Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology.

Hyponatremia can complicate thiazide use in a minority of susceptible individuals and can result in significant morbidity and even mortality. Risk factors for thiazide-associated hyponatremia include age, female sex, and possibly low body mass. A genetic susceptibility has recently been uncovered. Although frequently developing early after thiazide treatment initiation, many cases of hyponatremia present after months or years of use. Many cases are asymptomatic or have mild symptoms, but seizures and/or coma may develop, especially in those with acute onset. The pathophysiology is incompletely understood and includes some combination of excessive fluid intake, cation (sodium and potassium) depletion, osmotic inactivation of sodium, and reduced ability to excrete free water. Reduced distal delivery of filtrate, reduced solute load (urea), direct inhibition of the sodium-chloride cotransporter, and increased collecting duct permeability to water mediated by some combination of antidiuretic hormone, prostaglandins, and thiazides themselves may contribute to this diluting defect. The predominant pathophysiologic mechanism(s) varies from patient to patient. The cornerstone of therapy is cessation of thiazide use, cation repletion, and oral fluid restriction. If severely symptomatic, 3% saline solution may be indicated. Overly rapid correction of chronic hyponatremia must be avoided in all cases.

Transplant glomerulopathy.

In the renal allograft, transplant glomerulopathy represents a morphologic lesion and not a specific diagnosis. The hallmark pathologic feature is glomerular basement membrane reduplication by light microscopy or electron microscopy in the absence of immune complex deposits. Transplant glomerulopathy results from chronic, recurring endothelial cell injury that can be mediated by HLA alloantibodies (donor-specific antibodies), various autoantibodies, cell-mediated immune injury, thrombotic microangiopathy, or chronic hepatitis C. Clinically, transplant glomerulopathy may be silent, detectable on protocol biopsy, or present with overt manifestations, including up to nephrotic range proteinuria, hypertension, and declining glomerular filtration rate. In either case, transplant glomerulopathy is associated with reduced graft survival. This review details the morphologic features of transplant glomerulopathy found on light microscopy, immunofluorescence microscopy, and electron microscopy. The pathophysiology of the causes and risk factors are discussed. Clinical manifestations are emphasized and potential therapeutic modalities are examined.

Acute Kidney Injury Following Failed Total Hip and Knee Arthroplasty.

BACKGROUND: Acute kidney injury (AKI) can complicate primary total joint arthroplasty (TJA) of the hip and knee, although the incidence of AKI following revision TJA including prosthetic joint infection (PJI) is poorly defined. We assessed the incidence and risk factors for AKI following revision TJA including surgical treatment of PJI with placement of an antibiotic-loaded cement (ALC) spacer. METHODS: We retrospectively reviewed 3218 consecutive failed TJAs. Patients with aseptic failure were compared to those with PJI. AKI was determined by RIFLE creatinine criteria. PJIs treated with placement of ALC were compared to PJIs without. Risk factors for AKI were determined by multivariable analysis within the whole group and within those with PJI. RESULTS: AKI developed in 3.4% of 2147 patients revised for aseptic reasons and in 45% of 281 with PJI, including 29% of 197 receiving an ALC and 82% of 84 patients treated with other procedures. By multivariable analysis, age, surgery for PJI, total number of surgeries, and estimated GFR 60-90 compared to >90 cc/min/1.73 m2 were significantly associated with AKI in the whole cohort. Among PJI patients, age, Charlson comorbidity index, and reimplantation surgery were associated with AKI by multivariable analysis. No differences were found between patients with PJI treated with or without ALC. No modifiable factors were found. CONCLUSION: AKI develops following aseptic revision TJA at a rate similar to primary TJA, but at a significantly higher rate following surgery for PJI with or without placement of ALC.

Membranous nephropathy in the kidney allograft.

Membranous nephropathy (MN) may occur in a kidney transplant as recurrence of the original disease (rMN) or as a de novo MN (dnMN). rMN often occurs early, within the first year, and often in a mild or subclinical fashion. Recurrence cannot be predicted by clinical features at the time of transplantation. The natural history is increasing proteinuria over time, with less chance for spontaneous remission compared to primary MN (pMN). Antiphospholipase A2 receptor (PLA2R) antibodies should be evaluated in all patients with pMN at the time of transplantation and serially. If titers persist or rise, biopsy is indicated. Irrespective of PLA2R status, any case with proteinuria reaching 1 g/day should be biopsied. No randomized controlled trials have been published regarding treatment of rMN. Observational data support use of rituximab. Given the progressive nature of rMN and lack of spontaneous remissions, a period of observation does not seem justifiable. dnMN occurs with about equal frequency as rMN and shares features of secondary MN in native kidneys. Causes include viral infections (e.g., hepatitis B or C), which should be treated. In some cases, dnMN may represent an atypical alloimmune response. The role of rituximab in dnMN is undefined.

Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized.

Sensitization following renal allograft failure (AF) is highly variable. Some patients remain non-sensitized (NS), while others become highly sensitized (HS). We studied 66 NS patients who experienced AF after initial kidney transplantation. Post-failure, two main groups of NS panel reactive antibody (PRA) class I and II <10% and HS patients (PRA class I or II ≥80%) were identified. The impact of acute rejection (AR), immunosuppression withdrawal (ISW) at AF, allograft nephrectomy, graft intolerance syndrome (GIS), and both standard serologic and eplet-based mismatches (MM) in inducing HS status after failure was examined. Late PRA testing post-failure revealed 18 patients remained NS and 34 patients became HS. African American recipients, ISW at AF, DQB1 eplet MM, and presence of GIS were associated with becoming HS. Presence of total zero eplet MM, zero DQA1/B1 eplet MM, continuation of immunosuppression after failure, and a hyporesponsive immune status characterized by recurrent infections were features of NS patients. DQ eplet MM represents a significant risk for becoming HS after AF. Studies comparing ISW vs. continuation in re-transplant candidates with high baseline DQ eplet MM burden should be performed. This may provide insights if sensitization post-AF can be lessened.

Chronic Kidney Disease Linearly Predicts Outcomes After Elective Total Joint Arthroplasty.

BACKGROUND: Kidney disease is associated with increased complications in total joint arthroplasty (TJA). The purpose of this study was to determine the association of kidney disease severity as measured by the chronic kidney disease (CKD) staging system with complications after TJA. METHODS: A retrospective review of 12,308 primary TJAs (6361 hips and 5947 knees) from 2008 to 2013 was performed. The following preoperative variables were obtained from medical records: chemistry 7 panel, Elixhauser comorbidities, and demographic factors. CKD stages were defined based on estimated glomerular filtration rate (eGFR) in mL/min/1.73m(2): (1) 90+, (2) 60-89, (3A) 45-59, (3B) 30-44, (4) 15-29, and (5) <15. Multivariate analysis was performed to assess the independent influence of CKD stage on the aforementioned end points. RESULTS: Patients with CKD stage greater than 2 demonstrated an increased odds of receiving transfusions (P = .001), length of stay >3 days (P = .010), acute kidney injury (P < .001), septic revisions (P = .002), and in-hospital complications (P < .001) compared with all patients with eGFR ≥60 when controlling for potential confounders. Only CKD stage 3A was significantly associated with septic revisions (90 days, P = .004; 2 years P = .002). In addition, the relationship between eGFR and the previously mentioned complications increased linearly rather than demonstrating a clear threshold at which the risk increased substantially. CONCLUSION: Severe CKD is associated with increased transfusion, length of stay, and in-hospital complications; and complications increased linearly with disease severity. Surgeons should be cognizant of this increase when evaluating TJA patients with renal disease.

Humoral Immune Response and Allograft Function in Kidney Transplantation.

HLA antibodies can damage a kidney transplant. In January 2013, consensus guidelines from The Transplantation Society were published regarding technical aspects of HLA antibody determination, as well as their potential significance in the pre- and posttransplantation periods. During the past 2 years, new studies have been reported, but controversies remain. In this article, these new data related to HLA antibodies in kidney transplantation are reviewed and compared to relevant prior research. Pretransplantation sensitization issues are discussed, including the new more sensitive assays (flow cytometry and solid-phase immunoassays such as Luminex single-antigen bead assays). A positive complement-dependent cytotoxicity crossmatch remains an absolute contraindication to transplantation, although a positive flow cytometry crossmatch is only a relative contraindication. Positivity only by solid-phase assays increases the risk for acute rejection and transplant loss, but acceptable cutoffs are not defined. The sensitizing effect of red blood cell transfusions is substantiated. Following allograft failure, continued immunosuppression decreases the risk of sensitization, whereas overall, the effect of nephrectomy remains uncertain. Regarding the posttransplantation period, new data are available concerning the timing and significance of donor-specific antibodies (DSA). Whereas some centers report DSA appearance after years, others detect DSA within months. The prominence of class II DSA, especially DQ, in the posttransplantation period is noted. The relevance of non-HLA antibodies is discussed, including anti-endothelial cell antibodies, major histocompatibility complex class I chain-related protein A antibodies, and angiotensin II type 1 receptor autoantibodies.

Humoral immunity in renal transplantation: epitopes, Cw and DP, and complement-activating capability--an update.

Humoral immune responses can destroy a renal allograft. In January 2013, Consensus Guidelines were published regarding testing and management concerns with respect to antibodies in transplantation. New studies have been reported over the past two yr and controversies remain. We review here the new data in light of the Consensus Guidelines and the relevant prior research with emphasis on antibody characteristics and potential for pathogenicity. The heart of immune recognition, epitopes, is stressed, including the realization that DQ (and probably DP) epitopes may be determined not only by eplets within a given α- or ß-chain, but also by specific α- and ß-chain pairings. The significance of Cw and DP loci are discussed. To better understand which donor-specific antibodies are pathogenic, IgG subclass determination has been studied, and in in vitro complement fixation assays, such as the C4d and C1q assays, have been evaluated.

Idiopathic membranous nephropathy and IgG4: an interesting relationship.

Idiopathic membranous nephropathy (iMN) is a single-organ autoimmune disease characterized by subepithelial deposition of immune complexes containing IgG4 resulting in proteinuria, nephrotic syndrome, and, in some, end-stage renal disease. The pathogenesis involves a chronic IgG4 response against specific podocyte antigens which have now been at least partially defined in the neonatal, early childhood, and adult varieties. More has recently been learned about the genetic predisposition as well. This review discusses the pathophysiology of iMN in light of these discoveries and what is known about the genesis and potential clinical ramifications of an antigen specific IgG4 response.

Controversies in Hypertension V: Resistant and Refractory Hypertension.

Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15% of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regimen, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by volume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated. The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (α-ß blockade, centrally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit for resistance, but its role in refractory hypertension remains to be defined.

Diversity in the HLA-I Recognition of HLA-F Monoclonal Antibodies: HLA-F or HLA-Ib Monospecific, HLA-E or HLA-G Bispecific Antibodies with or without HLA-Ia Reactivity.

Previous investigators have used various anti-HLA-F monoclonal antibodies (mAbs) to demonstrate that the tissue distribution of HLA-F is highly restricted. Notably, these mAbs differed in their immunodiagnostic capabilities. Specifically, mAbs Fpep1.1 and FG1 detected HLA-F intracellularly in B cells but not on the cell surface, whereas mAb 3D11 detected HLA-F on the cell surface. The presence of HLA-F on T cells was recognized by mAb FG1 but not by mAb Fpep1.1. mAb 3D11 detected HLA-F on the cell surface of activated B cells and on peripheral blood lymphocytes, but not on the normal cells. Importantly, mAb 3D11 revealed that HLA-F exists as a heavy chain (HC) monomer, rather than as an HC associated with B2m. Although these mAbs are believed to be specific to HLA-F, their monospecificity has not been formally established, which is critical for immunodiagnostic and therapeutic purposes. Previously, we investigated the diversity of HLA class I reactivities of anti-HLA-E mAbs using HLA-I coated multiplex bead assays on a Luminex platform. We reported that more than 80% of the HLA-E mAbs were cross-reactive with other HLA-I molecules, with exceptionally few truly HLA-E-monospecific mAbs. In the present investigation, we generated IgG mAbs against HCs of HLA-F in Balb/C mice and examined the cross-reactivity of anti-HLA-F mAbs with other HLA-I alleles using a multiplex bead assay on the Luminex platform. Beads coated with an array of HLA homo- and heterodimers of different HLA-Ia (HLA-A, HLA-B, and HLA-C) and Ib (HLA-E, HLA-F, and HLA-G) alleles were used to examine the binding of the anti-HLA-F mAbs. Only two mAbs were HLA-F monospecific, and five were HLA-Ib restricted. Several anti-HLA-F mAbs cross-reacted with HLA-E (n = 4), HLA-G (n = 3), HLA-Ia alleles (n = 9), HLA-G and HLA-Ia (n = 2), and HLA-Ib and HLA-Ia (n = 6). This monospecificity and polyreactivity were corroborated by the presence of HLA-F monospecific and HLA-I-shared sequences. This study emphasizes the need to monitor the mono-specificity of HLA-F for reliable immunodiagnostics and passive immunotherapy.

Opportunities and Limitations of Renal Denervation: Where Do We Stand?

Hypertension is a primary contributor to cardiovascular disease, and the leading risk factor for loss of quality adjusted life years. Up to 50% of the cases of hypertension in the United States remain uncontrolled. Additionally, 8%-18% of the hypertensive population have resistant hypertension; uncontrolled pressure despite 3 different antihypertensive agents. Recently, catheter-based percutaneous renal denervation emerged as a method for ablating renal sympathetic nerves for difficult-to-control hypertension. Initial randomized (non-sham) trials and registry analyses showed impressive benefit, but the first sham-controlled randomized controlled trial using monopolar radiofrequency ablation showed limited benefit. With refinement of techniques to include multipolar radiofrequency, ultrasound denervation, and direct ethanol injection, randomized controlled trials demonstrated significant blood pressure improvement, leading to US Food and Drug Administration approval of radiofrequency- and ultrasound-based denervation technologies. In this review article, we summarize the major randomized sham-controlled trials and societal guidelines regarding the efficacy and safety of renal artery denervation for the treatment of uncontrolled hypertension.

The specificity of acute and chronic microvascular alterations in renal allografts.

The diagnosis of an antibody-mediated rejection (AMR) is made when there is evident histologic injury in the presence of detectable donor-specific alloantibodies (DSA) and diffuse peritubular capillary C4d staining (C4d-pos). In the presence of only detectable DSA or C4d-pos, the tissue injury is currently considered "presumptive" for antibody causation. In acute antibody-mediated rejection (AAMR), diagnostic morphologic features include microvascular inflammation (MVI), specifically glomerulitis and peritubular capillaritis. In the case of chronic active AMR (CAAMR), these inflammatory lesions have progressed to chronic microvascular injury, transplant glomerulopathy (TG) and peritubular capillary basement membrane multilayering (PTCBMML). Either TG or PTCBMML is sufficient morphological evidence for a diagnosis of CAAMR. Unfortunately, these lesions are not specific. MVI, TG, and PTCBMML are found in the setting of cell-mediated immunity, as well as in association with non-alloimmune mechanisms. The available treatments for AMR and CMR are different, and it is important to ascertain the dominant mechanism when approaching an individual patient. At present, no gold standard exists to establish the specific pathogenesis in the more ambiguous cases. We detail here the differential diagnosis of MVI, TG, and PTCBMML.

Immunosuppressive treatment of idiopathic membranous nephropathy: the dilemma continues.

Idiopathic membranous nephropathy(IMN) is one of the most common causes of nephrotic syndrome (NS) in adults and may progress to end-stage renal disease(ESRD). Given the variable course, it remains unclear who to treat with immunosuppression(IS) and with what regimen. Corticosteroids, alkylating agents, calcineurin inhibitors (CNIs), and antimetabolities have all been used in randomized controlled trials (RCTs). Previous meta-analyses of these trials were unable to demonstrate a benefit on death or progression to ESRD compared to no treatment or placebo. Since the last round of these analyses (in 2004) additional RCTs have been published. The Cochrane Central Register of Controlled Trials and Medline were searched from 2003 until February 2012 for new RCTs in the treatment of IMN to update the database. Twelve trials were found. Due to significant heterogeneity of patients and regimens, they are discussed qualitatively only and are integrated with prior RCTs and relevant observational data. In conclusion, patients with non-nephrotic proteinuria should not be offered IS therapy. Those with NS and declining renal function should be treated. The best evidence supports a combined steroid and alkylating agent regimen. Calcineurin inhibitors clearly produce short-term benefit (proteinuria reduction and remission) but their ability to favorably affect death or ESRD remains unproven. There is little support for antimetabolite use. Other agents (rituximab and adrenocorticotropin) require further study. For the large group of patients with NS but normal renal function it remains a dilemma who to treat and with regimen.

The case for intervention bias in the practice of medicine.

Bias is an inclination to present or hold a partial perspective at the expense of possibly equal or more valid alternatives. In this paper, we present a series of conditional arguments to prove that intervention bias exists in the practice of medicine. We then explore its potential causes, consequences, and criticisms. We use the term to describe the bias on the part of physicians and the medical community to intervene, whether it is with drugs, diagnostic tests, non-invasive procedures, or surgeries, when not intervening would be a reasonable alternative. The recognition of intervention bias in medicine is critically important given today's emphasis on providing high-value care and reducing unnecessary and potentially harmful interventions.

The Histological Spectrum and Clinical Significance of T Cell-mediated Rejection of Kidney Allografts.

T cell-mediated rejection (TCMR) remains a significant cause of long-term kidney allograft loss, either indirectly through induction of donor-specific anti-HLA alloantibodies or directly through chronic active TCMR. Whether found by indication or protocol biopsy, Banff defined acute TCMR should be treated with antirejection therapy and maximized maintenance immunosuppression. Neither isolated interstitial inflammation in the absence of tubulitis nor isolated tubulitis in the absence of interstitial inflammation results in adverse outcomes, and neither requires antirejection treatment. RNA gene expression analysis of biopsy material may supplement conventional histology, especially in ambiguous cases. Lesser degrees of tubular and interstitial inflammation (Banff borderline) may portend adverse outcomes and should be treated when found on an indication biopsy. Borderline lesions on protocol biopsies may resolve spontaneously but require close follow-up if untreated. Following antirejection therapy of acute TCMR, surveillance protocol biopsies should be considered. Minimally invasive blood-borne assays (donor-derived cell-free DNA and gene expression profiling) are being increasingly studied as a means of following stable patients in lieu of biopsy. The clinical benefit and cost-effectiveness require confirmation in randomized controlled trials. Treatment of acute TCMR is not standardized but involves bolus corticosteroids with lymphocyte depleting antibodies for severe, refractory, or relapsing cases. Arteritis may be found with acute TCMR, active antibody-mediated rejection, or mixed rejections and should be treated accordingly. The optimal treatment ofchronic active TCMR is uncertain. Randomized controlled trials are necessary to optimally define therapy.

Controversies in Hypertension IV: Renal Denervation.

Renal denervation is not a cure for hypertension. Although more recent sham-controlled trials were positive, a significant minority of patients in each trial were unresponsive. The optimal patient or patients need to be defined. Combined systolic/diastolic hypertension appears more responsive than isolated systolic hypertension. It remains uncertain whether patients with comorbidities associated with higher adrenergic tone should be targeted, including obesity, diabetes, sleep apnea, and chronic kidney disease. No biomarker can adequately predict response. A key to a successful response is the adequacy of denervation, which currently cannot be assessed in real time. It is uncertain what is the optimal denervation methodology: radiofrequency, ultrasound, or ethanol injection. Radiofrequency requires targeting the distal main renal artery plus major branches and accessory arteries. Although denervation appears to be safe, conclusive data on quality of life, improved target organ damage, and reduced cardiovascular events/mortality are required before denervation can be generally recommended.

Controversies in Hypertension III: Dipping, Nocturnal Hypertension, and the Morning Surge.

A comprehensive approach to hypertension requires out-of-office determinations by home or ambulatory monitoring. The 4 phenotypes comparing office and out-of-office pressures in treated and untreated patients include normotension, hypertension, white-coat phenomena, and masked phenomena. Components of out-of-office pressure may be equally as important as mean values. Nighttime pressures are normally 10%-20% lower than daytime (normal "dipping") pressures. Abnormalities include dipping more than 20% (extreme dippers), less than 10 % (nondippers), or rising above daytime (risers) and have been associated with elevated cardiovascular risk. Nighttime pressure may be elevated (nocturnal hypertension) in isolation or together with daytime hypertension. Isolated nocturnal hypertension theoretically changes white-coat hypertension to true hypertension and normotension to masked hypertension. Pressure normally peaks in the morning hours ("morning surge") when cardiovascular events are most common. Morning hypertension may result from residual nocturnal hypertension or an exaggerated surge and has been associated with enhanced cardiovascular risk, especially in Asian populations. Randomized trials are needed to determine whether altering therapy based solely on either abnormal dipping, isolated nocturnal hypertension, or an abnormal surge is justified.

A systematic review and meta-analysis of all sham and placebo controlled trials for resistant hypertension.

INTRODUCTION: There is a lack of consensus regarding the best add on therapy for treatment of resistant hypertension (RH). This is likely secondary to a paucity of data on the comparative effectiveness of proposed therapies for RH. METHODS: Placebo-controlled and sham-controlled randomized clinical trials testing therapies for the treatment of RH were included in this meta-analysis. Therapies with two or more studies were included as subgroups in this meta-analysis. The primary outcomes being tested were 24-hr systolic blood pressure (SBP) and office SBP. RESULTS: Eight studies were identified that tested mineralocorticoid receptor antagonist (MRA) including 1,414 participants. The raw mean difference (RMD) between MRA and placebo control was statistically significant for 24-hour SBP (-10.56 mmHg; 95% confidence interval (CI) -12.82 to -8.30), 24-hour diastolic (DBP) (-5.48 mmHg; 95% CI -8.48 to -2.58), office SBP (-11.97 mmHg; 95% CI -16.41 to -7.54), and office DBP (-4.14 mmHg; 95% CI -5.62 to -2.65). Six studies were identified that tested renal denervation (RD) including 989 participants. The RMD between RD and sham control was not statistically significant for 24-hour SBP (-1.84 mmHg; 95% CI -3.92 to 0.24), 24-hour DBP (-0.66 mmHg; 95% CI -1.85 to 0.54), office SBP (-1.57 mmHg; 95% CI -6.04 to 2.89), and office DBP (-1.49 mmHg; 95% CI -3.52 to 0.55). Four studies were identified that tested endothelin receptor antagonists (ERA) including 1,193 participants. The raw mean difference (RMD) between ERA and placebo control was statistically significant for 24-hr systolic (SBP) (-7.02 mmHg; 95% CI -9.15 to -4.90, 24-hr diastolic (DBP) (-6.22 mmHg; 95% CI -7.61 to -4.82), office SBP (-5.84 mmHg; 95% CI -10.08 to -1.60), and office DBP (-3.73 mmHg; 95% CI -5.87 to -1.59). DISCUSSION: MRA lowers BP in patients with RH more than RD, which seems to have little to no effect in RH. ERAs lead to a statistically significant reduction in BP but the confidence in efficacy is limited due to the low number of studies and differences in trial population. Individual factors and their impact on treatment response in RH should be investigated in future research.