improvement in neurological function following kidney transplant alone has not been a consistent finding in the literature. Though some small studies have shown a small early improvement [16,17], this has not borne out
by other, larger studies [18–20] and the relatively good neurological function in these patients might be at least partly explained by the fact that the study inevitably includes only survivors. Post-pancreatic transplant mortality rates have been shown to be higher in patients with peripheral neuropathy [11] and if this also applies to renal transplantation, then transplant patients with neuropathy would be less likely than those without neuropathy to survive and be included in this study. Although certain associations between nephropathy and neuropathy have been identified by this study, they are relatively weak as evidenced by the low correlation coefficients (all less than 0.45). This indicates that other, unmeasured factors, are of some importance. Those patients identified as having no neuropathy are the most interesting ones, as they may provide information on specific risk factors for specific complications. Two hypotheses for their existence are of particular interest. They may represent patients with some protective factor against neuropathy. Thus, despite diabetic control having been bad enough to result in both nephropathy and retinopathy, neurological function has been preserved. Alternatively, some patients may be especially vulnerable to nephropathy, whilst succumbing to neuropathy at more normal rates. A significant proportion of such patients would be expected to have normal neurological tests, despite having developed nephropathy. Thus, this group merits further study directed at such risk and protective factors, some of which may be genetic.
5. Conclusion The study has shown that a significant proportion of patients with diabetic nephropathy do not have neuropathy and that better glycaemic control, younger age and shorter diabetes duration are only part of the explanation.
References [1] P.J. Watkins, Diabetic nephropathy-prevalence, complications and treatment, Diabetic Med. 2 (1985) 7 – 12.
J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61 [2] A. Grenfell, P.J. Watkins, Clinical diabetic nephropathy: natural history and complications, Clin. Endocrinol. Metab. 15 (1986) 783–805. [3] D.J. Fernando, A. Hutchison, A. Veves, R. Gokal, A.J.M. Boulton, Risk factors for non-ischaemic foot ulceration in diabetic nephropathy, Diabetic Med. 8 (1991) 223 – 225. [4] J.A. Pugh, R. Medina, M. Ramirez, Comparison of the course to end-stage renal disease of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic nephropathy, Diabetologia 36 (1993) 1094–1098. [5] R.B. Khauli, A.C. Novick, W.E. Braun, D. Steimuller, C. Buszta, M. Goormastic, Improved results of cadaver renal transplantation in the diabetic patient, J. Urol. 130 (1983) 867 – 870. [6] P.G. Wiles, S.M. Pearce, P.J. Rice, J.M. Mitchell, Vibration perception threshold: influence of age, height, sex and smoking and calculation of accurate centile values, Diabetic Med. 8 (1991) 157–161. [7] M.J. Young, J.L. Breddy, A. Veves, A.J.M. Boulton, The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study, Diabetes Care 17 (1994) 557–560. [8] M.J. Young, A.J.M. Boulton, A.F. MacLeod, D.R.R. Williams, P.H. Sonksen, A multicentre study of the prevalence of diabetic peripheral neuropathy in the UK hospital clinic population, Diabetologia 36 (1993) 150– 154. [9] W.R. Kennedy, X. Navarro, D.E. Sutherland, Neuropathy profile of diabetic patients in a pancreas transplantation program, Neurology 45 (1995) 773–780. [10] J.V. Selby, D. Zhang, Risk factors for lower extremity amputations in persons with diabetes, Diabetes Care 18 (1995) 509 – 516. [11] X. Navarro, W.R. Kennedy, R.B. Loewenson, D.E. Sutherland, Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction and mortality in
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diabetes mellitus, Diabetes 39 (1990) 802 – 806. [12] The Diabetes Control and Complications Trial Research Group, The effect of intensive diabetes therapy on the development and progression of neuropathy, Ann. Intern. Med. 122 (1995) 561 – 568. [13] S. Tesfaye, L.K. Stevens, J.M. Stephenson, et al., Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM complications study, Diabetologia 39 (1996) 1377 – 1384. [14] R.E. Maser, A.R. Steenkiste, J.S. Dorman, et al., Epidemiological correlates of diabetic neuropathy. report from Pittsburgh epidemiology of diabetes complications study, Diabetes 38 (1989) 1456 – 1461. [15] D.P. Walters, W. Gatting, M.A. Mullee, R.D. Hill, The prevalence of diabetic distal sensory neuropathy in an English community, Diabetic Med. 9 (1992) 349 – 353. [16] G. Solders, H. Wilczek, R. Gunnarsson, G. Tyden, A. Persson, C.G. Groth, Effects of combined pancreatic and renal transplantation on diabetic neuropathy: a two year follow-up study, Lancet 329 (1987) 1232 – 1235. [17] G. Solders, G. Tyden, A. Persson, C.G. Groth, Improvement of nerve conduction in diabetic neuropathy. A follow up study 4 years after combined pancreatic and renal transplantation, Diabetes 41 (1992) 946 – 951. [18] G. Comi, G. Galardi, S. Amadio, et al., Neurophysiological study of the effect of combined kidney and pancreas transplantation on diabetic neuropathy: a 2-year followup evaluation, Diabetologia 34 (Suppl 1) (1991) S103 – S107. [19] W. Muller-Felber, R. Landgraf, R. Scheuer, et al., Diabetic neuropathy 3 years after successful pancreas and kidney transplantation, Diabetes 42 (1993) 1482 – 1486. [20] J.S. Najarian, D.B. Kaufman, D.S. Fryd, et al., Longterm survival following kidney transplantation in 100 type 1 diabetic patients, Transplantation 47 (1989) 106 – 113.
Does peripheral neuropathy invariably accompany nephropathy in type 1 diabetes mellitus? J.E. Shaw a,*, R. Gokal b, S. Hollis c, A.J.M. Boulton a b
a Department of Medicine, Manchester Royal Infirmary, Manchester, UK Department of Renal Medicine, Manchester Royal Infirmary, Manchester, UK c Medical Statistics Unit, Lancaster Uni6ersity, Lancaster, UK
Received 12 November 1997; received in revised form 12 November 1997; accepted 25 November 1997
Abstract In patients with Type 1 diabetes mellitus complicated by diabetic nephropathy and retinopathy, it is usually believed that significant neuropathy is almost universal, but few studies have directly addressed this. This study assessed neuropathy in 91 such subjects, using vibration perception thresholds (VPT) and the neuropathy disability score (NDS). A total of 34% of subjects had no neuropathy on age adjusted VPT (z score) and 26% had no neuropathy on NDS. The severity of neuropathy as measured by VPT z score was related to increasing glycated haemoglobin (P =0.02) and male sex (P= 0.03), and NDS was independently associated with age (P B 0.0001) and HbA1c (P=0.003). These factors together accounted for only 12 and 31% of the total variance in VPT z score and NDS, respectively. In conclusion, the study has shown that a significant proportion of patients with diabetic nephropathy are free of neuropathy, but the full explanation for their protection from neuropathy is unclear. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Diabetic neuropathy; Diabetic nephropathy; Diabetes mellitus; Renal transplantation
1. Introduction Peripheral neuropathy is a common diabetic complication and since, like retinopathy and * Corresponding author. Present address: International Diabetes Institute, 260 Kooyong Road, Caulfield 3162, Victoria, Australia. Tel.: + 61 3 92585050; fax: +61 3 92585090; e-mail: [email protected]
nephropathy, it is related to age, diabetes duration and glycaemic control, it is often assumed that in the presence of significant nephropathy and retinopathy, neuropathy is inevitable [1,2]. Studies of neuropathy in this population, however, are limited. Fernando et al. demonstrated that mean vibration perception threshold (VPT) and nerve conduction velocity are abnormal in patients with microalbuminuria and more so in
0168-8227/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 1 6 8 - 8 2 2 7 ( 9 7 ) 0 0 1 2 2 - 8
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J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61
those with overt nephropathy [3]. Pugh et al. examined the case notes of patients starting renal replacement therapy and found a diagnosis of neuropathy recorded in 84% of patients with Type 1 diabetes and 60% of those with Type 2 diabetes [4] and all of the 48 patients assessed prior to renal transplantation [5], were reported to have neuropathy. That the group as a whole has, on average, worse neurological function than nonnephropathic patients is clear even from this small number of studies, but data on the full spectrum of neurological function in patients with nephropathy has not previously been reported. Such information would, however, be valuable not only for quantifying the risk of foot problems (ulceration and lower limb amputation), but also for understanding the links between the different diabetic complications. In particular, the authors suspected that there existed a group of patients with significant nephropathy, but minimal neuropathy. Such a group would be interesting, as it may provide insights into the pathogenesis of and susceptibilities to the different complications. The study’s aim was therefore to describe the range of neuropathy in patients with Type 1 diabetes, complicated by nephropathy and to test the hypothesis that patients with nephropathy can be free of significant neuropathy.
2. Methods All patients with Type 1 diabetes attending a special diabetic nephropathy clinic within an 18month period were included in the study. Type 1 diabetes was defined as onset before age 40 and commencement of insulin within 2 years of diagnosis. Nephropathy was judged to be present if proteinuria was greater than 0.20 g/24 h and attributed to diabetes if the patient had retinopathy and there were no clinical signs suggestive of an alternative cause. Neuropathy was assessed by measuring the VPT at the great toe of the dominant foot, using a biothesiometer (Arnold Horwell, London, UK). The mean of three trials was used and a z score was derived after logarithmic transformation and correction for age, height and sex [6]. A z score of ‘0’ represents the 50th percen-
tile of the non-diabetic reference population and a score of ‘2’ represents the 97.5th percentile. Neuropathy was classified as absent (zB 2.0), mild (z= 2.0–3.0), moderate (z= 3.0–4.0) and severe (z\ 4.0). The raw VPT data were also used, as categorisation of severity, according to risk of ulceration, has been previously reported [7]. Based on this, neuropathy was classified as absent (0– 15V), mild (16–24V), moderate (25–39V) and severe (\ 39V). A clinical assessment of neuropathy was carried out using the modified neuropathy disability score (NDS), encompassing ankle reflexes, vibration, pain and temperature sensation [8]. Neuropathy was classified as absent (0– 2), mild (3–5), moderate (6–8) and severe (9–10). Serum creatinine, HbA1c and 24 h urinary protein was also measured.
2.1. Statistical methods Data were presented as means9 S.D. Logarithmic transformation was applied to creatinine and urinary protein (after replacing zeros by 0.1) and these data presented as geometric mean× /} anti-logged S.D. In order to identify associations with neuropathy, VPT (raw and z score) and NDS were treated as continuous variables and correlated with other factors using Spearman’s rank correlation. The most significant associations were determined by stepwise regression. Transplant patients were excluded from calculations for creatinine and 24-h urinary protein, as their current renal status does not reflect their past history.
3. Results A total of 91 subjects with Type 1 diabetes and nephropathy were studied. A total of 21 patients had previously undergone renal transplantation. Of these, 20 subjects were on cyclosporin, 15 on prednisolone, two on azathioprine and one on FK506. Background data on the subjects are shown in Table 1. For the whole group of 91 patients, the mean values for VPT, z score and NDS were 25V, 2.74 and 5.3, respectively, indicating high levels of neuropathy. Table 2 shows the percentage of subjects classified into each category
439 10 42 9 10 449 11
91 21 70
Age (year)
53
57 71
16 9 9 14 9 8 16 9 10
27 99
Age at onset (year)
27 9 8 28 9 6
% Male Diabetes duration (year)
182×/} 1.8
178×/}1.7 166×/} 1.4
Creatinine (mmol/l)
Data shown are the mean 9S.D. Creatinine and urinary protein are shown as geometric mean×/} anti-logged S.D. * P= 0.002 transplant versus non-transplant.
Whole group Transplants only Non-transplants
n
Table 1 Background data of all subjects
1.7×/} 2.5*
1.3×/}3.0 0.4×/}2.6*
24 h urine protein (g)
9.891.7
9.6 91.7 9.2 9 1.5
HbA1c
2.70 91.47
2.749 1.48 2.87 9 1.52
VPT z score
24 9 15
259 16 25 9 16
Raw VPT (V)
5.59 3.2
5.39 3.3 4.8 9 3.6
NDS
J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61 57
J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61
58
Table 2 The percentage of subjects in each category of neuropathy Neuropathy category
VPT z score
Raw VPT
NDS
Absent Mild Moderate Severe
34 19 26 22
40 22 12 26
26 27 24 24
the proportion of subjects free of neuropathy differed between those with background and proliferative retinopathy. Correlations between factors potentially associated with neuropathy and each of NDS and VPT z score are shown in Table 4. Using stepwise regression analysis and entering HbA1c first, HbA1c (P=0.02) and sex (P= 0.03) were independently associated with z score and together accounted for 12% of the variance in z score. Entering age first, age (PB 0.0001) and HbA1c (P=0.003) were independently associated with NDS and together accounted for 31% of the variance.
Data given as percentage values. Not all the columns add up to exactly 100%, as figures have been rounded.
of neuropathy by the three measurements and demonstrates that a substantial number of subjects are free of neuropathy. Of the subjects, 15% had no neuropathy as judged by both a normal NDS (B 3) and normal VPT z score (B 2.0) and 20% had a normal NDS and normal raw VPT (B 15V). Table 3 shows how a number of factors vary according to neuropathy classified by z score. Males had a higher mean ( +6 S.D.) z score than females (3.03 +6 1.48 versus 2.34 +6 1.40, P= 0.03), but there was no significant sex difference in NDS (5.53 versus 5.08, P \0.1). Transplant patients were evenly distributed between the neuropathy groups and had similar mean neuropathy scores to non-transplant patients (Table 1). The proportion of transplant patients free of neuropathy was 24% when considering either NDS and z score, or NDS and raw VPT. All 91 subjects had retinopathy and in only nine (five male, one transplant) was this background retinopathy. Neither the mean scores of the neuropathy measurements, nor
4. Discussion The data presented in this study confirm that although neuropathy is common and often severe in patients with nephropathy, up to one third appear to be free of neuropathy. This is quite different from earlier results from patients awaiting renal transplantation [5], in whom neuropathy was reported to affect all 48 patients studied. However, the diagnostic criteria were unclear in that study. In a large group of IDDM patients assessed prior to pancreatic transplantation (290 patients, of whom 139 also underwent kidney transplantation) Kennedy et al. found that only 7–13% had no neuropathy [9]. Whilst our study used simple clinical and quantitative sensory methods, which have been shown to correlate with foot ulceration and amputation [7,10],
Table 4 Correlations between neuropathy and other parameters VPT z score
Age Diabetes duration Age at onset HbA1c Creatinine 24 h urine protein
NDS
Correlation coefficient
P value
Correlation coefficient
P value
0.224 0.151 0.114 0.215 0.218 0.144
0.02 0.08 0.14 0.02 0.04 0.13
0.432 0.228 0.233 0.279 0.161 −0.135
0.00001 0.02 0.01 0.005 0.10 0.15
Spearman’s rank correlation used. Data on creatinine and 24 h urine protein exclude transplant patients.
48 41 71 74
B2.0 2.0–3.0 3.0–4.0 \4.0 23 18 25 26
% Transplants
41 9 10 39 9 9 46 912 46 9 8
Age (year) 27 98 23 99 29 98 29 97
Diabetes duration (year)
Values are given as percentages and mean 9S.D. Creatinine and urinary protein are shown as geometric mean×/}anti-logged S.D. Data on creatinine and 24 h urine protein exclude transplant patients.
% Male
VPT z score
Table 3 Associations with neuropathy as categorised by VPT z score
1498 16 911 18 9 10 16 98
Age at onset (year)
163×/} 1.7 158×/} 1.5 179×/} 2.0 256×/}2.0
Creatinine (mmol/l)
1.5×/}2.4 1.7×/}2.8 1.9×/}2.4 1.8×/} 3.0
24 h urine protein (g)
9.0 9 1.3 10.0 9 1.8 9.6 9 1.7 10.39 1.8
HbA1c
J.E. Shaw et al. / Diabetes Research and Clinical Practice 39 (1998) 55–61 59
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Kennedy used an array of electrophysiological measurements and the relevance of subtle abnormalities in these parameters is not always clear in patients with longstanding diabetes. Furthermore, in an earlier report from Minneapolis, Navarro et al. reported that using less detailed electrophysiological investigations, 28% of patients being evaluated for pancreatic transplantation had no neuropathy [11]. As in other populations, better glycaemic control and younger age was associated with lesser degrees of neuropathy [12,13]. Age remained a significant association even when VPT was age corrected by the z score. Diabetes duration showed a less clear association than age, perhaps indicating that age is more important than duration in the development of neuropathy. HbA1c maintained its association when transplant patients, who may have improved their control posttransplant, were excluded. Amongst this group of patients in whom renal damage has arisen mainly from a combination of chronically poor glycaemic control and a long disease duration, it is surprising that age and HbA1c retain their usual association with neuropathy. Although conclusions are limited by the cross-sectional nature of the study, this seems to show the absence of a plateau effect between HbA1c and neuropathy and that neuropathy continues to become more severe and prevalent across a wide range of worsening glycaemic control. There was a strong association between male sex and neuropathy. This finding has not appeared in other studies [8,13 – 15] which have shown the prevalence of neuropathy to be unaffected by sex. Transplant patients had a similar pattern of neuropathy to non-transplant patients, although it might have been expected that as the study has shown a weak correlation of neuropathy and creatinine and that transplant patients have the most severe renal disease, they would also have very severe neuropathy. Improvement in neurological function following kidney transplant alone has not been a consistent finding in the literature. Though some small studies have shown a small early improvement [16,17], this has not borne out
by other, larger studies [18–20] and the relatively good neurological function in these patients might be at least partly explained by the fact that the study inevitably includes only survivors. Post-pancreatic transplant mortality rates have been shown to be higher in patients with peripheral neuropathy [11] and if this also applies to renal transplantation, then transplant patients with neuropathy would be less likely than those without neuropathy to survive and be included in this study. Although certain associations between nephropathy and neuropathy have been identified by this study, they are relatively weak as evidenced by the low correlation coefficients (all less than 0.45). This indicates that other, unmeasured factors, are of some importance. Those patients identified as having no neuropathy are the most interesting ones, as they may provide information on specific risk factors for specific complications. Two hypotheses for their existence are of particular interest. They may represent patients with some protective factor against neuropathy. Thus, despite diabetic control having been bad enough to result in both nephropathy and retinopathy, neurological function has been preserved. Alternatively, some patients may be especially vulnerable to nephropathy, whilst succumbing to neuropathy at more normal rates. A significant proportion of such patients would be expected to have normal neurological tests, despite having developed nephropathy. Thus, this group merits further study directed at such risk and protective factors, some of which may be genetic.
5. Conclusion The study has shown that a significant proportion of patients with diabetic nephropathy do not have neuropathy and that better glycaemic control, younger age and shorter diabetes duration are only part of the explanation.
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