Irreversible Kidney Injury Research Articles

Tubulointerstitial injury in proteinuric chronic kidney diseases.

Proteinuria is an independent risk factor for chronic kidney disease progression and cardiovascular diseases. Apart from its prognostic role, the load of proteins that pass across the disrupted glomerular capillary wall trigger multiple pathophysiologic processes. These include, among others, intratubular complement activation and excessive proximal tubular reabsorption of filtered proteins, especially albumin and albumin-bound free fatty acids, which can set off several pathways of cellular damage. The activation of these pathways can cause apoptosis of proximal tubular cells and paracrine effects that incite the development of interstitial inflammation and fibrosis, ultimately leading to irreversible kidney injury. In this review, we provide a comprehensive overview of the current understanding on the mechanisms underlying the tubular toxicity of ultrafiltered proteins in the setting of proteinuric chronic kidney diseases. The acquired knowledge is expected to be instrumental for the development of novel therapeutic classes of medications to be tested on top of standard of care with optimized renin-angiotensin-aldosterone blockade and sodium-glucose cotransporter-2 inhibition, in order to further improve the clinical outcomes of patients with proteinuric chronic kidney diseases.

Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets.

Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation. CKD is a leading global health burden that is asymptomatic in early stages but can ultimately cause kidney failure. Its etiology is complex and involves dysregulated signaling pathways that lead to fibrosis. Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury. While current therapies are limited, the search for more effective diagnostic and treatment modalities is intensive. Although biopsy with histology is the most accurate method of diagnosis and staging, imaging techniques such as diffusion-weighted magnetic resonance imaging and shear wave elastography ultrasound are less invasive ways to stage fibrosis. Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression. Newer antifibrotic agents that suppress the downstream inflammatory mediators involved in the fibrotic process are in clinical trials, and potential therapeutic targets that interfere with TGF-β signaling are being explored. Small interfering RNAs and stem cell-based therapeutics are also being evaluated. Further research and clinical studies are necessary in order to avoid dialysis and kidney transplantation.

A giant neobladder stone with insignificant symptoms: A case report and literature review.

Giant neobladder lithiasis after orthotopic bladder replacement is an infrequent but important long-term complication, which should be diagnosed and treated early. If left untreated, it may eventually lead to irreversible acute kidney injury and seriously affect the quality of life of patients. Here, we present a rare case of a patient who presented with a massive neobladder stone after radical cystectomy done with orthotopic neobladder construction, followed by a challenging stone extraction process. A 70-year-old female patient presented with a massive neobladder stone 14 years after radical cystectomy done with orthotopic neobladder construction. A computed tomography scan showed a large elliptic stone. The patient underwent suprapubic cystolithotomy surgery, which removed her giant-sized stone in the neobladder. The size of the bladder stone that was removed was 13 cm × 11.5 cm × 9 cm, with a total weight of 903 g. To date, the follow-up time of treatment is 4 months, and in our patient, no pain, urinary tract infections, or other abnormalities suggestive of fistula were found. Imaging examination is useful for detecting neobladder lithiasis occurring after orthotopic neobladder construction. Our experience demonstrates that open cystolithotomy is an appropriate therapeutic method for treating the late-stage complication of a giant neobladder stone.

Secreted Proteins, Lipids and Low‐Molecular‐Weight Metabolites as Early Biomarkers of Human Proximal Tubular Cell Exposure to Nephrotoxic Agents

Mitochondria and other organelles are early and sensitive targets for numerous nephrotoxic drugs and environmental contaminants. To prevent irreversible kidney injury from such chemical exposures it is critical to identify indicators (biomarkers) that correspond with the exposures before significant injury occurs. Primary cultures of human proximal tubular (hPT) cells were used as the model system to test the hypothesis that exposure to low, physiologically relevant concentrations of these agents causes release of proteins, lipids and metabolites into the extracellular space that correlate with specific exposures and cytotoxicity. Previous work with the nephrotoxic and mitochondrial‐targeting toxicant S‐(1,2‐dichlorovinyl)‐L‐cysteine (DCVC) confirmed that a large proportion (43%) of proteins recovered in the extracellular medium was of mitochondrial origin. Three of the most abundant proteins detected, for which levels were increased by 5‐ to 10‐fold by DCVC, were sulfite oxidase (mitochondrial), keratins (cytoskeletal), and HSP90 (cytoplasm). Comparisons of proteins detected in media from cells exposed to cisplatin (CDDP) vs. Control or polymyxin B (PmxB) vs. Control showed several commonly increased proteins. As with results from DCVC exposure, keratins and HSP90 were detected. The only mitochondrial protein that increased in abundance in supernatants from toxicant‐treated cells was carbamoyl‐phosphate synthase (1.4‐ and 2.3‐fold higher in supernatants from CDDP‐ and PmxB‐treated cells, respectively). Metabolomic analysis showed moderate changes (429 features at raw P < 0.05) for CDDP‐treated cells vs. Control and moderate to high changes (619 features at raw P < 0.05) for PmxB‐treated cells vs. Control. For CDDP. There was consistently lower release of 2‐aminoadipate 6‐semialdehyde and differences in purines, lipid species, and several amino acids. For PmxB, there was consistently lower release of aminoadipic acid and 2‐aminoadipate 6‐semialdehyde and differences in release of lipid species and lower release of phosphoenolpyruvate. These findings support the overall hypothesis and identify multiple candidate biomarkers of early exposure to diverse nephrotoxicants.

Prescriptive Analytics Determining Which Patients Undergoing Simultaneous Liver-Kidney Transplant May Benefit From High-Risk Organs.

Simultaneous liver-kidney transplant is a treatment option for patients with end-stage liver disease and concomitant irreversible kidney injury. We developed a decision toolto aid transplant programs to advise their candidates for simultaneous liver-kidney transplant on accepting high-risk grafts versus waiting for lower-risk grafts. To find the critical decision factors, we used the prescriptive analytic technique of microsimulation.All probabilities used in the simulation model were calculated from Organ Procurement and Transplantation Network data collected from February 27, 2002 to June 30, 2018. The simulated patient population results revealed, on average, that high-risk candidates for simultaneous liver-kidney transplant who accept highrisk organs have 254.8 ± 225.4 weeks of life compared with 285.6 ± 232.4 weeks if they waited for better organs. However, critical decision factors included the specific organ offer rates within individual transplant programs and the rank of the candidate in each program's waitlist. Thus, for programs with lower organ offer rates or for candidates with a rare blood type, a high-risk simultaneous liver-kidney transplant candidate might accept a high-risk organ for longer survival. Our model can be utilized to determine when acceptance of high-risk organs for patients being considered for simultaneous liver-kidney transplant would lead to survival benefit, based on probabilities specific for their program.

A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

BackgroundThe use of T cells expressing chimeric antigen receptor (CAR T) engineered to target CD19 constitutes breakthrough treatment for relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL). Despite improved outcomes, high relapse rate remains a challenge to overcome. Here, we report the clinical results and the pharmacokinetics of bispecific CD19/22 CAR T in patients with R/R B-NHL.MethodsWe performed a prospective, single-arm study of bispecific CD19/22 CAR T cells in R/R B-NHL. We analyzed the safety and efficacy and investigated the kinetic profiles of the CAR T cells. CAR transgene levels were measured using quantitative polymerase chain reaction, and correlation analyses of pharmacodynamic markers and product characteristics, disease conditions, clinical efficacy and adverse events were performed.ResultsFrom August 2017 to September 2020, a total of 32 patients with CD19/22 CAR T administration were analyzed. The overall response rate was 79.3%, and the complete response rate was 34.5%. The progression-free survival (PFS) and overall survival (OS) rates at 12 months were 40.0% and 63.3%, respectively. Among patients who had a CR at 3 months, the PFS and OS rates at 12 months were 66.7% and 100%, respectively. Severe cytokine release syndrome (sCRS) (grade 3 and higher) occurred in nine patients (28.1%). Grade 3 or higher neurologic events occurred in four patients (12.5%). One patient died from irreversible severe CRS-associated acute kidney injury. Long-term CAR T cells persistence correlated with clinical efficacy (133 days vs 22 days, P = 0.004). Patients treated with more than three prior therapies and presenting extranodal organ involvement had lower maximal concentration (Cmax) values than other patients. Responders had higher Cmax and area under the curve values than non-responders. Tumour burden and Cmax were potentially associated with the severity of CRS.ConclusionsThis study demonstrates the safety and potential clinical efficacy of bispecific CD19/22 CAR T cells in patients with R/R B-NHL and highlights the importance of measuring kinetic parameters in PB to predict efficacy and safety in clinical applications of CAR T cell therapy.Clinical Trial Registration https://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

A Distributed System Improves Inter-Observer and AI Concordance in Annotating Interstitial Fibrosis and Tubular Atrophy.

Histologic examination of interstitial fibrosis and tubular atrophy (IFTA) is critical to determine the extent of irreversible kidney injury in renal disease. The current clinical standard involves pathologist's visual assessment of IFTA, which is prone to inter-observer variability. To address this diagnostic variability, we designed two case studies (CSs), including seven pathologists, using HistomicsTK- a distributed system developed by Kitware Inc. (Clifton Park, NY). Twenty-five whole slide images (WSIs) were classified into a training set of 21 and a validation set of four. The training set was composed of seven unique subsets, each provided to an individual pathologist along with four common WSIs from the validation set. In CS 1, all pathologists individually annotated IFTA in their respective slides. These annotations were then used to train a deep learning algorithm to computationally segment IFTA. In CS 2, manual and computational annotations from CS 1 were first reviewed by the annotators to improve concordance of IFTA annotation. Both the manual and computational annotation processes were then repeated as in CS1. The inter-observer concordance in the validation set was measured by Krippendorff's alpha (KA). The KA for the seven pathologists in CS1 was 0.62 with CI [0.57, 0.67], and after reviewing each other's annotations in CS2, 0.66 with CI [0.60, 0.72]. The respective CS1 and CS2 KA were 0.58 with CI [0.52, 0.64] and 0.63 with CI [0.56, 0.69] when including the deep learner as an eighth annotator. These results suggest that our designed annotation framework refines agreement of spatial annotation of IFTA and demonstrates a human-AI approach to significantly improve the development of computational models.

Multicenter Clinicopathologic Correlation of Kidney Biopsies Performed in COVID-19 Patients Presenting With Acute Kidney Injury or Proteinuria

Rationale & ObjectiveKidney biopsy data inform us about pathologic processes associated with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We conducted a multicenter evaluation of kidney biopsy findings in living patients to identify various kidney disease pathology findings in patients with coronavirus disease 2019 (COVID-19) and their association with SARS-CoV-2 infection.Study DesignCase series.Setting & ParticipantsWe identified 14 native and 3 transplant kidney biopsies performed for cause in patients with documented recent or concurrent SARS-CoV-2 infection treated at 7 large hospital systems in the United States.ObservationsMen and women were equally represented in this case series, with a higher proportion of Black (n = 8) and Hispanic (n = 5) patients. All 17 patients had SARS-CoV-2 infection confirmed by reverse transcriptase–polymerase chain reaction, but only 3 presented with severe COVID-19 symptoms. Acute kidney injury (n = 15) and proteinuria (n = 11) were the most common indications for biopsy and these symptoms developed concurrently or within 1 week of COVID-19 symptoms in all patients. Acute tubular injury (n = 14), collapsing glomerulopathy (n = 7), and endothelial injury/thrombotic microangiopathy (n = 6) were the most common histologic findings. 2 of the 3 transplant recipients developed active antibody-mediated rejection weeks after COVID-19. 8 patients required dialysis, but others improved with conservative management.LimitationsSmall study size and short clinical follow-up.ConclusionsCases of even symptomatically mild COVID-19 were accompanied by acute kidney injury and/or heavy proteinuria that prompted a diagnostic kidney biopsy. Although acute tubular injury was seen among most of them, uncommon pathology such as collapsing glomerulopathy and acute endothelial injury were detected, and most of these patients progressed to irreversible kidney injury and dialysis.

SAT-433 RENAL CORTICAL NECROSIS IN NON-HEMORRHAGIC DENGUE FEVER- A RARE CASE REPORT

Dengue fever is a tropical febrile illness caused by one of the 4 genotypes of dengue virus. Acute Kidney Injury (AKI) is a rare complication of Dengue Fever and is usually associated with severe forms of the disease as in Dengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS). We present a patient diagnosed as a case of Dengue fever without Shock or any Hemorrhagic manifestation, developing Acute Cortical Necrosis and requiring maintenance Haemodialysis. Patient was admitted with Acute febrile illness, diagnosis of Dengue Fever was confirmed by positive IgM for Dengue. He underwent extensive diagnostic workup to rule out other causes of Acute Kidney Injury. 30 year old married, male, patient was admitted complaints of Abdominal pain and fever since 3 days with history of decreased urine output since one day. There was no history of any Malena or hematemesis or any chronic illness like Hypertension or Diabetes. Blood pressure was within normal limit. His blood investigations revealed Hb 12.7g/dl, Total Leucocyte count-10860/cumm, Platelet counts-3,65000/cumm, Hematocrit-37.3%, Reticulocyte count-1%, ESR-02, APTT-26, INR was 1.20, Peripheral Smear showed Normocytic Normochromic RBCS with no schistocytes. SGPT-92, SGOT-94, Total bilirubin-0.8, Total Serum Proteins-6.2g/dl, Serum Albumin-3.5g/dl, Serum Globulin-2.7g/dl, Lipase-65, Amylase-73, LDH-1297, TSH-1.67, RBS-102, Blood urea-111mg/dl, Serum Creatinine-6.27mg/dl, Na-138, K-4.3, Bicarbonate-18.1mmol/L, Creatinine Phosphokinase-193, C3 level was normal, Calcium-8.4mg/dl, iPTH-75 pg/ml, Dengue Serology showed positive IgM for Dengue, Malaria antigen was negative. His Direct coombs test, Antinuclear Antibody, ANCA c & p, Lupus anticoagulant, Antiphospholipid antibody, Anticardiolipin antibodies, Protein C and S deficiency were negative.G6PD quantitative was within normal limits and Sickling test was negative. His heavy metal screening was also negative. Urine RM showed Protein 3+, WBCs-03, RBCs-02(isomorphic type). Patient was initially managed with Intravenous fluids and later Haemodialysis was started in view of severe acidosis and fluid overload. He underwent extensive radiological evaluation with Ultrasonography of Abdomen showing normal liver echoes with bilateral normal sized kidney and intact corticomedullary differentiation with decreased cortical blood flow on power doppler, CT Contrast study of Abdomen confirmed poor renal cortical blood flow. Renal Biopsy was done which showed Cortical Necrosis with near complete thrombotic occlusion in medium sized vessels. In view of persistent Anuria, the patient was put on maintenance Haemodialysis. Irreversible Kidney Injury is an extremely rare complication of Dengue fever as most of the patients of AKI recover with supportive treatment. In our case a young patient with a short clinical history of Dengue Fever presented with AKI. Renal Biopsy showed Renal Cortical Necrosis with medium sized vessels showing near complete occlusion of vascular lamina by thrombi suggesting Thrombotic Microangiopathy. Hence, delay in recovery of AKI in Dengue patients presenting without Hemorrhage or shock should prompt the clinician to evaluate further regarding the underlying pathological mechanisms of Acute Kidney Injury.

Improving the outcomes for pregnancies in the context of kidney disease

Renal disease in pregnancy is a rare pathology, but it raises several problems in terms of normal pregnancy evolution. Among pregnant women with renal injury, the rate of complications such as spontaneous abortion, preeclampsia, hypertension, intrauterine growth restriction, premature birth, fetal and neonatal mortality are much higher. For a good understanding of the pathology and a correct management of pregnant women with renal disease, it is necessary to know the normal pregnancy changes and the differentiation of chronic kidney disease from the acute injuries occurring during pregnancy. It is useful to ensure counseling prior to conception and to perform all prophylactic measures in order to prevent pregnancy complications and subsequent decline in renal function in all cases of pregnant women with chronic renal insufficiency. Treatment of acute renal failure in pregnancy involves therapy of the underlying condition that caused renal injury, prevention of irreversible kidney injury and pre-vention of maternal and fetal secondary complications. Monitoring carefully this cate-gory of pregnant women, although additional risks strike, often results in favorabl pregnancy evolution.

Varicella-zoster virus-induced rhabdomyolysis: A case report and literature review

Infection is a possible cause of rhabdomyolysis. We describe the case of a 63-year-old male with malaise and erythematous papules on the right C5–C7 dermatomes, consistent with herpes zoster. Serum antibody and Tzanck tests of the skin lesion were positive. Increased serum creatine kinase (CK) and myoglobin levels and cola-colored urine indicated the development of rhabdomyolysis. Acute kidney injury was also observed. After excluding other possible predisposing factors, the patient was diagnosed with varicella-zoster virus (VZV)-induced rhabdomyolysis. Extracellular volume with alkalized fluids and topical acyclovir was administered. While CK levels declined to normal by day 13, the renal function was not restored. The skin lesion crusted by day 8 and scaled off gradually by day 13. Our case and literature review highlighted the necessity for systemic antiviral treatment and that poor VZV infection control could lead to irreversible kidney injury. In addition, systemic acyclovir should be administered carefully due to its complication of nephrotoxicity.

Retained Foreign Body in Urinary Bladder Presenting as Acute Renal Failure

Retained foreign bodies in urinary bladder can lead to stone formation. Urease splitting bacteria play a role in providing alkaline environment that lead to deposition of magnesium and calcium deposits. We described a severe presentation of a case which lead to permanent irreversible kidney injury ending up on permanent dialysis.

External Validation of a Pretransplant Biomarker Model (REVERSE) Predictive of Renal Recovery After Liver Transplantation.

In patients with end-stage liver disease, the ability to predict recovery of renal function following liver transplantation (LT) remains elusive. However, several important clinical decisions depend on whether renal dysfunction is recoverable after LT. We used a cohort of patients undergoing LT to independently validate a published pre-LT model predictive of post-transplant renal recovery (Renal Recovery Assessment at Liver Transplant [REVERSE]: high osteopontin [OPN] and tissue inhibitor of metalloproteinases-1 [TIMP-1] levels, age<57, no diabetes). Serum samples pre-LT and 4-12 weeks post-LT (n=117) were analyzed for kidney injury proteins from three groups of recipients: (1) estimated glomerular filtration rate (eGFR)<30 mL/minute/1.73 m2 prior to and after LT (irreversible acute kidney injury [AKI]), (2) eGFR<30 mL/minute/1.73 m2 prior to LT and >50 mL/minute/1.73 m2 after LT (reversible AKI [rAKI]) (3) eGFR>50 mL/minute/1.73 m2 prior to and after LT (no AKI). In patients with elevated pre-LT serum levels of OPN and TIMP-1, recovery of renal function correlated with decreases in the level of both proteins. At 4 weeks post-LT (n=77 subset), the largest decline in OPN and TIMP-1 was seen in the rAKI group. Validation of the REVERSE model in this independent data set had high area under the curve (0.78) in predicting full post-LT renal recovery (sensitivity 0.86, specificity 0.6, positive predictive value 0.81, negative predictive value 0.69). Our eGFR findings were confirmed using measured GFR. Conclusion: The REVERSE model, derived from an initial training set combining plasma biomarkers and clinical characteristics, demonstrated excellent external validation performance characteristics in an independent patient cohort using serum samples. Among patients with kidney injury pre-LT, the predictive ability of this model may prove beneficial in clinical decision-making both prior to and following transplantation.

A rare entity of acute renal failure: retained foley

Retained foreign bodies in the urinary bladder are not uncommon. They can present in the form of irritative or obstructive symptoms. In literature, a variety of retained foreign bodies have been described. Methods of introduction can be an iatrogenic, accidental, postoperative complication, or migration from perivesicular vicinity. We described a severe presentation of a case where a retained foley ended up in the formation of large calculous formation. Our patient presented with acute renal failure resulting in irreversible kidney injury. Open cystostomy was done to remove the stone and retained foley and the patient was discharged with permanent dialysis arrangement.

Adverse Events During Hemodialysis in LVAD Recipients

Introduction Over the past decade, implantable left ventricular assist devices (LVAD) have become an acceptable alternative to support patients with advanced heart failure, either as a bridge to transplantation or as destination therapy for patients who are not candidates for heart transplantation. As the number of LVAD implantation increases, greater number of LVAD recipients requiring long term renal replacement therapy (RRT), usually chronic hemodialysis (HD), will be seen. This is due to common simultaneous chronic kidney disease in patients with heart failure, but more frequently due to irreversible acute kidney injury occurring in the peri-implantation period. There though is limited data on HD in LVAD recipients. We sought to assess adverse events that required early termination of HD sessions in HeartWare LVAD recipients while they were hospitalized after LVAD implantation. Methods Between 2015 and 2017 at the University of Maryland Medical Center, 7 patients required HD after LVAD implantation. These 7 patients had a total of 92 HD sessions during their hospitalizations. The average age of the patients was 46 +/- 11.9 years old. Two patients had ESRD and were on HD prior to LVAD implantation. The remaining five patients had CKD but were not on HD. The pre-LVAD creatinine average for all 7 patients was 2.55 +/- 1.8. After LVAD implantation, all of the patients were initially on continuous renal replacement therapy before being transitioned to HD. HD was started anywhere from within 2 to 57 days after LVAD implantation. Results LVAD settings were typically not adjusted during HD sessions. Additionally, during HD all patients were on midodrine, vasopressors, or fludrocortisone to help increase blood pressure. There were seven HD sessions that required early termination due to symptomatic hypotension (3), asymptomatic hypotension (2), sinus tachycardia and cramping and discomfort. The average duration of all HD sessions was 172 minutes and the average duration of HD sessions that were terminated early was 148 minutes. Low flow LVAD alarms did not activate during any of the sessions. Conclusion 7 out of 92 sessions required early termination and the most common reasons (5 out of 7) were related to hypotension. Complications related to blood pressure was also found to be the most common reason for termination of HD in previous study of HD sessions in Heartmate LVAD patients. As a result of continuous-flow technology, in most LVAD recipients, there is an absence of pulse, precluding the standard assessment of blood pressure, making assessment of blood pressure during dialysis difficult. There needs to be more research on how to address this in addition to how to optimize and change LVAD settings during HD sessions.

GYY4137, a Slow-Releasing Hydrogen Sulfide Donor, Ameliorates Renal Damage Associated with Chronic Obstructive Uropathy

Chronic obstructive uropathy can cause irreversible kidney injury, atrophy and inflammation, which can ultimately lead to fibrosis. Epithelial-mesenchymal transition is a key trigger of fibrosis that is caused by up-regulation of TGF-β1 (transforming growth factor-β1) and ANGII (angiotensin II). H2S is an endogenously produced gasotransmitter with cytoprotective properties. We sought to elucidate the effects of the slow-releasing H2S donor GYY4137 on chronic ureteral obstruction and evaluate the potential mechanisms. Following unilateral ureteral obstruction male Lewis rats were given daily intraperitoneal administration of phosphate buffered saline vehicle (obstruction group) or phosphate buffered saline plus 200μmol/kg GYY4137 (obstruction plus GYY4137 group) for 30 days. Urine and serum samples were collected to determine physiological parameters of renal function and injury. Kidneys were removed on postoperative day 30 to evaluate histopathology and protein expression. Epithelial-mesenchymal transition in LLC-PK1 pig kidney epithelial cells was induced with TGF-β1 and treated with GYY4137 to evaluate potential mechanisms via invitro scratch wound assays. H2S treatment decreased serum creatinine and the urine protein-to-creatinine excretion ratio after unilateral ureteral obstruction. In addition, H2S mitigated cortical loss, inflammatory damage and tubulointerstitial fibrosis. Tissues showed decreased expression of epithelial-mesenchymal transition markers upon H2S treatment. Epithelial-mesenchymal transition progression in LLC-PK1 was alleviated upon invitro administration of GYY4137. To our knowledge our findings demonstrate for the first time the protective effects of H2S in chronic obstructive uropathy. This may represent a potential therapeutic solution to ameliorate renal damage and improve the clinical outcomes of urinary obstruction.

Oral anticoagulants and risk of nephropathy.

Anticoagulant-related nephropathy, a recently recognized entity, manifests as unexplained acute kidney injury in the setting of excessive anticoagulation with oral agents. Histologic findings in warfarin-related nephropathy include glomerular hemorrhage and renal tubular obstruction by red blood cells. Affected patients are at increased risk of mortality as well as irreversible kidney injury. Patients with chronic kidney disease are particularly vulnerable to this complication. Similar case reports of anticoagulant-related nephropathy have been linked to the more novel oral anticoagulant, dabigatran. Anticoagulant-related nephropathy has been successfully reproduced in rat models. These animal models shed light on the pathogenesis of the disease including the potential role of direct thrombin and protease-activated receptor-1 inhibition. Warfarin and dabigatran also cause an increase in systolic blood pressure in rats, a risk factor for developing nephropathy. This article reviews the current evidence for anticoagulant-related nephropathy and provides data for the suggested possible mechanisms underlying this adverse effect.

Targeted spontaneous reporting of suspected renal toxicity in patients undergoing highly active anti-retroviral therapy in two public health facilities in Uganda.

BackgroundAlthough the national HIV control programme in Uganda has a well-established system for monitoring disease progression and treatment outcomes, monitoring of adverse drug reactions (ADRs) is inadequate. In order to address under-reporting of ADRs, the National Pharmacovigilance Centre, in collaboration with the HIV control programme, piloted a targeted spontaneous reporting (TSR) system as a complementary method to traditional spontaneous reporting.MethodsFrom April 2012 to March 2014, all cases of suspected renal toxicity in 10,225 patients on tenofovir-based regimens were monitored in the regional pharmacovigilance centres of Masaka and Mbale. The identification of renal toxicity was performed using serum creatinine, urinalysis, and other signs and symptoms of kidney injury.ResultsThere was one suspected renal toxicity reported for every 200 patients on a tenofovir-based regimen. Some of the serious reactions reported were death in two cases and bone demineralisation in five patients. Most of patients had been on treatment for 2 years. Those that had been on tenofovir for more than 4 years had raised serum creatinine levels, emphasising the importance of monitoring for the risk of renal damage for longer. We also found that the reporting rate of suspected ADRs for all medicines in the two sites increased almost fivefold during the implementation period.ConclusionAlthough the occurrence of suspected tenofovir renal toxicity of HIV patients is low, there is need to monitor those at risk so as to prevent irreversible kidney injury. TSR can complement spontaneous reporting for collecting safety data on particular drugs and increase ADR reporting rates.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-015-0277-9) contains supplementary material, which is available to authorized users.

Hepatology Highlights

Hepatology Highlights

Predictive usefulness of urinary biomarkers for the identification of cyclosporine A-induced nephrotoxicity in a rat model.

The main side effect of cyclosporine A (CsA), a widely used immunosuppressive drug, is nephrotoxicity. Early detection of CsA-induced acute nephrotoxicity is essential for stop or minimize kidney injury, and timely detection of chronic nephrotoxicity is critical for halting the drug and preventing irreversible kidney injury. This study aimed to identify urinary biomarkers for the detection of CsA-induced nephrotoxicity. We allocated salt-depleted rats to receive CsA or vehicle for 7, 14 or 21 days and evaluated renal function and hemodynamics, microalbuminuria, renal macrophage infiltration, tubulointerstitial fibrosis and renal tissue and urinary biomarkers for kidney injury. Kidney injury molecule-1 (KIM-1), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), fibronectin, neutrophil gelatinase-associated lipocalin (NGAL), TGF-β, osteopontin, and podocin were assessed in urine. TNF-α, IL-6, fibronectin, osteopontin, TGF-β, collagen IV, alpha smooth muscle actin (α -SMA) and vimentin were assessed in renal tissue. CsA caused early functional renal dysfunction and microalbuminuria, followed by macrophage infiltration and late tubulointerstitial fibrosis. Urinary TNF-α, KIM-1 and fibronectin increased in the early phase, and urinary TGF-β and osteopontin increased in the late phase of CsA nephrotoxicity. Urinary biomarkers correlated consistently with renal tissue cytokine expression. In conclusion, early increases in urinary KIM-1, TNF-α, and fibronectin and elevated microalbuminuria indicate acute CsA nephrotoxicity. Late increases in urinary osteopontin and TGF-β indicate chronic CsA nephrotoxicity. These urinary kidney injury biomarkers correlated well with the renal tissue expression of injury markers and with the temporal development of CsA nephrotoxicity.