Immediate drop of urine osmolality upon tolvaptan initiation predicts impact on renal prognosis in patients with ADPKD.

BACKGROUND AND HYPOTHESIS: Tolvaptan, a vasopressin V2 receptor antagonist, is used for treating autosomal dominant polycystic kidney disease (ADPKD). We focused on changes in urinary osmolality (U-Osm) after tolvaptan initiation to determine whether they were associated with the therapeutic response to tolvaptan. METHODS: This was a single-centre, prospective, observational cohort study. Seventy-two patients with ADPKD who received tolvaptan were recruited. We analysed the relationship between changes in U-Osm and annual estimated glomerular filtration rate (eGFR) in terms of renal prognostic value using univariable and multivariable linear regression analyses. RESULTS: The mean value of U-Osm immediately before tolvaptan initiation was 351.8 ± 142.2 mosm/kg H2O, which decreased to 97.6 ± 23.8 mosm/kg H2O in the evening. The decrease in U-Osm was maintained in the outpatient clinic 1 month later. However, the values of U-Osm showed higher variability (160.2 ± 83.8 mosm/kg H2O) than did those in the first evening of tolvaptan administration. Multivariate analysis revealed that the baseline eGFR, baseline urinary protein, and U-Osm change in the evening of the day of admission (initial U-Osm drop) were significantly correlated with the subsequent annual change in eGFR. CONCLUSIONS: U-Osm can be measured easily and rapidly, and U-Osm change within a short time after tolvaptan initiation may be a useful index for the renal prognosis in actual clinical practice.

[Bone disease in the field of CKD-MBD].

The pathophysiology and treatment for renal bone disease have made remakable progress. Moreover, osteocyte reseach has made tremendous progress. In the clinical aspect, (1) hyperphosphatemia, (2) hyperparathyroid and hypoparathyroid bone disease in patients with chronic kidney disease, (3) increased serum level of fibroblast growth factor 23 (FGF-23) and(4) reduced level of Klotho should be taken into consideration when analyzing these conditions. On the other hand, hyperphosphatemia must be successfully treated. Hyperparathyroid bone disease has been successfully treated with vitamin D sterol, cinacalcet hydrochloride and parathyroidectomy, however, the treatment of hypoparathyroidism inpatient with diabetes or non-diabetes met with high hurdles. We must treat these patients in thinking about osteocytic perilacunar/canalicular system.

Renal hyperparathyroidism.

The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with Klotho-FGF-endocrine axes, which must be solved definitively as early as possible. It was revealed that the expression of fgf23 is activated by calciprotein particles, which induces vascular ossification. And it is well known that phosphorus overload directly increases parathyroid hormone and hyperparathyroid bone disease develops in those subjects. On the other hand, low turnover bone disease is often recently. Both the patients with chronic kidney disease suffering from hyperparathyroid bone disease or low turnover bone disease are associated with increased fracture risk. Micropetrosis may be one of the causes of increased fracture risk in the subjects with low turnover bone disease. In this chapter, we now describe the diagnosis, pathophysiology and treatments of renal hyperparathyroidism.

[Is bone biopsy necessary for the diagnosis of metabolic bone diseases? Necessity of bone biopsy].

Histological analysis of undecalcified bone biopsy specimens is a valuable clinical and research tool for studying the etiology, pathogenesis and treatment of metabolic bone diseases. In case of osteoporosis, bone biopsy is not usually required for the diagnosis ; however, bone histomorphometry may be useful in rare cases with unusual skeletal fragility. Bone histomorphometry also provides valuable information on the mechanism of action, safety and efficacy of new anti-osteoporosis drugs. Bone histomorphometry is useful for the diagnosis and the assessment of treatment response in rickets/osteomalacia and in CKD-MBD (chronic kidney disease-mineral and bone disorders) . In Japan, bone biopsy is often performed to establish the diagnosis of Paget's disease of bone, especially to differentiate it from metastatic bone disease.

[Morphological analysis of bone dynamics and metabolic bone disease. A case report of recurrent renal hyperparathyroidism].

A 39-years-old chronic hemodialysis patient who developed recurrent hyperparathyroidism after total parathyroidectomy with immediate autotransplantation (PTX-AT) is now reported. The patient had undergone bilateral nephrectomy due to bilateral renal cell carcinoma at 4 and 5 years after the initiation of dialysis, followed by the treatment with interleukin-2 administration. Secondary hyperparathyroidism was treated by PTX-AT, followed by confirmation of reduced bone turnover. The parathyroid glands were huge and the total weight of the parathyroid glands was 14.3 gr. Pathological examination revealed nodular hyperplastic parathyroid tissue in all four glands. However, the serum intact parathyroid hormone (iPTH) increased again at 7 years after the PTX, and bone biopsy revealed high turnover bone disease. The recurrent hyperparathyroidism was treated with cinacalcet hydrochloride to reduce the serum iPTH level.

Micropetrosis in hemodialysis patients.

Micropetrosis develops as a result of stagnation of calcium, phosphorus and bone fluid, which appears as highly mineralized bone area in the osteocytic perilacunar/canalicular system regardless of bone turnover of the patients. And microcracks are predisposed to increase in these areas, which leads to increased bone fragility. However, micropetrosis of hemodialysis (HD) patients has not been discussed at all. Micropetrosis area per bone area (Mp.Ar/B·Ar) and osteocyte number per micropetrosis area (Ot.N/Mp.Ar) were measured in nine HD patients with renal hyperparathyroidism (Group I), twelve patients with hypoparathyroidism within 1 year after the treatment of renal hyperparathyroidism (Group II) and seven patients suffering from hypoparathyroidism for over two years (Group III). And bone mineral density (BMD) and tissue mineral density (TMD) were calculated using µCT to evaluate bone mineral content of iliac bone of the patients. These parameters were compared among the three groups. Only Mp.Ar/B·Ar was statistically greater in Group II and III compared to Group I in the parameters of bone mineral content and micropetrosis. However, the other parameters were not statistically different among the three groups. In long-term HD patients, BMD and TMD may be modified by the causes of renal insufficiency and the treatment of renal bone disease. We concluded that Mp.Ar/B·Ar was greater in patients with long-term hypoparathyroidism than both those with short-term hypoparathyroidism and with renal hyperparathyroidism. Special attention should be paid to avoid long-term hypoparathyroidism of the patients from the view point of increased fracture risk caused by increased micropetrosis area.

The Importance of Biologically Active Vitamin D for Mineralization by Osteocytes After Parathyroidectomy for Renal Hyperparathyroidism.

Hypomineralized matrix is a factor determining bone mineral density. Increased perilacunar hypomineralized bone area is caused by reduced mineralization by osteocytes. The importance of vitamin D in the mineralization by osteocytes was investigated in hemodialysis patients who underwent total parathyroidectomy (PTX) with immediate autotransplantation of diffuse hyperplastic parathyroid tissue. No previous reports on this subject exist. The study was conducted in 19 patients with renal hyperparathyroidism treated with PTX. In 15 patients, the serum calcium levels were maintained by subsequent administration of alfacalcidol (2.0 µg/day), i.v. calcium gluconate, and oral calcium carbonate for 4 weeks after PTX (group I). This was followed in a subset of 4 patients in group I by a reduced dose of 0.5 µg/day until 1 year following PTX; this was defined as group II. In the remaining 4 patients, who were not in group I, the serum calcium (Ca) levels were maintained without subsequent administration of alfacalcidol (group III). Transiliac bone biopsy specimens were obtained in all groups before and 3 or 4 weeks after PTX to evaluate the change of the hypomineralized bone area. In addition, patients from group II underwent a third bone biopsy 1 year following PTX. A significant decrease of perilacunar hypomineralized bone area was observed 3 or 4 weeks after PTX in all group I and II patients. The area was increased again in the group II patients 1 year following PTX. In group III patients, an increase of the hypomineralized bone area was observed 4 weeks after PTX. The maintenance of a proper dose of vitamin D is necessary for mineralization by osteocytes, which is important to increase bone mineral density after PTX for renal hyperparathyroidism. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Bone formation by minimodeling is more active than remodeling after parathyroidectomy.

Bone formation using the process known as minimodeling forms only lamellar bone in the absence of prior bone resorption even in uremic patients. In patients undergoing parathyroidectomy for secondary hyperparathyroidism, we compared the contribution of minimodeling to remodeling during the change in bone volume. Iliac bone biopsies were used to measure parameters related to minimodeling and remodeling before, at 3 to 4 weeks and 10 to 12 weeks after parathyroidectomy. Osteoblast surface due to minimodeling was greater than the entire bone osteoblast surface before and at 10 to 12 weeks after parathyroidectomy, but not 3 to 4 weeks after surgery. Minimodeling significantly increased osteoid volume 3 to 4 weeks after parathyroidectomy. The rate of change of osteoid volume by minimodeling was greater than that of osteoid volume during the first 3 to 4 weeks after surgery, indicating osteoid formation was more active at the minimodeling surface than at the entire bone surface. Furthermore, higher mineral apposition rates at the minimodeling sites than at remodeling sites yielded increased minimodeling bone volume at 10 to 12 weeks after surgery. Our results show that bone formation by minimodeling is more active than by remodeling and accounts, in part, for the increase of bone volume following parathyroidectomy.

Osteocytic perilacunar/canalicular turnover in hemodialysis patients with high and low serum PTH levels.

Osteocytic perilacunar/canalicular turnover in hemodialysis patients has not yet been reported. Osteocyte lacunae in lamellar bone and woven bone were classified as eroded surface-, osteoid surface-, and quiescent surface-predominant osteocyte lacunae (ES-Lc, OS-Lc, QS-Lc, respectively) in 55 hemodialysis patients with either high- (n = 45) or low- (n = 10) parathyroid hormone levels, and 19 control subjects without chronic kidney disease. We calculated the area and number of ES-Lc, OS-Lc, and QS-Lc. The mineralized surface on the osteocyte lacunar walls was measured in each group, and compared among the three groups. The shapes of the osteocyte lacunar walls were validated by backscattered electron microscopy. While the number of ES-Lc per bone area (N.ES-Lc/B.Ar) was higher than the number of OS-Lc per bone area (N.OS-Lc/B.Ar) in all groups, N.ES-Lc/B.Ar and N.OS-Lc/B.Ar were greater in high-parathyroid hormone group than in low-parathyroid hormone and control groups. The total volume of ES-Lc per bone area (ES-Lc.Ar/B.Ar) was greater than the total volume of OS-Lc per bone area (OS-Lc.Ar/B.Ar) in both parathyroid hormone groups. However, both lacunar erosion and lacunar formation increased proportionally, suggesting that global coupling between them was maintained. N.ES-Lc/B.Ar was higher in woven bone than in lamellar bone. The rate of OS-Lc stained by tetracycline hydrochloride, the mineralized lacunar surface and the mean area of OS-Lc with Tc obtained from both parathyroid hormone groups were greater than those in the control group. We conclude that osteocytic perilacunar/canalicular turnover is increased in hemodialysis patients with high parathyroid hormone levels. Osteocytic perilacunar/canalicular turnover depends, at least in part, on serum parathyroid hormone level. However, the ideal PTH level for osteocytic perilacunar/canalicular turnover could not be determined but osteocytic osteolysis was predominant in both the high- and low-PTH groups in this study. Thus, attention should be paid to bone loss from the viewpoint of osteocytic perilacunar/canalicular turnover in hemodialysis patients.

Minimodeling reduces the rate of cortical bone loss in patients with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism often causes progressive cortical thinning because of increased bone resorption at the endocortical surface and increases cortical porosity because of increased resorption at the intracortical surface. Because bone formation by minimodeling has not yet been reported in cortical bone, we investigated the effects of cortical minimodeling on the decrease in rate of bone loss. METHODS: Thirty-five patients with secondary hyperparathyroidism were enrolled. Remodeling and minimodeling parameters at the endocortical and periosteal surfaces, as well as at the intracortical surface, were measured. Relationships between remodeling parameters and minimodeling parameters at each surface were investigated by using linear regression analysis. Cortical bone specimens were classified into 3 groups according to cortical width and cortical porosity values. Relationships of minimodeling parameters at the endocortical surface with cortical width and at the intracortical surface with cortical porosity were investigated. RESULTS: Some minimodeling parameters showed positive correlations with serum parathyroid hormone levels and remodeling parameters. Minimodeling bone volume at the endocortical surface was greater in the narrow-cortical-width group than wide-cortical-width group, possibly slowing the progression of cortical thinning. Minimodeling volume at the intracortical surface was greater in the high-porosity than low-porosity group, possibly slowing the progression of intracortical resorption space enlargement. Minimodeling of the periosteal surface was found in 1 specimen. CONCLUSION: Results show enhanced cortical minimodeling in patients with secondary hyperparathyroidism, possibly representing the decrease in rate of cortical bone loss.

Characteristics of patients on hemodialysis therapy for more than 30 years.

Since its experimental introduction in 1960, hemodialysis has become a widely performed and relatively safe procedure. Therapeutic strategies have been developed, and the numbers of long-term survivors of hemodialysis therapy have been increasing. Hemodialysis therapy was introduced at Sangenjaya Hospital in October 1970, and the 16 patients who have survived for more than 30 years on hemodialysis therapy since its introduction at the hospital were enrolled in this study to investigate the characteristics of long-term hemodialysis patients. For comparison, 50 patients on hemodialysis for less than 30 years were also studied (21 patients with <10 years hemodialysis, 13 with 10-20 years hemodialysis and 16 with 20-30 years hemodialysis). Background information (age, gender, and cause of renal disease), dialysis dose (single pool [sp.] Kt/V), mineral metabolism (serum phosphate), anemia management (serum hemoglobin), and nutrition (serum albumin and reduced interdialytic weight gain) were assessed. Hemodialysis was instituted at 28.7 +/- 6.4 years of age. The primary cause of end-stage renal disease was chronic glomerulonephritis in all of the patients except one, and in that patient it was polycystic kidney disease. As an index of the dialysis dose, sp. Kt/V was 1.2 +/- 0.11. As an index of mineral metabolism, serum phosphate was 5.4 +/- 0.9 mg/dL. As an index of anemia management, serum hemoglobin was 10.2 +/- 1.2 g/dL. As indexes of nutrition, serum albumin was 4.0 +/- 0.2 g/dL and interdialytic weight gain was 4.43 +/- 1.36%. The sp. Kt/V-value, serum phosphate, serum hemoglobin and interdialytic weight gain did not differ between the four different hemodialysis duration groups. Serum albumin was lower in the >30 group (4.0 +/- 0.2 g/dL) than in the <10 group (4.2 +/- 0.3 g/dL) (P = 0.046). As the duration of hemodialysis has increased, the age at hemodialysis induction has become younger. The cause of the renal failure was chronic glomerulonephritis in most of the cases. None had diabetic nephropathy. Improvement of the prognosis of patients with diabetic nephropathy is required. Most of the indexes of these patients nearly satisfied the recommended values.

Management of Osteoporosis in Chronic Kidney Disease.

Chronic kidney disease (CKD) patients with coexisting osteoporosis are becoming common. Many of the therapeutic agents used to treat osteoporosis are known to be affected by the renal function. It is generally thought that osteoporosis in G1 to G3 CKD patients can be treated as in non-CKD patients with osteoporosis. In stage 4 or more advanced CKD patients and CKD patients on dialysis with osteoporosis, however, bisphosphonates must be used with caution, bearing in mind the potential development of such disorders as adynamic bone disease. The use of vitamin D preparations in low doses is relatively safe. In postmenopausal women, raloxifene must be administered with caution. When using denosumab, the serum calcium concentrations should be monitored carefully to prevent the development of hypocalcemia, and active vitamin D preparations should be administered concomitantly. The present article provides an overview of the management of osteoporosis in CKD patients.

[Two cases of hemodialysis patients with absolute hypoparathyroidism or normal parathyroid function who were suffering from prostate carcinoma].

In recent years, the incidence of prostate carcinoma in patients with renal failure is increasing. But it is difficult to diagnose the occurrence of this neoplasm because of decrease of urinary volume in these patients. Two hemodialysis patients (age: 64, 68 years, the duration of hemodialysis: 10, 8 years) suffering from prostate carcinoma were treated with androgen deprivation therapy, which accelerates bone resorption. (This kind of osteoporosis is often treated by bisphosphonate, but this treatment is prohibited in hemodialysis patients.) Both serum testosterone and estradiol went down to the extremely lower levels in these patients. Thereafter, one (case 2) of them was maintained under absolute hypoparathyroidism by the conservative therapy with vitamin D. As a result, bone mineral density of the patient (case 2) was well maintained during one year. In conclusion, hypoparathyroidism was helpful to prevent bone loss in patients receiving androgen deprivation therapy.

Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: Successful parathyroidectomy for secondary hyperparathyroidism alleviates bone pain and is followed by the development of hypophosphatemia and hypocalcemia, as well as an increase in bone mineral density. An increase in osteoblast surface (Ob.S/BS) is not observed several months after surgery. In this study, we investigated early bone changes at 1 week after parathyroidectomy and the mechanism underlying an increase in bone mineral density. METHODS: Fourteen patients with severe secondary hyperparathyroidism underwent iliac bone biopsy before and 1 week after parathyroidectomy. Changes in histomorphometric parameters, including osteoclast surface (Oc.S/BS), eroded surface (ES/BS), erosion depth (E.De), fibrosis volume (Fb.V/TV), Ob.S/BS, osteoid volume (OV/BV), osteoid surface (OS/BS), and osteoid thickness (O.Th), were investigated. Changes in texture of mineralized bone and osteoid seams were also investigated. RESULTS: Oc.S/BS (P < 0.001), ES/BS (P < 0.01), and E.De (P < 0.001) decreased, but Fb.V/TV did not change at 1 week postoperatively. In particular, osteoclasts disappeared in almost all patients. Ob.S/BS (P < 0.001) increased, and cuboidal osteoblasts were proliferating on the trabecular surface where osteoclasts had existed before parathyroidectomy. As a result, newly developed osteoblasts coexisted with fibrous tissue after surgery. OV/BV (P < 0.005), OS/BS (P < 0.005), and O.Th (P < 0.005) increased, with lamellar osteoid volume showing a particular increase. Bone mineralization continued despite the low postoperative serum parathyroid hormone level. CONCLUSION: A rapid decrease in serum parathyroid hormone level after parathyroidectomy appears to suppress bone resorption, as well as cause a transient marked increase in bone formation and an increase in normal lamellar osteoid seams.

[Diagnosis and classification of renal osteodystrophy].

Bone histomorphometry is essential to diagnosis of renal osteodystrophy. Sherrard et al classified renal osteodystrophy into the 5 groups according to Fb.V/TV, OV/BV and BFR/TV of cancellous bone (Osteitis fibrosa, Mixed uremic osteodystrophy, Osteomalacia, Mild lesion, Aplastic disease). In addition, because endocortical bone loss is generally irreversible, the evaluation of this region in the transiliac bone biopsy specimen also seems to be important.

[Impact of parathyroidectomy on bone histology].

Impacts of total parathyroidectomy and autotransplantation on bone histology were evaluated in secondary hyperparathyroidism. Low turnover bone disease accompanied with fibrous tissue developed at 4 weeks after surgery, and osteoclasts disappeared. In addition, fibrous tissue also disappeared at 12 weeks. Even though serum PTH level indicated quite low in some cases, bone resorption exceeded bone formation at 1 years after surgery. So we should pay special attention to the decrease in bone mineral density in the long term in these cases.

Impact of lanthanum carbonate on cortical bone in dialysis patients with adynamic bone disease.

Among the most serious problems in patients with chronic kidney disease (CKD) is fragility of cortical bone caused by cortical thinning and increased cortical porosity; the cortical fragility is sometimes irreversible, with fractures generally initiating from cortical bone. Therefore, development of treatments for problems of cortical bone is urgently desired. Cortical bone has the three surfaces, including the periosteal surface, intracortical spaces and endocortical surface. Bone turnover at the endocortical surface and intracortical resorption spaces are increased as compared with that at cancellous surface. Bone growth sometimes depends on apposition at the periosteal surface. We treated hyperphosphatemia in two hemodialysis patients with adynamic bone disease with 750-1500 mg/day of lanthanum carbonate, which is a non-calcium containing phosphate binder; the treatment resulted in a decrease of the serum phosphorus levels (P levels), without significant change of the serum intact parathyroid hormone levels. We now report that treatment of these patients with lanthanum carbonate increased mineralization of the periosteal surface, increased bone mass within the intracortical resorption spaces and increased mineralization of the minimodeling surface at the endocortical surface. In addition, woven bone volume in cortical bone was decreased and mineralization of bone units, namely, osteons, was increased. Although these findings were not observed across all surfaces of the cortical bone in the patients, it is expected that lanthanum carbonate would increase the cortical stability in CKD patients, with consequent reduction in the fracture rate in these patients.

Is gastrectomy-induced high turnover of bone with hyperosteoidosis and increase of mineralization a typical osteomalacia?

Gastrectomy (GX) is thought to result in osteomalacia due to deficiencies in Vitamin D and Ca. Using a GX rat model, we showed that GX induced high turnover of bone with hyperosteoidosis, prominent increase of mineralization and increased mRNA expression of both osteoclast-derived tartrate-resistant acid phosphatase 5b and osteocalcin. The increased 1, 25(OH)2D3 level and unchanged PTH and calcitonin levels suggested that conventional bone and Ca metabolic pathways were not involved or changed in compensation. Thus, GX-induced bone pathology was different from a typical osteomalacia. Gene expression profiles through microarray analysis and data mining using Ingenuity Pathway Analysis indicated that 612 genes were up-regulated and 1,097 genes were down-regulated in the GX bone. These genes were related functionally to connective tissue development, skeletal and muscular system development and function, Ca signaling and the role of osteoblasts, osteoclasts and chondrocytes. Network analysis indicated 9 genes (Aldehyde dehydrogenase 1 family, member A1; Aquaporin 9; Interleukin 1 receptor accessory protein; Very low density lipoprotein receptor; Periostin, osteoblast specific factor; Aggrecan; Gremlin 1; Angiopoietin-like 4; Wingless-type MMTV integration site family, member 10B) were hubs connected with tissue development and immunological diseases. These results suggest that chronic systemic inflammation might underlie the GX-induced pathological changes in bone.

Prevalence of intracranial artery calcification in hemodialysis patients--a case-control study.

BACKGROUND: Intracranial artery calcification has been reported to be an independent risk factor for ischemic stroke. Also, existence of a positive correlation has been reported between the presence of arterial calcification and that of ischemic changes in the area supplied by such arteries. While intracranial artery calcification has frequently been observed on computed tomographic (CT) images of the brain in hemodialysis patients, its prevalence has not been reported previously. We investigated our hemodialysis outpatients to determine the prevalence of intracranial artery calcification in these patients in comparison with that in healthy controls. METHODS: Brain CT examinations were performed in 107 patients under maintenance hemodialysis therapy. For comparison, 43 representatives of the general population who underwent a brain CT examination as part of a health checkup were also studied as control subjects. RESULTS: Intracranial calcifications were more frequently found among hemodialysis patients (87.9%) than among control subjects (53.5%, P = 0.0003), and the prevalences of calcification in each of the intracranial arteries in the two groups were as follows: vertebral artery (65.5% vs. 25.6%, P = 0.0002), internal carotid artery (62.1% vs. 18.6%, P < 0.0001), basilar artery (34.5% vs. 34.9%, ns), anterior cerebral artery (0 vs. 2.3%, ns), middle cerebral artery (24.1% vs. 20.9%, ns), and posterior cerebral artery (5.2% vs. 4.7%, ns). CONCLUSIONS: A much higher rate of intracranial artery calcification was observed in hemodialysis patients than in the general population, and the most frequently involved sites of calcification in these patients were the relatively large intracranial arteries.

Association of peripheral artery disease and long-term mortality in hemodialysis patients.

BACKGROUND: Peripheral artery disease (PAD) is a common complication in hemodialysis patients. The ankle-brachial blood pressure index (ABI) has been widely used to screen for subclinical PAD. In the present study, we investigated the association between ABI and long-term (up to 8.8 years) mortality among hemodialysis patients. METHODS: A total of 86 consecutive patients receiving maintenance hemodialysis who underwent an ABI examination between 2001 and 2003 were retrospectively enrolled in this study. Patients with an ABI of less than 0.9 were considered as having PAD; those with an ABI of more than 0.9 in both legs were considered as being free from PAD. We examined the relationship between mortality and several risk factors. RESULTS: During the follow-up period, 43 deaths were recorded. In the univariate regression analysis, the mortality hazard ratio (HR) of patients with PAD was 1.67 (95% confidence interval [CI], 1.18-2.28). Other predictive variables for mortality included male gender, age, and diabetes mellitus (P = 0.006, P = 0.024, and P = 0.023, respectively). A multivariate Cox analysis identified PAD and male gender as independent predictors of mortality (P = 0.033 and P = 0.028, respectively). The impact of age and diabetes mellitus on mortality was no longer significant in the multivariate analysis. CONCLUSION: After a relatively long-term observation period, a multivariate analysis indicated that PAD acted independently of other risk factors, including advanced age and the presence of diabetes mellitus. ABI measurements can be used to identify high-risk hemodialysis patients requiring intensive follow-up care.