Patients with CKD were recruited from the outpatient nephrologic and neurologic clinics and dialysis center of National Taiwan University Hospital, Taipei, and its Yun-Lin Center, Douliou, Yunlin County, southwestern Taiwan, from January 2006 to December 2007. The diagnosis and staging of CKD were based on renal function studies. Patients had to be regularly followed up, and patients with ESKD had to receive regular dialysis therapy if needed. The simplified Modification of Diet in Renal Disease Study equation was used to determine the estimated glomerular filtration rate (eGFR) (eGFR, mL/min/1.73 m2 = 186.3 × [Serum Creatinine Level in Milligrams per Deciliter]−1.154 × Age−0.203 × [0.742 for Women]). The CKD classifications were defined according to the US National Kidney Foundation in 200226: stage 3 CKD, eGFR = 30 to 59 mL/min/1.73 m2; stage 4 CKD, eGFR = 15 to 29 mL/min/1.73 m2; and stage 5 CKD, eGFR <15 mL/min/1.73 m2. The inclusion criteria were (1) persistent renal function impairment for longer than 3 months and (2) moderate to severe reduction in the eGFR (≥CKD stage 3) or well-established renal failure. The duration of renal disease was defined as the interval from the first occasion of abnormal renal function to the time of recruitment. Neurological evaluation included sensations mediated by small (pinprick and thermal) and large (vibration) sensory nerves. The pinprick, thermal, and vibratory sensations were tested with a monofilament (10 g), ice water (4°C, for coldness), and hot water (45°C, for warmth), and 128-Hz tuning fork (for vibration), respectively. Patients were classified as having small-fiber neuropathy if there was reduced sensation to pinprick or thermal stimuli. Large-fiber neuropathy was defined according to reduced vibratory sensation, absence of ankle jerk, or weakness of the toes or feet. Data on previous medical diseases, including diabetes mellitus, autoimmune diseases, chronic infections, drug and toxin exposure, alcoholism, malignancies, vitamin B12 level, erythropoietin use and its total dose in the past 6 months, and other systemic disease, were recorded. To avoid comorbidities that might affect the peripheral nerve system or confound the clinical evaluations, patients with dementia or other neurological diseases, diabetes mellitus, autoimmune syndromes, a malignancy, toxin exposure, vitamin B12 deficiency, or alcoholism were excluded. Each patient underwent skin biopsy, NCS, and autonomic function tests. The procedures of immunohistochemical staining, quantitation of IENF density, NCS, autonomic function tests, and statistical analysis are detailed in the eAppendix. The Ethics Committee of National Taiwan University Hospital approved this study. Informed consent was obtained from each subject before the procedures.