Ryo Kido

How Do Living Kidney Donors Develop End-Stage Renal Disease?

The clinical course and risk factors for developing end‐stage renal disease (ESRD) after heminephrectomy in living kidney donors have scarcely been investigated. We reviewed medical records and identified eight case donors who developed chronic kidney disease (CKD) stage 5 or ESRD, and subsequently investigated the association between postoperative clinical courses and changes in renal function. To conduct a case‐control study, we also selected a control group comprising 24 donors who had maintained stable renal function and were matched for age, sex and follow‐up time since donation. Except for one donor who developed ESRD caused by a traffic accident, none of the donors developed progressive renal dysfunction immediately after donation. Their renal functions remained stable for a long period of time, but started to decline after developing new comorbidities, especially risk factors known as progression factors (proteinuria or hypertension) or accelerating factors (cardiovascular [CV] event or infection) of CKD. As compared with the control donors, incidence of postoperative persistent proteinuria, acute CV event, severe infection and hospitalization due to accelerating factors of CKD were significantly higher in the case donors. These results suggest the importance of long‐term (more than 10 years) follow‐up of donors with special attention on the risk factors of CKD.

Abnormal Mineral Metabolism and Mortality in Hemodialysis Patients With Secondary Hyperparathyroidism: Evidence From Marginal Structural Models Used to Adjust for Time-Dependent Confounding

BACKGROUND Hemodialysis patients with mineral and bone disorders (MBDs) have an abnormally high relative risk of death, but their absolute risk of death is unknown. Further, previous studies have not accounted for possible time-dependent confounding of the association between MBD markers and death due to the effect of markers of MBD on treatments, which subsequently may affect MBD markers. STUDY DESIGN Multicenter, 3-year, prospective, case-cohort study. SETTING & PARTICIPANTS 8,229 hemodialysis patients with secondary hyperparathyroidism (parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators) at 86 facilities in Japan. PREDICTORS Serum phosphorus, calcium, and parathyroid hormone levels. OUTCOME All-cause mortality. MEASUREMENTS Marginal structural models were used to compute absolute differences in all-cause mortality associated with different levels of predictors while accounting for time-dependent confounding. RESULTS The association between phosphorus level and mortality appeared U-shaped, although only higher phosphorus level categories reached statistical significance: compared to those with phosphorus levels of 5.0-5.9 mg/dL (1.61-1.93 mmol/L), patients with the highest (≥9.0 mg/dL [≥2.90 mmol/L]) phosphorus levels had 9.4 excess deaths/100 person-years (rate ratio, 2.79 [95% CI, 1.26-6.15]), whereas no association was found for the lowest phosphorus category (<3.0 mg/dL [<0.97 mmol/L]; rate ratio, 1.54 [95% CI, 0.87-2.71]). Similarly, hypercalcemia (≥10.0 mg/dL [≥2.50 mmol/L]) was associated with excess deaths, and the highest level of hypercalcemia (≥11.0 mg/dL [≥2.75 mmol/L]) was associated with 5.8 excess deaths/100 person-years (rate ratio, 2.38 [95% CI, 1.77-3.21]) compared to those with levels of 9.0-9.4 mg/dL (2.25-2.37 mmol/L). Abnormally high parathyroid hormone levels were not associated with excess deaths. LIMITATIONS Possible residual confounding. CONCLUSIONS These results reinforce the idea that serum calcium (in addition to phosphorus) level is an important predictor of the absolute risk of death in hemodialysis patients with secondary hyperparathyroidism.

Persistent Glomerular Hematuria in Living Kidney Donors Confers a Risk of Progressive Kidney Disease in Donors After Heminephrectomy

Although glomerular hematuria is likely a sign of chronic kidney disease that will develop into overt nephropathy after donation, it remains unclear whether prospective donors with hematuria should be excluded. We reviewed the medical records of 242 donors who donated at our institution from 2001 to 2007 and surveyed the prevalence of hematuria pre‐ and postdonation. We then investigated the association of hematuria with proteinuria postdonation and trends in glomerular filtration rate. Before donation, 8.3% of 242 donors presented with persistent hematuria, a finding that was significantly associated with dysmorphic hematuria before donation. Most cases of predonation persistent hematuria persisted after donation, and the overall prevalence increased to 15.3%. During a median follow‐up period of 2.3 years after donation, 8.3% developed persistent proteinuria, with incidence being significantly higher in donors having persistent hematuria with dysmorphic red blood cells (d‐RBC) both before and after donation. Postdonation persistent hematuria with d‐RBC was also associated with a progressive decline in renal function. These results indicate that persistent glomerular hematuria is strongly associated with a higher incidence of postdonation progressive kidney disease. Potential donors with persistent glomerular hematuria should be excluded, while those with isolated hematuria need to be evaluated with heightened caution.

The relative role of fibroblast growth factor 23 and parathyroid hormone in predicting future hypophosphatemia and hypercalcemia after living donor kidney transplantation: a 1-year prospective observational study

BACKGROUND Kidney transplantation (KTx) restores many of the disorders accompanying end-stage renal failure. However, hypercalcemia and hypophosphatemia are both common complications after renal transplantation. Prospective observation of these complications has not been well described and pre-transplant predictors also remain unknown. This prospective observational cohort study was carried out to clarify pre-transplant risk factors of persistent hypophosphatemia and/or hypercalcemia at 12 months after transplantation. METHODS Consecutive living donor KTx recipients (n = 39) at Tokyo Womens Medical University were prospectively recruited. Parameters of bone and mineral metabolism including intact parathyroid hormone (iPTH) and full-length fibroblast growth factor (FGF) 23 were followed. RESULTS FGF23 decreased to comparable levels for renal function while hyperparathyroidism persisted at 12 months after transplantation. Multivariate linear regression analysis revealed that pre-transplant iPTH correlated with hypercalcemia at 12 months and pre-transplant FGF23 was the best pre-transplant predictor of persistent hypophosphatemia at 12 months. CONCLUSIONS It is intriguing that although FGF23 is not a causal factor for hypophosphatemia at 12 months post-transplantation, it is a significant predictor of this common complication.

Use of Renin-Angiotensin System Inhibitors Is Associated with Reduction of Fracture Risk in Hemodialysis Patients

Background Patients with chronic kidney disease, especially those undergoing dialysis treatment and having secondary hyperparathyroidism, have a high risk of bone fracture. The renin-angiotensin system (RAS) is associated with osteoclastic bone resorption. We aimed to examine whether the use of RAS inhibitors reduces the incidence of fracture in hemodialysis patients. Methods and Findings This was a multicenter, 3-year, prospective, observational study. From 2008 to 2011, maintenance hemodialysis patients with secondary hyperparathyroidism (N = 3,276) treated with angiotensin converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) at baseline were followed for a mean of 2.7 years. The association between the use of ACEI/ARB and hospitalization rate owing to fracture was examined by using Cox regression models. Effect modifications by the severity of secondary hyperparathyroidism (intact parathyroid hormone [iPTH] level), sex, and systolic blood pressure were also examined. The incidence proportion of fracture-related hospitalization was 5.42% throughout the observation period. ACEI/ARB use was associated with a lower rate of fracture-related hospitalization (adjusted hazard ratio, 0.65; 95% confidence interval [CI], 0.45–0.92). This association was not significantly affected by sex (P = 0.56) or systolic blood pressure levels (P = 0.87). The hazard ratios adjusted by iPTH levels were qualitatively different, but not statistically significant (P = 0.11): 0.77 (95% CI, 0.42–1.39), 0.38 (95% CI, 0.20–0.73), 0.59 (95% CI, 0.29–1.21), and 1.29 (95% CI, 0.58–2.42) for the first, second, third and fourth quartiles of iPTH, respectively. Conclusions Use of RAS inhibitors is associated with a lower rate of fracture-related hospitalization in hemodialysis patients with secondary hyperparathyroidism. Trial Registration ClinicalTrials.gov NCT00995163

Decreases in PTH in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism: Associations with Changing Practice Patterns

BACKGROUND AND OBJECTIVES Control of serum concentrations of calcium (Ca), phosphorus (P), and parathyroid hormone (PTH) is essential for management of secondary hyperparathyroidism (SHPT). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This is a planned interim analysis of a longitudinal cohort study. The settings are dialysis facilities in Japan. Eligible patients comprise all those who were receiving hemodialysis at one of 86 participating facilities and who have SHPT. Using data from a random sample (n = 3276) of the participants from January 2008 through June 2009, we measured changes in the percentages of patients who were within the national guideline-specified target ranges of Ca (8.4 to 10 mg/dl), P (3.5 to 6.0 mg/dl), and intact PTH (iPTH) (60 to 180 pg/ml), and changes in prescriptions of drugs targeting SHPT. We used regression models to identify factors affecting the achievement of the guideline-specified targets. RESULTS There were no notable changes in the percentage of patients who were within the guideline for Ca, P, or both. The percentage who were within the iPTH guideline increased from 14.5% to 43.3% (P < 0.001). There were no remarkable changes in the percentage of patients receiving vitamin D or phosphate binders. The percentage who received cinacalcet increased from 0% to 29%. Prescription of cinacalcet was associated with improvement or target-achievement for iPTH and for Ca by 16.8 percentage points (95% CI: 8.1 to 17.0) and by 12.6 percentage points (13.7 to 19.9), respectively. CONCLUSIONS In the routine care of hemodialysis patients, increasing use of cinacalcet was associated with better control of SHPT.

The effect of different apheresis modalities on coagulation factor XIII level during antibody removal in ABO-blood type incompatible living related renal transplantation

Apheresis therapy is used to remove pathogenic antibodies within the recipient blood during ABO-incompatible living related renal transplantation (LRRT). Factor XIII (FXIII) is a coagulating factor. Its deficiency reportedly engenders perioperative bleeding. This study compared apheresis modalities from the perspective of the FXIII level. Cases 1-3 were treated only with double-filtration plasmapheresis (DFPP) without (case 1) or with (cases 2 and 3) fresh frozen plasma (FFP) supplementation. Cases 4 and 5 were treated with simple plasma exchange (PEx) with FFP supplementation for the last session. Cases 1-3 showed a marked (case 1, 8.6%) or moderate (case 2, 26.2%; case 3, 28.4%) decrease in FXIII on the day before the procedure after the last apheresis session, although cases 4 (81.9%) and 5 (66.2%) did not. Case 1 experienced perioperative bleeding. The last session is usually performed the day before the surgical procedure. Therefore, FXIII elimination by DFPP might cause bleeding complications because of its slow recovery. The fact warrants that the last apheresis modality during the course might be PEx from the viewpoint of FXIII depletion.

Natural history of mineral and bone disorders after living-donor kidney transplantation: a one-year prospective observational study.

Mineral and bone disorders (MBD), including hypercalcemia and hypophosphatemia, are common complications after renal transplantation; however, the natural course of these disorders has not been well documented, and the pathogenesis of persistent post‐transplant MBD still remains elusive. This study was carried out to show the natural history of mineral metabolism in recipients after living‐donor kidney transplantation and also to clarify post‐transplant risk factors of persistent hypercalcemia and/or hypophosphatemia at 12 months after transplantation. Living‐donor kidney transplant recipients (N = 34) at Tokyo Womens Medical University were prospectively and consecutively recruited. Parameters of MBD, including intact parathyroid hormone and full‐length fibroblast growth factor 23, were followed. Serum calcium levels increased until the fourth week post‐transplantation, after which it reached a plateau; and serum phosphate decreased substantially at one week post‐kidney transplantation, but recovered to the reference level at two months. Fibroblast growth factor 23 gradually decreased to comparable levels for renal function, while hyperparathyroidism persisted for 12 months after transplantation. Multivariate linear regression analysis revealed that intact parathyroid hormone was the best correlating factor with both hypercalcemia and persistent hypophosphatemia at 12 months. This study suggests the need for testing of other interventions used for treatment of hyperparathyroidism which may help to offer better management of MBD after kidney transplantation.

Laboratory and imaging features of kidney involvement in autoimmune pancreatitis: incidence, correlation, and steroid therapy response.

AIM Autoimmune pancreatitis (AIP) is a rare subtype of chronic pancreatitis. AIP has been suggested to be complicated by tubulointerstitial nephritis or glomerulonephritis, implying that the kidney is involved as a phenotype of IgG4-positive multi-organ lymphoproliferative syndrome; however, the clinical significance of this novel entity is not well-defined. METHODS We conducted a retrospective cohort analysis of 47 (male, 39; female, 8) AIP patients. RESULTS The patients (mean age, 70.3 +/- 9.5 years) had a mean observation period of 4.1 years. Before treatment, renal dysfunction with an eGFR of 30 and 15 ml/min/1.73 m2 developed only in 10.6% (5/47) and 2.1% (1/47) of the patients, respectively. Nevertheless, urinary N-acetyl-beta-D-glucosaminidase and alpha1-microglobulin levels were elevated in 78.6% (11/14) and 30.8% (4/13) of the patients, respectively. Renal involvement in contrast-enhanced CT imaging was present in 18.2% (8/44) of the patients and was associated with proteinuria (p = 0.04) and a decrease in eGFR (p < 0.01). Furthermore, a follow-up CT study (mean, 545 days) revealed improved kidney lesions in 80.0% (4/5) of the patients after oral corticosteroid administration. In contrast, first-time kidney involvements appeared newly in 3.6% (1/28) of the patients after steroid therapy for nonrenal AIP symptoms, and in 14.3% (1/7) of the patients under no specific therapy (p = 0.02). CONCLUSION Although severe renal failure develops rarely in AIP patients, renal abnormalities have been significantly detected by biochemical and radiological tests. Oral corticosteroid administration, even when not targeting symptomatic nephropathy, can treat and prevent kidney involvements in AIP.

Association of Serum Bicarbonate with Bone Fractures in Hemodialysis Patients: The Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D)

Background/Aims: Bone fracture is often complicated in hemodialysis (HD) patients. Metabolic acidosis is related to bone disease and muscle wasting, but it is not known whether acid-base disturbance is associated with the risk of bone fractures. The aim of this study was to clarify the association of serum bicarbonate level with bone fracture in HD patients. Methods: Using a subcohort of the Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D), 890 prevalent HD patients (age: 62 years old, male: 62.8%, duration of dialysis: 8.3 years) with secondary hyperparathyroidism were studied. After measuring predialysis serum bicarbonate at a 2-day interdialytic interval, we prospectively followed them every 3 months, and examined the occurrence of any type of bone fracture or hospitalization due to fracture over a 3-year observation period. Results: Seventy-four bone fractures and 47 hospitalizations due to fracture were observed during the follow-up period. HD patients with serum bicarbonate <20 mmol/l had a 1.93 (95% CI 1.01-3.71)-fold higher risk for all-cause fractures than those with serum bicarbonate of 20.0-21.9 mmol/l. A higher bicarbonate level (≥22 mmol/l) was also related to an increased risk of bone fracture. A restricted cubic regression spline disclosed that the higher or the lower than 21.0 mmol/l of serum bicarbonate, the greater the risk for bone fracture. Conclusion: Both a lower level and a higher level of predialysis bicarbonate concentration were associated with risk of bone fracture in HD patients with secondary hyperparathyroidism.