Treatment strategies of the thromboembolic risk in kidney failure patients with atrial fibrillation.

The incidence and prevalence of atrial fibrillation (AF) in patients affected by kidney failure, i.e. glomerular filtration rate <15 ml/min/1.73 m2, is high and probably underestimated. Numerous uncertainties remain regarding how to prevent thromboembolic events in this population because both cardiology and nephrology guidelines do not provide clear recommendations. The efficacy and safety of oral anticoagulant therapy (OAC) in preventing thromboembolism in patients with kidney failure and AF has not been demonstrated for either vitamin K antagonists (VKA) or direct anticoagulants (DOAC). Moreover, it remains unclear which is more effective and safer between them, because estimated creatinine clearance < 25-30 ml/min was an exclusion criterion of the randomized control trials (RCTs). Three RCTs comparing DOACs and VKAs in kidney failure failed to reach the primary endpoint because they were underpowered. The left atrial appendage is the main source of thromboembolism in the presence of AF. Left atrial appendage closure (LAAC) has recently been proposed as an alternative to OAC. RCTs comparing the efficacy and safety of LAAC vs. OAC in kidney failure were terminated prematurely due to recruitment failure. A recent prospective study showed a reduction in thromboembolic events in hemodialysis patients with AF and undergoing LAAC compared to patients taking or not taking OAC. We review current treatment standards and discuss recent developments in managing the thromboembolic risk in kidney failure patients with AF. The importance of shared decision-making with the multidisciplinary team and the patient, to consider individual risks and benefits of each treatment option is underlined.

Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy.

RATIONALE & OBJECTIVE: Bone biopsy remains the gold standard for diagnosing renal osteodystrophy as comparable noninvasive alternatives have yet to be established. This study investigated the diagnostic accuracy of biochemical markers of skeletal remodeling to predict bone turnover. STUDY DESIGN: Cross-sectional retrospective diagnostic test study. SETTING & PARTICIPANTS: Patients with chronic kidney disease glomerular filtration rate categories 4-5, including patients treated with dialysis (G4-G5D) and kidney transplant recipients with successful transiliac bone biopsies. TESTS COMPARED: Bone turnover as determined by bone histomorphometry was compared with the following biochemical markers: full-length (amino acids 1-84) "biointact" parathyroid hormone (PTH), bone-specific alkaline phosphatase (BsAP), intact procollagen type I N-terminal propeptide (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b). OUTCOME: Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC), sensitivity, specificity, and negative and positive predictive values. Optimal diagnostic cutoffs were determined in an exploration cohort (n = 100) and validated in a separate cohort (n = 99). RESULTS: All biomarkers differed across categories of low 33 (17%), normal 109 (55%), and high 57 (29%) bone turnover. AUC values were in the range of 0.75-0.85. High negative predictive values (≥90%) were found for both high and low bone turnover, indicating the ability to rule out both conditions using the suggested biomarker cutoffs. The highest diagnostic performances were seen with combinations of biomarkers, with overall diagnostic accuracies of 90% for high turnover, and 78% for low turnover. Results were comparable for kidney transplant candidates and recipients in a sensitivity analysis. LIMITATIONS: The single-center approach and heterogeneity of the study cohort are main limitations of this study. CONCLUSIONS: We conclude that the diagnostic performance of biochemical markers of bone turnover is acceptable, with clinical utility in ruling out both high and low turnover bone disease.

Patterns of renal osteodystrophy 1 year after kidney transplantation.

BACKGROUND: Renal osteodystrophy is considered common, but is not well characterized in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry and novel bone biomarkers 1 year after kidney transplantation. METHODS: A transiliac bone biopsy and dual-energy X-ray absorptiometry scans were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24-h urine samples were collected simultaneously. RESULTS: The median age was 57 ± 11 years, 71% were men and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26% and high in just four cases (3%). Hyperparathyroidism with hypercalcaemia was present in 13% of patients, of which only one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 versus 53 ρg/mL), a higher fractional excretion of phosphate (40 versus 32%) and lower levels of phosphate (2.68 versus 3.18 mg/dL) and calcidiol (29 versus 37 ng/mL) compared with patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization. CONCLUSIONS: The majority of kidney transplant recipients, including patients with osteoporosis, have normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphataemia represent potential interventional targets to improve bone health post-transplant.

Static histomorphometry allows for a diagnosis of bone turnover in renal osteodystrophy in the absence of tetracycline labels.

A bone biopsy with prior tetracycline labeling is the gold standard to diagnose renal osteodystrophy. In cases of missing tetracycline labels, it is still paramount to gain clinically relevant information from the extracted bone sample, by evaluating the static histomorphometry. This study investigates the diagnostic performance of static histomorphometry for the evaluation of high and low bone turnover. Transiliac bone biopsies taken pre- or post- kidney transplantation, of sufficient quality for a full histomorphometric analysis were included (n = 205). The cohort was randomly split to provide separate exploration and validation subsets. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover, and all were significant predictors of both high and low bone turnover (AUC 0.71-0.84). Diagnostic performance was very good for high turnover, as a combination of static parameters resulted in negative and positive predictive values (NPV and PPV) of 80% and 96%, respectively. For low turnover, the combined model resulted in PPV of 71% and NPV of 82%. We conclude that in the absence of tetracycline labels, static histomorphometry provide an acceptable alternative for a diagnosis of bone turnover in renal osteodystrophy.

Aspiration Pneumonia After External Dacryocystorhinostomy Under Local Anesthesia Without Sedation: A Case Report.

Amid the global coronavirus disease 2019 (COVID-19) outbreak, an 89-year-old male with chronic kidney disease presented with acute dacryocystitis and a persistent dry cough. After a course of antibiotics, external dacryocystorhinostomy was performed under local anesthesia without sedation. During planned hemodialysis in the early hours after the procedure, the patient developed nausea and hematemesis followed by severe dyspnea and hypoxemia. The patient was diagnosed with aspiration pneumonia, a previously unreported complication in lacrimal surgery.

Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion.

Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion.

Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance.

BACKGROUND: Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported. METHODS: To study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or 7 weeks (long-term exposure). We also performed unbiased proteomic analyses of arterial samples coupled to functional bioinformatic annotation analyses to investigate molecular signaling events associated with toxin-mediated arterial calcification. RESULTS: Long-term exposure to either toxin at serum levels similar to those experienced by patients with CKD significantly increased calcification in the aorta and peripheral arteries. Our analyses revealed an association between calcification events, acute-phase response signaling, and coagulation and glucometabolic signaling pathways, whereas escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Additional metabolic linkage to these pathways revealed that IS and PCS exposure engendered a prodiabetic state evidenced by elevated resting glucose and reduced GLUT1 expression. Short-term exposure to IS and PCS (before calcification had been established) showed activation of inflammation and coagulation signaling pathways in the aorta, demonstrating that these signaling pathways are causally implicated in toxin-induced arterial calcification. CONCLUSIONS: In CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.

Reliability of serum creatinine-based formulae estimating renal function in non-critically ill surgery patients: Focus on augmented renal clearance.

WHAT IS KNOWN AND OBJECTIVES: Formulae estimating glomerular filtration rate (GFR) are frequently used to guide drug dosing. The objectives of this prospective single-center study were to evaluate agreement between these equations and measured creatinine clearance (CrCl) in non-critically ill surgery patients with normal kidney function and augmented renal clearance (ARC, CrCl ≥ 130 mL/min/1.73 m²), to determine predictors for disagreement, define a GFR estimator cut-off value identifying ARC and determine the ARC prevalence and duration in non-critically ill surgical patients. METHODS: Hospitalized adult non-critically ill abdominal and trauma surgery patients were eligible for inclusion. Measured CrCl based on an 8-hour urinary collection (CrCl8h ) was used as the primary method for determining kidney function. Agreement between equations and measured CrCl8h was assessed in terms of precision, defined as a bias within ±10 mL/min/1.73 m². Predictors for disagreement were identified for the most precise estimator using an ordinal logistic regression model with negative bias, agreement and positive bias as outcome variables. A receiver operating characteristic (ROC) analysis was performed to identify an estimator cut-off predicting ARC, which was subsequently applied for the daily proportion of patients displaying ARC and ARC duration. RESULTS AND DISCUSSION: During the study period (14/11/2013 - 13/05/2014), in 232 adult non-critically ill abdominal and trauma surgery patients, all estimators tend to underestimate CrCl8h (mean bias ranging from 17 to 22 mL/min/1.73 m²), especially in patients displaying ARC (mean bias ranging from 44 to 56 mL/min/1.73 m²). eGFRCKD-EPI performed the best. Younger age and low ASA score independently predicted underestimation of CrCl8h . Three different eGFRCKD-EPI cut-offs with decreasing sensitivity and increasing specificity (84, 95 and 112 mL/min/1.73 m²) identified, respectively, 65%, 44% and 14% patients displaying ARC. The median ARC duration was 4, 4 and 3 days, respectively. WHAT IS NEW AND CONCLUSION: In surgical patients, eGFR frequently underestimates measured CrCl, especially in young patients with low ASA score. eGFR cut-offs predicting ARC were identified.

Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy.

Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50-100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens.

A liquid chromatography - tandem mass spectrometry method to measure a selected panel of uremic retention solutes derived from endogenous and colonic microbial metabolism.

Chronic kidney disease (CKD) is associated with an increased risk of mortality and cardiovascular disease, which is, at least partly, mediated by the accumulation of so-called uremic retention solutes. Although there has been an increasing interest in the behavior of these solutes, derived from both the endogenous and colonic microbial metabolism, methods to simultaneously and accurately measure a broad panel of relevant uremic retention solutes remain scarce. We developed a highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. A high throughput sample preparation was used with extraction of analytes from 50 µl serum using Ostro plate technology. For most solutes, stable isotopes labelled metabolites were used as internal standards. Chromatography was achieved using an Acquity UPLC CSH Fluoro Phenyl column. The total run time was 8 min, the mobile phase was a gradient of 0.1% formic acid in Milli-Q water and pure methanol at a flow rate of 0.5 ml min(-1). Detection was performed using a tandem mass spectrometer with alternated positive and negative electrospray ionization. Calibration curves were linear for all solutes. Precision was assessed according to the NCCLS EP5-T guideline, being below 15% for all metabolites. Mean recoveries were between 83 and 104% for all metabolites. The validated method was successfully applied in a cohort of 488 patients with CKD. We developed and validated a sensitive and robust UPLC-MS/MS method for quantification of 15 uremic retention solutes derived from endogenous and colonic microbial metabolism. This method allows for studying the behavior and relevance of these solutes in patients with CKD.

Two Cases of Heavy Chain MGUS.

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of "heavy chain MGUS" have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.

Immunologic Changes Implicated in the Pathogenesis of Focal Segmental Glomerulosclerosis.

Focal segmental glomerulosclerosis is a histological pattern on renal biopsy caused by diverse mechanisms. In its primary form, a circulatory factor is implicated in disease onset and recurrence. The natural history of primary FSGS is unpredictable, since some patients are unresponsive towards immunosuppressive measures. Immunologic changes, leading to a proinflammatory or profibrotic milieu, have been implicated in disease progression, namely, glomerular scarring, eventually leading to end-stage renal disease. Among these, interleukin-1ß, tumor-necrosis factor-α (TNF-α), and transforming growth factor-ß1 (TGF-ß1) have emerged as important factors. Translating these findings into clinical practice dampened the enthusiasm, since both TNF-α and TGF-ß1 blockade failed to achieve significant control of the disease. More recently, a role of the complement system has been demonstrated which in fact may be another attractive target in clinical practice. Rituximab, blocking CD20-bearing cells, demonstrated conflicting data regarding efficacy in FSGS. Finally, the T-cell costimulating molecule B7-1 (CD80) is implicated in development of proteinuria in general. Blockade of this target demonstrated significant benefits in a small cohort of resistant patients. Taken together, this review focuses on immunology of FSGS, attributable to either the disease or progression, and discusses novel therapeutic approaches aiming at targeting immunologic factors.

Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study.

Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria <0.3 g/24 h, the hazard ratios for graft failure were 1.14 (95% confidence interval [95% CI], 0.81 to 1.60; P=0.50), for proteinuria 0.3-1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; P<0.001), for proteinuria 1.0-3.0 g/24 h, and 3.01 (95% CI, 1.75 to 5.18; P<0.001), for proteinuria >3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P<0.001) than at 1, 2, and 5 years after transplant (AUC 0.73, 0.71, and 0.77, respectively, all P<0.001). Independent determinants of proteinuria were repeat transplantation, mean arterial pressure, transplant glomerulopathy, microcirculation inflammation, and de novo/recurrent glomerular disease. The discriminatory power of proteinuria for these intragraft injury processes was better in biopsy samples obtained >3 months after transplant (AUC 0.73, P<0.001) than in those obtained earlier (AUC 0.56, P<0.01), with 85% specificity but lower sensitivity (47.8%) for proteinuria >1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis.

Microscopic nephrocalcinosis in chronic kidney disease patients.

BACKGROUND: Experimental data indicate that microscopic calcium phosphate deposition in the kidney (nephrocalcinosis) may accelerate progression of chronic kidney disease (CKD). Data on the prevalence, risk factors and implications of nephrocalcinosis in CKD patients are scarce. A mineral metabolism disorder could play an important pathogenetic role, as suggested by recent protocol biopsy findings in incident renal transplant recipients. METHODS: Kidney biopsy cylinders of CKD patients, collected between January 1989 and December 2007, were screened for the presence of nephrocalcinosis. Only patients with ≥1 parathyroid hormone (PTH) level available within 180 days of the biopsy were eligible for inclusion (n = 211). Demographics and mineral metabolism parameters were retrieved from medical files. Data on renal death (up to December 2012) were obtained from the Flemish ESRD registry. Baseline biopsies from 110 deceased kidney transplant donors served as controls. RESULTS: The prevalence of nephrocalcinosis in kidney donors and patients with CKD 1-2, CKD 3-4 and CKD 5-5D was 4.6, 14.3, 20.2 and 54.0%, respectively (P < 0.0001). Among CKD patients, patients with nephrocalcinosis were characterized by lower estimated GFR, lower serum bicarbonate level and higher serum PTH and calcium level. In multivariate regression analysis, high serum PTH, calcium and creatinine level, and low serum bicarbonate level were all significantly and independently associated with nephrocalcinosis. Serum phosphorus level, but not nephrocalcinosis predicted renal death, independent of renal function. CONCLUSIONS: Our data demonstrate that prevalence rates of nephrocalcinosis increase with increasing CKD stage to reach more than 50% in end-stage renal disease patients and suggest that acid-base and mineral metabolism disturbances are implicated in its pathogenesis.

The histology of kidney transplant failure: a long-term follow-up study.

BACKGROUND: The relative impact on renal allograft outcome of specific histological diagnoses versus nonspecific chronic histological damage remains unclear. METHODS: All 1,197 renal allograft recipients who were transplanted at a single center between 1991 and 2001 were included. All posttransplant renal allograft indication biopsies performed in this cohort during follow-up (mean, 14.5±2.80 years after transplantation) were rescored according to the current histological criteria and associated with death-censored graft outcome. RESULTS: In this cohort, 1,365 allograft indication biopsies were performed. Specific diagnoses were present in 69.4% of graft biopsies before graft loss, but 30.6% of grafts did not have specific diagnoses in the last biopsy before graft loss. Only 14.6% of the patients did never have any specific disease diagnosed before graft loss. Extensive interstitial fibrosis and tubular atrophy without a clear cause was identified as the single cause of graft loss in only 6.9% of the cases. Acute T-cell-mediated rejection and changes suggestive of acute antibody-mediated rejection, diagnosed after the first year posttransplant, associated independently with graft survival. Transplant glomerulopathy increased over time after transplantation and represented a major risk for graft loss, as well as de novo or recurrent glomerular pathologies and polyomavirus nephropathy. Chronic histological injury associated with graft outcome, independent of specific diagnoses. CONCLUSION: Renal allograft loss is multifactorial. Chronic histological damage and specific diseases had additive and independent impact on graft outcome. Chronic damage should be taken into account in prognostication of renal allograft outcome and could be implemented in treatment algorithms for specific diseases of kidney allografts.

Postimplantation X-ray parameters predict functional catheter problems in peritoneal dialysis.

Functional catheter problems are a major challenge for peritoneal dialysis (PD) programs. Here we performed a retrospective single-center study of 110 consecutive patients receiving a first PD catheter (swan neck double-cuff Missouri curled catheters, open surgical technique). Using postimplantation X-ray, the following categories were defined: swan neck angle (posterioanterio view (PA): under 45°, 45-90°, over 90°), inclination (angle between intramural part of catheter and horizontal line; lateral view: greater than/equal to 30°, under 30°), and the position of silicone bead relative to spine (PA view: L1-2, L3-4, lower) and catheter tip (PA view: hypogastric, umbilical, subcostal). Covariates included demographics, body size, previous abdominal surgery, and abdominal wall hernias. During a mean follow-up of 36 months, the time to first functional catheter problem was significantly associated with both the swan neck angle and inclination. The need for surgical intervention was significantly associated with inclination only. Technique failure was not associated with any parameter. In multivariate analysis, inclination was the sole variable significantly associated with functional catheter problems (hazard ratio 3.65 [1.98-6.72]) and the need for surgical intervention (hazard ratio 2.86 [1.19-6.88]). Thus, our study defines a set of X-ray variables that predict functional PD catheter problems and can be used for troubleshooting in individual cases as well as for education and internal audit purposes.

Cardiovascular disease relates to intestinal uptake of p-cresol in patients with chronic kidney disease.

BACKGROUND: Serum p-cresyl sulfate (PCS) associates with cardiovascular disease in patients with chronic kidney disease. PCS concentrations are determined by intestinal uptake of p-cresol, human metabolism to PCS and renal clearance. Whether intestinal uptake of p-cresol itself is directly associated with cardiovascular disease in patients with renal dysfunction has not been studied to date. METHODS: We performed a prospective study in patients with chronic kidney disease stage 1 - 5 (NCT00441623). Intestinal uptake of p-cresol, under steady state conditions, was estimated from 24 h urinary excretion of PCS. Primary endpoint was time to first cardiovascular event, i.e., cardiac death, myocardial infarction/ischemia, ventricular arrhythmia, cardiovascular surgery, ischemic stroke or symptomatic peripheral arterial disease. Statistical analysis was done using Kaplan-Meier estimates and Cox proportional hazard analyses. RESULTS: In a cohort of 200 patients, median 24 h urinary excretion of PCS amounted to 457.47 µmol (IQR 252.68 - 697.17). After a median follow-up of 52 months, 25 patients reached the primary endpoint (tertile 1/2/3: 5/6/14 events, log rank P 0.037). Higher urinary excretion of PCS was directly associated with cardiovascular events (univariate hazard ratio per 100 µmol increase: 1.112, P 0.002). In multivariate analysis, urinary excretion of PCS remained a predictor of cardiovascular events, independent of eGFR (hazard ratio 1.120, P 0.002). CONCLUSIONS: In patients with chronic kidney disease, intestinal uptake of p-cresol associates with cardiovascular disease independent of renal function. The intestinal generation and absorption of p-cresol may be therapeutic targets to reduce cardiovascular disease risk in patients with renal dysfunction.

The soluble urokinase receptor is not a clinical marker for focal segmental glomerulosclerosis.

The soluble urokinase receptor (suPAR) promotes proteinuria and induces focal segmental glomerulosclerosis (FSGS)-like lesions in mice. A serum suPAR concentration cutoff of 3000 pg/ml has been proposed as a clinical biomarker for patients with FSGS. Interestingly, several studies in patients with glomerulopathy found an inverse correlation between the estimated glomerular filtration rate (eGFR) and suPAR. As patients with FSGS present at different eGFRs, we studied the relationship between eGFR and suPAR in a cohort of 476 non-FSGS patients and 54 patients with biopsy-proven idiopathic FSGS. In the non-FSGS patients, eGFR was the strongest significant determinant of suPAR. The proposed cutoff for suPAR in FSGS patients was exceeded in 17%, 39%, and 88% in patients with eGFRs of more than 60, 45-60, and 30-45 ml/min per 1.73 m(2), respectively. In patients with eGFR of <30 ml/min per 1.73 m(2), suPAR exceeded the cutoff in 95% of patients. Levels of suPAR in patients with idiopathic FSGS overlapped with non-FSGS controls and for any given eGFR did not discriminate FSGS cases from non-FSGS controls. In the overall cohort, there was a negative association between idiopathic FSGS and suPAR, and idiopathic FSGS was not an independent predictor of FSGS concentration over 3000 pg/ml. Thus, this study does not support an absolute, eGFR-independent, suPAR concentration cutoff as a biomarker for underlying FSGS pathology and questions the validity of relative, eGFR-dependent suPAR cutoff values.

Intrarenal resistive index after renal transplantation.

BACKGROUND: The intrarenal resistive index is routinely measured in many renal-transplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear. METHODS: In a single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis. All patients were followed for at least 4.5 years after transplantation. RESULTS: Allograft recipients with a resistive index of at least 0.80 had higher mortality than those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 5.20 [95% confidence interval {CI}, 2.14 to 12.64; P<0.001]; 3.46 [95% CI, 1.39 to 8.56; P=0.007]; and 4.12 [95% CI, 1.26 to 13.45; P=0.02], respectively). The need for dialysis did not differ significantly between patients with a resistive index of at least 0.80 and those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 1.95 [95% CI, 0.39 to 9.82; P=0.42]; 0.44 [95% CI, 0.05 to 3.72; P=0.45]; and 1.34 [95% CI, 0.20 to 8.82; P=0.76], respectively). At protocol-specified biopsy time points, the resistive index was not associated with renal-allograft histologic features. Older recipient age was the strongest determinant of a higher resistive index (P<0.001). At the time of biopsies performed because of graft dysfunction, antibody-mediated rejection or acute tubular necrosis, as compared with normal biopsy results, was associated with a higher resistive index (0.87 ± 0.12 vs. 0.78 ± 0.14 [P=0.05], and 0.86 ± 0.09 vs. 0.78 ± 0.14 [P=0.007], respectively). CONCLUSIONS: The resistive index, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft. (ClinicalTrials.gov number, NCT01879124 .).