Severe Depletion of Intraepidermal Nerve Fibers in Skin Biopsies of Pancreas Transplant Recipients

Bouc̆ek, P; Havrdova, T.; Voska, Luděk; Lodererová, Alena; Saudek, F; Lipar, K.; Janoušek, L; Adamec, M; Sommer, Claudia

doi:10.1016/j.transproceed.2005.09.047

Cited by 25 publications

(27 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we have demonstrated a highly significant loss of corneal nerve fibers in type 1 diabetic patients undergoing pancreas transplantation, which confirms previous studies demonstrating severe neuropathy in patients undergoing pancreas transplantation (13)(14)(15). However, despite this considerable baseline damage, we have shown a significant improvement in corneal NFD and NFL within 6 months of transplantation, indicating an early repair process with the restoration of euglycemia.…”

Section: After Transplantationsupporting

confidence: 91%

“…This result is in keeping with the lack of improvement in heart rate variability 43 months after simultaneous pancreas and kidney transplantation (SPK) (14). Neuropathy is, of course, extremely severe at this stage, as evidenced recently by the demonstration of severe intraepidermal nerve fiber depletion in pancreas transplant recipients, suggesting that long-term follow-up is necessary to assess posttransplant nerve fiber regeneration (15).…”

supporting

confidence: 61%

“…However, autonomic function did not improve (13), as confirmed by another recent study (14). At this stage, most patients receiving transplantation will have severe nerve fiber damage as evidenced by marked depletion of intraepidermal nerve fibers (15). In addition, concomitant uremia, which often coexists in these patients, may contribute to nerve damage and limit repair, although renal transplantation in patients with diabetic nephropathy has not been shown to halt progression of neuropathy (26), and there was no difference in outcomes when pancreas alone transplantation was compared with combined pancreas and renal transplantation (13).…”

Section: After Transplantationmentioning

confidence: 75%

See 2 more Smart Citations

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

et al. 2007

View full text Add to dashboard Cite

OBJECTIVE -Corneal confocal microscopy (CCM) is a rapid, noninvasive, clinical examination technique that quantifies small nerve fiber pathology. We have used it to assess the neurological benefits of pancreas transplantation in type 1 diabetic patients. RESEARCH DESIGN AND METHODS-In 20 patients with type 1 diabetes undergoing simultaneous pancreas and kidney transplantation (SPK) and 15 control subjects, corneal sensitivity was evaluated using noncontact corneal esthesiometry, and small nerve fiber morphology was assessed using CCM.RESULTS -Corneal sensitivity (1.54 Ϯ 0.28 vs. 0.77 Ϯ 0.02, P Ͻ 0.0001), nerve fiber density (NFD) (13.8 Ϯ 2.1 vs. 42 Ϯ 3.2, P Ͻ 0.0001), nerve branch density (NBD) (4.04 Ϯ 1.5 vs. 26.7 Ϯ 2.5, P Ͻ 0.0001), and nerve fiber length (NFL) (2.23 Ϯ 0.2 vs. 9.69 Ϯ 0.7, P Ͻ 0.0001) were significantly reduced, and nerve fiber tortuosity (NFT) (15.7 Ϯ 1.02 vs. 19.56 Ϯ 1.34, P ϭ 0.04) was increased in diabetic patients before pancreas transplantation. Six months after SPK, 15 patients underwent a second assessment and showed a significant improvement in NFD (18.04 Ϯ 10.48 vs. 9.25 Ϯ 1.87, P ϭ 0.001) and NFL (3.60 Ϯ 0.33 vs. 1.84 Ϯ 0.33, P ϭ 0.002) with no change in NBD (1.38 Ϯ 0.74 vs. 1.38 Ϯ 1.00, P ϭ 1.0), NFT (15.58 Ϯ 1.20 vs. 16.30 Ϯ 1.19, P ϭ 0.67), or corneal sensitivity (1.23 Ϯ 0.39 vs. 1.54 Ϯ 00.42, P ϭ 0.59).CONCLUSIONS -Despite marked nerve fiber damage in type 1 diabetic patients undergoing pancreas transplantation, small fiber repair can be detected within 6 months of pancreas transplantation using CCM. CCM is a novel noninvasive clinical technique to assess the benefits of therapeutic intervention in human diabetic neuropathy. Diabetes Care 30:2608-2612, 2007S omatic polyneuropathy is one of the most common long-term complications of diabetes and is the main initiating factor for foot ulceration and lower extremity amputation (1,2). As 80% of amputations are preceded by foot ulceration, an effective means of detecting and treating peripheral neuropathy would have a major medical, social, and economic impact. With the exception of optimal glycemic control, there are currently no licensed treatments that prevent, slow, or arrest the development of neuropathy (1). The development of new treatments is of paramount importance, but they are hampered by a lack of clinically relevant surrogate end points favored by regulatory authorities (1). We have relied on tests that quantify predominantly large nerve fiber dysfunction, which were principally developed to aid diagnosis and not to assess nerve repair and hence a therapeutic response (3). Thus, nerve conduction studies are useful but only detect an abnormality in large myelinated nerve fibers, whereas thermal and pain thresholds assess thinly myelinated (A␦) and unmyelinated (C) fiber function. Heart rate variability during respiratory stimuli indicates parasympathetic vagal efferent function, and blood pressure change during orthostatic manipulation evaluates sympathetic vasomotor efferents.Although these tests correlate with axonal los...

show abstract

Section: After Transplantationsupporting

confidence: 91%

supporting

confidence: 61%

Section: After Transplantationmentioning

confidence: 75%

See 1 more Smart Citation

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Recent studies revealed that subjects with both type 1 and type 2 diabetes, but not those with metabolic syndrome, display epidermal nerve fiber loss (33)(34)(35)(36)(37). In our study, 11-week-old ob/ob mice developed a dramatic (78%) reduction in INFD compared with age-matched nondiabetic controls.…”

Section: Diabetes Vol 55 December 2006supporting

confidence: 52%

The Leptin-Deficient (ob/ob) Mouse

et al. 2006

View full text Add to dashboard Cite

Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocininduced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice (ϳ11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable (ϳ78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with fidarestat (16 mg ⅐ kg ؊1 ⅐ d ؊1 ), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)-positive nuclei in sciatic nerve, spinal cord, and DRGs of fidarestattreated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes. Diabetes 55: 3335-3343, 2006 P eripheral diabetic neuropathy (PDN) is a devastating complication of diabetes and a leading cause of foot amputation (1,2). Clinical indications of PDN include increased vibration and thermal perception thresholds that progress to sensory loss, occurring in conjunction with degeneration of all fiber types in the peripheral nerve. A proportion of patients with PDN also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain that sometimes coexist with loss of normal sensory function (3). Functional, metabolic, neurotrophic, and morphological abnormalities of PDN have extensively been explored in animal models of type 1 diabetes and, in particular, in streptozotocin-induced diabetic rats (4 -8) and mice (9,10). In contrast, manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models remain remarkably understudied despite the fact that the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes.The epidemic of obesity in the developed countries is driving a ...

show abstract

“…To assess nerve regeneration following pancreas transplantation, Kennedy et al (3) proposed the use of skin biopsies with quantification of intraepidermal nerve fiber density (IENFD). Previously, we documented severe IENFD reduction in lower-limb skin biopsies performed at the time of pancreas transplantation (4). Here we present assessment of IENFD following a mean of 2.5 years of normoglycemia.…”

mentioning

confidence: 78%

Epidermal Innervation in Type 1 Diabetic Patients

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE -To assess the effect of normoglycemia following simultaneous pancreas/ kidney transplantation (SPK) on neurological function and intraepidermal nerve fiber density (IENFD) in patients with type 1 diabetes.RESEARCH DESIGN AND METHODS -We performed vibration perception threshold (VPT) testing and autonomic function testing (AFT) and assessed IENFD in skin biopsies from the lower thigh and upper calf in 14 healthy control subjects and 18 patients with type 1 diabetes at the time of and at 21-40 (median 29) months post SPK.RESULTS -At baseline, significantly increased VPTs, pathological AFT results, and severe reduction in IENFD were present in SPK recipients. After SPK, an increase of IENFD in the thigh of more than one epidermal nerve fiber per millimeter was noted in three patients (median 4.1, range 1.9 -10.2), but changes were not significant for the group as a whole.CONCLUSIONS -We conclude that either irreversible nerve damage might be present in some SPK recipients or that longer periods of normoglycemia might be needed to allow nerve regeneration.

show abstract

Severe Depletion of Intraepidermal Nerve Fibers in Skin Biopsies of Pancreas Transplant Recipients

Cited by 25 publications

References 4 publications

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

The Leptin-Deficient (ob/ob) Mouse

Epidermal Innervation in Type 1 Diabetic Patients

Contact Info

Product

Resources

About