Immunological mechanisms underlying clinical phenotypes and noninvasive diagnosis of immune checkpoint inhibitor-induced kidney disease.

Immune checkpoint inhibitors (ICIs) have become a mainstay of cancer therapy, with over 80 FDA-approved indications. Used in a variety of settings and in combination with each other and with traditional chemotherapies, the hyperactive immune response induced by ICIs can often lead to immune-related adverse events in bystander normal tissues such as the kidneys, lungs, and the heart. In the kidneys, this immune-related adverse event manifests as acute interstitial nephritis (ICI-AIN). In the era of widespread ICI use, it becomes vital to understand the clinical manifestations of ICI-AIN and the importance of prompt diagnosis and management of these complications. In this review, we delve into the clinical phenotypes of ICI-AIN and how they differ from traditional drug-induced AIN. We also detail what is known about the mechanistic underpinnings of ICI-AIN and the important diagnostic and therapeutic implications behind harnessing those mechanisms to further our understanding of these events and to formulate effective treatment plans to manage ICI-AIN.

Immune checkpoint inhibitor-associated nephritis-treatment standard.

Over the last 13 years, the use of immune checkpoint inhibitor (ICI) therapy has grown remarkably, owing to their unprecedented anti-tumor efficacy in certain tumor groups. With increased use of ICIs, we are seeing immune-related adverse events (irAEs) more frequently. Renal irAEs, such as ICI-associated acute kidney injury (ICI-AKI), are reported in 2%-5% of patients treated with ICIs, with acute tubulointerstitial nephritis (ATIN) as the most common histopathologic lesion, though various forms of glomerulonephritis have also been reported. Modifiable risk factors for ICI-AKI include concurrent use of ATIN-associated drugs, like proton pump inhibitors, non-steroidal anti-inflammatory drugs and antibiotics, and dual ICI therapy with both Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) and Programmed Cell Death Protein 1 and its ligand (PD1/PDL-1) blockade. Kidney biopsies remain the diagnostic modality of choice, though several promising non-invasive biomarkers, which have not yet been broadly clinically validated have emerged. The treatment of ICI-AKI involves holding ICIs, discontinuation of ATIN-associated drugs and initiation of immunosuppression with corticosteroids as first-line therapy. With prompt treatment initiation, most patients achieve full or partial renal recovery, allowing for re-challenge with ICI. However, a subset of patients will require additional steroid-sparing therapies for corticosteroid-dependent or refractory ICI-AKI. Here we review developments in our understanding of the pathophysiology of ICI-AKI, the approach to diagnosis (with a focus on the emergence of novel diagnostic tools), prognostic factors and the current evidence for establishing treatment standards for ICI-AKI. As the evidence base remains largely retrospective, we identify questions that would benefit from future prospective studies in the diagnosis, management and prognostication of ICI-AKI.

[Acute interstitial nephritis: clinical presentation and diagnosis]. / Néphrite interstitielle aiguë : quand la suspecter et quelle prise en charge ?

Acute interstitial nephritis is characterized by renal inflammation and interstitial edema. The clinical presentation is pauci-symptomatic and often non-specific. Acute interstitial nephritis typically presents with acute renal failure, alone or with fever, eosinophilia, hematuria, sterile pyuria and small range proteinuria. An early diagnosis is crucial to prevent the morbidity and mortality associated with renal function decline. The most frequent etiology of this disease is drug-induced. A kidney biopsy is not systematically required to establish the diagnosis. It should be considered in the absence of renal function improvement 5 to 7 days after withdrawal of the causal agent. Although the benefits of glucocorticoid treatment have not been proven to date, its use may be associated with a better kidney function recovery.

La néphrite interstitielle aiguë est caractérisée par une inflammation dans le compartiment interstitiel rénal. La présentation clinique est paucisymptomatique. Elle se présente généralement par une insuffisance rénale aiguë qui peut être accompagnée de fièvre, d'éosinophilie, d'hématurie, de leucocyturie stérile et de protéinurie non néphrotique. Son diagnostic précoce est crucial pour prévenir la morbi-mortalité liée au déclin de la fonction rénale. L'étiologie la plus fréquente est médicamenteuse. Le diagnostic par la ponction-biopsie rénale n'est pas systématique, mais doit être considéré en l'absence d'amélioration de la fonction rénale 5 à 7 jours après l'arrêt de la substance incriminée. Le principal traitement consiste en l'interruption du médicament incriminé et à l'administration de corticostéroïdes.

Acute interstitial nephritis and nephrogenic diabetes insipidus following treatment with sulfamethoxazole-trimethoprim and temozolomide.

We report a case of acute interstitial nephritis with associated nephrogenic diabetes insipidus in a patient treated with temozolomide and sulfamethoxazole-trimethoprim for glioblastoma multiforme. Kidney biopsy demonstrated focal tubulointerstitial change with tubular dilatation, epithelial change and interstitial inflammation. The patient's kidney function improved with cessation of sulfamethoxazole-trimethoprim and treatment with hydrochlorothiazide for nephrogenic diabetes insipidus. Recommencement of temozolomide did not result in further deterioration in kidney function. In this case report, we discuss the novel association between sulfamethoxazole-trimethoprim-induced acute interstitial nephritis and nephrogenic diabetes insipidus, and suggest possible mechanisms involved.

Prognosis of severe drug-induced acute interstitial nephritis requiring renal replacement therapy.

OBJECTIVE: Drug-induced acute interstitial nephritis (DAIN) is often associated with improved outcomes, whereas some patients may still progress to chronic kidney disease (CKD). The aim of this study was to evaluate the prognosis of patients with severe DAIN requiring renal replacement therapy (RRT) at baseline, and to explore the risk factors of progression to CKD. METHODS: We performed a retrospective study of patients with severe DAIN confirmed by renal biopsies in our center over a 10 years period, all the patients received RRT at presentation. The clinical and pathological characteristics at baseline were recorded, and the outcomes (renal function recovered or progressed to CKD) during follow-ups were also evaluated. Univariate and multivariate logistic regression analysis were performed to identify the independent risk factors of progression to CKD. RESULTS: Seventy-two patients who met the inclusion criteria were enrolled, 13 patients (18.0%) progressed to CKD (GFR < 60 ml/min/1.73 m2) after at least 6 months of follow-up, the remaining 59 patients achieved a favorable renal function recovery. Compared with patients who achieved renal function recovery (recovery group), the patients progressed to CKD (progression group) were older and had longer interval from symptom onset to treatment with steroids. The peak serum cystatin C concentration was higher in progression group than recovery group. Higher score of interstitial fibrosis/tubular atrophy (IFTA) and more interstitial inflammatory cells infiltration were detected in renal tissue in progression group. According to multivariable analysis, higher peak cystatin C concentration (OR = 2.443, 95% CI 1.257, 4.746, p = 0.008), longer interval to treatment with corticosteroids (OR = 1.183, 95% CI 1.035, 1.352, p = 0.014) were independent risk factors of progression to CKD. The cutoff value of cystatin C concentration was 4.34 mg/L, at which the sensitivity and specificity were 76.9% and 89.3%, respectively; the cutoff value of interval to treatment with corticosteroids was 22.5 days, at which the sensitivity and specificity were 81.8% and 79.5%, respectively. CONCLUSION: Renal function was reversible in majority of patients with severe DAIN requiring RRT when early identification and treatment. Higher peak cystatin C concentration and longer interval to treatment with corticosteroids associated with worse renal prognosis.

Acute Tubulointerstitial Nephritis in Clinical Oncology: A Comprehensive Review.

Acute kidney injury in patients who suffer a malignancy is a common complication. Due to its high prevalence and effective treatment, one of the most frequent causes that both oncologists and nephrologists must be aware of is acute tubulointerstitial nephritis (ATIN). ATIN is an immunomediated condition and the hallmark of the disease, with the presence of a tubulointerstitial inflammatory infiltrate in the renal parenchyma. This infiltrate is composed mainly of T lymphocytes that can be accompanied by macrophages, neutrophils, or eosinophils among other cells. One of the major causes is drug-related ATIN, and some antineoplastic treatments have been related to this condition. Worthy of note are the novel immunotherapy treatments aimed at enhancing natural immunity in order to defeat cancer cells. In the context of the immunosuppression status affecting ATIN patients, some pathogen antigens can trigger the development of the disease. Finally, hematological malignancies can also manifest in the kidney leading to ATIN, even at the debut of the disease. In this review, we aim to comprehensively examine differential diagnosis of ATIN in the setting of a neoplastic patient.

Case report: a 58 -year -old man with small kidneys and elevated liver enzymes.

BACKGROUND: The conjunction of hepatitis and renal disease can be seen in several clinical context, including karyomegalic nephritis (KIN). Karyomegalic nephritis (KIN) is a rare genetic disease, with less than 50 cases reported, which incidence is probably underestimated. We report here an unusual case presentation of KIN with obtention of several organ biopsies and a novel mutation leading to the disease. CASE PRESENTATION: A 58 year old Caucasian without relevant family history presents with advanced chronic kidney disease, elevated liver enzymes and recurrent pulmonary infection. Familial history was negative. Renal biopsy revealed a chronic tubulo-intertsitial nephritis with enlarged and irregular hyperchromatic nuclei. Karyomegalic nephritis (KIN) was confirmed by genetic testing with a non-sense mutation and a deletion in the Fanconi anemia associated nuclease 1 (FAN1) gene. CONCLUSIONS: KIN is rare disease to be suspected in the presence of renal disease, biological hepatitis and recurrent pulmonary infections, even without a familial history. Diagnosis of this condition is crucial to perform family screening, avoid progression factors, and adapt post transplantation immunosuppression. Finally, avoiding familial heterozygote donors appears of major importance in this condition.

Bone marrow-derived mesenchymal stem cells attenuate tubulointerstitial injury through multiple mechanisms in UUO model.

Current evidence supports the use of bone marrow-derived mesenchymal stem cells (MSCs) for a diverse range of clinical applications, and many studies have shown that MSCs have renal-protective effects, but the mechanism is not well understood. Therefore, in this study, we aim to further identify whether MSCs can attenuate renal fibrosis by decreasing tubulointerstitial injury in a unilateral ureteral obstruction (UUO) model. In this study, we cultured MSCs and then transplanted them into a UUO model through the tail vein. Histology, cell proliferation, peritubular capillary (PTC) loss and myofibroblast markers were examined on days 3, 7 and 14 after surgery. We demonstrated that renal interstitial fibrosis in the MSC group was significantly attenuated compared with the UUO and DMEM groups. Moreover, MSC treatment inhibited the loss of PTCs and increased parenchymal cell proliferation. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by MSC infusion. Furthermore, MSCs attenuated tubulointerstitial infiltration of macrophages in UUO mice. Tubulointerstitial damage plays a very important role in the progression of chronic kidney disease (CKD). PTC loss, macrophage recruitment, and myofibroblast activation are directly correlated with the development of renal tubulointerstitial fibrosis. Our results suggest that MSC infusion in the UUO model is a promising therapeutic strategy for promoting kidney repair.

Acute interstitial nephritis with podocyte foot-process effacement complicating Plasmodium falciparum infection.

BACKGROUND: Malarial acute renal failure (MARF) is a component of the severe malaria syndrome, and complicates 1-5% of malaria infections. This form of renal failure has not been well characterized by histopathology. CASE PRESENTATION: A 44 year-old male presented to the emergency department with a 5-day history of fever and malaise after returning from Nigeria. A blood film was positive for Plasmodium falciparum. His creatinine was 616 µmol/L coming from a normal baseline of 89 µmol/L. He had a urine protein:creatinine ratio of 346 mg/mmol (4.4 g/L). He required dialysis. A renal biopsy showed acute interstitial nephritis with podocyte foot-process effacement. He was treated with artesunate and his renal function improved. At 1 year follow-up his creatinine had plateaued at 120 µmol/L with persistent low-grade proteinuria. CONCLUSION: Acute interstitial nephritis and podocyte foot-process effacement might be under-recognized lesions in MARF. Studying the mechanisms of MARF could give insight into the immunopathology of severe malaria.

Acute kidney injury in interstitial nephritis.

PURPOSE OF REVIEW: The purpose of this review is to describe the most common causes of acute interstitial nephritis (AIN), the diagnostic work-up and the therapeutic management. RECENT FINDINGS: Several case series and registries have found an increasing incidence of AIN, especially among older patients. Drug-induced AIN still represents the most common cause. Early withdrawal of the culprit drug together with corticosteroid therapy remain the mainstay of treatment, although recent studies have shown that prolonged treatment beyond 8 weeks does not further improve kidney function recovery. SUMMARY: AIN is a common cause of acute kidney injury, and therefore, physicians should suspect this entity especially in patients exposed to multiple medications. While immune-allergic reaction to numerous drugs is the most common cause of AIN, other underlying systemic diseases may also be involved, and therefore, every patient should undergo a complete diagnostic evaluation. Kidney biopsy provides the definitive diagnosis of AIN, and certain histologic features may help to identify the underlying condition. In drug-induced AIN, an early discontinuation of the culprit drug is the mainstay of therapy, and unless a rapid recovery of kidney function is observed, a course of glucocorticoid therapy should be initiated.

Renal involvement in primary Sjögren's syndrome: natural history and treatment outcome.

OBJECTIVES: Overt renal disease in primary Sjögren's syndrome (pSS) manifests as interstitial nephritis and glomerulonephritis. This single centre study aims to describe the natural history and treatment outcome of renal disease in pSS. METHODS: pSS patients with renal disease were identified, and clinical features, renal biopsy findings, treatment details and renal outcome were recorded. RESULTS: Of the 20 pSS patients with renal disease, 14 had interstitial nephritis (IN), 3 had glomerulonephritis (GN) and 3 had both entities. In the IN group, 3 patients presented with chronic kidney disease (CKD), 4 with renal tubular acidosis (RTA), 2 with symptomatic hypokalaemia, 4 with renal colic and 1 with haematuria/proteinuria. Eight of 14 patients with IN received systemic immunosuppression (IS) during renal disease course and in 6 patients no beneficial effect was observed on renal function, hypokalaemia and RTA. Six of 14 IN patients developed CKD while 5 of them preserved normal renal function during follow-up. In the GN group, 2 patients presented with CKD, 3 with proteinuria/haematuria and 1 with nephrotic proteinuria. GN renal biopsy findings revealed membranoproliferative (MPGN) (n=3), focal segmental glomerulosclerosis (n=1) and fibrillary glomerulopathy (n=1). All 3 MPGN patients had cryoglobulinaemia and in 1 patient cryoglobulinaemic MPGN was clinically diagnosed. All GN patients were treated with immunosuppressive therapy, with stabilisation or improvement of renal function in the 4 cryoglobulinaemia-associated GN patients only. CONCLUSIONS: Interstitial nephritis follows a slow course and does not improve with systemic immunosuppression while GN has a favourable treatment response in those with MPGN pathology.

IgG4-related kidney disease and retroperitoneal fibrosis: An update.

The most representative kidney lesion of IgG4-related disease (IgG4-RD) is plasma cell-rich tubulointerstitial nephritis (TIN) with distinctive imaging findings including multiple low-density lesions on contrast-enhanced computed tomography. In addition, membranous glomerulonephritis is a representative glomerular lesion of this disease. Recent advances have clarified that inflammation with IgG4-positive plasma cell infiltrates is not restricted to the renal parenchyma, but can be seen in outside the renal capsule, around medium-sized arteries such as lobar arteries, around nerves, and in the renal pelvis and periureter. Hypocomplementemia is a very important feature of IgG4-TIN, and serum complement level might serve as a convenient biomarker to predict relapse. Although good responsiveness to glucocorticoid has been considered characteristic of IgG4-RD, delayed start of treatment is associated with partial scarring in the kidneys on imaging study. Therefore, steroid therapy should be immediately initiated as soon as the diagnosis of IgG4-TIN is made. Future analyses of pathogenesis will be needed to more precisely define the optimal therapeutic strategies for the various subsets of Ig4-RD patients.

The Syndrome of Tubulointerstitial Nephritis With Uveitis (TINU).

The syndrome of tubulointerstitial nephritis and uveitis (TINU) is a multisystemic autoimmune disorder that may occur in response to various environmental triggers, including drugs and microbial pathogens. Evidence exists of HLA antigen-related genetic predisposition to developing TINU. The resulting inflammation affects chiefly the ocular uvea and renal tubules, although other organs may be involved. TINU is uncommon; only about 200 cases are on record since its original description 40 years ago, although it is possible that new ones are no longer being reported. Although its incidence is highest in children and adolescents, all ages may be affected. Renal and ocular inflammation may be clinically severe and persistent, but the prognosis for the majority of patients with TINU is favorable. Owing to its low prevalence, no standard therapeutic protocols have been established, but most reported cases have been treated with corticosteroids or other immunomodulatory agents. TINU has many features in common with sarcoidosis, the main clinical entity from which it must be distinguished. This article begins with an illustrative case vignette, followed by an overview of the syndrome and current theories regarding its pathogenesis.

Interstitial Nephritis Secondary to Vedolizumab Treatment in Crohn Disease and Safe Rechallenge Using Steroids: A Case Report.

Vedolizumab is a gut-selective humanized monoclonal antibody that binds selectively to the α4 ß7 integrin and acts as a lymphocyte-homing antagonist. It is indicated in ulcerative colitis and Crohn disease. We report a case of acute interstitial nephritis following vedolizumab infusion in a 55-year-old white woman treated for severe Crohn disease resistant to several therapies. Other kidney disease causes were ruled out. Glucocorticoids were administrated, leading to full renal recovery. In the absence of other therapeutic options, vedolizumab was re-administered along with transient corticosteroids; this treatment was well tolerated. Fewer than 10 cases of immunoallergic acute interstitial nephritis following treatment with monoclonal antibody have previously been reported in the literature. The pathophysiology of delayed-type hypersensitivity secondary to monoclonal antibody therapeutics is discussed in this case report.

Tubulointerstitial nephritis: diagnosis, treatment, and monitoring.

Tubulointerstitial nephritis (TIN) is a frequent cause of acute kidney injury (AKI) that can lead to chronic kidney disease (CKD). TIN is associated with an immune-mediated infiltration of the kidney interstitium by inflammatory cells, which may progress to fibrosis. Patients often present with nonspecific symptoms, which can lead to delayed diagnosis and treatment of the disease. Etiology can be drug-induced, infectious, idiopathic, genetic, or related to a systemic inflammatory condition such as tubulointerstitial nephritis and uveitis (TINU) syndrome, inflammatory bowel disease, or immunoglobulin G4 (IgG4)-associated immune complex multiorgan autoimmune disease (MAD). It is imperative to have a high clinical suspicion for TIN in order to remove potential offending agents and treat any associated systemic diseases. Treatment is ultimately dependent on underlying etiology. While there are no randomized controlled clinical trials to assess treatment choice and efficacy in TIN, corticosteroids have been a mainstay of therapy, and recent studies have suggested a possible role for mycophenolate mofetil. Urinary biomarkers such as alpha1- and beta2-microglobulin may help diagnose and monitor disease activity in TIN. Screening for TIN should be implemented in children with inflammatory bowel disease, uveitis, or IgG4-associated MAD.

Clinical profile and outcome of patients with biopsy-proven acute interstitial nephritis in Cape Town: a 10-year review
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BACKGROUND: Acute interstitial nephritis (AIN) is a common cause of acute kidney injury that has not been adequately characterized in Sub-Saharan Africa (SSA) despite an increasing use of potentially inciting agents for the treatment of human immunodeficiency virus (HIV) and tuberculosis in the region. METHODS: A retrospective audit of records of patients with biopsy-proven AIN diagnosed at Groote Schuur Hospital, Cape Town from the 1st of January, 2006, to the 31st of December, 2015. RESULTS: 54 patients with biopsy-proven AIN were reviewed. The majority were of black African origin (59.2%), with HIV (42.8%) and HIV-tuberculosis coinfection (30.5%) as the most common comorbidities. Drug-related AIN was seen in 38 (67.9%) patients, with rifampicin as the most often implicated medication. Probable drug-related AIN was seen in 3 (5.4%) patients, infection-related AIN in 8 (14.3%), and unspecified causes in 4 (7.4%). AIN was suspected in 44.6% of patients before biopsy. 18 patients (34%) received hemodialysis, while 19 (35.2%) were treated with corticosteroids. Complete renal recovery at 30 and 90 days was seen in 23 (42.6%) patients and 24 (45.3%) patients, respectively, with the majority seen among those with drug-induced AIN. Six (11.1%) patients died; 4 (10.5%) of the patients were in the drug-related group. There was no correlation between degree of interstitial inflammation and severity of renal failure (p = 0.10). On multivariate logistic regression, drug-related causes of AIN were predictive of complete recovery at day 30 (OR 16.63; 95% CI: 1.71 - 161.6, p = 0.02), and presence of interstitial fibrosis reduced likelihood of recovery (OR 0.03; 95% CI 0.002 - 0.46, p = 0.012). Steroid use did not influence partial recovery (OR 0.59, 95% CI 0.17 - 1.77; p = 0.32) or complete recovery (OR 3.38, 95% CI 0.38 - 30.39, p = 0.28). CONCLUSIONS: AIN is common in patients with HIV or those on treatment for tuberculosis. Drug-related AIN is often associated with improved outcomes. This is particularly reassuring in the SSA region where the use of potentially-inciting medications is rife from a high burden of HIV and tuberculosis.
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Urinary sediment miRNAs reflect tubulointerstitial damage and therapeutic response in IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. The clinical spectrum of IgAN varies from minor urinary abnormalities to rapidly progressive renal failure. Evaluation of the disease by repeated renal biopsy is not practical due to its invasive procedure. Urinary sediment miRNAs promise to serve as non-invasive biomarkers to assess kidney injury of IgAN. METHODS: Fifty two biopsy-proven IgAN patients and twenty five healthy controls were enrolled in the study. Urinary sediment miRNAs were extracted. Expressions of miR-34a, miR-205, miR-21, miR-146a and miR-155 were quantified by real-time quantitative polymerase chain reaction (RT-QPCR). The receiver operating characteristic (ROC) curve was used to investigate the value of the miRNAs for predicting diagnosis of IgAN and evaluating histopathological injury. The patients were treated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and followed up. The roles of miRNAs in reflecting therapeutic efficacy and disease progression were analyzed. RESULTS: 1. The IgAN group had significantly lower urinary miR-34a, miR-205, and miR-155, but higher miR-21 levels than controls. The ROC revealed that urinary miR-34a ≤ 0.047, miR-205 ≤ 0.209, miR-21 ≥ 0.461 and miR-155 ≤ 0.002 could distinguish patients with IgAN from healthy ones. In addition, miR-205 ≤ 0.125 and miR-21 ≥ 0.891 can distinguish IgAN patients with severe tubular atrophy/interstitial fibrosis from those with mild tubular atrophy/interstitial fibrosis. 2. After a mean 15.19 months follow-up, the reduction of proteinuria (g/24 h/year) was positively correlated with baseline urinary miR-21 and inversely correlated with miR-205. The levels of baseline eGFR and miR-205 in the complete remission group were significantly higher than non-complete remission group (p < 0.001; p = 0.018), while proteinuria, miR-21 and miR-146a were lower than non-complete remission group (p = 0.002; p = 0.021; p = 0.009). But multivariate analysis revealed that only baseline eGFR correlated with the remission of IgAN (p = 0.001, OR = 1.042). CONCLUSIONS: The levels of some urinary sediment miRNAs, especially baseline miR-21 and miR-205, may be used as potential prognostic markers for evaluating the tubulointerstitial damage of IgAN. Furthermore, baseline levels of urinary miRNAs may be predictors of therapeutic efficacy and disease progression.

Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.

Secreted fibroblast-derived miR-34a induces tubular cell apoptosis in fibrotic kidney.

Tubular epithelial cell apoptosis contributes to tubulointerstitial fibrosis but its regulation remains unclear. Here, in fibrotic kidney induced by unilateral ureteral obstruction (UUO), we demonstrate that miR-34a is markedly upregulated in tubulointerstitial spaces and microvesicles isolated from obstructed kidney. However, miR-34a is not de novo synthesized by proximal tubular epithelial cells but by fibroblasts after incubation with TGF-ß1. miR-34a is markedly upregulated in microvesicles isolated from the cell culture medium of TGF-ß1-treated fibroblasts. These microvesicles act as a vector for delivery of upregulated miR-34a from fibroblasts to tubular cells. The fibroblast-derived miR-34a-containing microvesicles induce the apoptosis of tubular cells. The exogenous miR-34a regulates tubular apoptosis by modulating the expression of the anti-apoptotic protein Bcl-2. Moreover, injection of exogenous miR-34a-containing microvesicles enhances tubular cell apoptosis in mice. This study suggests that secreted fibroblast miR-34a transported by microvesicles induces tubular cell apoptosis in obstructed kidney. This study reveals a new mechanism whereby microvesicle-mediated communication of miRNA between fibroblasts and tubular cells is involved in regulating tubular cell apoptosis, which might provide new therapeutic targets for renal tubulointerstitial fibrosis.