Prospective study of the effect of rituximab on kidney function in membranous nephropathy.

Background: Patients with membranous nephropathy (MN) and poor kidney function or active disease despite previous immunosuppression are underrepresented in clinical trials. It is unknown how effective rituximab is in this population. Methods: This prospective, multi-centre, single-arm, real-world study of patients with active MN [urine protein-creatinine ratio (uPCR) >350 mg/mmol and serum albumin <30 g/L, or a fall in estimated glomerular filtration rate (eGFR) of at least 20% or more over at least 3 months] evaluated rituximab in those with contraindications to calcineurin inhibitors and cytotoxic therapy. The primary outcome was change in rate of eGFR decline before and after rituximab. Complete or partial remission were defined as uPCR <30 mg/mmol or uPCR <350 mg/mmol with a ≥50% fall from baseline, respectively. Results: A total of 180 patients [median age 59 years, interquartile range (IQR) 48-68] received rituximab and were followed up for a median duration of 17 months. Seventy-seven percent had prior immunosuppression. Median eGFR and uPCR at baseline were 49.2 mL/min/1.73 m2 (IQR 34.4-80.6) and 766 mg/mmol (IQR 487-1057), respectively. The annual rate of decline of eGFR fell from 13.9 to 1.7 mL/min/1.73 m2/year following rituximab (Z score = 2.48, P < .0066). At 18 months 12% and 42% of patients were in complete or partial remission, respectively. Rituximab was well tolerated; patient survival was 95.6% at 2 years and in patients in whom eGFR was available, kidney survival was 93% at 2 years. Conclusion: Rituximab significantly reduced the rate of eGFR decline in active MN including those who had received prior immunosuppression or with poor baseline kidney function.

PLA2R Antibody Does Not Outperform Conventional Clinical Markers in Predicting Outcomes in Membranous Nephropathy.

Introduction: The prognostic value of PLA2R antibody (Ab) test in clinical practice remains unclear. We aimed to evaluate its ability in predicting hard outcomes in primary membranous nephropathy (PMN) after adjustments to conventional markers of disease activity. Methods: A total of 222 patients diagnosed with PMN from January 2003 to July 2019 having had a serum PLA2R Ab test, were included from 3 centers in the north of England. Baseline conventional markers, PLA2R-Ab-status (positive vs. negative), Ab-titer (high vs. low), and time of testing (pre-PLA2R era vs. PLA2R era) were evaluated for association with outcomes. Primary outcome was time to progression (composite of doubling of creatinine, stage 5 chronic kidney disease, or death). Secondary outcomes were time to partial remission (PR) and time to immunosuppression. Cox proportional hazard testing was used. Results: During a median follow-up of 5.26 years, progression was seen in 65 (29.3%) and PR in 179 of 222 patients (80.6%). There was a clear association of estimated glomerular filtration rate (eGFR) (standardized hazard ratio [HRZ] = 0.767, P < 0.05) and urine protein-to-creatinine ratio (uPCR) (HRZ = 1.44, P < 0.005) with time to progression among all patients, and eGFR (HRZ = 0.606, P < 0.005) in Ab-positive patients. Baseline Ab-positivity was not associated with time to progression (adjusted hazard ratio [aHR] = 0.93, P = 0.71) or time to PR (aHR = 0.84, P = 0.13). Similarly, baseline high Ab-titer was not associated with time to progression (aHR = 1.07, P = 0.77) or time to PR (aHR = 0.794, P = 0.08). Conclusion: Once adjusted to conventional markers of disease activity, baseline PLA2R Ab-positivity or Ab-titer do not predict disease progression or time to PR. Further studies are needed to harness the utility of PLA2R Ab test in prognostication in PMN.

Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors - including angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) - slow the progression of mild or moderate chronic kidney disease. However, the results of some studies have suggested that the discontinuation of RAS inhibitors in patients with advanced chronic kidney disease may increase the estimated glomerular filtration rate (eGFR) or slow its decline. METHODS: In this multicenter, open-label trial, we randomly assigned patients with advanced and progressive chronic kidney disease (eGFR, <30 ml per minute per 1.73 m2 of body-surface area) either to discontinue or to continue therapy with RAS inhibitors. The primary outcome was the eGFR at 3 years; eGFR values that were obtained after the initiation of renal-replacement therapy were excluded. Secondary outcomes included the development of end-stage kidney disease (ESKD); a composite of a decrease of more than 50% in the eGFR or the initiation of renal-replacement therapy, including ESKD; hospitalization; blood pressure; exercise capacity; and quality of life. Prespecified subgroups were defined according to age, eGFR, type of diabetes, mean arterial pressure, and proteinuria. RESULTS: At 3 years, among the 411 patients who were enrolled, the least-squares mean (±SE) eGFR was 12.6±0.7 ml per minute per 1.73 m2 in the discontinuation group and 13.3±0.6 ml per minute per 1.73 m2 in the continuation group (difference, -0.7; 95% confidence interval [CI], -2.5 to 1.0; P = 0.42), with a negative value favoring the outcome in the continuation group. No heterogeneity in outcome according to the prespecified subgroups was observed. ESKD or the initiation of renal-replacement therapy occurred in 128 patients (62%) in the discontinuation group and in 115 patients (56%) in the continuation group (hazard ratio, 1.28; 95% CI, 0.99 to 1.65). Adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events (108 vs. 88) and deaths (20 vs. 22). CONCLUSIONS: Among patients with advanced and progressive chronic kidney disease, the discontinuation of RAS inhibitors was not associated with a significant between-group difference in the long-term rate of decrease in the eGFR. (Funded by the National Institute for Health Research and the Medical Research Council; STOP ACEi EudraCT number, 2013-003798-82; ISRCTN number, 62869767.).

The role of static bone histomorphometry in diagnosing renal osteodystrophy.

BACKGROUND: Bone biopsy is the gold standard test to diagnose renal osteodystrophy (ROD). There is a preference to perform bone biopsy during renal transplantation but tetracycline bone labelling is usually not possible. We aimed to test if histomorphometry static parameters can identify low and high bone turnover as assessed by dynamic measurement using double tetracycline labelling. METHODS: 43 CKD stages 4-5D had trans-iliac bone biopsy using a 4 mm Jamshidi trephine and needle after tetracycline labelling. Quantitative histomorphometry was performed using the Bioquant Osteo histomorphometry system. Normal bone turnover was defined as bone formation rate/bone surface (BFR/BS) of 18-38 µm3/µm2/year. Static parameters of bone turnover included osteoblast surface/bone surface (Ob.S/BS, %), osteoclast surface/bone surface (Oc.S/BS, %) and erosion surface/bone surface (ES/BS, %). Receiver operating characteristics (ROC) analysis was used to evaluate diagnostic accuracy of these static parameters for low and high bone turnover (based on BFR/BS). RESULTS: Median (IQR) for BFR/BS in this study was 32.12 (17.76-48.25) µm3/µm2/year. 26% of patients had low, 34% had normal and 40% had high bone turnover. The area under the ROC curve (AUC) for Ob.S/BS, Oc.S/BS and ES/BS were non-significant indicating poor accuracy for identifying low bone turnover. The AUC for Ob.S/BS was 0.697 (95% CI 0.538 to 0.827) indicating fair accuracy for identifying high bone turnover. Oc.S/BS and ES/BS had non-significant AUCs for high bone turnover. CONCLUSIONS: Static histomorphometry parameters for bone turnover are unable to replace dynamic parameter in diagnosing ROD. Tetracycline bone labelling is still required.

Vascular calcification relationship to vascular biomarkers and bone metabolism in advanced chronic kidney disease.

BACKGROUND: Vascular calcification (VC) and renal osteodystrophy are important complications of advanced chronic kidney disease (CKD). High resolution peripheral quantitative computed tomography (HRpQCT) is able to assess bone microstructure in renal osteodystrophy and lower leg arterial calcification (LLAC) is usually seen as an incidental finding. LLAC can be a useful quantitative assessment of VC in CKD but the relationship between LLAC and vascular biomarkers and bone is unknown. We aimed to assess the relationship between LLAC and biomarkers, bone turnover and microstructure. METHODS: In this cross-sectional study, fasting blood samples were taken from 69 CKD stages 4-5D patients and 68 healthy controls. HRpQCT of distal tibia and radius were performed. 43 CKD patients had trans-iliac bone biopsy after tetracycline labelling. RESULTS: LLAC was more severe in CKD than controls (median [IQR] 1.043 [0.05-16.52] vs 0 [0-0.55] mgHA, p < 0.001). CKD patients with diabetes (28%) had significantly higher LLAC compared to non-diabetic CKD (median [IQR] 24.07 [3.42-61.30] vs 0.23 [0-3.78] mgHA, p < 0.001). LLAC mass in CKD correlated with serum phosphate (rho = 0.29, p < 0.05), calcium x phosphate product (rho = 0.31, p < 0.05), intact parathyroid hormone (rho = 0.38, p < 0.01), intact fibroblast growth factor-23 (iFGF23) (rho = 0.40, p = 0.001), total alkaline phosphatase (rho = 0.41, p < 0.001), bone alkaline phosphatase (rho = 0.29, p < 0.05), osteocalcin (rho = 0.32, p < 0.05), osteoprotegerin (rho = 0.40, p = 0.001) and dephosphorylated-uncarboxylated matrix Gla protein (rho = 0.31, p < 0.05). LLAC in CKD also correlated with worse distal tibia cortical bone mineral density, thickness and porosity. No association was found between LLAC and bone turnover, mineralization or volume on biopsy in CKD. In multivariate analysis, only age, diabetes, iPTH and iFGF23 were independently associated with LLAC in CKD. CONCLUSIONS: High levels of PTH and FGF23, along with older age and the presence of diabetes may all play independent roles in the development of LLAC in advanced CKD.

Diagnostic Accuracy of Biomarkers and Imaging for Bone Turnover in Renal Osteodystrophy.

Background Renal osteodystrophy is common in advanced CKD, but characterization of bone turnover status can only be achieved by histomorphometric analysis of bone biopsy specimens (gold standard test). We tested whether bone biomarkers and high-resolution peripheral computed tomography (HR-pQCT) parameters can predict bone turnover status determined by histomorphometry.Methods We obtained fasting blood samples from 69 patients with CKD stages 4-5, including patients on dialysis, and 68 controls for biomarker analysis (intact parathyroid hormone [iPTH], procollagen type 1 N-terminal propeptide [PINP], bone alkaline phosphatase [bALP], collagen type 1 crosslinked C-telopeptide [CTX], and tartrate-resistant acid phosphatase 5b [TRAP5b]) and scanned the distal radius and tibia of participants by HR-pQCT. We used histomorphometry to evaluate bone biopsy specimens from 43 patients with CKD.Results Levels of all biomarkers tested were significantly higher in CKD samples than control samples. For discriminating low bone turnover, bALP, intact PINP, and TRAP5b had an areas under the receiver operating characteristic curve (AUCs) of 0.82, 0.79, and 0.80, respectively, each significantly better than the iPTH AUC of 0.61. Furthermore, radius HR-pQCT total volumetric bone mineral density and cortical bone volume had AUCs of 0.81 and 0.80, respectively. For discriminating high bone turnover, iPTH had an AUC of 0.76, similar to that of all other biomarkers tested.Conclusions The biomarkers bALP, intact PINP, and TRAP5b and radius HR-pQCT parameters can discriminate low from nonlow bone turnover. Despite poor diagnostic accuracy for low bone turnover, iPTH can discriminate high bone turnover with accuracy similar to that of the other biomarkers, including CTX.

Bone Disease after Kidney Transplantation.

Bone and mineral disorders occur frequently in kidney transplant recipients and are associated with a high risk of fracture, morbidity, and mortality. There is a broad spectrum of often overlapping bone diseases seen after transplantation, including osteoporosis as well as persisting high- or low-turnover bone disease. The pathophysiology underlying bone disorders after transplantation results from a complex interplay of factors, including preexisting renal osteodystrophy and bone loss related to a variety of causes, such as immunosuppression and alterations in the parathyroid hormone-vitamin D-fibroblast growth factor 23 axis as well as changes in mineral metabolism. Management is complex, because noninvasive tools, such as imaging and bone biomarkers, do not have sufficient sensitivity and specificity to detect these abnormalities in bone structure and function, whereas bone biopsy is not a widely available diagnostic tool. In this review, we focus on recent data that highlight improvements in our understanding of the prevalence, pathophysiology, and diagnostic and therapeutic strategies of mineral and bone disorders in kidney transplant recipients.

Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease: the STOP-ACEi trial.

BACKGROUND: Blood pressure (BP) control and reduction of urinary protein excretion using agents that block the renin-angiotensin aldosterone system are the mainstay of therapy for chronic kidney disease (CKD). Research has confirmed the benefits in mild CKD, but data on angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use in advanced CKD are lacking. In the STOP-ACEi trial, we aim to confirm preliminary findings which suggest that withdrawal of ACEi/ARB treatment can stabilize or even improve renal function in patients with advanced progressive CKD. METHODS: The STOP-ACEi trial (trial registration: current controlled trials, ISRCTN62869767) is an investigator-led multicentre open-label, randomized controlled clinical trial of 410 participants with advanced (Stage 4 or 5) progressive CKD receiving ACEi, ARBs or both. Patients will be randomized in a 1:1 ratio to either discontinue ACEi, ARB or combination of both (experimental arm) or continue ACEi, ARB or combination of both (control arm). Patients will be followed up at 3 monthly intervals for 3 years. The primary outcome measure is eGFR at 3 years. Secondary outcome measures include the number of renal events, participant quality of life and physical functioning, hospitalization rates, BP and laboratory measures, including serum cystatin-C. Safety will be assessed to ensure that withdrawal of these treatments does not cause excess harm or increase mortality or cardiovascular events such as heart failure, myocardial infarction or stroke. RESULTS: The rationale and trial design are presented here. The results of this trial will show whether discontinuation of ACEi/ARBs can improve or stabilize renal function in patients with advanced progressive CKD. It will show whether this simple intervention can improve laboratory and clinical outcomes, including progression to end-stage renal disease, without causing an increase in cardiovascular events.

Sclerostin levels in CKD patients: an important, but not definitive, step on the way to clinical use.

Sclerostin, an inhibitor of the Wnt signaling pathway, inhibits bone formation. In a study of vascular biopsies of patients undergoing kidney transplantation, Qureshi et al. demonstrate that circulating sclerostin levels are associated with vascular calcification (VC). This adds to an emerging body of literature implicating sclerostin as a key link between chronic kidney disease-mineral and bone disorder and cardiovascular disease. Some confounders of this association remain, and the mechanisms by which sclerostin promotes VC have yet to be elucidated.

Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis.

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor ß1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1.

Fragility fractures and osteoporosis in CKD: pathophysiology and diagnostic methods.

Both chronic kidney disease (CKD) and osteoporosis are major public health problems associated with an aging population. Osteoporosis is characterized by reduced bone mineral density, while CKD results in qualitative changes in bone structure; both conditions increase the predisposition to fragility fractures. There is a significant coprevalence of osteoporotic fractures and CKD, particularly in the elderly population. Not only is the risk of fracture higher in the CKD population, but clinical outcomes are significantly worse, with substantial health care costs. Management of osteoporosis in the CKD population is particularly complex given the impact of renal osteodystrophy on bone quality and the limited safety and hard outcome data for current therapy in patients with severe CKD or on dialysis therapy. In this review, we discuss the pathophysiology of osteoporosis, the impact of CKD on bone strength, and the role of novel imaging techniques and biomarkers in predicting underlying renal osteodystrophy on bone histomorphometry in the context of CKD.

Management of heparin-induced thrombocytopenia (HIT) in patients with systemic vasculitis and pulmonary haemorrhage.

Heparin-induced thrombocytopenia (HIT) is a relatively uncommon but potentially fatal complication of the use of heparin in haemodialysis. It is associated with a risk of venous and arterial thrombosis due to the formation of a heparin-platelet factor 4 antibody. Early recognition and immediate treatment of HIT are crucial to reduce the morbidity and mortality rate. Here, we report two patients with acute kidney injury due to anti-glomerular membrane (GBM) glomerulonephritis and granulomatosis with polyangiitis respectively who developed haemoptysis and pulmonary haemorrhage complicated by HIT. We discuss the diagnostic and management challenges of such patients.

Transplantation in the obese: separating myth from reality.

The prevalence of obesity among patients requiring renal replacement therapy continues to increase inexorably. While observational data have suggested that obesity may be associated with better outcomes among patients on dialysis, many centres have been reluctant to transplant obese patients because of concerns over adverse outcomes in the short and long term. In this review, we evaluate data about the safety of weight loss on dialysis and critically review the impact of pre-transplant body mass index and sarcopenia on post-transplant outcomes. We also highlight comparative data on outcomes of obese patients on dialysis versus those undergoing kidney transplantation. We conclude that while obesity can increase the risk of complications such as wound infections or delayed graft function, selected obese patients can achieve good outcomes after transplantation with the risk being broadly comparable to other recipient co-morbidities such as diabetes mellitus.

Progressive chronic kidney disease secondary to tubulointerstitial nephritis in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by the presence of anti-mitochondrial antibodies (AMA). Whilst asymptomatic distal tubular acidosis (DTA) is the commonest renal lesion reported in PBC, tubulointerstitial nephritis (TIN) has also been reported as a rare association. Although PBC could be a familial disorder, there have been no previous reports of familial chronic TIN in association with PBC. We report a case of progressive chronic kidney disease (CKD) due to TIN in a mother and daughter known to suffer from PBC and review the previously reported literature. Both showed good response to steroids.

Stopping renin-angiotensin system inhibitors in chronic kidney disease: predictors of response.

BACKGROUND/AIMS: Renin-angiotensin system (RAS) inhibitors are considered first-line agents for hypertensive patients with progressive chronic kidney disease (CKD). In a previous study, we showed that stopping RAS inhibitors increased estimated glomerular filtration rate (eGFR) in a significant number of advanced CKD patients. The present study tries to address who would benefit and whether this benefit is predictable. METHODS: Forty-three CKD stage 4 patients had RAS inhibitors stopped and were followed for at least 24 months. Compared outcome groups were 'alive', 'renal replacement therapy (RRT)' or 'died'. Improvement in eGFR was used in a receiver-operating characteristic curve and finds the best predictor for surviving without RRT. RESULTS: Patients who survived without RRT were all hypertensive and had a higher eGFR increment after stopping the drugs. Those with eGFR improvement ≥5 ml/min/1.73 m(2) were the most likely to survive long term without RRT (log-rank test, p = 0.03). They had a significant increment in blood pressure that correlated with eGFR improvement (r = 0.403, p = 0.013). CONCLUSION: A significant increase in eGFR after stopping RAS inhibitors suggests that long-term survival without RRT is more likely. Our findings question the universal preemptive indication of RAS inhibitors in advanced CKD and suggest that they can be safely stopped, at least in some patients.

A critique of the UK NICE guidance for the detection and management of individuals with chronic kidney disease.

The increasing global prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) has significant public health and economic implications. The recently published UK National Institute for Health and Clinical Excellence (NICE) clinical guidelines for the early identification and management of CKD provide a framework of disease management for both primary and secondary care with the stated aim of reducing the progression of CKD and the associated risk of cardiovascular death. Identification of at-risk individuals with proteinuria and inhibition of the renin-angiotensin system are the cornerstones of this strategy. However, the vast majority of patients with CKD will not develop ESRD and it is far from clear whether the NICE recommendations will reduce either ESRD or cardiovascular death associated with CKD.