Association Between Causative Pathogen and Occurrence of Infection-Related Glomerulonephritis in Infective Endocarditis.

Among patients with pathologically proven infective endocarditis, the association of pathogen with occurrence of infection-related glomerulonephritis (IRGN) was examined in 48 case patients with IRGN and 192 propensity score-matched controls. Bartonella was very strongly associated with IRGN (odds ratio, 38.2 [95% confidence interval, 6.7-718.8]; P < .001); other microorganisms were not.

Podocyte density is reduced in kidney allografts with high-risk APOL1 genotypes at transplantation.

Variants in apolipoprotein L1 (APOL1) gene are associated with nondiabetic kidney diseases in black subjects and reduced kidney transplant graft survival. Living and deceased black kidney donors (n = 107) were genotyped for APOL1 variants. To determine whether allografts from high-risk APOL1 donors have reduced podocyte densities contributing to allograft failure, we morphometrically estimated podocyte number, glomerular volume, and podocyte density. We compared allograft loss and eGFR trajectories stratified by APOL1 high-risk and low-risk genotypes. Demographic characteristics were similar in high-risk (n = 16) and low-risk (n = 91) donors. Podocyte density was significantly lower in high-risk than low-risk donors (108 ± 26 vs 127 ± 40 podocytes/106 um3 , P = .03). Kaplan-Meier graft survival (high-risk 61% vs. low-risk 91%, p-value = 0.049) and multivariable Cox models (hazard ratio = 2.6; 95% CI, 0.9-7.8) revealed higher graft loss in recipients of APOL1 high-risk allografts over 48 months. More rapid eGFR decline was seen in recipients of high-risk APOL1 allografts (P < .001). At 60 months, eGFR was 27 vs. 51 mL/min/1.73 min2 in recipients of APOL1 high-risk vs low-risk kidney allografts, respectively. Kidneys from high-risk APOL1 donors had worse outcomes versus low-risk APOL1 genotypes. Lower podocyte density in kidneys from high-risk APOL1 donors may increase susceptibility to CKD from subsequent stresses in both the recipients and donors.

IgA Vasculitis in Adults: a Rare yet Challenging Disease.

PURPOSE OF REVIEW: IgA vasculitis (IgAV) is a rare and poorly understood systemic vasculitis in adults. Its diagnosis and treatment remain a challenge. Herein, we review the clinical manifestations, diagnosis, management, and prognosis of IgAV in adults. RECENT FINDINGS: The clinical course of IgAV in adults appears to be different from pediatric IgAV, especially due to its higher risk of evolving into end-stage renal disease. Rising awareness and interest in adult-onset IgA vasculitis has resulted in recent increasing number of publications on different treatment experiences. However, there is still controversy over the role of glucocorticoid (GC) and different immunosuppressive therapies such as cyclophosphamide, rituximab, and mychophenolate mofetil for more severe IgAV. Data regarding potential benefits of targeting the mucosal immune system, toll-like receptors, complements, and tyrosine kinase inhibitors in the treatment of IgA nephropathy are emerging. High quality evidence or guidelines in the treatment of severe IgAV are lacking and there is still a great need for controlled trials.

C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.

C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease.

Deficiency of fibroblast growth factor-inducible 14 (Fn14) preserves the filtration barrier and ameliorates lupus nephritis.

TNF ligand superfamily member 12, also known as TNF-related weak inducer of apoptosis (TWEAK), acts through its receptor, fibroblast growth factor-inducible 14 (Fn14), to mediate several key pathologic processes involved in tissue injury relating to lupus nephritis. To explore the potential for renal protection in lupus nephritis by targeting this pathway, we introduced the Fn14 null allele into the MRL-lpr/lpr lupus mouse strain. At 26-38 weeks of age, female Fn14-knockout MRL-lpr/lpr mice had significantly lower levels of proteinuria compared with female wild-type MRL-lpr/lpr mice. Furthermore, Fn14-knockout mice had significantly improved renal histopathology accompanied by attenuated glomerular and tubulointerstitial inflammation. There was a significant reduction in glomerular Ig deposition in Fn14-knockout mice, despite no detectable differences in either serum levels of antibodies or splenic immune cell subsets. Notably, we found that the Fn14-knockout mice displayed substantial preservation of podocytes in glomeruli and that TWEAK signaling directly damaged barrier function and increased filtration through podocyte and glomerular endothelial cell monolayers. Our results show that deficiency of the Fn14 receptor significantly improves renal disease in a spontaneous lupus nephritis model through prevention of the direct injurious effects of TWEAK on the filtration barrier and/or modulation of cytokine production by resident kidney cells. Thus, blocking the TWEAK/Fn14 axis may be a novel therapeutic intervention in immune-mediated proliferative GN.

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice.

BACKGROUND: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain. Neuropsychiatric disease affects about 40 % of SLE patients, most frequently manifesting as depression, memory deficits, and general cognitive decline. One important and yet unresolved question is whether neuropsychiatric SLE (NPSLE) is a complication of systemic autoimmunity or whether it is primarily driven by brain-intrinsic factors. METHODS: To dissect the relative contributions of the central nervous system from those of the hematopoietic compartment, we generated bone marrow chimeras between healthy control (MRL/+) and lupus-prone MRL/Tnfrsf6 (lpr/lpr) mice (MRL/+ → MRL/lpr), as well as control chimeras. After bone marrow reconstitution, mice underwent extensive behavioral testing, analysis of brain tissue, and histological assessment. RESULTS: Despite transfer of healthy MRL/+ bone marrow and marked attenuation of systemic disease, we found that MRL/+ → MRL/lpr mice had a behavioral phenotype consisting of depressive-like behavior and visuospatial memory deficits, comparable to MRL/lpr → MRL/lpr control transplanted mice and the behavioral profile previously established in MRL/lpr mice. Moreover, MRL/+ → MRL/lpr chimeric mice displayed increased brain RANTES expression, neurodegeneration, and cellular infiltration in the choroid plexus, as well as blood brain barrier disruption, all in the absence of significant systemic autoimmunity. CONCLUSIONS: Chimeric MRL/+ → MRL/lpr mice displayed no attenuation of the behavioral phenotype found in MRL/lpr mice, despite normalized serum autoantibodies and conserved renal function. Therefore, neuropsychiatric disease in the MRL/lpr lupus-prone strain of mice can occur absent any major contributions from systemic autoimmunity.

Macrophage depletion ameliorates nephritis induced by pathogenic antibodies.

Kidney involvement affects 40-60% of patients with lupus, and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, "off target" effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, and BUN seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with lupus nephritis. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis.

Toward a working definition of C3 glomerulopathy by immunofluorescence.

Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1-3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of 'C3 only' captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, 'C3 only' is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation.

Rituximab treatment for fibrillary glomerulonephritis.

BACKGROUND: Approximately 50% of patients with fibrillary glomerulonephritis (GN) progress to end-stage renal disease (ESRD) within 2 years of diagnosis, and no standard therapy exists. The data on rituximab therapy for fibrillary GN are limited and have inconsistent outcomes. Here, we report the largest case series to date using rituximab for fibrillary GN. METHODS: Retrospective chart reviews were conducted on 12 patients with fibrillary GN who were treated with rituximab (1 g i.v. × 2 doses or 375 mg/m(2) × 4 doses) at the Center for Glomerular Diseases at Columbia University Medical Center. Non-progression of disease was defined as stable/improved serum creatinine (SCr) with a minimum of 1 year of follow-up. RESULTS: The median SCr was 2.1 (range 0.7-2.7) mg/dL, median estimated glomerular filtration rate (eGFR) 39 (range 21-98) mL/min/1.73 m(2) and median proteinuria 4497 (range 210-7542) mg/day at the time of rituximab initiation. Four patients had received immunosuppression before rituximab, and nine received immunosuppression after rituximab, with four receiving a second rituximab course. Four of 12 patients were non-progressors, 3 of 12 had progressive renal dysfunction without reaching ESRD, and 5 patients reached ESRD. The median follow-up for patients who did not reach ESRD was 38 (range 14-76) months after rituximab treatment. Non-progressors had lower SCr values, higher eGFRs and shorter median duration from diagnosis to treatment than progressors. No serious adverse events were noted. CONCLUSIONS: Rituximab therapy was associated with non-progression of renal disease in 4 of 12 patients. At the time of treatment, these non-progressors had better renal function and shorter time from diagnosis to treatment than progressors.

Renal cortical infarction following treatment with sumatriptan in a kidney allograft recipient.

Renal cortical infarction is a rare cause of acute kidney injury that results from inadequate blood flow to the kidney, most commonly as a consequence of thrombotic or embolic occlusion of the renal artery or profound hypoperfusion. We report the case of a 78-year-old female kidney transplant recipient who developed a migraine headache, took sumatriptan, and soon after developed pain over the allograft and oligoanuric acute kidney injury. Kidney allograft biopsy showed renal cortical infarction. The mechanism of action of sumatriptan involves vasoconstriction, which counters the vasodilatation that is central to the pathogenesis of migraines. This case raises important questions regarding the safety of triptans with calcineurin inhibitors (which also act to vasoconstrict), particularly in elderly patients.

BK polyoma virus nephropathy in the native kidney.

BACKGROUND: While BK polyoma virus nephropathy (PVN) is a well-recognized cause of renal allograft dysfunction, PVN of native kidneys is likely under-recognized. METHODS: We present the pathologic features, risk factors and outcomes of eight cases of PVN in native kidneys. RESULTS: The cohort included eight males aged 16-73 years (mean 47.4) with an immunocompromised state (mean duration 3.15 years) attributable to: hematologic malignancies (n = 6), for which three had undergone bone marrow transplant; lung transplant (n = 1) and combined tuberculosis and diabetes (n = 1). Seven patients were receiving specific immunosuppressive therapies. Patients were biopsied for acute kidney injury (AKI) with rise in mean creatinine levels from baseline 1.6 to 2.8 mg/dL. Pathology showed BK PVN with characteristic intranuclear inclusions staining positive for SV40 T antigen and negative for JC virus (JCV), with positive serum and/or urine PCR for BK virus. One patient had focal medullary JCV co-infection. Two patients also had renal infiltration by chronic lymphocytic leukemia (CLL). Six patients received specific therapy directed to PVN (cidofovir or leflunomide). Follow-up ranged from 2 to 20 (mean 10) months. Despite marked decrease in serum BK viral copy numbers, creatinine continued to rise in six cases (mean 3.7 mg/dL in four, requiring dialysis in two) and three patients died of malignancy, opportunistic infection or renal failure. Advanced histologic stage of PVN, ineffective antiviral therapy, co-morbidities and persistent immunocompromised state likely contributed to the poor outcomes. CONCLUSION: A high level of suspicion in immunocompromised patients is needed to diagnose PVN in an early stage that may respond more favorably to antiviral therapy.

The changing pattern of glomerular disease in HIV and hepatitis C co-infected patients in the era of HAART.

Previous reports have suggested a poor renal prognosis in patients with HIV and HCV co-infection with a preponderance of immune complex mediated glomerular disease on biopsy. Although the benefits of HAART on HIVAN are known, its impact on co-infected patients is unclear. We describe the renal biopsy findings and renal outcome in 29 co-infected patients in the HAART era and compare them to findings in 14 historical controls reported from our institution in the pre-HAART era. Our present cohort was predominantly male and Black with the majority reporting a history of intravenous (i.v.) drug use. Renal biopsy findings included 16 patients with immune complex mediated glomerular disease and 14 patients with FSGS, of which only 3 had collapsing features and/or tubular microcysts typical of HIVAN. Five patients had other biopsy diagnoses not directly related to viral infection. Median renal survival in our cohort was 15.6 months - significantly better than the 1.7 months seen our pre-HAART cohort. The modern cohort's improved renal outcome occurred despite older patients, longer HIV infection and similar levels of renal insufficiency. Our data indicate a changing epidemiology and natural history of renal disease in the HAART era with less immune complex mediated glomerular disease and more non-collapsing FSGS of the usual type. The marked improvement is likely to be multifactorial, including use of antiretroviral and anti-HCV therapies, RAAS antagonists, earlier nephrology referral and generally improved medical care.

Pathology after eculizumab in dense deposit disease and C3 GN.

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.

ANCA-associated glomerulonephritis in the very elderly.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune glomerulonephritis (GN) is the most common finding in very elderly patients biopsied for acute kidney injury. Appropriate treatment strategies in this age group are currently undefined since it is unclear whether the benefits of immunosuppression exceed the risks. We retrospectively evaluated a cohort of 78 cases of biopsy-proven pauci-immune GN in individuals aged >80 years of whom 72% were p-ANCA and 20% were c-ANCA positive. The patients treated with immunosuppression had a significantly lower incidence of end-stage renal disease (ESRD) 1 year after biopsy (36%) compared with untreated patients (73%; P=0.03). Only peak serum creatinine before biopsy and the use of immunosuppression influenced progression to ESRD. There was no significant difference in the 1-year mortality rates between these groups (46 vs 64%; P=0.3). However, when follow-up was extended beyond 2 years, immunosuppression was associated with a lower risk of death (HR 0.33, 95% CI 0.11-0.97) and death or ESRD (HR 0.16, 95% CI 0.06-0.42) in multivariable models.

Acute kidney injury in the setting of AIDS, bland urine sediment, minimal proteinuria and normal-sized kidneys: a presentation of renal lymphoma.

Acute kidney injury in HIV patients is primarily related to HIV-mediated viral or immunological disease or to treatment-related toxicity (tenofovir). Neoplasms are a rare cause of non-obstructive acute kidney injury, primarily because when they occur, they manifest as discrete masses and not as diffuse infiltration of the renal parenchyma. Diffusely infiltrating tumors include carcinoma of the renal pelvis invading the renal parenchyma, renal lymphoma, squamous cell carcinoma (from lung) metastasizing to the kidney and infiltrating sarcomatous type of renal cell carcinoma. To be classified as a true case of renal lymphoma, the tumor should have escaped detection on routine imaging preceding biopsy, and lymphoma-associated renal failure/nephrotic proteinuria should have given rise to the indication for kidney biopsy. We present here a case of an acute kidney injury due to renal lymphoma in a patient with acquired immune deficiency syndrome that manifested clinically as bland urine sediment, minimal proteinuria and normal-sized kidneys. Chemotherapy resulted in complete reversal of acute kidney injury.

Development of focal segmental glomerulosclerosis after anabolic steroid abuse.

Anabolic steroid abuse adversely affects the endocrine system, blood lipids, and the liver, but renal injury has not been described. We identified an association of focal segmental glomerulosclerosis (FSGS) and proteinuria in a cohort of 10 bodybuilders (six white and four Hispanic; mean body mass index 34.7) after long-term abuse of anabolic steroids. The clinical presentation included proteinuria (mean 10.1 g/d; range 1.3 to 26.3 g/d) and renal insufficiency (mean serum creatinine 3.0 mg/dl; range 1.3 to 7.8 mg/dl); three (30%) patients presented with nephrotic syndrome. Renal biopsy revealed FSGS in nine patients, four of whom also had glomerulomegaly, and glomerulomegaly alone in one patient. Three biopsies revealed collapsing lesions of FSGS, four had perihilar lesions, and seven showed > or =40% tubular atrophy and interstitial fibrosis. Among eight patients with mean follow-up of 2.2 yr, one progressed to ESRD, the other seven received renin-angiotensin system blockade, and one also received corticosteroids. All seven patients discontinued anabolic steroids, leading to weight loss, stabilization or improvement in serum creatinine, and a reduction in proteinuria. One patient resumed anabolic steroid abuse and suffered relapse of proteinuria and renal insufficiency. We hypothesize that secondary FSGS results from a combination of postadaptive glomerular changes driven by increased lean body mass and potential direct nephrotoxic effects of anabolic steroids. Because of the expected rise in serum creatinine as a result of increased muscle mass in bodybuilders, this complication is likely underrecognized.

The Crystalline Nephropathies.

Crystalline nephropathies are a unique form of kidney disease characterized by the histologic finding of intrarenal crystal deposition. The intrinsic nature of some molecules and ions combined with a favorable tubular fluid physiology leads to crystal precipitation and deposition within the tubular lumens. Crystal deposition promotes kidney injury through tubular obstruction and both direct and indirect cytotoxicities. Further kidney injury develops from inflammation triggered by these crystals. From a clinical standpoint, the crystalline nephropathies are associated with abnormal urinalysis and urinary sediment findings, tubulopathies, acute kidney injury (AKI), and/or chronic kidney disease (CKD). Urine sediment examination is often helpful in alerting clinicians to the possibility of crystal-related kidney injury. The identification of crystals within the kidneys on biopsy by pathologists prompts clinicians to evaluate patients for medication-related kidney injury, dysproteinemia-related malignancies, and certain inherited disorders. This review will focus on the clinical and pathologic aspects of these 3 categories of crystalline nephropathies.

Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury.

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. SIGNIFICANCE: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/3/713/F1.large.jpg.

Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities.

Tenofovir, a widely prescribed antiretroviral medication for treatment of HIV-1 infection, is infrequently associated with renal dysfunction and biopsy findings of acute tubular necrosis. We examined the clinical and pathological findings in 13 cases of tenofovir nephrotoxicity (7 men and 6 women, mean age of 51.1±9.6 years). Patients received tenofovir therapy for a mean of 19.6 months (range, 3 weeks to 8 years; median 8 months). Nine patients presented with acute kidney injury, and four had mild renal insufficiency with subnephrotic proteinuria. Mean baseline serum creatinine was 1.3±0.3 mg/dl, reaching 5.7±4.0 mg/dl at the time of biopsy, with mean proteinuria of 1.6±0.3 g/day. Glycosuria was documented in seven patients, five of whom were normoglycemic. Renal biopsy revealed toxic acute tubular necrosis, with distinctive proximal tubular eosinophilic inclusions representing giant mitochondria visible by light microscopy. Electron microscopy showed mitochondrial enlargement, depletion, and dysmorphic changes. Clinical follow-up after tenofovir discontinuation was available for 11 of 13 patients (mean duration 13.6 months). Significant recovery of renal function occurred in all patients, including four who required transient hemodialysis. Our study shows that tenofovir nephrotoxicity is a largely reversible form of toxic acute tubular necrosis targeting proximal tubules and manifesting distinctive light microscopic and ultrastructural features of mitochondrial injury.