Prolonged immunosuppression does not improve risk of sensitization or likelihood of retransplantation after kidney transplant graft failure.

The optimum approach towards immunosuppression withdrawal following kidney transplant failure is unclear. Prolonged weaning may be associated with reduced sensitization, less graft nephrectomy and greater likelihood of retransplantation, but conversely increased risk of infection, malignancy and death. We conducted a single-centre retrospective analysis of patients experiencing graft failure between 2007 and 2017, comparing rates of sensitization, retransplantation, nephrectomy, infection, malignancy and death between patients who had immunosuppression weaned over <90 vs. 90-180 vs. >180 days. Patient survival after immunosuppression withdrawal over <90 vs. 90-180 vs. >180 days was 73.3%, 72.1% and 80.4%, respectively (P = 0.35), with no differences in cPRA (80.06 vs. 81.21 vs. 85.42, P = 0.66) or retransplantation rate [24/31 (77.4%) vs. 21/35 (60.0%) vs. 22/36 (61.1%), P = 0.13]. There was significantly less nephrectomy after late immunosuppression cessation [10/42 (23.8%) vs. 7/42 (16.7%) vs. 3/43 (7.0%), P = 0.01] but no differences in infections or malignancy. On competing risk regression (death as competing risk) controlling for cofactors including age, nephrectomy and rejection, prolonged immunosuppression did not predict likelihood of retransplantation (SHR 1.000, P = 0.88). Prolonged immunosuppression withdrawal does not reduce sensitization or improve retransplantation rates but is associated with less nephrectomy. Immunosuppression withdrawal should be tailored to individual circumstances after graft failure.

Bone microarchitecture in patients undergoing parathyroidectomy for management of secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) leads to complex bone disease, affecting both trabecular and cortical bone, and increased fracture risk. Optimal assessment of bone in patients with CKD is yet to be determined. High-resolution magnetic resonance imaging (MRI) can provide three-dimensional assessment of bone microarchitecture, as well as determination of mechanical strength with finite element analysis (FEA). METHODS: We conducted a single-centre, cross-sectional study to determine bone microarchitecture with MRI in CKD patients with SHPT undergoing parathyroidectomy. Within two weeks of surgery, MRI was performed at the distal tibia and biochemical markers of SHPT (parathyroid hormone [PTH] and alkaline phosphatase [ALP]) were collected. Trabecular and cortical topological parameters as well as bone mechanical competence using FEA were assessed. Correlation of MRI findings of bone was made with biochemical markers. RESULTS: Twenty patients with CKD (15 male, 5 female) underwent MRI at the time of parathyroidectomy (16 on dialysis, 3 with functioning kidney transplant, one pre-dialysis with CKD stage 5). Median PTH at the time of surgery was 138.5 pmol/L [39.6-186.7 pmol/L]. MRI parameters in patients were consistent with trabecular deterioration, with erosion index (EI) 1.01 ±â€¯0.3, and trabecular bone volume (BV/TV) 10.8 ±â€¯2.9%, as well as poor trabecular network integrity with surface-to-curve ratio (S/C) 5.4 ±â€¯2.3. There was also evidence of reduced cortical thickness, with CTh 2.698 ±â€¯0.630 mm, and FEA demonstrated overall poor bone mechanical strength with mean elastic modulus of 2.07 ±â€¯0.44. CONCLUSION: Patients with severe SHPT requiring parathyroidectomy have evidence of significant changes in bone microarchitecture with trabecular deterioration, low trabecular and cortical bone volume, and reduced mechanical competence of bone.

Residual kidney function in nocturnal vs conventional haemodialysis patients: a prospective observational study.

BACKGROUND: Residual kidney function (RKF) provides substantial volume and solute clearance even after dialysis initiation. Preservation of RKF is associated with improved outcomes including mortality in patients on both peritoneal and haemodialysis (HD). Factors predicting RKF loss are unclear, including HD modality. Nocturnal haemodialysis (NHD) may result in less aggressive fluid and solute shifts, however, retrospective data suggests frequent NHD may accelerate RKF decline. The aim of the study was to determine if decline in RKF differs between patients undergoing conventional haemodialysis (CHD) versus NHD. METHODS: A prospective observational study of incident HD patients was undertaken comparing patients undertaking CHD (4-5 h, 3 days/week) and NHD (8 h, 3-5 nights/week). Change in RKF was measured by urea and creatinine clearance (48-h interdialytic urine collection) and glomerular filtration rate (GFR) (Cr51-EDTA nuclear scan) at initiation of dialysis (baseline) and 12 months. RESULTS: A total of 18 incident HD patients were recruited (8 CHD, 10 NHD). Three patients withdrew after baseline (n = 15). Baseline RKF was similar between groups with mean nuclear GFR of 13.3 ± 4.1 mL/min in the CHD cohort vs 13.5 ± 4.6 mL/min in the NHD group (p = 0.89). Baseline urine volume was 2399 ± 950 mLs and 2794 ± 1662 mLs in the CHD and NHD, respectively (p = 0.57). Nuclear GFR declined from time 0 to 12 months to 9.3 ± 2.5 mL/min and 10.4 ± 4.3 mL/min in the CHD and NHD, respectively (p = 0.52). There was a significant decline in 48-h urine volume over 12 months with a mean volume of 1943 ± 1087.0 mLs in the CHD compared to 601.7 ± 315.3 mLs in the NHD (p = 0.01). No significant difference was found in other measures of RKF between groups over 12 months. CONCLUSION: This small prospective cohort study found that the loss of residual urine volume was greater in the NHD vs the CHD cohort but there was no difference in other measures of RKF.

Magnetic resonance imaging based assessment of bone microstructure as a non-invasive alternative to histomorphometry in patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) adversely affects bone microarchitecture and increases fracture risk. Historically, bone biopsy has been the 'gold standard' for evaluating renal bone disease but is invasive and infrequently performed. High-resolution magnetic resonance imaging (MRI) quantifies bone microarchitecture noninvasively. In patients with CKD, it has not been compared with results derived from bone biopsy or with imaging using dual energy X-ray absorptiometry (DXA). METHODS: Fourteen patients with end-stage kidney disease (ESKD) underwent MRI at the distal tibia, bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA; hip and spine) and transiliac bone biopsies with histomorphometry and microcomputed tomography (micro-CT). All patients had biomarkers of mineral metabolism. Associations were determined by Spearman's or Pearson's rank correlation coefficients. RESULTS: MRI indices of trabecular network integrity, surface to curve ratio (S/C) and erosion index (EI), correlated to histomorphometric trabecular bone volume (S/C r = 0.85, p = 0.0003; EI r = -0.82, p = 0.001), separation (S/C r = -0.58, p = 0.039; EI r = 0.79, p = 0.0012) and thickness (S/C, r = 0.65, p = 0.017). MRI EI and trabecular thickness (TbTh) also correlated to micro-CT trabecular separation (EI r = 0.63, p = 0.02; TbTh r = -0.60, p = 0.02). Significant correlations were observed between histomorphometric mineralization and turnover indices and various MRI parameters. MRI-derived trabecular parameters were also significantly related to femoral neck BMD. CONCLUSIONS: This study highlights the heterogeneity of bone microarchitecture at differing skeletal sites. MRI demonstrates significant, relevant associations to important bone biopsy and DXA indices and warrants further investigation to assess its potential to non-invasively evaluate changes in bone structure and quality over time.

De novo or early conversion to everolimus and long-term cancer outcomes in kidney transplant recipients: A trial-based linkage study.

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.

Deterioration of Cortical Bone Microarchitecture: Critical Component of Renal Osteodystrophy Evaluation.

BACKGROUND: Cortical bone is a significant determinant of bone strength and its deterioration contributes to bone fragility. Thin cortices and increased cortical porosity have been noted in patients with chronic kidney disease (CKD), but the "Turnover Mineralization Volume" classification of renal osteodystrophy does not emphasize cortical bone as a key parameter. We aimed to assess trabecular and cortical bone microarchitecture by histomorphometry and micro-CT in patients with CKD G5 and 5D (dialysis). METHODS: Transiliac bone biopsies were performed in 14 patients undergoing kidney transplantation (n = 12) and parathyroidectomy (n = 2). Structural parameters were analysed by histomorphometry and micro-CT including trabecular bone volume, thickness (TbTh), number (TbN) and separation and cortical thickness (CtTh) and porosity (CtPo). Indices of bone remodelling and mineralisation were obtained and relationships to bone biomarkers examined. Associations were determined by Spearman's or Pearson's rank correlation coefficients. RESULTS: By micro-CT, trabecular parameters were within normal ranges in most patients, but all patients showed very low CtTh (127 ± 44 µm) and high CtPo (60.3 ± 22.5%). CtPo was inversely related to TbN (r = -0.56; p = 0.03) by micro-CT and to TbTh (r = -0.60; p = 0.024) by histomorphometry and correlated to parathyroid hormone values (r = 0.62; p = 0.021). By histomorphometry, bone turnover was high in 50%, low in 21% and normal in 29%, while 36% showed abnormal patterns of mineralization. Significant positive associations were observed between osteoblast surface, osteoclast surface, mineralization surface and bone turnover markers. CONCLUSIONS: Deterioration of cortical -microarchitecture despite predominantly normal trabecular parameters reinforces the importance of comprehensive cortical evaluation in patients with CKD.

Histological and Extended Clinical Outcomes After ABO-Incompatible Renal Transplantation Without Splenectomy or Rituximab.

BACKGROUND: Excellent short-term results have been reported in ABO-incompatible (ABOi) renal transplant recipients managed solely with antibody removal and conventional immunosuppression. However, long-term clinical outcomes with this regimen and predictive information from protocol biopsies are lacking. METHODS: We compared outcome data in ABOi and ABO-compatible (ABOc) recipients receiving this regimen approximately 4 years posttransplant, and histology from biopsies approximately 12 months posttransplant. RESULTS: Patient and graft survivals among 54 ABOi recipients were 98.1% and 90.7%, respectively, at 4 years. Graft function was similar between ABOi (creatinine, 140.3 µmol/L) and ABOc recipients (creatinine, 140.2 µmol/L) (P = 0.99), with no significant change over the study period in either group (Δcreatinine, -0.83 vs 6.6 µmol/L) (P = 0.59). There was no transplant glomerulopathy in biopsies from either group. Interstitial fibrosis (IF) and tubular atrophy (TA) was present in 7 (28%) of 25 ABOi compared with 7 (20.6%) of 34 ABOc (P = 0.52). Progression of IF/TA from implantation was noted in 6 (24%) of 25 ABOi and 6 (17.6%) of 34 ABOc, respectively. C4d staining without antibody-mediated rejection was present in 13 (52%) 25 early posttransplant biopsies from ABOi recipients by immunohistochemistry, but in only 4 (16%) of 25 at 12 months. CONCLUSIONS: ABO-incompatible renal transplant performed with antibody removal and conventional immunosuppression continues to provide excellent patient and graft survival, and stable renal function over 4 years. Coupled with absent transplant glomerulopathy and low rates of progressive IF/TA on earlier biopsies, this suggests that ABOi with conventional immunosuppression and antibody removal, without rituximab or splenectomy, can achieve long-term outcomes comparable to ABO-compatible transplantation.

Emerging role of high-resolution imaging in the detection of renal osteodystrophy.

The term renal osteodystrophy refers to changes in bone morphology induced by chronic kidney disease (CKD) and represents the skeletal component of the entity 'chronic kidney disease - mineral and bone disorder'. Changes in turnover, mineralization, mass and microarchitecture impair bone quality, compromising strength and increasing susceptibility to fractures. Fractures are more common in CKD compared with the general population and result in increased morbidity and mortality. Screening for fracture risk and management of renal osteodystrophy are hindered by the complex, and still only partially understood, pathophysiology and the inadequacy of currently available diagnostic methods. Bone densitometry and bone turnover markers, although potentially helpful, have significant limitations in patients with CKD, and the 'gold standard' test of bone biopsy is infrequently performed in routine clinical practice. However, recent advances in high-resolution bone microarchitecture imaging may offer greater potential for quantification and assessment of bone structure and strength and, when used in conjunction with serum biomarkers, may allow non-invasive testing for a diagnostic virtual bone biopsy.

Endogenous relaxin is a naturally occurring modulator of experimental renal tubulointerstitial fibrosis.

Relaxin is a naturally occurring regulator of collagen turnover. In this study, we determined the role of endogenous relaxin in the pathogenesis of primary tubulointerstitial fibrosis after unilateral ureteric obstruction (UUO). Four- to 6-wk-old relaxin (RLX) gene-knockout (RLX(-/-)) and age-matched wild-type (RLX(+/+)) mice, with equivalent baseline collagen levels, were subjected to UUO. Obstructed and contralateral kidneys were collected at d 0, 3, and 10 after surgery and analyzed for changes in inflammatory and fibrosis-related markers. UUO was associated with a progressive increase in fibrosis in all obstructed, but not contralateral kidneys. The increase in total collagen (hydroxyproline analysis) was associated with more alpha-smooth muscle actin (alpha-SMA) staining (myofibroblasts) and interstitial collagen sub-types (SDS-PAGE; types I, III, and V), whereas gelatin zymography demonstrated increased expression of matrix metalloproteinase-2 after surgery. By d 10 after UUO, there was a 5-fold decrease in RLX mRNA expression (quantitative RT-PCR) in RLX(+/+) animals. Total collagen and alpha-SMA expression were significantly greater in the obstructed kidneys of RLX(-/-) mice 3 d after UUO (both P < 0.05 vs. RLX(+/+) D3 after UUO), but comparable to that in RLX(+/+) animals 10 d after UUO. Administration of recombinant H2 relaxin to RLX(-/-) mice 4 d before UUO ameliorated the increase in collagen and alpha-SMA expression (both P < 0.05 vs. untreated RLX(-/-) mice) by d 3 after UUO. Expression of monocyte chemoattractant protein-1 and macrophage infiltration (inflammation) in addition to that of matrix metalloproteinases was unaffected by genotype after UUO. These combined data demonstrate that endogenous RLX acts as a modulating factor in tubulointerstitial fibrosis, a hallmark of progressive renal disease. This is likely to be via direct effects on renal myofibroblast function.

Impact of statin treatment on 1-year functional and histologic renal allograft outcome.

BACKGROUND: Statins are antilipidemic agents that exhibit a variety of cellular effects independent of their lipid-lowering action. A retrospective study was undertaken to establish the impact of statins on graft outcome in the first year posttransplantation. METHODS: Data from patients with uniform immunosuppression (cyclosporine, mycophenolate mofetil, and prednisolone) who underwent transplantation at the authors' unit from 1997 to 2002 were reviewed. Patients prescribed statins were compared with those not on a statin. Mean change in creatinine clearance (CrCl) from 3 to 12 months posttransplantation was calculated. Histomorphometric analysis was used to quantify fractional interstitial area and collagen III deposition in matched preperfusion and 12-month protocol biopsy specimens. RESULTS: Seventy-seven patients met study criteria: statin, n=44 patients; nonstatin, n=33 patients. Median time to commencing a statin was 5 weeks. At 3 months, CrCl (+/-SEM) was similar: 51.6+/-2.9 mL/min (statin) versus 51.3+/-1 mL/min (nonstatin). At 12 months, the mean change in CrCl was 4.1+/-1 mL/min (statin) compared with -2.0+/-1.8 mL/min (nonstatin), resulting in a difference of 6.13 mL/min at 12 months (P<0.005). Mean preperfusion fractional interstitial areas were similar (23.9+/-1.6%; P=not significant [NS]). On 12-month biopsy specimens, the fractional interstitial area had increased to 34+/-3.2% in the nonstatin group (P<0.005), with no change in the statin group. Interstitial collagen III deposition was similar in preperfusion biopsy specimens (10.4+/-1%; P=NS), but at 12 months it was significantly greater in the nonstatin group (17.6+/-1%; P<0.05) CONCLUSIONS: Early introduction of statins may be associated with improved 1-year graft outcome.

Wegener's granulomatosis in pregnancy: a novel approach to management.

Wegener's granulomatosis rarely is diagnosed in women of childbearing age and is, thus, uncommonly encountered in pregnancy. Although conventional treatment with steroids and cyclophosphamide controls disease activity in 90% of patients, the associated teratogenicity of such a regimen warrants careful consideration in pregnancy. We describe successful remission induction with the use of intravenous immunoglobulin and steroids alone in a woman diagnosed with de novo Wegener's granulomatosis during the first trimester of pregnancy.

Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro.

BACKGROUND: Renal fibroblasts are important effector cells in tubulointerstitial fibrosis, with experimental antifibrotic strategies focusing on the functional down-regulation of these cells. Several experimental models of fibrosis have provided evidence for the effectiveness of the polypeptide hormone relaxin as a potential antifibrotic agent. This study was conducted to further elucidate the antifibrotic mechanisms of relaxin on renal fibroblasts in vitro. METHODS: Rat cortical fibroblasts were obtained from outgrowth culture of renal tissue isolated from kidneys 3 days post-unilateral ureteric obstruction and constituted 100% of cells studied. A relaxin radio-receptor assay was used to establish binding of relaxin to renal fibroblasts in vitro. Functional studies then examined the effects of H2 relaxin (0, 1, 10 and 100 ng/ml) on fibroblast kinetics, expression of alpha-smooth muscle actin (alpha-SMA), total collagen synthesis, collagenase production and collagen-I lattice contraction. CTGF mRNA expression was also measured by northern analysis. RESULTS: H2 relaxin bound with high affinity to rat renal fibroblasts, but receptor numbers were low. Consistent with its previously reported bimodal effect, transforming growth factor (TGF-beta 1) reduced fibroblast proliferation, an effect abrogated by H2 relaxin. Fibroblasts exposed to H2 relaxin (100 ng/ml) for 24 h demonstrated decreased immunostaining for alpha-SMA and reduced alpha-SMA protein expression compared with controls. There was a trend for a relaxin-mediated reduction in total collagen synthesis and alpha 1(I) mRNA expression with large dose-related increases in collagenase protein expression being observed. TGF-beta 1-stimulated collagen-I lattice contraction was significantly inhibited following co-incubation with 100 ng/ml relaxin. Incremental doses of H2 relaxin had no significant effect on CTGF mRNA expression. CONCLUSIONS: The findings of this study suggest that the antifibrotic effects of relaxin involve down-regulation of fibroblast activity, increase in collagenase synthesis and restructuring of collagen-I lattices, which are consistent with its known physiological role of matrix remodelling. Although there appears to be an interaction between TGF-beta 1 and H2 relaxin, this does not appear to involve a reduction in CTGF mRNA expression.