Derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin: cohort study.

OBJECTIVE: To develop and externally validate a prediction model for severe cisplatin associated acute kidney injury (CP-AKI). DESIGN: Multicenter cohort study. SETTING: Six geographically diverse major academic cancer centers across the US. PARTICIPANTS: Adults (≥18 years) receiving their first dose of intravenous cisplatin, 2006-22. MAIN OUTCOME MEASURES: The primary outcome was CP-AKI, defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of intravenous cisplatin. Independent predictors of CP-AKI were identified using a multivariable logistic regression model, which was developed in a derivation cohort and tested in an external validation cohort. For the primary model, continuous variables were examined using restricted cubic splines. A simple risk model was also generated by converting the odds ratios from the primary model into risk points. Finally, a multivariable Cox model was used to examine the association between severity of CP-AKI and 90 day survival. RESULTS: A total of 24 717 adults were included, with 11 766 in the derivation cohort (median age 59 (interquartile range (IQR) 50-67)) and 12 951 in the validation cohort (median age 60 (IQR 50-67)). The incidence of CP-AKI was 5.2% (608/11 766) in the derivation cohort and 3.3% (421/12 951) in the validation cohort. Each of the following factors were independently associated with CP-AKI in the derivation cohort: age, hypertension, diabetes mellitus, serum creatinine level, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose. A simple risk score consisting of nine covariates was shown to predict a higher risk of CP-AKI in a monotonic fashion in both the derivation cohort and the validation cohort. Compared with patients in the lowest risk category, those in the highest risk category showed a 24.00-fold (95% confidence interval (CI) 13.49-fold to 42.78-fold) higher odds of CP-AKI in the derivation cohort and a 17.87-fold (10.56-fold to 29.60-fold) higher odds in the validation cohort. The primary model had a C statistic of 0.75 and showed better discrimination for CP-AKI than previously published models, the C statistics for which ranged from 0.60 to 0.68 (DeLong P<0.001 for each comparison). Greater severity of CP-AKI was monotonically associated with shorter 90 day survival (adjusted hazard ratio 4.63 (95% CI 3.56 to 6.02) for stage 3 CP-AKI versus no CP-AKI). CONCLUSION: This study found that a simple risk score based on readily available variables from patients receiving intravenous cisplatin could predict the risk of severe CP-AKI, the occurrence of which is strongly associated with death.

Development and Validation of a Risk Model for Predicting Contrast-Associated Acute Kidney Injury in Patients With Cancer: Evaluation in Over 46,000 CT Examinations.

BACKGROUND. Patients with cancer undergo frequent CT examinations with iodinated contrast media and may be uniquely predisposed to contrast-associated acute kidney injury (CA-AKI). OBJECTIVE. The purpose of this study was to develop and validate a model for predicting the risk of CA-AKI after contrast-enhanced CT in patients with cancer. METHODS. This retrospective study included 25,184 adult patients (12,153 men, 13,031 women; mean age, 62.3 ± 13.7 [SD] years) with cancer who underwent 46,593 contrast-enhanced CT examinations between January 1, 2016, and June 20, 2020, at one of three academic medical centers. Information was recorded regarding demographics, malignancy type, medication use, baseline laboratory values, and comorbid conditions. CA-AKI was defined as a 0.3-mg/dL or greater increase in serum creatinine level from baseline within 48 hours after CT or a 1.5-fold or greater increase in the peak measurement within 14 days after CT. Multivariable models accounting for correlated data were used to identify risk factors for CA-AKI. A risk score for predicting CA-AKI was generated in a development set (n = 30,926) and tested in a validation set (n = 15,667). RESULTS. CA-AKI occurred after 5.8% (2682/46,593) of CT examinations. The final multivariable model for predicting CA-AKI included hematologic malignancy, diuretic use, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, chronic kidney disease (CKD) stage 3a, CKD stage 3b, CKD stage 4 or 5, serum albumin level less than 3.0 g/dL, platelet count less than 150 × 103/µL, 1+ or greater proteinuria on baseline urinalysis, diabetes mellitus, heart failure, and contrast medium volume 100 mL or greater. A risk score (range, 0-53 points) was generated with these variables. The most points (13) were for CKD stage 4 or 5 and for albumin level less than 3 g/dL. The frequency of CA-AKI progressively increased in higher risk categories. For example, in the validation set, CA-AKI occurred after 2.2% of CT examinations in the lowest risk category (score ≤ 4) and after 32.7% of CT examinations in the highest risk category (score ≥ 30). The Hosmer-Lemeshow test result indicated that the risk score was a good fit (p = .40). CONCLUSION. A risk model in which readily available clinical data are used to predict the likelihood of CA-AKI after contrast-enhanced CT in patients with cancer was developed and validated. CLINICAL IMPACT. The model may help facilitate appropriate implementation of preventive measures in the care of patients at high risk of CA-AKI.

Cisplatin Nephrotoxicity: Novel Insights Into Mechanisms and Preventative Strategies.

Cisplatin is a highly effective chemotherapeutic agent that has been used for more than 50 years for a variety of cancers; however, its use is limited by toxicity, including nephrotoxicity. In this in-depth review, we discuss the incidence of cisplatin-associated acute kidney injury, as well as common risk factors for its development. Cisplatin accumulates in the kidney tubules and causes AKI through various mechanisms, including DNA damage, oxidative stress, and apoptosis. We also discuss the spectrum of nephrotoxicity, including acute and chronic impairment of kidney function, electrolyte disturbances, and thrombotic microangiopathy. We discuss the limited options for the diagnosis, prevention, and management of these complications, along with factors that may impact future therapy with or without cisplatin. We conclude with directions for future research in this expanding and important area.

Acute kidney injury in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. METHODS: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. RESULTS: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. CONCLUSIONS: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Comparison of Equations To Estimate Glomerular Filtration Rate and Their Impact on Frequency of Cisplatin-associated Acute Kidney Injury.

Background: Accurate estimation of kidney function is essential for patient selection and drug dosing in patients with cancer. eGFR equations are necessary for decision making and monitoring. Our aim was to identify which of these equations-estimated creatinine clearance (eCrCl) by Cockcroft-Gault (CG), eGFR by Modification of Diet in Renal Disease (eGFRMDRD), CKD Epidemiology Collaboration (eGFRCKD-EPI) or the recently proposed Janowitz-Williams equation (eGFRJ-W)-would be most suitable for GFR estimation among patients with cancer receiving cisplatin. Methods: We assembled a cohort of 5274 patients with cancer treated with cisplatin-based chemotherapy at two large cancer centers. We ascertained the frequency of cisplatin-associated AKI (C-AKI) defined as a ≥0.3 mg/dl rise in serum creatinine over baseline. We compared baseline eGFR and eCrCl using Bland-Altman (B-A) plots, coefficients of variation (CV), and concordance correlation coefficients. We calculated the positive predictive value (PPV), negative predictive value (PPV), accuracy, and area under the curve (AUC). Results: Patients were predominantly middle aged (median 58 years, IQR 49-66 years), overweight (median BMI 26.2, IQR 23.1-29.8 kg/m2), and White (88%), with a median baseline creatinine of 0.8 mg/dl and median cisplatin dose of 99 mg. C-AKI developed in 12% of the cohort. eGFRCKD-EPI had the highest PPV and AUC. eGFRCKD-EPI and eGFRMDRD, along with their BSA-modified counterparts, had the closest agreement with the lowest CV (7.2, 95% CI, 7.0 to 7.3) and the highest concordance. C-AKI was lowest when using eGFRCKD-EPI to define eGFR ≥60 ml/min per 1.73 m2. Conclusions: On the basis of its superior diagnostic performance, eGFRCKD-EPI should be used to estimate GFR in patients being considered for cisplatin-based chemotherapy.

Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma.

OBJECTIVES: Cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin has been used successfully to treat malignant pleural mesothelioma, a highly aggressive malignancy that is rapidly fatal in most cases. We hypothesized that the combination of ischemic injury with nephrotoxic injury from cisplatin would result in high rates of acute kidney injury. METHODS: We conducted an observational study in 503 patients to study the risks and outcomes of acute kidney injury after surgical resection of malignant pleural mesothelioma. Eligible subjects underwent extrapleural pneumonectomy or pleurectomy/decortication with or without hyperthermic intraoperative chemotherapy. Acute kidney injury was defined as an increase in creatinine of 26.5 µmol/L or greater within 48 hours of surgery or a 50% or greater increase over 7 days. RESULTS: Acute kidney injury developed in 243 patients (48.3%). Severe acute kidney injury requiring renal replacement therapy developed in 16 patients (3.2%). Major significant predictors for acute kidney injury included male sex (odds ratio, 2.98; P < .001), intraoperative cisplatin administration (odds ratio, 3.12; P < .001), previous cisplatin exposure (odds ratio, 1.96; P = .02), hypertension (odds ratio, 1.57; P = .02), and longer surgical time (odds ratio, 1.15 per hour; P = .02). Compared with patients without acute kidney injury, those with severe acute kidney injury had longer length of stay (26 vs 13 days) and a 2.71-fold increased risk of death in multivariable-adjusted models. CONCLUSIONS: Acute kidney injury is common after cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin and is associated with poor long-term outcomes. Strategies to prevent postoperative acute kidney injury are needed to improve multimodal treatment of malignant pleural mesothelioma.

Incidence of Hyponatremia in Patients With Indwelling Peritoneal Catheters for Drainage of Malignant Ascites.

Importance: Indwelling peritoneal catheters (IPCs) are frequently used to drain tense, symptomatic, malignant ascites. Large-volume drainage may lead to hyponatremia owing to massive salt depletion. To date, no studies have examined the epidemiology of hyponatremia after placement of an IPC. Objective: To evaluate the incidence of hyponatremia after IPC placement, the risk factors associated with its development, and how it is managed. Design, Setting, and Participants: This cohort study retrospectively reviewed the medical records of 461 patients who had IPCs placed during the period between 2006 and 2016 at a tertiary care hospital in Boston, Massachusetts, of whom 309 patients met the inclusion criteria. Data analysis was performed from June to November 2019. Main Outcomes and Measures: Main outcomes were the incidence of hyponatremia (with a serum sodium level <135 mEq/L) after IPC placement, the risk factors for its development, and how it was managed. We also examined the clinical course of a subset of 21 patients with hypovolemic hyponatremia. Results: Of the 309 eligible patients with laboratory results both before IPC placement and 2 days or more after IPC placement, 189 (72.1%) were female, and the mean (SD) age was 59 (12) years. The overall incidence of hyponatremia after IPC placement was 84.8% (n = 262), of whom 21 patients (8.0%) had severe hyponatremia. The mean (SD) decrease in serum sodium level before vs after IPC placement was 5 (5.1) mEq/L and decreased by 10 mEq/L or more among 52 patients (16.8%). Patients with hyponatremia prior to IPC placement had an 8-fold higher adjusted odds of having persistent hyponatremia after IPC placement (odds ratio, 7.9; 95% CI, 2.9-21.7). Patients with hepatopancreatobiliary malignant neoplasms were more likely to develop hyponatremia (78 of 262 patients with hyponatremia [29.8%] vs 7 of 47 patients without hyponatremia [14.9%]). Hyponatremia was either unrecognized or untreated in 189 patients (72.1%). Conclusions and Relevance: Although the placement of an IPC is often a palliative measure, hyponatremia is common and is often untreated or unrecognized. Patients at highest risk, such as those with hyponatremia at baseline and those with hepatopancreatobiliary malignant neoplams, should be evaluated carefully prior to IPC placement and may warrant closer monitoring after placement. In all cases, hyponatremia should be evaluated and managed within the context of a patient's overall goals of care.

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study.

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, ß2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

Acute Kidney Injury and Electrolyte Abnormalities After Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Diffuse Large B-Cell Lymphoma.

RATIONALE & OBJECTIVE: Cytokine release syndrome is a well-known complication of chimeric antigen receptor T-cell (CAR-T) therapy and can lead to multiorgan dysfunction. However, the nephrotoxicity of CAR-T therapy is unknown. We aimed to characterize the occurrence, cause, and outcomes of acute kidney injury (AKI), along with the occurrence of electrolyte abnormalities, among adults with diffuse large B-cell lymphoma receiving CAR-T therapy. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We reviewed the course of 78 adults receiving CAR-T therapy with axicabtagene ciloleucel or tisagenlecleucel at 2 major cancer centers between October 2017 and February 2019. Baseline demographics, comorbid conditions, medications, and laboratory values were obtained from electronic health records. AKI was defined using KDIGO (Kidney Disease: Improving Global Outcomes) criteria. The cause, clinical course, and outcome of AKI events and electrolyte abnormalities in the first 30 days after CAR-T infusion were characterized using data contained in electronic health records. RESULTS: Among 78 patients receiving CAR-T therapy, cytokine release syndrome occurred in 85%, of whom 62% were treated with tocilizumab. AKI occurred in 15 patients (19%): 8 had decreased kidney perfusion, 6 developed acute tubular necrosis, and 1 patient had urinary obstruction related to disease progression. Those with acute tubular necrosis and obstruction had the longest lengths of stay and highest 60-day mortality. Electrolyte abnormalities were common; hypophosphatemia, hypokalemia, and hyponatremia occurred in 75%, 56%, and 51% of patients, respectively. LIMITATIONS: Small sample size; AKI adjudicated by retrospective chart review; lack of biopsy data. CONCLUSIONS: In this case series of patients with diffuse large B-cell lymphoma receiving CAR-T therapy, AKI and electrolyte abnormalities occurred commonly in the context of cytokine release syndrome.

Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study.

BACKGROUND: Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse. METHODS: We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. RESULTS: Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. CONCLUSIONS: This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.

"Pleurex Desalination" in Malignancy-related Ascites: A Novel Mechanism of Hyponatremia.

OBJECTIVE: Pleurex catheters are a form of palliative therapy for patients, offering relief from symptomatic ascites while also affording greater independence and flexibility; however, aggressive drainage can lead to significant total body sodium losses. We describe the course of patients with "Pleurex desalination," an under-appreciated cause of hypovolemic hyponatremia, highlighting its unique pathophysiology and providing recommendations on how to manage these complex patients. PATIENTS AND METHODS: We included representative patients with "Pleurex desalination" who were evaluated and treated by the renal consult service at Brigham and Women's between 2017 and 2019. RESULTS: We identified 3 patients who were hospitalized with "Pleurex desalination" and had complete data on serum and urine studies, as well as treatment course. We demonstrate that patients with "Pleurex desalination" were removing up to 1 to 2 L of ascitic fluid a day and were admitted with signs and symptoms of profound hypovolemia and hyponatremia. Patients worsened with administration of diuretics and salt restriction and improved with aggressive fluid resuscitation in the form of hypertonic saline, normal saline, and/or intravenous albumin. CONCLUSION: "Pleurex desalination" is an under-recognized cause of hyponatremia; at-risk patients require close observation and periodic resuscitation with intravenous, volume-expanding fluids.

Chromogranin A Tubulopathy: Differing Histopathologic Patterns of Acute Tubular Injury in the Setting of Neuroendocrine Neoplasms.

INTRODUCTION: Neoplasms of neuroendocrine derivation or differentiation may express specific peptides, some of which are capable of producing clinical symptomatology and others used as biomarkers: one such peptide being chromogranin A (CGA). Herein, we describe histopathologic changes present in kidney specimens from patients with such neoplasms, and illustrate 2 patterns of acute tubular injury (ATI) attributable to CGA. METHODS: Eleven patients with a history of a neoplasm of neuroendocrine derivation or differentiation and having histopathologic sampling of the kidney were retrospectively identified, 3 of whom had ATI with either engorgement of the proximal tubular epithelium by resorbed material or tubular cast formation. RESULTS: Two patterns of ATI were observed. One characterized by acutely injured proximal tubular cells engorged with resorption granules that expressed CGA via immunoperoxidase staining. Another pattern was characterized by intraluminal tubular cast material associated with ATI that did not exhibit restriction of immunoglobulin light chains (LCs), but immunoperoxidase staining for CGA revealed that the cast material was composed of the neuroendocrine-associated peptide. The level of serum CGA does not appear to necessarily equate to developing either of these 2 patterns of ATI. CONCLUSIONS: Patients with a neoplasm of neuroendocrine derivation or differentiation may develop ATI, and in certain cases may be secondary to CGA renal tubular deposition.

Development and Validation of a Risk Prediction Model for Acute Kidney Injury After the First Course of Cisplatin.

Purpose Cisplatin-associated acute kidney injury (C-AKI) is common. We sought to develop and validate a predictive model for C-AKI after the first course of cisplatin. Methods Clinical and demographic data were collected on patients who received cisplatin between 2000 and 2016 at two cancer centers. C-AKI was defined as a 0.3 mg/dL rise in serum creatinine within 14 days of receiving cisplatin. Using multivariable logistic regression models with C-AKI as the primary outcome, we created a scoring model from the development cohort (DC) and tested it in the validation cohort (VC). Results C-AKI occurred in 13.6% of 2,118 patients in the DC and in 11.6% of 2,363 patients in the VC. Factors significantly associated with C-AKI included age 61 to 70 years (odds ratio [OR], 1.64 [95% CI, 1.21 to 2.23]; P = .001) and 71 to 90 years (OR, 2.97 [95% CI, 2.06 to 4.28]; P < .001) compared with ≤ 60 years; cisplatin dose 101 to 150 mg (OR, 1.58 [95% CI, 1.14 to 2.19]; P = .007) and > 150 mg (OR, 3.73 [95% CI, 2.68 to 5.20]; P < .001) compared with ≤ 100 mg; a history of hypertension (OR, 2.10 [95% CI, 1.54 to 2.72]; P < .001) compared with no hypertension; and serum albumin 2.0 to 3.5 g/dL (OR, 2.21 [95% CI, 1.62 to 3.03]; P < .001) compared with > 3.5 g/dL. The baseline estimated glomerular filtration rate was not significantly associated with the risk of C-AKI. The c-statistics of the score-based model in the DC and the VC were 0.72 (95% CI, 0.69 to 0.75) and 0.70 (95% CI, 0.67 to 0.73), respectively. Scores of 0, 3.5, and 8.5 were associated with a probability of C-AKI of 0.03 (95% CI, 0.03 to 0.05), 0.12 (95% CI, 0.11 to 0.14), and 0.51 (95% CI, 0.43 to 0.60), respectively. Conclusion A score-based model created by using the patient's age, cisplatin dose, hypertension, and serum albumin is predictive of C-AKI.

Paraprotein-Related Kidney Disease: Glomerular Diseases Associated with Paraproteinemias.

Paraproteins are monoclonal Igs that accumulate in blood as a result of abnormal excess production. These circulating proteins cause a diversity of kidney disorders that are increasingly being comanaged by nephrologists. In this review, we discuss paraprotein-related diseases that affect the glomerulus. We provide a broad overview of diseases characterized by nonorganized deposits, such as monoclonal Ig deposition disease (MIDD), proliferative GN with monoclonal Ig deposits (PGNMID), and C3 glomerulopathy, as well as those characterized by organized deposits, such as amyloidosis, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemic GN, and rarer disorders, such as monoclonal crystalline glomerulopathies, paraprotein-related thrombotic microangiopathies, and membranous-like glomerulopathy with masked IgGκ deposits. This review will provide the nephrologist with an up to date understanding of these entities and highlight the areas of deficit in evidence and future lines of research.

Chronic Kidney Disease and Sleeping Disordered Breathing (SDB).

The outlines of the current manuscript are: 1. Re-establish the link between hypertension and SDB including prevalence, mechanism, and reversal of process (i.e. improvement in hypertension with improvement in SDB), why it is important-cardiovascular mortality with numbers. 2. Re-establish the link between hypertension and CKD including same points as above. Then ask if both CKD and SDB are combined, what happens to hypertension and cardiovascular mortality. 3. Lastly, talk about links between CKD and SDB on how each process feeds on the other and is a growing, common problem.

Influence of rostral fluid shift on upper airway size and mucosal water content.

STUDY OBJECTIVE: Fluid displacement from the legs during recumbency while in bed might narrow the upper airway (UA) in association with nuchal fluid accumulation that may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to test the hypothesis that rostral fluid displacement from the legs causes a greater decrease in UA cross-sectional area (UA-XSA) and a greater increase in UA mucosal water content (UA-MWC) and internal jugular venous volume (IJVVol) in subjects with OSA than in those without OSA. METHODS: Subjects underwent baseline assessment of leg fluid volume (LFV) measured by bio-electrical impedance, as well as UA-XSA and UA-MWC by magnetic resonance imaging. They were then randomly assigned to a 20-min period either with or without application of lower body positive pressure (LBPP) of 40 mm Hg, followed by a 15-min washout period, after which they crossed over to the other arm of the study. Measurements of LFV, UA-MWC, and UA-XSA were repeated after each arm of the study. RESULTS: In 12 subjects without sleep apnea, UA-XSA increased and UA-MWC decreased significantly, whereas in 12 subjects with OSA, UA-XSA decreased and UA-MWC increased significantly in response to LBPP. The changes in UA-XSA and UA-MWC in response to LBPP differed significantly between the 2 groups (p = 0.006 and p < 0.001, respectively), despite similar changes in LFV and IJVVol. CONCLUSIONS: Our results suggest that rostral fluid shift may contribute to the pathogenesis of OSA at least partly through narrowing of the UA due to transudation of fluid into the UA mucosa.

Contrasting effects of lower body positive pressure on upper airways resistance and partial pressure of carbon dioxide in men with heart failure and obstructive or central sleep apnea.

OBJECTIVES: This study sought to test the effects of rostral fluid displacement from the legs on transpharyngeal resistance (Rph), minute volume of ventilation (Vmin), and partial pressure of carbon dioxide (PCO2) in men with heart failure (HF) and either obstructive (OSA) or central sleep apnea (CSA). BACKGROUND: Overnight rostral fluid shift relates to severity of OSA and CSA in men with HF. Rostral fluid displacement may facilitate OSA if it shifts into the neck and increases Rph, because pharyngeal obstruction causes OSA. Rostral fluid displacement may also facilitate CSA if it shifts into the lungs and induces reflex augmentation of ventilation and reduces PCO2, because a decrease in PCO2 below the apnea threshold causes CSA. METHODS: Men with HF were divided into those with mainly OSA (obstructive-dominant, n = 18) and those with mainly CSA (central-dominant, n = 10). While patients were supine, antishock trousers were deflated (control) or inflated for 15 min (lower body positive pressure [LBPP]) in random order. RESULTS: LBPP reduced leg fluid volume and increased neck circumference in both obstructive- and central-dominant groups. However, in contrast to the obstructive-dominant group in whom LBPP induced an increase in Rph, a decrease in Vmin, and an increase in PCO2, in the central-dominant group, LBPP induced a reduction in Rph, an increase in Vmin, and a reduction in PCO2. CONCLUSIONS: These findings suggest mechanisms by which rostral fluid shift contributes to the pathogenesis of OSA and CSA in men with HF. Rostral fluid shift could facilitate OSA if it induces pharyngeal obstruction, but could also facilitate CSA if it augments ventilation and lowers PCO2.

Relationship of pharyngeal water content and jugular volume with severity of obstructive sleep apnea in renal failure.

BACKGROUND: In patients with end-stage renal disease (ESRD), fluid overload may contribute to their high prevalence of obstructive sleep apnea (OSA) by increasing the amount of fluid displaced from the legs into the neck overnight, and possibly compressing the upper airway (UA). Indeed, in ESRD patients, the amount of overnight rostral fluid displacement from the legs is related to the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index, AHI). We, therefore, hypothesized that in ESRD patients, the greater the UA-mucosal water content (UA-MWC) and internal jugular vein volume (IJVVol), the higher the AHI. METHODS: We studied 20 patients with ESRD on thrice weekly hemodialysis who had undergone diagnostic polysomnography (age 41.0 ± 12.3 years, with a body mass index (BMI) of 25.8 ± 6.3 kg/m(2) and an AHI of 20.2 ± 26.8). The leg fluid volume (LFV) was measured by bioelectric impedance. The IJVVol and MWC were measured by UA magnetic resonance imaging (MRI). RESULTS: The only significant independent correlates of the AHI were IJVVol (r = 0.801, P < 0.0001) and UA-MWC (r = 0.720, P = 0.0005) which together explained 72% of its variability. CONCLUSIONS: These data suggest that fluid overload via increased IJVVol, and UA-MWC, contributes to the pathogenesis of OSA in patients with ESRD. These findings help us to explain the high prevalence of OSA in ESRD patients, and attenuation of OSA in association with nocturnal dialysis. They also suggest the need for randomized trials to determine whether more aggressive fluid removal in ESRD patients will alleviate OSA.