Development and external validation of a diagnostic model for biopsy-proven acute interstitial nephritis using electronic health record data.

BACKGROUND: Patients with acute interstitial nephritis (AIN) can present without typical clinical features, leading to a delay in diagnosis and treatment. We therefore developed and validated a diagnostic model to identify patients at risk of AIN using variables from the electronic health record. METHODS: In patients who underwent a kidney biopsy at Yale University between 2013 and 2018, we tested the association of >150 variables with AIN, including demographics, comorbidities, vital signs and laboratory tests (training set 70%). We used least absolute shrinkage and selection operator methodology to select prebiopsy features associated with AIN. We performed area under the receiver operating characteristics curve (AUC) analysis with internal (held-out test set 30%) and external validation (Biopsy Biobank Cohort of Indiana). We tested the change in model performance after the addition of urine biomarkers in the Yale AIN study. RESULTS: We included 393 patients (AIN 22%) in the training set, 158 patients (AIN 27%) in the test set, 1118 patients (AIN 11%) in the validation set and 265 patients (AIN 11%) in the Yale AIN study. Variables in the selected model included serum creatinine {adjusted odds ratio [aOR] 2.31 [95% confidence interval (CI) 1.42-3.76]}, blood urea nitrogen:creatinine ratio [aOR 0.40 (95% CI 0.20-0.78)] and urine dipstick specific gravity [aOR 0.95 (95% CI 0.91-0.99)] and protein [aOR 0.39 (95% CI 0.23-0.68)]. This model showed an AUC of 0.73 (95% CI 0.64-0.81) in the test set, which was similar to the AUC in the external validation cohort [0.74 (95% CI 0.69-0.79)]. The AUC improved to 0.84 (95% CI 0.76-0.91) upon the addition of urine interleukin-9 and tumor necrosis factor-α. CONCLUSIONS: We developed and validated a statistical model that showed a modest AUC for AIN diagnosis, which improved upon the addition of urine biomarkers. Future studies could evaluate this model and biomarkers to identify unrecognized cases of AIN.

Urine interleukin-9 and tumor necrosis factor-α for prognosis of human acute interstitial nephritis.

BACKGROUND: We previously demonstrated that urine interleukin (IL)-9 and tumor necrosis factor (TNF)-α can distinguish acute interstitial nephritis (AIN) from other causes of acute kidney injury. Here we evaluated the role of these biomarkers to prognosticate kidney function in patients with AIN. METHODS: In a cohort of participants with biopsy-proven, adjudicated AIN, we tested the association of histological features and urine biomarkers (IL-9 and TNF-α) with estimated glomerular filtration rate measured 6 months after diagnosis (6 m-eGFR) controlling for eGFR before AIN and albuminuria. We also evaluated subgroups in whom corticosteroid use was associated with 6 m-eGFR. RESULTS: In the 51 (93%) of the 55 participants with complete data, median (interquartile range) eGFR before and 6 m after AIN were 41 (27-69) and 28 (13-47) mL/min/1.73 m2, respectively. Patients with higher severity of interstitial fibrosis had lower 6 m-eGFR, whereas those with higher tubulointerstitial infiltrate had higher 6 m-eGFR. IL-9 levels were associated with lower 6 m-eGFR only in the subset of patients who did not receive corticosteroids [6m-eGFR per doubling of IL-9, -6.0 (-9.4 to -2.6) mL/min/1.73 m2]. Corticosteroid use was associated with higher 6 m-eGFR [20.9 (0.2, 41.6) mL/min/1.73 m2] only in those with urine IL-9 above the median (>0.66 ng/g) but not in others. CONCLUSIONS: Urine IL-9 was associated with lower 6 m-eGFR only in participants not treated with corticosteroids. Corticosteroid use was associated with higher 6 m-eGFR in those with high urine IL-9. These findings provide a framework for IL-9-guided clinical trials to test efficacy of immunosuppressive therapy in patients with AIN.

Update on the Native Kidney Biopsy: Core Curriculum 2019.

The kidney biopsy is an invaluable tool that has become the gold standard for the diagnosis of pathologic kidney diseases since the early 1950s. Throughout the years, immunohistologic and ultrastructural microscopy techniques have improved and provide more information on the cause and classification of kidney diseases than that available from simple light microscopy alone. Kidney biopsy has become a preferred method to obtain critical information that can be used in conjunction with serologic, urinary, and genetic testing to diagnose a variety of kidney diseases, both acute and chronic. The kidney biopsy procedure carries relatively low risk and yields substantial information. Potential complications include bleeding requiring transfusion, gross hematuria, arteriovenous fistula formation, and perinephric hematoma, among others. Percutaneous kidney biopsies are typically performed using real-time ultrasound or computed tomographic imaging. This Core Curriculum briefly outlines the history of the kidney biopsy, then discusses indications, complications, and specific procedural aspects.

Optimizing waiting duration for renal transplants in the setting of renal malignancy: is 2 years too long to wait?

BACKGROUND: For potential transplant recipients with a prior history of renal malignancy, no evidence-based recommendations currently exist with regard to waiting duration on dialysis. We aim to improve decision making by evaluating the impact of waiting duration on the outcomes of kidney cancer patients awaiting renal transplantation. METHODS: The United States Renal Data System was used to identify patients with a known cause of end-stage renal disease (ESRD) from 1983 to 2007. Evaluation of overall survival (OS) was performed with Kaplan-Meier estimates and Cox proportional hazards models. Fine-Gray competing risk models were used to assess cancer-specific mortality (CSM) and non-cancer-specific mortality (NCSM). RESULTS: Of 1 374 175 patients with ESRD, 228 984 (16.7%) received transplantation. Transplant recipients with renal malignancy-associated ESRD (RM-ESRD) had longer waiting durations than those with other known causes of ESRD (2.4 versus 1.3 years; P < 0.0001). RM-ESRD patients who had shorter waiting durations (0-2 years) had better OS than those who waited longer (2+ years) (10-year OS 69.0 versus 46.7%, respectively; P < 0.0001), with similar CSM (10-year CSM 10.3 versus 10.2%, respectively; P = 0.883), whereas NCSM was worse for those with longer waiting durations (10-year NCSM 20.7 versus 44.3%, respectively; P < 0.0001). On Cox modeling, the status of RM-ESRD was not a significant predictor (P = 0.07), while longer waiting duration remained significant (P < 0.0001). CONCLUSION: We found that CSM was not affected by waiting duration, while NCSM significantly improved with shorter wait times. These findings suggest that the OS of potential transplant recipients with RM-ESRD may be improved by reducing waiting duration.

Comparison of amyloid deposition in human kidney biopsies as predictor of poor patient outcome.

BACKGROUND: Amyloidosis leads to deposition of abnormal protein with beta-pleated sheet structure in specific compartments of the affected organs. The histological localization of these amyloid deposits determines the overall survival of the patient. METHODS: In this study we have assessed the histological localization and severity of amyloid deposition in 35 patients with biopsy-proven renal amyloidosis and have compared those to clinical parameters, histo-pathological injury criteria and respective patient outcome. Comparisons were statistically analyzed using thus comparison between the different study groups, which was done using Student t-test and analysis of variance. RESULTS: We find that the glomerulus is by far the most commonly and most severely affected renal compartment and patients with severe glomerular amyloidosis advance faster towards end stage renal disease (ESRD) and death, compared to those patients without glomerular amyloid deposits. Patients with severe glomerular amyloidosis showed higher serum creatinine and urine protein levels, while patients with severe vascular amyloidosis showed higher levels of interstitial inflammatory infiltrate. CONCLUSION: In kidneys affected by amyloidosis, the amyloid proteins are predominantly deposited along vessels, especially the small vessels including glomerular capillary loops. The severity of glomerular amyloid deposition enhances the risk of developing ESRD and increases the risk for premature death.

Acute kidney injury from cherry concentrate in a patient with CKD.

Nutraceuticals are supplements and medical foods that offer numerous health benefits. However, these substances may have adverse effects on multiple organ systems, leading to significant morbidity. I present a patient with chronic kidney disease who experienced hemodynamically mediated acute kidney injury and hyperkalemia after daily consumption of cherry concentrate. The method of injury was most likely cyclooxygenase inhibition by the compounds in cherries that mimic the mechanism of action of nonsteroidal anti-inflammatory medications. Ceasing cherry concentrate consumption led to improvements in both the patient's hyperkalemia and kidney injury. Physicians should be aware of the potentially harmful side effects of cherry concentrate and approach the use of cherry extract or concentrate with caution in patients with underlying kidney disease.

Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid.

Bile acid nephropathy, also known as cholemic nephrosis or nephropathy, is an entity that can be seen in patients with severe cholestatic liver disease. It typically is associated with acute kidney injury (AKI) with various forms of hepatic disease. Most often, patients with severe obstructive jaundice develop this lesion, which is thought to occur due to direct bile acid injury to tubular cells, as well as obstructing bile acid casts. Patients with end-stage liver disease also can develop AKI, in which case a more heterogeneous lesion occurs that includes hepatorenal syndrome and acute tubular injury/necrosis. In this circumstance, acute tubular injury develops from a combination of hemodynamic changes with some contribution from direct bile acid-related tubular toxicity and obstructive bile casts. We present a case of AKI due to bile acid nephropathy in a bodybuilder who developed severe cholestatic liver disease in the setting of anabolic androgenic steroid use.

Extra-renal manifestations of autosomal dominant polycystic kidney disease (ADPKD): considerations for routine screening and management.

Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease, marked by progressive increase of bilateral renal cysts, resulting in chronic kidney disease (CKD) and often leading to end-stage renal disease (ESRD). Apart from renal cysts, patients often have extra-renal disease, involving the liver, heart and vasculature. Other less common but equally important extra-renal manifestations of ADPKD include diverticular disease, hernias, male infertility and pain. Extra-renal disease burden is often asymptomatic, but may result in increased morbidity and mortality. If the disease burden is significant, screening may prove beneficial. We review the rationale for current screening recommendations and propose some guidelines for screening and management of ADPKD patients.

Light chain crystalline kidney disease: diagnostic urine microscopy as the "liquid kidney biopsy".

Multiple myeloma (MM) is a plasma cell disorder, which often causes parenchymal kidney disease. Light chain (LC) cast nephropathy represents the most common renal lesion. In some instances, LC crystals precipitate within renal tubular lumens and deposit within proximal tubular cell cytoplasms. Importantly, urine microscopy in such patients can provide insight into the underlying LC-related lesion. Here we present two patients with MM complicated by acute kidney injury (AKI) where LC crystalline casts were observed on urinary sediment analysis. Kidney biopsy revealed acute tubular injury with LC crystal casts within both tubular lumens and renal tubular epithelial cell cytoplasms. These findings suggest that the urinary sediment may be a non-invasive way to diagnose LC crystalline-induced AKI in patients with MM.

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.

Babesiosis-induced acute kidney injury with prominent urinary macrophages.

Babesia is an obligate intracellular erythrocyte parasite that can infect humans. Severe symptomatic disease from massive hemolysis and multiorgan system failure, including acute kidney injury (AKI), occurs. Acute tubular injury from a combination of volume depletion and heme pigment toxicity from profound hemolysis is the most common cause of AKI. We present a case of severe babesiosis complicated by dialysis-requiring AKI with the unique finding of large macrophages containing engulfed erythrocyte fragments in urine sediment. This urinary finding raised the possibility of another diagnosis distinct from acute tubular injury. Subsequent kidney biopsy demonstrated infection-associated acute interstitial nephritis.

Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis.

BackgroundAcute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.MethodsIn a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group.ResultsIn aptamer-based assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 × 10-5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 [1.8-20]). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86-1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 × 10-6).ConclusionWe identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN.FundingThis study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O'Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Urine Uromodulin as a Biomarker of Kidney Tubulointerstitial Fibrosis.

BACKGROUND AND OBJECTIVES: Uromodulin, produced exclusively in the kidney's thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair. RESULTS: We found urine uromodulin to be correlated with serum creatinine (rho=-0.43; P<0.001), bicarbonate (0.20; P<0.001), and hemoglobin (0.11; P=0.03) at the time of biopsy but not with urine albumin (-0.07; P=0.34). Multivariable models controlling for prebiopsy GFR, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy and glomerulosclerosis (interstitial fibrosis/tubular atrophy: -3.5% [95% confidence intervals, -5.7% to -1.2%] and glomerulosclerosis: -3.3% [95% confidence intervals, -5.9% to -0.6%] per two-fold difference in uromodulin). However, when both interstitial fibrosis/tubular atrophy and glomerulosclerosis were included in multivariable analysis, only interstitial fibrosis/tubular atrophy was independently associated with uromodulin (interstitial fibrosis/tubular atrophy: -2.5% [95% confidence intervals, -4.6% to -0.4%] and glomerulosclerosis: -0.9% [95% confidence intervals, -3.4% to 1.5%] per two-fold difference in uromodulin). In mouse kidneys, uromodulin staining was found to be lower in the fibrotic model than in normal or repaired models. CONCLUSIONS: Higher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3.

Treatment of superior vena cava syndrome with kissing brachiocephalic stents and exchange of pacemaker leads.

Superior vena cava syndrome is an uncommon but challenging complication of patients undergoing hemodialysis through upper extremity access as well as of patients with indwelling pacemakers. This case report and Video demonstrate the multidisciplinary management of a complex patient with hemodialysis access and indwelling pacemaker for whom multiple attempts at balloon angioplasty for superior vena cava syndrome failed. A joint procedure between vascular surgery and cardiac electrophysiology teams was performed to exchange the pacemaker leads and to place bilateral kissing stents in the brachiocephalic veins. The patient tolerated the procedure well and had no recurrence of symptoms.

Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis.

BACKGROUNDClinical diagnosis of acute interstitial nephritis (AIN) is challenging because of lack of a diagnostic biomarker and requires a kidney biopsy. We hypothesized that AIN is mediated by specific T cell subsets such that specific T cell cytokine levels could serve as biomarkers to distinguish AIN from other causes of acute kidney disease (AKD).METHODSWe enrolled consecutive sampling participants who underwent a kidney biopsy for AKD evaluation at 2 centers between 2015 and 2018. Three pathologists independently established AIN diagnosis through review of kidney biopsies. Through univariable and multivariable analysis of 12 selected urine and plasma cytokines, we identified 2 that were diagnostic of AIN.RESULTSOf the 218 participants, 32 (15%) were diagnosed with AIN by all 3 pathologists. Participants with AIN had consistently higher levels of urine TNF-α and IL-9 than those with other diagnoses, including acute tubular injury, glomerular diseases, and diabetic kidney disease, and those without any kidney disease. As compared with participants in the lowest quartile, we noted higher odds of AIN in participants in the highest quartiles of TNF-α levels (adjusted odds ratio, 10.9 [1.8, 65.9]) and IL-9 levels (7.5 [1.2, 45.7]) when controlling for blood eosinophils, leukocyturia, and proteinuria. Addition of biomarkers improved area under receiver operating characteristic curve over clinicians' prebiopsy diagnosis (0.84 [0.78, 0.91]) vs. 0.62 [(0.53, 0.71]) and a model of current tests (0.84 [0.76, 0.91] vs. 0.69 [0.58, 0.80]).CONCLUSIONSInclusion of urinary TNF-α and IL-9 improves discrimination over clinicians' prebiopsy diagnosis and currently available tests for AIN diagnosis.FUNDINGSupported by NIH awards K23DK117065, T32DK007276, K24DK090203, K23DK097201, R01DK113191, UG3-DK114866, P30DK079310; the Robert E. Leet and Clara Guthrie Patterson Trust; and American Heart Association award 18CDA34060118.

Kidney Biopsy-Related Complications in Hospitalized Patients with Acute Kidney Disease.

BACKGROUND AND OBJECTIVES: Patients are informed of the risk of kidney biopsy-related complications using data from nonhospitalized patients, which may underestimate the risk for hospitalized patients. We evaluated the rate and risk factors of kidney biopsy-related complications in hospitalized patients with acute kidney disease (AKD) to better estimate the risk in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used data from the Yale biopsy cohort to evaluate rates of kidney biopsy-related complications including adjudicated procedure-related bleeding requiring blood transfusions or angiographic interventions, medium- or large-sized hematomas, reimaging after biopsy including abdominal ultrasonography or computed tomography, and death in hospitalized patients with AKD (including AKI). We evaluated univariable and multivariable association of risk factors with transfusions. We compared rates of complications between hospitalized and nonhospitalized patients. RESULTS: Between 2015 and 2017, 159 hospitalized patients underwent a kidney biopsy for AKD evaluation, of which 80 (51%) had stage 1 AKI, 42 (27%) had stage 2 (or higher) AKI, and 27 (17%) had AKD (without AKI). Of these, 12 (8%; 95% confidence interval [95% CI], 5% to 15%) required a transfusion, three (2%; 95% CI, 1% to 5%) required an intervention, 11 (7%; 95% CI, 4% to 12%) had hematoma, and 31 (20%; 95% CI, 14% to 26%) required reimaging after biopsy. Of the four (3%; 95% CI, 1% to 6%) deaths during hospitalization, none were related to the biopsy. Female sex, lower platelet count, and higher BUN were associated with postbiopsy transfusions on univariable and multivariable analyses. Trainee as proceduralist and larger needle gauge were associated with transfusions in univariable, but not multivariable, analysis. Nonhospitalized patients had lower rates of transfusion than hospitalized patients, although the latter also had lower prebiopsy hemoglobin and greater surveillance after biopsy. CONCLUSIONS: Hospitalized patients experience higher risk of postbiopsy complications than previously reported and several factors, such as lower platelet count, female sex, and higher BUN, are associated with this risk.

A Survey of Patient Attitudes Toward Participation in Biopsy-Based Kidney Research.

INTRODUCTION: As part of the precision medicine initiative, the National Institutes of Health/National Institute of Diabetes and Digestive Kidney Diseases has proposed collecting human kidney tissue to discover novel therapeutic targets from patients with kidney diseases. Patient attitudes on participating in kidney biopsy-based research are largely unknown. METHODS: We evaluated attitudes toward donating kidney tissue to research among participants who had experienced a clinically indicated kidney biopsy, through a survey conducted 9 months (interquartile range, 5-13 months) after their biopsy. RESULTS: Of the 177 participants contacted, 117 (66%) participated in the survey. A total of 85 participants (73%) reported that they would allow additional needle passes during a clinically indicated biopsy to donate kidney tissue for research. As reasons for participating in such a study, the participants reported the desire to help others and to contribute to science, and the lack of additional burden while participating in such a study. In a multivariable logistic model, older and African American participants had lower odds of allowing an additional pass for research (odds ratio: age ≥65 years [vs. ≤40], 0.15 [95% confidence interval, 0.03-0.73]; African Americans (vs. all others), 0.15 [95% confidence interval, 0.05-0.44]). However, participants' self-reported biopsy complications such as pain, anxiety, and hematuria did not affect their willingness to allow additional passes. A total of 23 participants (20%) stated that they would agree to undergo a biopsy for research even if it was not clinically indicated. CONCLUSION: Among patients who had experienced a kidney biopsy, a majority were amenable to additional needle passes to donate kidney tissue for research during a future, clinically indicated biopsy, whereas a minority would undergo a biopsy for research purpose only.