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A 67-year-old man was referred to the renal team following an episode of acute kidney injury on a background of chronic kidney disease. He had a 9-year history of steroid-sensitive arthritis, epigastric pain and isolated submandibular gland enlargement. He was noted to have a raised eosinophil count, total serum protein and total immunoglobulin G4 (IgG4) level as well as a serum hypocomplementaemia. A renal biopsy showed a tubulointerstitial nephritis with lymphoplasmacytic infiltrates, fibrosis and IgG4-positive plasma cells on immunohistochemistry. A diagnosis of IgG4-related disease was made based on clinical presentation and pathology. Renal function improved with glucocorticoids and the patient was successfully transitioned to azathioprine as a steroid-sparing agent.

A 70-year-old man received pembrolizumab as a second-line treatment for squamous cell lung cancer of the lower right lobe. After three courses, proteinuria and hematuria were observed, which worsened after seven courses. He was diagnosed with a combination of IgA nephropathy and active interstitial nephritis. Steroid pulse therapy was started, and the dose of prednisolone was gradually reduced from 60 mg/day. Renal dysfunction as an immune-related adverse event of pembrolizumab monotherapy for non-small cell lung cancer has been reported previously. Therefore, establishing a system for the early detection and treatment that distinguishes immune-related glomerular diseases is essential.

A 39-year-old woman was hospitalized for nephrotic syndrome. Laboratory test results showed increased serum creatinine levels and urinary excretions of beta-2-microglobulin, and N-acetyl-beta-D-glucosaminidase. A renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) and acute interstitial nephritis. Despite treatment with pulse steroid followed by oral high-dose glucocorticoids and cyclosporines, heavy proteinuria persisted. After low-density lipoprotein apheresis (LDL-A) therapy was initiated, her proteinuria gradually decreased, leading to complete remission. A repeat renal biopsy after treatment revealed no collapsing glomeruli. Immediate LDL-A should be performed to treat cases of collapsing FSGS poorly responding to other treatments.

Rosai-Dorfman-Destombes disease (RDD) is a non-Langerhans cell histiocytosis characterized by the accumulation of histiocytes inside the lymph nodes or extranodally. The association between RDD and IgG4-related disease (IgG4-RD) is discussed. We herein report a case of RDD manifesting as acute tubulointerstitial nephritis mimicking IgG4-RD. The first renal biopsy showed severe tubulointerstitial nephritis with infiltration of S100-positive histiocytes and IgG4-positive plasma cells; storiform fibrosis and obliterative phlebitis were not confirmed. After prednisolone therapy, IgG4-positive cells and S100-positive histiocytes were decreased, but the IgG4/IgG ratio increased despite clinical improvement. These findings indicated extranodal RDD in the kidney presenting as tubulointerstitial nephritis.

Introduction: Patients with AA amyloidosis may present with acute kidney injury that progresses to end-stage kidney disease in a short period of time. Acute allergic tubulointerstitial nephritis (aTIN) is a frequent cause of acute kidney injury in patients with AA amyloidosis. Although aTIN has a favorable prognosis in the general population, the course of aTIN in patients with AA amyloidosis was not previously reported. In this retrospective study, we determined the prognosis of aTIN superimposed on AA amyloidosis. Methods: Thirty-two patients with combined pathological diagnosis of AA amyloidosis + aTIN and 32 patients with isolated aTIN were compared in terms of 1-year renal functions after the biopsies were performed with an indication of acute kidney injury. Baseline renal functions and number of patients requiring hemodialysis at the time of biopsy was similar in both groups. Results: At the end of the 12-month follow-up period, 29 of 32 patients in the amyloidosis + aTIN group and 1 of 32 patients in the isolated aTIN group required dialysis. Most of these patients with AA amyloidosis had completely normal renal function before the episode of acute kidney injury and had clear exposures to drugs associated with aTIN. Conclusion: In contrary to the patients without AA amyloidosis, patients with AA amyloidosis have extremely high risk of permanent renal failure in case of development of aTIN. Great caution should be exercised in prescribing drugs that are associated with aTIN, in patients with AA amyloidosis.

Background: Our previous studies had shown pirfenidone (PFD) not only improved tubulointerstitial fibrosis (TIF) but also inhibited the expression of microRNA-21 (miR-21) in the renal tissue of unilateral urethral obstruction (UUO) rats. This study aims to investigate whether PFD can attenuate TIF through inhibiting miR-21 in UUO rats. Methods: Sprague Dawley rats were divided randomly into sham-operated group, UUO group, and PFD and olmesartan (Olm) treatment groups. Samples were collected on day 14. Expression of miR-21, TGF-β1, Smad3, and Smad7 mRNA in the renal tissue was detected using real-time quantitative PCR. Immunohistochemistry was performed to assess the protein expressions of collagen III, E-cadherin, and α-SMA. Automated capillary Western blotting was used to detect the quantitative expression of TGF-β1, Smad3, p-Smad3, Smad7, collagen III, E-cadherin, and α-SMA in renal tissues. The expression of miR-21 and Smad7 mRNA and the protein levels of collagen III and α-SMA were examined in the miR-21-overexpressing cell line, NRK-52E. Results: Compared with the UUO group, both PFD and Olm inhibited renal tubular dilation, diffused epithelial cell degeneration and necrosis, and reduced renal interstitial edema, inflammatory cell infiltration, and collagen fiber deposition, while no significant difference between PFD group and Olm group. Informatics-based approaches identified Smad7 as a likely candidate for regulation by miR-21. Compared with the sham group, miR-21 expression was upregulated in the UUO group resulting in the downregulation of Smad7 expression due to degradation. The overexpression of miR-21 in the in vitro model downregulated Smad7 and promoted EMT and ECM accumulation. Protein levels of TGF-β1, Smad3, p-Smad3, collagen III, and α-SMA were upregulated, while E-cadherin protein was downregulated in the UUO group than in the sham group. PFD rather than Olm decreased the expression of miR-21 and increased the expression level of Smad7 mRNA and then inhibited the TGF-β1/Smad3 signaling pathway. Olm only downregulated the TGF-β1/Smad3 signaling pathway. Conclusions: PFD improves TIF by downregulating the expression of miR-21, then elevating Smad7, and finally inhibiting the activation of the TGF-β1/Smad3 signaling pathway in UUO rats.

Immune check point inhibitors (ICIs) are now increasingly used for cancer therapy. At the same time, by activating the immune system, ICIs induce unique side effects, termed immune-related adverse events (irAEs). Renal irAEs, although uncommon, result in acute tubulointerstitial nephritis. Recently, because of an increase in ICI administration, renal irAEs, including glomerulonephritis, are being increasingly reported. A 69-year-old man presented with nephrotic syndrome after use of the ICI nivolumab. He underwent renal biopsy and was diagnosed with membranous nephropathy (MN) without acute tubulointerstitial nephritis. Immunofluorescence staining was negative for IgG4 and phospholipase A2 receptor (PLA2R), suggesting a malignancy-associated pattern. Oral glucocorticoid therapy was started as the standard treatment for irAEs, which resulted in complete remission of the nephrotic syndrome in 20 months. We suggest his MN was induced or accelerated by immune activation due to nivolumab. It means that ICIs possibly induce not only acute tubulointerstitial nephritis but also nephrotic syndrome due to MN as renal irAEs which is treatable with glucocorticoid.

Polyomavirus associated nephropathy (PyVAN) continues to be a burden in renal transplantation leading to allograft insufficiency or graft failure. A presumptive diagnosis of PyVAN is made based on the presence of BK polyomavirus in patients' plasma; however, kidney biopsy remains the gold standard to establish a definitive diagnosis. The Banff Working Group on PyVAN proposed a novel classification of definitive PyVAN based on polyomavirus replication/load level and the extent of interstitial fibrosis. The aim of our study was to test the newly defined classes of PyVAN using independent cohorts of 124 kidney transplant patients with PyVAN with respect to the initial presentation and outcome, and to compare our analysis to that previously reported. Detailed analysis of our cohort revealed that the proposed classification of PyVAN did not stratify or identify patients at increased risk of allograft failure. Specifically, while class 3 was associated with the worst prognosis, there was no significant difference between the outcomes in classes 1 and 2. We also found that the timing post-transplantation and inflammation in areas of interstitial fibrosis and tubular atrophy might be additional factors contributing to an unfavorable allograft outcome in patients with PyVAN.

Background Tubulointerstitial nephritis with uveitis syndrome is a rare disease affecting mainly children and young women. Tubulointerstitial nephritis with uveitis is a diagnosis of exclusion, requiring a high degree of clinical suspicion. Studies report recent infections or certain drugs as precipitating factors of a lymphocytic oculorenal immune response. The prognosis is usually favorable with topical and systemic corticosteroid therapy. Case presentation We report a literature review and the case of a 14-year-old white girl, who presented to the ophthalmology department with features of one-sided uveitis. Upon transfer of patient to nephrological care, diagnostic work-up revealed renal involvement. Renal biopsy showed a mixed-cell and granulomatous tubulointerstitial nephritis with some noncaseating granulomas, leading to a diagnosis of tubulointerstitial nephritis with uveitis syndrome. With topical ocular and systemic corticosteroid therapy, the patients’ condition improved over several weeks. Conclusions Our case highlights the importance of early recognition and treatment of this syndrome, where cross-specialty care typically leads to a favorable outcome.

The extracellular matrix (ECM) is a complex network of collagens, elastin, and interconnecting glycoproteins and proteoglycans that surround cells and provide structural support. The ECM is a dynamic structure, undergoing constant remodeling, and providing services beyond a simple barrier or scaffold (1). Recent studies have demonstrated that the ECM and the broad complement of interacting proteins ( e.g. the matrisome) play significant roles in inflammation and cell-to-cell interactions (2). Low-grade inflammation, a common feature of many kidney diseases, often contributes to aberrant ECM deposition and fibrosis. Significantly, renal fibrosis is a hallmark of renal dysfunction progression and CKD, leading to end-organ failure. Many of the proteins making up the renal ECM are spatially resolved into the glomerular (glomerular basement membrane, the mesangial matrix, and Bowman’s capsule) and tubulointerstitial (tubular basement membranes, tubular capillaries, and interstitial space) compartments. The most abundant proteins in the ECM are collagens, accounting for almost one third of ECM proteins (3). Type IV collagen is the most well described ECM protein in terms of kidney disease. Type IV collagen has six alpha chains that form three different trimer combinations, and the α3.α4.α5 heterotrimer is the most predominant in the glomerular basement membrane (3). Mutations in COL4A3 , COL4A4 , or COL4A5 genes are associated with Alport Syndrome, thin basement membrane disease, and familial FSGS (4,5). Proteomic analysis has identified collagens I, III, VI, VII, XII, XV, and XVIII within the glomerular ECM (6,7). Collagens I, II, III, V, VI, VII, and XV are normally expressed in the tubulointerstitium and increased expression have been associated with fibrosis (3). A recent proteomic analysis of kidneys across different age groups demonstrated consistent increases in collagen VI with aging kidneys (8). Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE), …

Ingestion of toxic trace elements in the human body has been considered one of the major reasons for renal dysfunction. Chronic kidney disease with uncertain etiological factors (CKDu) is a recently described clinical entity in which the disease is found in geographically isolated pockets in the dry zone of Sri Lanka. In CKDu regions, an increasing number of cases are reported with acute interstitial nephritis without any known reason (AINu). However, recent exposure to certain risk behaviors or nephrotoxins, or both, is suspected for the AINu. Consumption of foods that are contaminated with trace elements is one of the main pathways of human exposure to environmental toxins. The current study was carried out to assess the possibility of trace element-contaminated rice consumption on the etiopathogenesis of AINu. Samples of rice consumed by 32 clinically diagnosed AINu cases were collected and analyzed for possible nephrotoxic trace elements. Out of 32 patients, 26 were histologically confirmed with tubulointerstitial disease. The results revealed that the mean values of Cd, As, and Pb were 0.18, 0.055, and 0.135 mg/kg, with ranges of 0.020-1.06, 0.012-0.222, and 0.003-0.744 mg/kg (on dry weight basis), respectively. This study indicated that the investigated toxic trace element levels of rice consumed by AINu were reasonably below the recommended levels of the Codex Alimentarius Commission of FAO and WHO. Hence, it is less likely that rice consumption is to be a risk factor for the etiology of AINu.

Background Histological findings of kidney involvement have been rarely reported in pediatric patients with SARS-CoV-2 infection. Here, we describe clinical, laboratory, and histological findings of two pediatric cases with almost exclusive kidney involvement by SARS-CoV-2. Results A 10-year-old girl with IgA vasculitis nephritis underwent kidney biopsy, showing diffuse and segmental mesangial-proliferative glomerulonephritis, and steroid therapy was initiated. After the worsening of the clinical picture, including an atypical skin rash, she was diagnosed with SARS-CoV-2. The re-evaluation of initial biopsy showed cytoplasmatic blebs and virus-like particles in tubular cells at electron microscopy. Despite SARS-CoV-2 clearance and the intensification of immunosuppression, no improvement was observed. A second kidney biopsy showed a crescentic glomerulonephritis with sclerosis, while virus-like particles were no longer evident. The second patient was a 12-year-old girl with a 3-week history of weakness and weight loss. Rhinitis was reported the month before. No medications were being taken. Blood and urine analysis revealed elevated serum creatinine, hypouricemia, low molecular weight proteinuria, and glycosuria. A high SARS-CoV-2-IgG titre was detected. Kidney biopsy showed acute tubular-interstitial nephritis. Steroid therapy was started with a complete resolution of kidney involvement. Conclusion We can speculate that in both cases SARS-CoV-2 played a major role as inflammatory trigger of the kidney damage. Therefore, we suggest investigating the potential kidney damage by SARS-CoV-2 in children. Moreover, SARS-CoV-2 can be included among infectious agents responsible for pediatric acute tubular interstitial nephritis.

Acute interstitial nephritis can result due to exposure to any medication, toxins, infections or malignancy. In the midst of this Coronavirus (COVID‐19) pandemic, there has been a race for finding remedies to prevent the spread of and control the complications due to Severe Acute Respiratory Syndrome Coronavirus 2. Certain Indian medicinal herb concoctions like kabasura kudineer and nilavembu kudineer are being widely publicized to boost immunity and reduce the risk of developing COVID‐19. Little knowledge exists about the adverse effects of these herbal remedies. We report two patients who presented to us with vague complaints following the ingestion of kabasura kudineer and we diagnosed them with acute tubulointerstitial nephritis (ATIN). The temporal relationship of ingestion of these remedies to the development of ATIN calls for vigilance and caution with regular monitoring of renal functions especially in those with chronic kidney disease., SUMMARY AT A GLANCE Summary At A Glance: Certain herbal medicines are being prescribed to boost immunity and reduce the risk of developing COVID‐19 in India. Little is known about the adverse effects of these herbal remedies. This study reports the nephrotoxicity of the Kabasura Kudineer formulation which calls for attention to potentially serious adverse effects of some alternative medicine.

Tipifarnib is a novel targeted treatment for hematologic malignancies that is being recently studied for the treatment of advanced solid organ tumors with HRAS mutations. There have been scarce reports on kidney adverse events in initial phase I and II trials. We present a case of acute kidney injury in a patient that had started treatment with tipifarnib for advanced squamous cell carcinoma of the lung. Kidney biopsy revealed acute tubular necrosis together with acute interstitial nephritis. Tipifarnib was discontinued and the patient was started with high-dose corticosteroids with an early taper completing a five-week steroid course, with full recovery of kidney function.

The presence of intimal arteritis (v) in renal allograft biopsy specimens establishes the presence of acute T-cell mediated rejection (TCMR), Grade IIa-III, according to the Banff classification of rejection. The clinical significance of isolated v1 lesions (v1), characterized by arteritis alone, compared with lesions of arteritis with tubulointerstitial inflammation (i-t-v) has been controversial.We performed a retrospective review of 280 patients undergoing renal transplantation between 2005 and 2015 who received a "for cause" transplant biopsy using the Banff 2013 classification. Patients with TCMR grade IIa (n = 83) were subdivided into groups with isolated v1 arteritis and i-t-v. Pre- and postoperative renal function, graft survival, and overall survival were evaluated in all patients.Donor and recipient demographics were similar between groups. One month following treatment of rejection, patients with v1 disease had superior recovery of glomerular filtration rate vs patients with i-t-v (P.002). At a median follow-up of 41 months from transplant, death-censored graft survival was 92% vs 79% (P = .04), and overall survival was 98% vs 79% (P.004) in the isolated v1 and i-t-v groups, respectively.Despite having identical Banff classification of TCMR IIa, our results indicate that graft survival in patients with isolated v1 rejection is superior to those with i-t-v. Following corroboration with data from other centers, modification of the Banff classification scheme should be considered.

A 39-year-old man presented with peripheral eosinophilia, pulmonary eosinophilic infiltrate, and renal failure due to acute tubulointerstitial nephritis (TIN). He had experienced childhood asthma and was negative for anti-neutrophil cytoplasmic antibody (ANCA). He was tentatively diagnosed with ANCA-negative eosinophilic granulomatous polyangiitis (EGPA) or idiopathic hypereosinophilic syndrome (HES). Renal involvement of isolated TIN with eosinophil infiltration is rare in EGPA and HES and does not seem to have a good prognosis in the literature. However, his condition improved well with corticosteroids and mepolizumab. The revised classification of EGPA based on the etiology should dictate the proper treatment in suspected EGPA patients with nonsystemic vasculitis.

IgG4-related disease (IgG4-RD) is a newly recognized multi-organ fibro-inflammatory condition with characteristic histopathological findings of increased IgG4+ plasma cells in tissue and usually with increased IgG4 serum levels. Kidney involvement in IgG4-RD has been well described since 2006. Epstein-Barr virus (EBV) has reportedly been associated with nodal IgG4-RD, but not in extra-nodal disease. We report a case of renal IgG4-RD in the setting of acute EBV infection in a young healthy man, resulting in severe renal failure. Biopsy of kidney revealed IgG4+ plasma cell-rich tubulointerstitial nephritis, tissue eosinophilia, early-stage membranous nephropathy, and scattered EBV-positive cells. Oral prednisone and acyclovir only partially rescued his renal function.

Chronic interstitial nephritis in agricultural communities is a devastating kidney disease with a globally increasing prevalence. Its cause is unknown. Two predominant etiologies are hypothesised: recurrent episodes of dehydration and exposure to environmental toxins, such as agrochemicals and metals. In this review, we summarise arguments on: 1) why heat stress/dehydration is an unlikely cause of this disease and 2) why chronic interstitial nephritis in agricultural communities is to be considered a toxin-induced nephropathy. Mechanistically, we provide arguments for a putative role of pesticides on the one hand, and the calcineurin pathway on the other hand, both of which require further investigation. Finally, we summarise several important perspectives for research on chronic interstitial nephritis in agricultural communities. (C) 2020 Published by Elsevier Masson SAS on behalf of Societe francophone de nephrologie, dialyse et transplantation.

BackgroundInflammatory bowel diseases are characterized by chronic inflammation of the gastrointestinal tract. In particular, Crohn disease and ulcerative colitis represent the two most common types of clinical manifestations. Extraintestinal manifestations of inflammatory bowel diseases represent a common complications, probably reflecting the systemic inflammation. Renal involvement is reported in 4–23% of cases. However, available data are limited to few case series and retrospective analysis, therefore the real impact of renal involvement is not well defined.Case presentationWe report the case of a 10-years old male affected by very early onset unclassified-Inflammatory bowel diseases since he was 1-year old, presenting with a flare of inflammatory bowel diseases associated with acute kidney injury due to granulomatous interstitial nephritis. Of interest, at 7-year-old, he was treated for IgA nephropathy.To our knowledge, no previous reports have described a relapse of renal manifestation in inflammatory bowel diseases, characterized by two different clinical and histological phenotypes.ConclusionsThe link between the onset of kidney injuries with flares of intestinal inflammation suggest that nephritis maybe considered an extra-intestinal manifestation correlated with active inflammatory bowel disease. However, if granulomatous interstitial nephritis represents a cell-mediated hypersensitivity reaction than a true extraintestinal manifestation of inflammatory bowel diseases is still not clarified. We suggest as these renal manifestations here described may be interpreted as extraintestinal disorder and also considered as systemic signal of under treatment of the intestinal disease.

Tubulointerstitial nephritis (TIN) with IgM-positive plasma cells (IgMPC-TIN) is an autoimmune kidney disease characterized by IgM/CD138-double-positive plasma cell infiltration in the tubulointerstitium. A 50-year-old man developed IgMPC-TIN and presented with crystalline inclusions in the rough endoplasmic reticulum. Intracellular crystal formation is a rare finding in paraprotein-related kidney diseases, but this case showed no pathogenic monoclonal immunoglobulin. Prednisolone (PSL, 30 mg) improved the TIN, but PSL tapering resulted in the recurrence of TIN. Combination therapy with 15 mg PSL and 150 mg mizoribine ultimately stabilized TIN. This case offers original evidence concerning the pathophysiology and treatment strategy of IgMPC-TIN.

Renal toxicity from immune checkpoint inhibitors (ICIs) is an increasingly recognized cause of acute kidney injury among patients with cancer. ICI-associated acute kidney injuries typically present as acute interstitial nephritis and the timing of onset is highly variable. Herein, we present a case of a patient with relapsed metastatic melanoma previously treated with pembrolizumab who developed grade 3 immune-related renal toxicity after reintroduction of the same ICI, secondary to acute interstitial nephritis with accompanying high PR3-antineutrophil cytoplasmic antibody titer. The patient improved after steroid treatment and discontinuation of pembrolizumab. This case highlights the importance of not excluding ICI-related nephrotoxicity as a possible cause of renal failure, including in those who previously tolerated ICI treatment, since it is a treatable entity.

Genes of UMOD, HNF1B, MUC1, REN and SEC61A1 were reported to be associated with autosomal dominant tubulointerstitial kidney disease (ADTKD). 48 probands and their family members (N = 27) were enrolled in this genetic screening study. A combination of methods was employed for comprehensive molecular analysis of both copy number variations (CNVs) and single nucleotide variants (SNVs). 35 probands were followed for years. The phenotype-genotype and genotype-outcome correlation were inferred from these datasets. In this cohort, 18 probands were diagnosed with ADTKD, according to Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Moreover, 11 probands were diagnosed with ADTKD-UMOD, one with ADTKD-REN and one with ADTKD-HNF1B, based on molecularly confirmed pathogenic variants. The 11 UMOD variants were mainly located in codons 28 to 289 and half of the variants were found to change the cysteine amino acid. According to the follow-up data, suspected ADTKD individuals had a better prognosis compared to ADTKD individuals (p = 0.029). Individuals with a cysteine substitution in the UMOD gene appeared to have a better prognosis than individuals with other amino acid substitutions (p = 0.015).

Introduction Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits. Case presentation A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Conclusion Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.

The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.

Background Sarcoidosis is characterized by granulomatous inflammation in multiple organs. Renal involvement is rare, and granulomatous tubulointerstitial nephritis (TIN) is the predominant histologic feature. TIN is also a hallmark of tubulointerstitial nephritis and uveitis (TINU) syndrome. Diagnoses of both sarcoidosis and TINU syndrome are usually made by exclusion and by combining clinical and histological findings, and often remain misdiagnosed. The aim of this retrospective study was to determine the characteristics of renal sarcoidosis and TINU syndrome in Slovenia in the last decade (2010 - 2020). Materials and methods A thorough search of the national database of renal biopsies from January 2010 to December 2020 was performed. Inclusion criteria were TIN and a clinical history of either sarcoidosis or TINU syndrome. To compare the characteristics of our cohort with others, we also reviewed the global literature reported since 2010. Results 13 patients (9 female, 4 male) were included in our study. Indications for kidney biopsy were acute kidney injury (n = 8), acute exacerbation of chronic kidney disease (n = 4), and proteinuria (n = 1). Seven patients had clinical and histological evidence of sarcoidosis, and 6 patients were classified as having TINU syndrome. All patients were treated with corticosteroids. Of the 13 patients, 11 had improved kidney function 6 months after treatment, and proteinuria decreased in 9 patients. One patient was on dialysis at the time of diagnosis and remained so thereafter. Conclusion Renal sarcoidosis and TINU syndrome are rare but important causes of kidney injury, with a favorable long-term prognosis if properly diagnosed and treated in a timely manner.

Context: Determining whether SARS-CoV-2 causes direct infection of the kidneys is challenging due to limitations in imaging and molecular tools. Subject of Review: A growing number of conflicting kidney biopsy and autopsy reports highlight this controversial issue. Second Opinion: Based on the collective evidence, therapies that improve hemodynamic stability and oxygenation, or dampen complement activation, are likely to ameliorate acute kidney injury in COVID-19. At this time, whether inhibition of viral infection and replication directly modulates kidney damage is inconclusive.

Objects This study aimed to analyze the clinicopathological features of acute kidney disease (AKD) with renal oxalosis. Methods Data for biopsy-proven AKD with oxalosis diagnosed from Jan 2011 to Oct 2018 was collected. The underlying diseases, dietary habits, clinical and pathological characteristics of newly emerging kidney disease were analyzed. The long-term renal prognosis was observed. Results A total of 23 patients were included, comprised of 18 men and 5 women with a mean age of 51.6 ± 15.9 years. The peak Scr was 669.9 ± 299.8 μmol/L, and 95.7% of patients had stage 3 acute kidney injury (AKI). Drug-induced tubulointerstitial nephritis (TIN) was the most common cause (65.2%) of AKD, followed by severe nephrotic syndrome (17.4%). All patients had pathological changes indicating TIN, and 11 patients were complicated with the newly emerging glomerular disease (GD). The risk of oxalosis caused by increased enterogenous oxalate absorption accounted for only 26.1%, and others came from new kidney diseases. The majority (75%) of abundant (medium to severe) oxalosis occurred in patients without GD. There were no significant differences in the score for tubular injury (T-IS) and interstitial inflammation with different severities of oxalosis. Rate of Scr decrease (ΔScr%) at 2 weeks was negatively correlated with the severity of oxalosis (R = −0.542, p = 0.037), score for T-IS (R = −0.553, p = 0.033), and age (R = −0.736, p = 0.002). The decrease in Scr at 4 weeks was correlated with T-IS (R = −0.433), but had no correlation with oxalosis. Conclusions The present findings revealed that 95.7% of AKD with secondary renal oxalosis occurred in critically ill patients. AKD from tubular injury was the prominent cause. Severe oxalosis contributed to delayed early recovery of AKD.

Background IgG4-related kidney disease causes renal impairment of unknown pathogenesis that may progress to kidney failure. Although ectopic germinal centers contribute to the pathogenesis of the head and neck lesions of IgG4-related disease, the presence of tertiary lymphoid tissue (TLT) containing germinal centers in IgG4-RKD has rarely been reported. Case presentation We report a 72-year-old Japanese man who had IgG4-related tubulointerstitial nephritis (TIN) with TLT formation incidentally detected in a resected kidney with mass lesion of IgG4-related ureteritis in the ureteropelvic junction. During follow-up for past surgical resection of a bladder tumor, renal dysfunction developed and a ureter mass was found in the right ureteropelvic junction, which was treated by nephroureterectomy after chemotherapy. Pathology revealed no malignancy but abundant IgG4-positive cell infiltration, obliterative phlebitis and storiform fibrosis, confirming the diagnosis of IgG4-related ureteritis. In the resected right kidney, lymphoplasmacytes infiltrated the interstitium with focal distribution in the renal subcapsule and around medium vessels without storiform fibrosis, suggesting the very early stage of IgG4-TIN. Lymphocyte aggregates were also detected at these sites and consisted of B, T, and follicular dendritic cells, indicating TLT formation. IgG4-positive cells infiltrated around TLTs. Conclusions Our case suggests that TLT formation is related with the development of IgG4-TIN and our analysis of distribution of TLT have possibility to elucidate IgG4-TIN pathophysiology.

Background Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 – associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive. Case Presentation The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis. Conclusions Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.

Objectives: The determinants leading to different renal outcomes in community-acquired acute kidney injury (CA-AKI) and the influence of renal histological damage on the prognosis and recovery of CA-AKI are scarcely reported. Methods: Adult patients with CA-AKI admitted to Shanghai Changzheng Hospital with renal biopsy profiles from January 1, 2010, to December 31, 2018, were enrolled in our cohort. After 3 months of follow-up, clinical outcomes, including patient survival, dialysis requirement during hospitalization and at 3 months, CKD stage 3–5, and renal functional recovery at 3 months, were analyzed, and risk factors were identified. Results: A total of 294 patients with CA-AKI with renal pathology were identified for this cohort. Among 282 patients who survived 3 months after AKI, 59.6% completely recovered, 21.3% partially recovered, 21.3% progressed to stage 3–5 CKD without dialysis, and 17.7% maintained dialysis. Moreover, 70.4% of patients in the cohort presented with de novo intrinsic renal disease, except acute tubular necrosis or acute interstitial nephritis, on renal biopsy. In the multivariate analyses, clinical factors were more related to short-term outcomes and severity of CA-AKI, represented by mortality, in-hospital dialysis, and CRRT requirement, while pathological elements were more involved with CKD progression, including dialysis-dependent or stage 3–5 CKD, and renal function recovery at the 3-month follow-up. The detrimental influence of glomerular and arterial lesions on renal prognosis of CA-AKI was as critical as tubular and interstitial lesions. Conclusions: Clinical and pathological parameters both contribute to patient and renal outcomes after CA-AKI. The value of renal biopsy should be recognized in prognostic prediction.

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.

Mycoplasma hominis is a common colonizer of the lower genitourinary tract. Although its clinical relevance for causing urogenital infections in immunocompetent individuals is controversial, this bacterium has been involved in severe invasive infections in allograft recipients. In this report, we describe two cases of M. hominis infection in two young renal transplant recipients within the first month post-transplant. Although at first no epidemiological link between the two cases had been suspected, whole-genome sequencing (WGS) analysis showed that both isolates were identical, highly suggestive of an origin with the common organ donor. Supplementary Information The online version contains supplementary material available at 10.1007/s10096-020-04116-y.

Background Bacterial community-acquired atypical pneumonia is sometimes complicated by a myositis or by a renal parenchymal disease. Available reviews do not mention the concurrent occurrence of both myositis and acute kidney injury. Methods In order to characterize the link between bacterial community-acquired atypical pneumonia and both myositis and a renal parenchymal disease, we reviewed the literature (United States National Library of Medicine and Excerpta Medica databases). Results We identified 42 previously healthy subjects (35 males and 7 females aged from 2 to 76, median 42 years) with a bacterial atypical pneumonia associated both with myositis (muscle pain and creatine kinase ≥5 times the upper limit of normal) and acute kidney injury (increase in creatinine to ≥1.5 times baseline or increase by ≥27 μmol/L above the upper limit of normal). Thirty-six cases were caused by Legionella species (N = 27) and by Mycoplasma pneumoniae (N = 9). Further germs accounted for the remaining 6 cases. The vast majority of cases (N = 36) presented a diffuse myalgia. Only a minority of cases (N = 3) were affected by a calf myositis. The diagnosis of rhabdomyolysis-associated kidney injury was retained in 37 and that of acute interstitial nephritis in the remaining 5 cases. Conclusion Bacterial atypical pneumonia may occasionally induce myositis and secondary kidney damage.

The debate in this issue of Kidney360 involves the role of kidney biopsy in patients with cancer who develop AKI while receiving immune checkpoint inhibitors (ICPIs). The question is whether we need kidney tissue to diagnose the cause of AKI and guide management in these patients. Two expert onconephrologists, Ben Sprangers and Ilya Glezerman, present the pro and con sides of the debate, respectively. I will provide background on the ICPIs and their associated nephrotoxicity to lay the groundwork for the debate. The ICPIs are humanized mAbs against host immune checkpoints (CTLA-4 and PD-1 receptors and PD ligand-1) that are used to treat a number of different cancers. By attenuating the inhibitory effects of immune checkpoints on T cells, other immune cells, and cancer cells, these agents allow eradication of tumors that would otherwise evade immune destruction (1⇓⇓⇓–5). Although the ICPIs have greatly improved cancer therapy, immune-related adverse drug effects complicate their course (6,7). Extrarenal complications occur relatively commonly; however, drug nephrotoxicity is also observed (7⇓–9). In review articles containing published biopsy-proven cases, acute tubulointerstitial nephritis (ATIN) is most common (51 of 90; 57%), whereas acute tubular injury (ATI; n =13), various glomerulopathies ( n =20), and other kidney lesions ( n =6) have also been described (7⇓⇓–10). In addition, patients with cancer also develop AKI that is unrelated to the ICPI-related toxicity. These include AKI from ischemic and/or nephrotoxic tubular injury, various drug- or cancer-related glomerular injuries, …

A transdermal patch formulation of a non-steroidal anti-inflammatory drug (NSAID) used by a 44-year-old man resulted in acute interstitial nephritis and acute tubular injury. This patient also had a history of mild kidney dysfunction and osteoporosis. The NSAID patch had been prescribed after a traffic accident. He was also receiving a vitamin D analog and taking over-the-counter calcium supplements. Two months later, renal dysfunction and hypercalcemia were discovered. A renal biopsy showed acute interstitial nephritis and acute tubular injury. Once these agents were withdrawn, the renal function recovered. This is the first reported occurrence of biopsy-proven acute interstitial nephritis attributable to NSAID patch usage.

BackgroundA renal biopsy is needed to define active inflammatory infiltration and guide therapeutic management in drug-induced acute tubulointerstitial nephritis (D-ATIN). However, factors such as various contraindications, refusal of informed consent and limited technical support may stop the biopsy process. It is thus of great importance to explore approaches that could deduce probable pathologic changes.MethodsA total of 81 biopsy-proven D-ATIN patients were enrolled from a prospective cohort of ATIN patients at Peking University First Hospital. The systemic inflammation score (SIS) was developed based on the CRP and ESR levels at biopsy, and patients were divided into high-SIS, median-SIS, and low-SIS groups. The demographic data, clinicopathologic features, and renal outcomes were compared.ResultsThe SIS was positively correlated with inflammatory cell infiltration and was inversely correlated with interstitial fibrosis. The number of interstitial inflammatory cells increased significantly with increasing SISs. The proportions of neutrophils and plasma cells were the highest in the high-SIS group compared with the other two groups. Prednisone (30–40 mg/day) was prescribed in all patients. The high-SIS group tended to have more favorable renal restoration than the other two groups. By 12 months postbiopsy, a decreased eGFR (2) was observed in 66.7% of medium-SIS patients, 32.4% of high-SIS patients, and 30.4% of low-SIS patients.ConclusionThe SIS was positively correlated with active tubulointerstitial inflammation and therefore could help to aid therapeutic decisions in D-ATIN.

Background The present study aimed to investigate associations between long-term renal function, whether IgG4-related tubulointerstitial nephritis (TIN) was diagnosed by renal biopsy at initial examination, chronic kidney disease (CKD) stage, and histological stage in patients with IgG4-related TIN. Methods This study used a retrospective cohort design including almost all patients who underwent renal biopsy at Fujita Health University Hospital and Nagoya University or its affiliated hospitals in Aichi between April 2003 and March 2015 (n = 6977 renal biopsies). The primary outcome was longitudinal changes in eGFR. Main exposures were whether IgG4-related TIN was diagnosed by renal biopsy at the initial examination, CKD stage, and its histological stage. Linear mixed models were performed to examine associations. Results Of the 6977 samples, there were 24 patients (with 201 records due to repeated measures) with IgG4-related TIN (20 men, mean age, 68.7 ± 9.7 years). They were followed up 6.6 ± 2.8 years after the renal biopsy and underwent glucocorticoid treatment. We found significant increase in eGFR from the baseline to 2 and 6 months after treatment initiation, which was maintained until 60 months. Patients initially diagnosed with IgG4-related TIN had higher eGFR from the baseline (at the start of treatment) to 60 months than those who were not. Compared with patients with CKD stage 3, patients with CKD stages 4 and 5 had lower eGFR at the baseline and other time points. Patients with histological stage B had comparatively lower eGFR at each point than stage A patients. Those mean differences of eGFR were stable from the baseline to 60 months. Conclusions After the treatment initiation, renal function rapidly improved and maintained for a long period, even with advanced CKD stage. We showed importance of early diagnosis of IgG4-related TIN in maintaining eGFR.

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

Introduction Pembrolizumab is a monoclonal antibody approved for adult patients with advanced non–small-cell lung cancer (NSCLC). Although immune related adverse events are considered to be well tolerated, complications may occur and discontinuation of the treatment could be required. Case report A 62-year old patient diagnosed with advanced non-small cell lung cancer experienced a decline in the renal function after seven cycles with pembrolizumab. Management & outcome: After ruling out other common causes of interstitial nephritis, pembrolizumab was attributed as a cause of interstitial nephritis. At first, toxicity was managed with corticosteroids and closely monitoring the patient, but finally pembrolizumab had to be discontinued due to the kidney function did not recover. Discussion Renal and urinary disorders were reported in

Background Glycosuria is one of the manifestations of acute tubulointerstitial nephritis (ATIN), but may also be observed in other renal diseases. In this study, we investigated the value of non-diabetic glycosuria as a diagnostic clue for ATIN. Methods We retrospectively reviewed the medical records of adult patients who underwent a kidney biopsy as an evaluation for serum creatinine > 1.4 mg/dL. Patients with proteinuria in the nephrotic range, diabetes mellitus, or transplanted kidney were excluded. The laboratory abnormalities suggestive of tubular injury were compared between 28 patients (14 men and 14 women, mean age 48.5 ± 14.1 years) with ATIN and 116 patients (76 men and 40 women, mean age 53.1 ± 15.0 years) with other diagnoses. Results In ATIN, glycosuria (≥ 1+ on dipstick; 68%) was more frequent than hypophosphatemia (18%), hypouricemia (18%), hypokalemia (18%), and tubular proteinuria (40%). In other diagnoses, glycosuria (≥ 1+) was detected in 7 (6%) patients; 6 of them had the histological diagnosis of antineutrophil cytoplasmic antibody-associated glomerulonephritis. The presence of glycosuria (≥ 1+) had 68% sensitivity and 94% specificity for ATIN, with the positive likelihood ratio of 11.24 and the negative likelihood ratio of 0.34. Pyuria and low total CO2 were equally and more sensitive (68% and 71%, respectively) than glycosuria (≥ 1+), but had no diagnostic value due to low specificities (58% and 60%, respectively). Conclusion In non-diabetic, non-nephrotic patients undergoing a kidney biopsy for azotemia, 1+ or higher glycosuria, if present, was a good predictor of the diagnosis of ATIN.

Autosomal Dominant Tubulointerstitial Disease (ADTKD) is a dominantly inherited progressive non-glomerular disease. Several factors, such as a non-specific clinical presentation and relative rarity, impede the phenotyping of ADTKD into clinically relevant subtypes, and impair the appropriate implementation of genetic testing. The study by Olinger et al describe the largest multicenter ADTKD cohort, which is likely to become a key resource. The authors also provide a new clinical tool that could guide diagnosis and genetic testing.

Immunoglobulin A (IgA) nephropathy is one of the most common glomerulonephritis characterized by the deposition of IgA in glomerular mesangium. Karyomegalic interstitial nephritis (KIN) is a rare interstitial nephritis with potential hereditary factors. IgA nephropathy concomitant with KIN has not yet been reported. Herein, we describe the clinical course, ultrasonic images and gastrointestinal endoscopy findings of a 28-year-old-male patient with IgA nephropathy with KIN. The pathologic examination of the renal biopsy specimen demonstrated mild mesangial proliferative IgA nephropathy with KIN. Molecular genetic testing detected an abnormality in FAN1 gene. The heterozygous mutation was present on chromosome 15q13.3. However, IgA nephropathy with KIN is a rare disorder, and its pathogenesis is yet to be clarified.

Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease (CKD) or end-stage kidney disease (ESKD). An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19.

Renal tubulointerstitial fibrosis (TIF) is a common pathological feature of aristolochic acid (AA) nephropathy (AAN). G2/M arrest of proximal tubular cells (PTCs) is implicated in renal fibrosis of AAN, but the upstream regulatory molecule remains unknown. Hypoxia inducible factor-1α (HIF-1α) promotes renal fibrosis in kidney disease, but the role of HIF-1α in AAN is unclear. Evidence shows that HIF-1α and p21, a known inducer of cellular G2/M arrest, are closely related to each other. To investigate the role of HIF-1α in renal fibrosis of AAN and its effects on p21 expression and PTCs G2/M arrest, mice with HIF-1α gene knockout PTCs (PT-HIF-1α-KO) were generated, and AAN was induced by AA. In vitro tests were conducted on the human PTCs line HK-2 and primary mouse PTCs. HIF-1α and p21 expression, fibrogenesis, and G2/M arrest of PTCs were determined. Results showed that HIF-1α was upregulated in the kidneys of wild-type (WT) AAN mice, accompanied by p21 upregulation, PTCs G2/M arrest and renal fibrosis, and these alterations were reversed in PT-HIF-1α-KO AAN mice. Similar results were observed in HK-2 cells and were further confirmed in primary PTCs from PT-HIF-1α-KO and WT mice. Inhibiting p21 in HK-2 cells and primary PTCs did not change the expression of HIF-1α, but G2/M arrest and fibrogenesis were reduced. These data indicate that HIF-1α plays a key role in renal fibrosis in AAN by inducing PTCs G2/M arrest modulated through p21. HIF-1α may serve as a potential therapeutic target for AAN.

Background. IgG4-related disease is a new disease entity, but little attention was drawn to urinary system involvement besides nephritis or nephropathy. Here, we described clinical, radiological, and pathological manifestations of IgG4-related urinary disease (IgG4-RUD) and assess its treatment responses. Methods. We conducted a retrospective study enrolling 65 IgG4-RUD patients from an IgG4-related disease (IgG4-RD) cohort of the Peking Union Medical College Hospital. Clinical, laboratory, radiological, pathological data were collected, and treatment response to immunosuppressants were analysed. Results. IgG4-related interstitial nephritis (TIN, 32.3%), glomerular nephritis (GN, 7.7%), renal pelvis and ureter involvement (21.5%), abnormal radiology with quiescent clinical presentation (13.8%), and renal parenchymal lesion plus retroperitoneal fibrosis (RPF, 18.5%) were major lesion types of IgG4-RUD. All patients had elevated serum IgG4, 76.9% had hyperglobulinemia, and 92.3% had elevated serum IgE at diagnosis. IgG4-TIN patients presented with renal dysfunction, and 94.3% had low serum complement C3 and IgG4-GN presented with nephrotic syndrome, while renal pelvis and ureter involvement had normal renal function and urinalysis. IgG4-RPF with renal parenchymal involvement presented with acute renal dysfunction and required emergency medical intervention. Renal cortex low-density areas, parenchyma or pelvis nodular mass, bilateral enlargement of the kidney, and renal pelvis and ureter mass/wall thickening were specific image patterns of IgG4-RUD. Infiltration of plasma lymphocytes and storiform fibrosis were histopathological features of IgG4-RUD. Patients showed satisfactory responses to immunosuppressive treatment, but complete recovery of renal function was difficult to achieve in IgG4-TIN. Four patients (6.2%) experienced clinical relapses during the maintenance period. Conclusion. IgG4-RUD had diverse lesion types and distinctive manifestations. Radiological examinations were helpful for diagnosis and treatment evaluation. Patients showed good initial response to immunosuppressive treatment but relapses could occur at the maintenance period.

We herein report a 75-year-old man with non-small-cell lung cancer who developed tubulointerstitial nephritis due to pembrolizumab administration. He was successfully treated with atezolizumab following steroid administration. He was initially diagnosed with lung adenocarcinoma (T1bN3M1b, stage IV), with a programmed cell death-ligand 1 tumor proportion score of 25-49%. Although the tumor responded well to pembrolizumab, the drug was discontinued because of the diagnosis of tubulointerstitial nephritis on a renal biopsy. Tubulointerstitial nephritis was treated with 30 mg prednisolone, the dose of which was tapered to and maintained at 5 mg. Following lung cancer progression, atezolizumab was administered, and the tumor responded again. Its efficacy has been sustained for >15 months without recurrence of tubulointerstitial nephritis.

IgG4-related disease preferentially involves the kidney by tubulointerstitial nephritis with IgG4-positive plasma cell filtration and/or membranous glomerulonephritis. We reported the case of a 68-year-old man with IgG4-related tubulointerstitial nephritis combined with antiphospholipase A2 receptor (PLA2R)-related membranous glomerulonephritis, in which distinguishing between idiopathic PLA2R-related and IgG4-related secondary membranous glomerulonephritis was difficult. We diagnosed him as having IgG4-related disease, based on a serum IgG4 level of 170 mg/dL and the presence of IgG4-related parotiditis. On renal biopsy, there was tubulointerstitial nephritis with IgG4-positive plasma cell filtration, which was compatible with IgG4-related disease and membranous glomerulonephritis, with concomitant positive staining for PLA2R on immunofluorescence microscopy. The renal function immediately recovered after steroid treatment, probably because of the improvement in the tubulointerstitial lesions, but his nephrotic syndrome was steroid-resistant. Low-density lipoprotein (LDL) apheresis therapy was effective for membranous glomerulonephritis and increased his serum albumin from 1.4 to 2.8 g/dL. Although IgG4-related kidney disease usually accompanies secondary membranous glomerulonephritis, the positive PLA2R staining suggested a concomitant primary membranous glomerulonephritis. The recent treatment strategy, including LDL apheresis, for primary and secondary membranous glomerulonephritis was discussed briefly in this report.

The kidney is frequently involved by autoimmune rheumatic diseases. The renal manifestations may be variable, ranging from asymptomatic proteinuria and microscopic haematuria to nephrotic syndrome and rapidly progressive glomerulonephritis or vasculitis. In a number of cases the kidney involvement is related to the treatment of the original disease and may represent a major cause of morbidity and mortality. Thus, it is important for nephrologists and rheumatologists to remember that dysfunction of the kidney may be part of the primary systemic disorder or consequence of its pharmacotherapy. In the first part of this review we will analyse the kidney involvement in four autoimmune connective tissue diseases: systemic lupus erythematosus, Sjögren syndrome, polymyositis/dermatomyositis, and systemic sclerosis. Renal disease is common in lupus and is a main cause of morbidity and mortality. About 10% of patients with Sjögren syndrome may present interstitial nephritis or, more rarely, glomerulonephritis. Myoglobinuria and acute kidney injury is a frequent complication of polymyositis. Renal disease is one of the most serious complications of systemic sclerosis and may present with a dramatic renal crisis, characterized by malignant hypertension, oligo-anuria, and microangiopathic thrombocytopenic anaemia.

To evaluate the clinical/serological phenotype and outcomes of IgG4-related kidney disease. Case series of IgG4-related kidney disease from a cohort of 69 patients with IgG4-related disease. We defined kidney involvement as the presence of at least one of the following conditions: (A) laboratory parameters of kidney injury (proteinuria and/or elevated creatinine levels and/or hematuria); and/or (B) contrast-enhanced computed tomography features (multiple low-density lesions and/or nephromegaly and/or hypovascular solitary mass and/or renal pelvic lesion and/or perinephric lesions). We identified 17 patients with kidney involvement (24.6%), with a mean age of 53.6 ± 11.3 years; thirteen (76.5%) were male. Six patients fulfilled the laboratory criteria, six the imaging criteria, and five both. Five patients had a renal biopsy, the main histopathological diagnosis being IgG4 tubulointerstitial nephritis. Sixteen patients received glucocorticoids and 12 also immunosuppressors and/or biologics. Sixteen patients presented either total or partial renal remission at a median follow-up of 26 months, while one patient developed end-stage renal disease. Patients with kidney disease, as opposed to patients without kidney involvement, had a higher number of involved organs, higher IgG4-related disease responder index and IgG4 and IgG1 serum levels, higher prevalence of rheumatoid factor, and lower C3 and C4 levels. Our study emphasizes the systemic nature of IgG4-related disease, highlighting that renal involvement is usually present in a subset of patients with multisystemic disease, high IgG1 and IgG4 levels, and hypocomplementemia. Key Points • IgG4-RKD presents at a younger age in Mexican mestizo patients. • IgG4-RKD presents with proteinuria and kidney injury or as an asymptomatic imaging finding. • IgG4-RKD presents in the context of multisystemic disease, hypocomplementemia, and high IgG1 and IgG4 levels.

Anti-LDL Receptor-Related Protein 2 (Anti-LRP2) nephropathy is a rare form of kidney disease that affects the older patients and is characterized with acute kidney injury (AKI) and progressive renal tubular injury associated with IgG immune complex deposits along the basement membrane of proximal tubules, and circulating autoantibodies to the proximal tubule brush border protein LRP2 (megalin). We present the case of a 79-year-old man who was hospitalized for worsening malaise, abdominal distention and bilateral lower extremity edema, diagnosed with AKI and had nephrotic range proteinuria. Percutaneous kidney biopsy revealed tubulointerstitial nephritis with IgG immune complex deposits along the basement membrane of proximal tubules and brush borders. Immunofluorescence staining for LRP2 (megalin) showed similar granular tubular basement membrane deposits along the proximal tubules and proximal tubule brush borders. Electron microscopy revealed global podocyte foot process effacement. The patient was started on oral prednisolone 1 mg/kg and rituximab at a dose of 375 mg/m2 once weekly for 4 weeks with gradual tapering of prednisone. This case with AKI and nephrotic syndrome highlights the significant morphologic overlap with minimal change disease and anti-LRP2 nephropathy, which is associated with autoantibodies to the tubular brush border protein LRP2/megalin.