Long-term effects of denosumab on bone mineral density and turnover markers in patients undergoing hemodialysis.

INTRODUCTION: Denosumab, a fully human anti-RANKL monoclonal antibody, is a widely used osteoporosis treatment that is increasingly being used in patients undergoing dialysis; however, its long-term efficacy and safety in these patients remain unknown. MATERIALS AND METHODS: This observational study comprised individuals aged ≥ 20 years undergoing hemodialysis and receiving denosumab. After denosumab administration, we analyzed the long-term changes in bone mineral density (BMD) and levels of bone turnover markers (BTMs) and calcium. RESULTS: The study included 45 patients who have been receiving denosumab for a median duration of 3.8 (interquartile range, 2.5-6.7) years. Tartrate-resistant acid phosphatase 5b (TRACP-5b) levels decreased from a median of 595 (434-778) mU/dL at baseline to 200 (141-430) mU/dL after 6 months of denosumab administration (P < 0.001) and remained low thereafter. Similarly, bone-specific alkaline phosphatase (BAP) levels decreased from a median of 18.2 (15.9-25.8) µg/L at baseline to 12.4 (9.9-15.6) µg/L after 6 months (P < 0.001) and remained low thereafter. Meanwhile, BMD, as assessed with dual energy X-ray absorptiometry and measured at the distal 1/3 of the radius, did not decrease (0.465 ± 0.112 g/cm2 at baseline vs. 0.464 ± 0.112 g/cm2 after administration; P = 0.616). Regarding hypocalcemia, corrected calcium levels reached were the lowest at 7 days after administration and normalized within 30 days. CONCLUSION: The study showed long-term suppression of TRACP-5b and BAP levels and sustaining BMD after denosumab administration over an extended period in patients undergoing hemodialysis.

Association between serum magnesium levels and cognitive function in patients undergoing hemodialysis.

BACKGROUND: The relationship between chronic kidney disease-mineral and bone disorder (CKD-MBD) and cognitive function remains largely unknown. This cross-sectional study aimed to explore the association between CKD-MBD and cognitive function in patients on hemodialysis. METHODS: Hemodialysis patients aged ≥ 65 years without diagnosed dementia were included. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). CKD-MBD markers, serum magnesium, intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OHD), fibroblast growth factor (FGF)-23, and soluble α-klotho were measured. RESULTS: Overall, 390 patients with a median age of 74 (interquartile range, 70-80) years, mean serum magnesium level of 2.4 ± 0.3 mg/dL, and median MoCA and MMSE scores of 25 (22-26) and 28 (26-29), respectively, were analyzed. MoCA and MMSE scores were significantly higher (preserved cognitive function) in the high-magnesium group than in the low-magnesium group according to the unadjusted linear regression analysis (ß coefficient [95% confidence interval (CI)] 1.05 [0.19, 1.92], P = 0.017 for MoCA; 1.2 [0.46, 1.94], P = 0.002 for MMSE) and adjusted multivariate analysis with risk factors for dementia (ß coefficient [95% CI] 1.12 [0.22, 2.02], P = 0.015 for MoCA; 0.92 [0.19, 1.65], P = 0.014 for MMSE). CONCLUSIONS: Higher serum magnesium levels might be associated with preserved cognitive function in hemodialysis patients. Conversely, significant associations were not observed between cognitive function and intact PTH, 25-OHD, FGF-23, or soluble α-klotho levels.

Calcium-based phosphate binders and bone mineral density in patients undergoing hemodialysis: a retrospective cohort study.

BACKGROUND: Calcium supplements are commonly prescribed to prevent fractures in patients with osteoporosis. Nonetheless, they are generally eschewed in hemodialysis patients because they increase vascular calcification and induce cardiovascular disease. This retrospective cohort study aimed to investigate the effect of calcium-based phosphate binders (CBPB) on bone mineral density (BMD) in hemodialysis patients. METHODS: Outpatients on dialysis who underwent BMD measurement from January to December 2017, whose data on BMD trends and CBPB administration were recorded over the next 4 years, were enrolled. Patients receiving anti-osteoporotic medications were excluded. The association between the presence and duration of CBPB administration and changes in BMD was evaluated. RESULTS: The femoral neck's BMD decreased from 0.836 g/cm2 (0.702-0.952) to 0.764 g/cm2 (0.636-0.896) (P < 0.001) in the non-CBPB group (patients who never received CBPB over 4 years, n = 32). The CBPB group (n = 56) exhibited only a minute decrease from 0.833 g/cm2 (0.736-0.965) to 0.824 g/cm2 (0.706-0.939) (P = 0.004). Multivariate linear regression analysis revealed better BMD maintenance in the CBPB group [ß-coefficient (95% CI): 0.033 (0.001-0.065); P = 0.046] than in the non-CBPB group. Additionally, the prolonged-CBPB administration group showed superior BMD preservation [ß-coefficient (95% CI): 0.038 (0.001-0.076); P = 0.042]. CONCLUSION: CBPB administration may be associated with BMD maintenance.

Association between serum phosphate levels and anemia in non-dialysis patients with chronic kidney disease: a retrospective cross-sectional study from the Fuji City CKD Network.

BACKGROUND: Patients with chronic kidney disease (CKD) present high mortality and morbidity rates despite the availability of various therapies. Although CKD-mineral and bone disorder (MBD) and renal anemia are important factors in patients with CKD, only few studies have analyzed the relationship between them. Therefore, this study aimed to evaluate the relationship between CKD-MBD and anemia in patients with CKD who did not receive erythropoiesis-stimulating agent or iron therapies. METHODS: This retrospective cross-sectional study included patients with CKD aged ≥ 20 years with estimated glomerular filtration rate (eGFR) categories G2a to G5 who were referred to the Fuji City General Hospital between April 2018 and July 2019. The exclusion criterion was ongoing treatment for CKD-MBD and/or anemia. RESULTS: The data of 300 patients with CKD were analyzed in this study. The median age of patients was 71 (range, 56.5-79) years. The median eGFR was 34 (range, 20-48) mL/min/1.73 m2, and the mean hemoglobin (Hb) level was 12.7 g/dL (standard deviation, 2.3), which decreased as the CKD stage increased. In a multivariate linear regression analysis of anemia-related factors, including age, renal function (eGFR), nutritional status, inflammation, and iron dynamics (serum iron level, total iron-binding capacity, ferritin levels), the serum phosphate levels were significantly associated with the Hb levels (coefficient [95% confidence interval], -0.73 [-1.1, -0.35]; P < 0.001). Subgroup analysis revealed a robust association between serum phosphate levels and Hb levels in the low-ferritin (coefficient [95% confidence interval], -0.94 [-1.53, -0.35]; P = 0.002) and advanced CKD groups (coefficient [95% confidence interval], -0.89 [-1.37, -0.41]; P < 0.001). CONCLUSIONS: We found an association between high serum phosphate levels and low Hb levels in patients with CKD not receiving treatment for anemia. These results underscore the possibility of a mechanistic overlap between CKD-MBD and anemia.

Severe chronic kidney disease environment reduced calcium-sensing receptor expression in parathyroid glands of adenine-induced rats even without high phosphorus diet.

BACKGROUND: Chronic kidney disease (CKD) disrupts mineral homeostasis and its main underlying cause is secondary hyperparathyroidism (SHPT). We previously reported that calcium-sensing receptor (CaSR) mRNA and protein expression in parathyroid glands (PTGs) significantly decreased in a CKD rat model induced by a 5/6 nephrectomy that were fed a high phosphorus diet. However, there was a significant difference in the severity of CKD between high phosphorus and adequate phosphorus diet groups. Thus, it was unclear whether CKD environment or the high phosphorus diet influenced CaSR expression, and the underlying mechanism remains largely unknown. METHODS: CKD was induced in rats with 0.75% adenine-containing diet. CKD and control rats were maintained for 5 days and 2 weeks on diets with 0.7% or 1.3% phosphorus. For gene expression analysis, quantitative real-time polymerase chain reaction was performed with TaqMan probes. Protein expression was analyzed by immunohistochemistry. RESULTS: PTG CaSR expression significantly decreased in the presence of a severe CKD environment, even without the high phosphate load. Ki67 expressing cells in PTGs were significantly higher only in the CKD rats fed a high phosphorus diet. Furthermore, among the many genes that could affect CaSR expression, only vitamin D receptor (VDR) and glial cells missing 2 (Gcm2) showed significant changes. Moreover, Gcm2 was significantly reduced at an early stage without significant changes in serum calcium, phosphorus and 1,25(OH)2 vitamin D, and there was no significant reduction in CaSR and VDR expressions. Then, significantly elevated Ki67-positive cell numbers were also only observed in the early CKD PTGs with high-phosphorus diets. CONCLUSIONS: Our data suggest that the cause of the decreased PTG CaSR expression is the reduction in VDR and Gcm2 expression; Gcm2 may play a role in the onset and progression of SHPT.

Factors affecting the relationship between ionized and corrected calcium levels in peritoneal dialysis patients: a retrospective cross-sectional study.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) management in patients with end-stage renal disease is important owing to the risk of cardiovascular diseases. In clinical practice, we manage patients not by monitoring the levels of biologically active ionized calcium (iCa) but by monitoring total serum calcium or corrected calcium (cCa). We previously reported that iCa/cCa ratio was different between patients with hemodialysis and those with peritoneal dialysis (PD). In PD patients, several factors are expected to affect iCa/cCa ratio. Therefore, modifying the strategy to achieve better CKD-MBD management might be necessary; however, no reports have studied this to date. Therefore, we investigated the factors influencing iCa/cCa ratio in PD patients. METHODS: This retrospective cross-sectional study examined background and laboratory data, including iCa, collected at routine outpatient visits. The patients were divided into the first, second, and third tertile of iCa/cCa ratio groups to compare patient background and laboratory data. Multiple regression analysis was used to investigate the factors influencing iCa/cCa ratio. We used multiple imputation to deal with missing covariate data. RESULTS: In total, 169 PD patients were enrolled. In PD patients with lower iCa/cCa ratio, PD duration was longer and pH was higher. Urine volume and weekly renal Kt/V were lower in the patients with lower iCa/cCa ratio than in those with higher iCa/cCa ratio. iCa/cCa ratio and weekly renal Kt/V were directly correlated (r = 0.41, p < 0.01), and weekly renal Kt/V and pH were independent factors affecting iCa/cCa ratio (t = 2.86, p < 0.01 and t = - 5.42, p < 0.01, respectively). CONCLUSIONS: iCa levels were lower in PD patients with lower residual renal function (RRF) even though their cCa levels were equal to those with maintained RRF, warranting caution in the assessment and management of CKD-MBD in PD patients.

Clinical outcome of incident peritoneal dialysis patients with diabetic kidney disease.

BACKGROUND: Although peritoneal dialysis (PD) is becoming more widespread, PD among diabetic patients carries some concerns, such as worsened glycemic control due to constant exposure to glucose and operational errors due to diabetic complications. However, several technical advances could overcome these disadvantages. We, therefore, aimed to compare technical and patient survival between diabetic and non-diabetic PD patients. METHODS: We conducted a historical cohort study of 103 patients (mean age, 57 ± 16 years; 75 males, 32 diabetic patients) who started PD between January 2011 and January 2016. Kaplan-Meier survival analysis was used to compare technical and patient survivals between diabetic and non-diabetic patients. Multivariate Cox regression analysis was used to estimate the effects of the presence of diabetes on these outcomes. RESULTS: Technical and patient survivals did not differ significantly between groups (P = 0.62, P = 0.34, respectively). In addition, presence of diabetes affected neither technical nor patient survival in multivariate analysis (hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.58-2.82 and HR 0.80; 95% CI 0.22-2.68, respectively). CONCLUSIONS: Technical and patient survivals of diabetic PD patients were not inferior to those of non-diabetic PD patients. These results suggest that no hesitation is warranted in initiating PD for diabetic patients with end-stage renal disease.

Antibody-mediated rejection due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient.

Herein, we report a case of antibody-mediated rejection (ABMR) due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient. A 34-year-old female recipient was admitted at 2 years after delivery for an examination of an elevated serum creatinine (S-Cr) level. The patient had received a living kidney transplantation from her mother at 22 years of age, and her kidney graft function was almost stable. The episode biopsy showed peritubular capillaritis and transplant capillaropathy with C4d immunoreactivity in the peritubular capillaries. Additional examination revealed expression of a donor-specific antibody (DSA) against HLA-DQ5, leading to the diagnosis of chronic active ABMR. Intravenous immunoglobulin, plasma exchange, and rituximab were administered, and her S-Cr level was maintained stable. This case demonstrates a possible relationship between pregnancy/delivery and development of ABMR due to a de novo DSA in a female kidney transplant recipient.

Clinicopathological features and outcomes of kidney allografts in plasma cell-rich acute rejection: A case series.

Plasma cell-rich acute rejection (PCAR) is a rare type of acute rejection in renal transplantation. Despite aggressive immunotherapy, approximately 40-60% of patients develop graft loss within 1 year after an episode of PCAR. However, the reason for this outcome remains obscure. This study retrospectively identified six patients with PCAR diagnosed between 2009 and 2015 at a single university hospital. Clinicopathological data were collected. Five of the six patients were male, and mean age at the onset of PCAR was 49.0 ±14.5 years. None of the patients showed overall poor adherence to medication. Mean time to diagnosis was 302 ±234 days post-transplantation. All patients had preceding or concurrent viral infection. Four patients developed PCAR alone and two patients developed PCAR with antibody-mediated rejection. One of the six patients showed both severe tubulointerstitial and microvascular inflammation (total of Banff tubulitis 't' + interstitial inflammation 'i' + glomerulitis 'g' + peritubular capillaritis 'ptc' scores >10). This patient had progressive worsening of graft function and re-initiated dialysis at 74 months after a PCAR episode. In addition, three of the six patients had long-term recurrence of PCAR. With the recurrence of PCAR, patients with both moderate tubulointerstitial and microvascular inflammation (total of Banff 't' + 'i' + 'g' + 'ptc' scores >6) had progressive worsening of graft function. In summary, the present results suggest that concurrent moderate to severe tubulointerstitial and microvascular inflammation may lead to poor outcomes of graft function after a PCAR episode.

Successful treatment of recurrent immunoglobulin a nephropathy using steroid pulse therapy plus tonsillectomy 10 years after kidney transplantation: a case presentation.

BACKGROUND: Both prevention and treatment of recurrent immunoglobulin A nephropathy (IgAN) in kidney transplant recipients are important since recurrent IgAN seems to affect long-term graft survival. We present here a case of recurrent IgAN that was successfully treated using steroid pulse therapy plus tonsillectomy 10 years after kidney transplantation. CASE PRESENTATION: A 46-year-old male was admitted for an episode biopsy with a serum creatinine level of 1.8 mg/dl and proteinuria (0.7 g/day). Histological features showed recurrent IgAN (only focal segmental mesangial proliferation) and severe arteriolar hyalinosis partly associated with calcineurin inhibitor toxicity, with limited interstitial fibrosis and tubular atrophy (5%) (IF/TA) 8 years after transplantation. Sodium restriction and conversion from cyclosporine to tacrolimus successfully reduced his proteinuria to the level of 0.15 g/day. However, 2 years later, his proteinuria increased again (1.0 g/day) and a second episode biopsy showed global mesangial proliferation with glomerular endocapillary and extracapillary proliferation accompanied by progressive IF/TA (20%). The steroid pulse therapy plus tonsillectomy successfully decreased his proteinuria and he achieved clinical remission 3 years after this treatment. CONCLUSION: This case, presented with a review of relevant literature, demonstrates the difficulty and importance of the treatment of recurrent IgAN and calcineurin inhibitor arteriolopathy, especially in long-term kidney allograft management.

[Fragility Fractures in Hemodialysis Patients. Abnormal bone material characteristics of dialysis patients.]

The relationship between renal dysfunction and bone fragility is well known. Bone fragility, which is associated with an increased risk of bone fracture, affects quality of life and prognosis in patients with chronic kidney disease(CKD). The bone of patients with CKD is more fragile than the risk estimated by measurement of bone mineral density. Bone quality, which is defined by many factors including bone turnover, microarchitecture, collagen crosslinking, and matrix composition, is considered to be major cause of bone fragility of the patients with CKD. In this article, we will describe the bone quality of dialysis patients with CKD as representatives of patients with CKD.

Association Between GLCCI1 Promoter Polymorphism (Rs37972) and Post-Transplant Hypertension in Renal Transplant Recipients.

BACKGROUND/AIMS: Post-transplant hypertension is highly prevalent in renal transplant recipients and is a risk factor for graft loss, cardiovascular disease and death. Glucocorticoid is used to prevent rejection, but simultaneously increases the risk of post-transplant hypertension. The glucocorticoid-induced transcript 1 (GLCCI1) promoter polymorphism (rs37972) has been reported to be associated with response to glucocorticoid therapy in asthma. We therefore examined the association between GLCCI1 promoter polymorphism and post-transplant hypertension in renal transplant recipients. METHODS: We conducted a retrospective cohort study of renal transplantation at a single university hospital from October 2003 to January 2014. Fifty consecutive adult recipients were analyzed, with clinical data retrieved from a prospectively collected database. Genotyping was carried out using genomic DNA derived from recipient's blood. GLCCI1 immunoreactivity in vascular endothelial cells was quantitatively analyzed by immunohistochemical staining of recipients' native kidney biopsy-specimens. The primary outcome measure was post-transplant hypertension. RESULTS: Post-transplant hypertension was observed in 14/17 (82%) of recipients with CC, 18/20 (90%) with CT, and 2/13 (15%) with TT genotype. CC/CT genotype was significantly associated with post-transplant hypertension, even after adjustment for covariates (odds ratio, 10.6; 95% confidence intervals, 1.32 to 85.8; P = 0.026). In addition, we observed that GLCCI1 immunoreactivity in arteriolar endothelial cells was higher in kidney specimens obtained from recipients with a CC/CT genotype than a TT genotype (P = 0.021). CONCLUSION: GLCCI1 promoter polymorphism rs37972 may be associated with post-transplant hypertension.

Recurrence and graft loss after renal transplantation in adults with IgA vasculitis.

BACKGROUND: IgA vasculitis, a rare condition resulting in end-stage renal disease, is a small-vessel vasculitis that affects the kidney in 49-83 % of adults. The reported recurrence rate of IgA vasculitis in renal transplant recipients is 11.5-60 %, leading to graft loss in 0-50 % of these patients. However, limited data are available on recurrence and graft loss after renal transplantation. METHODS: We evaluated renal transplant recipients seen from 1987 to 2015 at the Jikei University School of Medicine and the Department of Urology, Tokyo Women's Medical University. Using a 1:2 match, 21 patients with IgA vasculitis and 42 controls were selected. The mean post-transplant follow-up was 121 ± 69 months for IgA vasculitis and 147 ± 66 months for the controls. RESULTS: The 15-year patient survival was 100 % in IgA vasculitis and 97.6 % in the controls (p = 0.22). The 5-, 10-, and 15-year graft survival rates were 95.2, 90.5, and 81 % in IgA vasculitis and 100, 90.5, and 88.1 % in the controls, respectively (p = 0.63). The recurrence rate was 28.6 % (6 of 21 cases) and half of them (3 of 6 cases) showed histological activity (ISKDC III). We treated them with methylprednisolone pulse therapy and/or tonsillectomy. None of the recurrence cases lost the allograft. CONCLUSION: The long-term patient and graft survival of IgA vasculitis in renal transplantation were comparable with the previous reports. The recurrence rate was 28.6 %, but none of the recurrent cases showed allograft loss in this study. We speculate that methylprednisolone pulse therapy and/or tonsillectomy prevent the progression of recurrent IgA vasculitis.

Risk factors for encapsulating peritoneal sclerosis: Analysis of a 36-year experience in a University Hospital.

AIM: Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication that occurs in peritoneal dialysis (PD) therapy. The present study aimed to identify the risk factors, especially peritonitis and biocompatible PD fluid. METHODS: The study included 703 patients who received PD between January 1980 and March 2015 at two centres. The patients were divided into two groups: those who had developed EPS (EPS group: n = 44) and those who had no documentary evidence of EPS (non-EPS group: n = 659). The independent risks of EPS were determined by univariate and multivariate logistic models. RESULTS: Encapsulating peritoneal sclerosis occurred in 44/703 (6.3%) patients between January 1980 and March 2015. In multivariate logistic models of risk factors correlated with EPS, dialysate to plasma creatinine ratio (D/P Cr) by peritoneal equilibration test (PET) and history of peritonitis were risk factors for EPS development (P < 0.01, respectively) in addition to PD duration. Especially, total duration of peritonitis, defined by period between onset and resolution of peritonitis, was an important risk factor for EPS development in patients with a history of peritonitis. Receiver operating characteristic (ROC) curve analysis revealed that cut-off point for EPS development was 36 days. Moreover, biocompatible PD fluid contributed to decreased EPS development. CONCLUSION: Both the longer duration of peritonitis and higher D/P Cr, as well as the longer PD duration, were risk factors for EPS development. Furthermore, use of biocompatible PD fluid contributed to the decrease in EPS development.

The prognostic values of caveolin-1 immunoreactivity in peritubular capillaries in patients with kidney transplantation.

The low sensitivity of C4d immunoreactivity in peritubular capillaries (PTCs) hinders its use in the diagnosis of chronic active antibody-mediated rejection (CAAMR). C4d-negative CAAMR was defined in the 2013 Banff classification, which included the expression of endothelial-associated transcripts (ENDATs). We previously showed that the ENDAT caveolin-1 (CAV-1) is a distinct feature of CAAMR. In this study, we investigated the prognostic value of CAV-1 immunoreactivity in PTCs in kidney transplant patients. Ninety-eight kidney transplant recipients were included in this study. The prognostic value of CAV-1 immunoreactivity in PTCs was evaluated by double immunostaining for CAV-1 and pathologische Anatomie Leiden endothelium (PAL-E, a PTC marker) in the PTCs of kidney allograft biopsy samples. The patients were divided into two groups: CAV-1/PAL-E<50% and CAV-1/PAL-E≥50%. Kaplan-Meier curves showed that CAV-1/PAL-E≥50% patients had a significantly worse prognosis than that of CAV-1/PAL-E<50% patients (log-rank; P<.001). C4d staining of PTCs was not associated with the development of graft failure (log-rank; P=.345), whereas in a multivariate Cox regression analysis, CAV-1 immunoreactivity in PTCs was independently associated with graft failure (hazard ratio: 11.1; P=.0324). CAV-1 immunoreactivity in PTCs may serve as a prognostic marker for kidney allograft survival.

The differences in acid-base status and the calcium parathyroid axis between peritoneal dialysis and hemodialysis.

BACKGROUND: Several guidelines have set the target levels of serum Ca, phosphorus, and parathyroid hormone (PTH) for better management of chronic kidney disease-mineral and bone disorders (CKDMBD) in dialysis patients. Although serum ionized Ca (iCa) is a biologically active component, corrected Ca (cCa) is used in clinical settings. However, the association between iCa and cCa is affected by acid-base status. We investigated the difference in acid-base and the calcium-parathyroid status between hemodialysis (HD) and peritoneal dialysis (PD). METHODS: The markers associated with CKD-MBD were measured in 142 patients receiving chronic dialysis (69 on PD and 73 on HD). RESULTS: Serum bicarbonate levels were significantly higher in the PD group than in the HD group (26.6 ± 2.8 vs. 22.9 ± 2.0 mEq/L, p < 0.01). The serum iCa levels and the iCa/cCa ratio were significantly lower in the PD group than in the HD group (iCa 1.07 ± 0.08 vs. 1.14 ± 0.08 mmol/L, p < 0.01; iCa/cCa ratio 45.5 ± 3.1% vs. 49.7 ± 3.2%, p < 0.01). The cCa levels were significantly higher in the PD group than in the HD group (9.4 ± 0.4 vs. 9.1 ± 0.4 mg/dL, p < 0.01). Intact PTH levels were significantly higher in the PD group than in the HD group (220 (40 - 581) vs. 133 (30 - 666) pg/mL, p < 0.01). CONCLUSIONS: We found that PD patients had lower iCa and higher PTH levels despite higher cCa levels as compared to HD patients. These results suggested that the assessment of both Ca and PTH should be different between PD and HD.

Successful treatment of recurrent Henoch-Schönlein purpura nephritis in a renal allograft with tonsillectomy and steroid pulse therapy.

We report a case of recurrent Henoch-Schönlein purpura nephritis (HSPN) treated successfully with a tonsillectomy and steroid pulse therapy in a kidney transplant patient. A 29-year-old woman was admitted to our hospital for an episode biopsy; she had a serum creatinine (S-Cr) of 1.0 mg/dL and 1.34 g/day proteinuria 26 months after kidney transplantation. Histological examination revealed increased amounts of mesangial matrix and mesangial hypercellularity with IgA deposition. Of note, one glomerulus showed focal endocapillary proliferation and tuft necrosis. We diagnosed active recurrent HSPN. Considering both the histological findings and refractory clinical course of the native kidney, she was treated for 3 consecutive days with steroid pulse therapy and a tonsillectomy. The patient's proteinuria decreased gradually to less than 150 mg/day 6 months later. A second biopsy 6 years after kidney transplantation showed an excellent response to treatment and revealed a marked reduction in both the mesangial matrix and mesangial hypercellularity, with trace IgA deposition. We conclude that a tonsillectomy and steroid pulse therapy appeared to be useful in this patient with active recurrent HSPN. This paper is the first to report a tonsillectomy and steroid pulse therapy as a therapeutic option for active recurrent HSPN. Further studies are needed to elucidate the efficacy and mechanisms of tonsillectomy with recurrent HSPN in kidney transplant patients.

Subclinical antibody-mediated rejection due to anti-human-leukocyte-antigen-DR53 antibody accompanied by plasma cell-rich acute rejection in a patient with cadaveric kidney transplantation.

A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human-leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell-rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte-antigen-DR53 and plasma cell-rich acute rejection.

Rare case of nephrocalcinosis in the distal tubules caused by hereditary renal hypouricaemia 3 months after kidney transplantation.

We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41-year-old man who underwent living-related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S-Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S-UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal, <10%) and UA clearance of 26.8 mL/min (normal, 7.3-14.7 mL/min) 3 days after kidney transplantation. The donor also had a relatively low S-UA of 2.4 mg/dL and high FEUA of 10.3%. Subsequent DNA direct sequencing followed by restriction fragment length polymorphism revealed that both the recipient's and donor's urate transporter 1 (URAT1) gene had a heterozygous nonsense mutation in exon 5 (C889T). Further, the immunoreactivity of antibodies for the C terminus of URAT1 revealed a partial deletion. De Galantha and von Kossa staining revealed that the nephrocalcinosis was due to urate crystals and calcium stones. Therefore, we diagnosed hereditary renal hypouricaemia. We directed the patient to avoid hard exercise, drink plenty of water, and alkalize the urine. The 1-year follow-up allograft biopsy showed no evidence of nephrocalcinosis in the distal tubules. This is the first report of nephrocalcinosis in the distal tubules as a diagnostic clue to hereditary renal hypouricaemia. We also review the related literature.

A refractory case of subclinical antibody-mediated rejection due to anti-HLA-DQ antibody in a kidney transplant patient.

We herein report a refractory case of subclinical antibody-mediated rejection (AMR) due to anti-HLA-DQ antibody in a kidney transplant patient. A 45-year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor-specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody-mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti-DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti-DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S-Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti-DQ DSAbs and the necessity for subsequent therapies in refractory cases.