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Background: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers., Summary: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important., (© 2017 S. Karger AG, Basel.)

Background/aims: Chronic kidney disease involves inflammation/oxidative stress, which contributes to progressive kidney injury., Methods: Male Sprague-Dawley rats underwent 5/6 nephrectomy (Nx) or sham Nx and were sacrificed after 2 days, 2 weeks and 4 weeks. Microarray analysis expression sets over time suggested the evolution of renal lymphocyte infiltration and antigen-presenting cell (APC) activation after 5/6Nx. RT-PCR analysis also confirmed the migration and activation of lymphocytes and APCs through the upregulation of CD3, CXCR3/CXCL10 and CCR7/CCL19 mRNA in remnant kidney (RK). Purified T lymphocytes from spleen and unilateral ureteral obstruction (UUO) kidney were incubated with oxidized low-density lipoprotein (Ox-LDL)-treated major histocompatibility complex class II (MHC II)-expressing APCs. Culture supernatant was collected for mouse IFN-γ ELISA and cell proliferation was measured., Results: Ox-LDL deposited predominantly in renal tubulointerstitial areas of RK, increased over time, and co-stained with lectin-like Ox-LDL receptor in affected renal tubular cells. Both Ox-LDL and renal-specific glycoprotein Tamm-Horsfall protein were identified in renal lymph nodes. Cells co-staining for major MHC II and Ox-LDL were observed in RK and draining renal lymph nodes after 5/6Nx. Similarly, Ox-LDL was also present in tubules after UUO, CD3-positive T cells were present in the interstitium, and Ox-LDL-treated MHC II-expressing APCs induced proliferation and IFN-γ production in renal tubulointerstitial T lymphocytes isolated from kidneys after UUO., Conclusions: These data demonstrate that the tubulointerstitial inflammatory infiltrate that accompanies chronic kidney disease reflects, at least in part, the development of autoimmunity to novel antigens generated during renal injury., (Copyright © 2012 S. Karger AG, Basel.)

Background: Acute interstitial nephritis (AIN) is a common cause of acute kidney injury and is characterised by a dense interstitial cellular infiltrate, which has not been well defined. Previous studies have demonstrated a correlation between Epstein-Barr virus (EBV) infection and AIN. The purpose of our study was to define the nature of the interstitial immune infiltrate and to investigate the possibility of renal infection with EBV., Methods: Seventy-eight patients with AIN were identified from renal biopsy reports in a single centre over an 18-year period. Immunohistochemical staining was performed to define the cellular infiltrate. In situ hybridization and immunohistology were used to detect EBV., Results: A positive correlation between CD68 macrophage infiltration and serum creatinine concentration at presentation was identified. IL-4, eotaxin, CCR3, CCR5 and VCAM-1 were all expressed in biopsies of AIN. Using in situ hybridization and immunohistochemistry, EBV was not detected in any of the AIN sections analysed., Conclusion: This study has assessed the nature of the interstitial infiltrate in AIN. EBV was not detected in the renal biopsies, suggesting that EBV is not a pathogenetic factor in AIN., (Copyright © 2011 S. Karger AG, Basel.)

Immunoglobulin light chains are low molecular weight proteins that are filtered through the glomerulus and reabsorbed into the proximal tubular epithelium by binding initially to a heteromeric receptor complex composed of megalin and cubilin. Saturation of this receptor-mediated endocytotic process results in the presence of free light chains in the distal nephron and urine. In the course of metabolism of monoclonal light chains, nephrotoxicity can occur, resulting in clinical manifestations that can include acute kidney injury and progressive chronic kidney disease. Patterns of tubulopathic renal injury include proximal tubular epithelial cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (also known as 'myeloma kidney'). Research efforts over the past two decades have refined understanding of the molecular mechanisms involved in light chain-mediated tubular injury and are the subject of this review., (Copyright © 2011 S. Karger AG, Basel.)

The renal response to deposition of monoclonal light chains represents a spectrum of pathologic changes that can be divided into glomerular or tubulo-interstitial processes. Involvement of the tubulo-interstitium can include activation of the proximal tubule, proximal tubule injury/cell death, and cast nephropathy. In these diseases, the culprit is not the intact immunoglobulin protein but instead the immunoglobulin light chain. Recent noninvasive tests, including immunofixation electrophoresis or quantification of serum free light chains, have increased the sensitivity for detection of an abnormality in circulating free light chains and are invaluable ancillary tools, but short of renal biopsy, the diagnosis of these diseases can prove challenging. A description of the pathobiology and overview of the approach to management of these light chain-mediated renal lesions is provided.

Background: We have shown that leukocytes collected from sites of interstitial inflammation in patients on hemodialysis have a disturbed expression of CD11b compared to cells from healthy subjects. The aim of the present study was to study adhesion molecule expression on granulocytes in the peripheral circulation and at sites of interstitial inflammation in patients with renal failure., Methods: Two skin blisters were raised in 10 patients and 19 healthy subjects and interstitial exudates collected (0 h). Skin chambers were applied and exposed to buffer or serum for 10 h in order to induce an intermediate and an intense interstitial inflammation. Cells and blister fluid were collected for determination of leukocyte count, CD11b/CD62L expression, interleukin-8 (IL-8) concentration in the interstitium and blister activity in terms of CD11b up-regulation., Results: At the sites of intermediate and intense inflammation, granulocytes from patients with renal failure showed significantly higher expression of CD62L (p < 0.01 and p < 0.001, respectively) and significantly lower expression of CD11b (p < 0.0001 and p < 0.0001, respectively) compared to corresponding cells from healthy subjects. The interstitial concentration of IL-8 was significantly lower at the sites of intermediate (p < 0.005) and intense inflammation (p < 0.05) in patients with renal failure compared to in healthy subjects. In order to explore whether the decreased CD11b expression observed in patients is due to the interstitial milieu, blister exudates from patients and healthy subjects were incubated with leukocytes from healthy blood donors. Blister exudates from patients had a similar capacity to mobilize CD11b on granulocytes in vitro compared with blister exudates from healthy subjects. There was no consistent correlation between the expression of adhesion molecules on granulocytes in the interstitium and the concentration of IL-8 or the total interstitial concentration of chemotactic mediators., Conclusion: Constitutive cellular determinants are probably involved in the disturbed expression of adhesion molecules on granulocytes at sites of interstitial inflammation in patients with renal failure., (Copyright 2004 S. Karger AG, Basel)

Epstein-Barr virus (EBV) DNA in renal tissue in acute interstitial nephritis (IN) has not been previously reported. An 18-year-old male presented with a sore throat, fever, cervical lymphadenopathy, and oliguric renal failure. The rapid slide test for heterophile antibodies associated with infectious mononucleosis was positive, and a renal biopsy showed an acute interstitial nephritis. A polymerase chain reaction (PCR) assay identified EBV DNA in the renal biopsy. In situ hybridization (ISH) for EBV RNA and immunohistochemistry for latent membrane protein 1 of EBV were negative. Hemodialysis and prednisone 60 mg PO OD were administered and the s-creatinine dropped from 1,224 to 75 micromol/l over 9 days. The identification of EBV DNA in the kidney raises the possibility that direct infection plays a role in acute IN associated with EBV., (Copyright 2002 S. Karger AG, Basel)

The TINU syndrome (tubulointerstitial nephritis and uveitis) was first described by Dobrin et al. in 1975. Since then, more than 50 cases have been documented each with diverse immunopathogenetic and genetic characteristics. The aim of this report is to describe a case of TINU associated with reduced complement levels. We profile a 48-year-old white female with persistently reduced C4 complement levels during the acute phase of the pathology and with an unaltered immunologic profile. Renal biopsy evidenced a significant lymphocytic interstitial infiltration. Immunohistochemical studies of the interstitium infiltrates was positive for the presence of the T (CD3) markers (CD4 > CD8). Steroid therapy yielded a complete regression of the symptomatology with normalization of the complement levels. We suggest that it is possible to hypothesize that the various immunologic alterations associated with TINU, including the transient reduction complement levels, may be secondary to multiple inflammatory mechanisms which express themselves throughout the pathology., (Copyright 2001 S. Karger AG, Basel)

Many forms of tubulointerstitial nephritis (TIN) may have an autoimmune origin. To understand the pathogenesis of autoimmune TIN it is important to examine suitable animal models where the initiation and development of tubulointerstitial diseases can be assessed with precision. Experimental models of autoimmune anti-tubular basement membrane (anti-TBM) disease for example have allowed to define the nephritogenic role of antibodies which target tubulointerstitial moieties. Several tubulointerstitial antigens which are recognized by specific anti-TBM antibodies have been characterized at a molecular level in these models. The CBA/CaH-kdkd mouse strain represents another model of TIN where complex T-cell networks are uniquely altered, resulting in cell-mediated interstitial nephritis. Characteristic tubular alterations (up-regulation of adhesion molecules and CD44, cytokine and chemokine secretion) are prominent in several models of experimental TIN, promoting T-cell and monocyte infiltration. The complex interplay between tubular epithelial cells and immune cells is probably a prerequisite for a coordinated immune response in many forms of TIN, resulting in autoimmune renal tubulointerstitial injury and ultimately in renal failure.

A 69-year-old male who had a long history of ocular myasthenia was treated with omeprazole for 3 months. Progressive renal insufficiency was discovered fortuitously. There were no clinical or laboratory manifestations of immunoallergy. Renal biopsy revealed severe granulomatous interstitial nephritis, tubular injury and fibrosis. Histology of a liver nodule disclosed hepatic granulomatous involvement. Withdrawal of omeprazole and a short course of corticosteroids were followed by improvement but not normalization of renal function. This is the eighth report of omeprazole-induced interstitial nephritis. In the present case as in 2 others in the literature, the patients had been followed up for an autoimmune disease previously, which suggests that in patients with such a background, patients should be examined regularly for renal functional impairment during treatment with omeprazole.

TGF-beta1 has been implicated as a profibrotic growth factor in the bulk of published experimental work regarding the actions of this cytokine in kidney disease. Such investigations have spanned a methodologic spectrum from in vivo analyses to cell culture work with purified growth factors and analyses of gene expression. Important correlative work using clinical specimens has established the presence of augmented TGF-beta expression in renal diseases characterized by excessive sclerosis or fibrosis. While in the aggregate this information supports a compelling argument in favor of TGF-beta having a predominant effect to accelerate progressive renal failure, the cytokine clearly also demonstrates effects which would tend to abrogate renal injury. We provide a summary of published and new experimental data outlining immunosuppressive and 'renal-protective' actions of TGF-beta1.

The process of injury and regeneration in different models of acute renal failure is accompanied by the transient interstitial accumulation of mononuclear leukocytes. The relationship between these accumulated cells and the onset and progression of the regeneration process resulting in the complete functional and morphological recovery is still a matter of debate. In this process cell subsets may either be selectively important or combine to a communicative network, signalling the cells at the site of injury. In a first trial to investigate this hypothesis, the CD8-positive subset of leukocytes, consisting mainly of cytotoxic and suppressor T lymphocytes and to a lesser extent of natural killer cells, was depleted in vivo in rats by means of a monoclonal antibody directed against CD8. Although the depletion obtained evidently prevented the infiltration of these cells into the renal interstitium, it could not influence neither the development nor the resolution of renal insufficiency in response to mercuric chloride administration as compared with control animals who had received an irrelevant isotype-matched monoclonal antibody. The extent of renal damage was unaffected as were onset and duration of renal epithelial cell proliferation. Consequently, these data do not support a major role for the CD8-positive cell subset per se in the development of acute nephrotoxic injury and subsequent regeneration.

Five patients with idiopathic interstitial nephritis and uveitis without bone marrow granulomas were followed-up for 1 year. Ophthalmological examination revealed bilateral anterior uveitis. Light microscopy of the renal tissue revealed predominant lymphocyte infiltration of the interstitium. Immunohistochemical analysis revealed a clear predominance of memory T lymphocytes (CD45RO+) in the interstitial and tubular infiltration. HLA typing, and immunophenotypic studies of peripheral blood mononuclear cells including absolute lymphocyte and monocyte counts were assessed. The patients' peripheral T-cell subpopulation did not significantly differ from control studies. With steroid treatment maintained during a period of 6-9 months renal function and uveitis responded dramatically in all patients. After 1-year follow-up, only 1 patient showed a relapse of uveitis, but there was complete clinical recovery of the nephritis in all 5 patients. The aim of this study was to describe the 1-year follow-up of 5 new cases of acute tubulointerstitial nephritis and uveitis syndrome, and assess some aspects of their cellular immunity.

Acute interstitial nephritis (AIN) and uveitis of unknown etiology developed in a 15-year-old girl. Symptoms and urinary abnormalities improved spontaneously but moderate renal dysfunction and anterior uveitis persisted. A repeat biopsy performed 2 years later showed focal tubulointerstitial changes, while bone marrow examination revealed granulomas. Simultaneously, antineutrophil cytoplasmic antibodies (ANCA) were detected, and decreases in T cell population and lymphocyte function were found. These immunological abnormalities normalized in parallel with clinical improvement with corticosteroid therapy, strongly suggesting that in some patients autoimmune disorders contribute to the pathogenesis of the disease.

The pathogenesis of renal interstitial fibrosis is not fully understood at present. As renal interstitial fibrosis occurs mainly in association with interstitial cell infiltrates, several cytokines, e.g. PDGF, TGF-beta, IL-6, are thought to play a major role in the induction and progression of renal interstitial fibrosis. In order to prove whether renal tubular epithelial cells produce cytokines which are known to modulate renal interstitial fibroblasts, RNA was isolated from human renal tubular epithelial cells and from human renal fibroblasts. The expression of specific cytokines and growth factors was analysed by Northern blot analysis using cDNA probes for IL-1 alpha, IL-1 beta, IL-6, INF-gamma, TNF-alpha, a-FGF, b-FGF, GM-CSF, PDGF-B and oligonucleotides for IL-2 and TGF-beta 1. In renal tubular epithelial cells from normal and diseased kidneys, mRNA transcripts for PDGF-B, IL-6 and GM-CSF could be detected. Quantitative analysis of the mRNA transcripts of the cytokines expressed revealed consistently higher amounts of GM-CSF and PDGF-B mRNA in tubular epithelial cells from diseased in comparison to normal kidneys. Furthermore, higher amounts of GM-CSF and PDGF-B mRNA transcripts were detected in tubular epithelial cells derived from kidneys with interstitial fibrosis as compared to tubular epithelial cells from diseased but nonfibrotic kidneys. Renal fibroblasts from normal and fibrotic kidneys showed a weak signal for IL-6, but PDGF-B and GM-CSF were not expressed in these cells. By means of colony assays, using human bone marrow cells in the presence or absence of neutralizing antibodies, the release of biologically active colony-stimulating factors GM-CSF and M-CSF by renal tubular epithelial cells from normal and diseased kidneys could be demonstrated. The present results probably indicate interactions between renal tubular epithelial cells and renal fibroblasts in the progression of renal diseases.

This study was designed to characterize the immunopathology of acute tubulointerstitial disease in nephrotoxic serum nephritis in nonsensitized rats. Groups of Lewis rats were studied at 12 time periods ranging from 10 min to 28 days after nephrotoxic serum injection. Nephritic rats developed interstitial nephritis during the acute heterologous phase of renal injury. Coincident with the focal deposition of nephrotoxic antibodies along tubular basement membranes at 24 h, an influx of polymorphonuclear cells and macrophages was evident. The most prominent infiltrate, present between days 3 and 7, was dominated by macrophages with smaller numbers of lymphocytes that were mainly cytotoxic T cells. Dual-labeling studies demonstrated the colocalization of linear tubular basement membrane deposits of the nephrotoxic antibody with focal clusters of interstitial lymphohemopoietic cells. Increased complement deposition was not evident along the tubular basement membranes; moreover, C3 depletion with cobra venom factor failed to attenuate the interstitial inflammation. During the late autologous phase of glomerulonephritis, tubular basement membrane deposits of rat IgG did not appear and the interstitial disease resolved. The results of this study demonstrate that the heterologous phase of nephrotoxic serum nephritis is an antibody-mediated disease directed against the basement membranes not only of the glomeruli but also of some tubules. Antibody deposition is followed by an acute influx of phagocytic cells to both regions of the kidney. These cells may play an important role in the genesis of acute interstitial injury and chronic interstitial fibrosis associated with antiglomerular basement membrane nephritis.

Experimental tubulointerstitial nephritis (TIN) was induced in Wistar rats and New Zealand white rabbits by direct intrarenal inoculation of Tamm-Horsfall glycoprotein (THG) or egg white component (egg white A). After five immunizations of THG or egg white A with complete Freund's adjuvant (CFA), direct intrarenal inoculation of THG or egg white A also induced more severe TIN in the inoculated kidney. By the 7th day, in 1 of the animals with immunizations and then intrarenal inoculation of THG, the inoculated kidney was swollen and appeared necrotic. By the 28th day, in 1 of those receiving immunizations and intrarenal inoculation of THG, the inoculated kidney became contracted. TIN was observed in three experimental models, namely (a) direct intrarenal inoculation of THG or egg white A; (b) five immunizations of THG and (c) immunizations and then intrarenal inoculations of THG or egg white A. The most severe TIN was observed in the latter model.

In two female pediatric cases of uveitis with proteinuria and glycosuria, kidney biopsy demonstrated the presence of interstitial nephritis. Peripheral leukocytes responded positively in vitro in the leukocyte migration inhibition test with renal tubular antigen, thus suggesting the possibility that the patients' lymphocytes infiltrating into the renal parenchyma might be sensitized against the renal tubular antigen. Urinary beta2-microglobulin was also demonstrable and its levels correlated fairly well with the clinical course of uveitis in both cases.

A soluble tubular basement membrane (TBM) antigen has been purified from murine kidneys. The isolated fibers were trypsinized and subjected to zone electrophoresis, Sephadex G-200 gel filtration, and DEAE-cellulose chromatography eluted with linear NaCl concentration gradient while monitoring the TBM antigen activity with specific antihuman TBM antigen. The molecular weight of TBM antigen was estimated to be 30,000 daltons by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The purified TBM antigen gave a single precipitin line against the specific antiserum and cross-reacted with the TBM antigen similarly purified from other animals such as goat, guinea pig and also with human TBM antigen in an immunodiffusion plate. BALB/c, C3H/He and C57BL/6 mice were immunized twice at 2 weeks' interval with the TBM antigen and adjuvant. Histologically typical interstitial nephritis occurred in BALB/c mice, whereas no nephritis developed in other strains of mice. The inflammatory changes were characterized by intense mononuclear cell infiltration, tubular destruction, and interstitial and periglomerular fibrosis. The serum-stained basement membrane of normal tubules and Bowman's capsules, and no antiglomerular basement membrane activity was detectable in the serum by immunofluorescence. This system provides a simple and useful model in interstitial nephritis in mice produced with a purified TBM antigen.

The pathogenic effect of antitubular basement membrane (TBM) antibodies in anti-TBM interstitial nephritis has been demonstrated. To determine the relative role of sensitized cells in inducing this lesion, lymph node cells (LNC) alone or a combination of LNC and peritoneal exudate cells were transferred from Brown Norway (BN) rats, previously immunized with TBM into unimmunized BN-recipient rats. Cells were transferred directly under the recipients' renal capsules. Although significant tubular lesions were induced by the cells, the lesions were usually mild and always focal. Hence, sensitized cells do not appear to be central to the pathogenesis of anti-TBM nephritis.

Unlabelled: The effect of antiproximal tubule basement membrane (TBM) and brush border (BB) antibodies on p-aminohippurate (PAH) transport was evaluated in a rat model of immunologically mediated interstitial nephritis. Immunized rats developed anti-TBM antibody titers ranging from 1 to 3,072 with continuous linear IgG and interrupted C3 deposits in the TBM. Circulating anti-BB antibodies were detected in half of the immunized rats in titers ranging from 1 to 128. Heavy IgG deposition was present in the BB when circulating anti-BB antibody titers exceeded eight and proteinuria was present. When anti-TBM antibody titers were 1,024 or greater the slice-to-medium PAH concentration ratio (S/M) was significantly reduced (p less than 0.001). Combined immunofluorescent microscopy and section freeze-dry autoradiography revealed normal cellular distribution of PAH-3H in all proximal tubules except in rat microscopic foci of interstitial nephritis in which concentrative transport was absent. However, luminal secretion of PAH-3H was strikingly reduced in tubules with heavy IgG BB deposits. 3-hour PAH secretion in vivo fell significantly in rats with circulating and tissue anti-BB antibodies. Antibody inhibition of PAH transport appeared to be independent of morphologic damage., Summary: Anti-TBM antibodies were associated with decreased slice uptake of PAH-3H while anti-BB antibodies were associated with decreased luminal PAH secretion in vitro and in vivo.

Experimental models of immunologically induced tubulo-interstitial nephritis (TIN) in rats are described. Antitubular basement membrane (anti-TBM) nephritis was demonstrated to be a TIN resulting from an antigen antibody reaction. Renal transplant rejection and the local graft-vs-host (GVH) reaction were cell-mediated immune reactions in which the antigen was possibly shared by kidney structures. A cellular immune reaction to locally applied antigens was shown to be the basis for another experimental model of TIN, possibly originating from activated mediator systems.

A 5-year-old Chinese girl had had absence seizures and received sodium valproate (VPA) treatment which provided good control. Six months later, she developed interstitial nephritis with proteinuria and microhematuria. Renal biopsy revealed interstitial nephritis with granular deposition of immunoglobulin G (IgG) and C3 in the renal tubular basement membrane (TBM). Ultrastructurally, dilated smooth endoreticular cisternae with mitochondrial degeneration in the tubular cells and scattered electron-dense deposits within the TBM were also noted. Serum circulating immune complexes were detectable, ACH50 and properdin factor B increased. Mononuclear cells (MNC) from the patient after in vitro incubation with VPA (100 micrograms/ml) induced interleukin-2 (IL-2) production and lymphoproliferative response. However, there was no response in controls. The serum VPA level ranged from 84 to 92 micrograms/ml. After VPA was stopped, the microhematuria and proteinuria disappeared. These observations indicate that VPA-induced interstitial nephritis represents a sequence of interrelationships among multiple immunologic factors.

14 children with proven or presumably immunologically mediated tubulo-interstitial nephritis are presented. In 2 patients anti-tubular basement membrane antibodies were detected. In 6 immunofluorescence microscopy showed granular deposits of immunoglobulin and/or complement likely representing interstitial location of immune complexes. The findings by immunofluorescence were not significant in the remaining 6 patients. However, the association of renal disease to extra-renal disorders, namely chronic active hepatitis and ulcerative colitis, or uveitis or the presence of an epithelioid granuloma with multinucleated giant cells suggests that in such patients an immunologic disorder might be responsible for the tubulo-interstitial nephritis.

Experimental drug-induced allergic nephritis (DIAN) was mediated by an antihapten antibody. It has been postulated that DIAN is induced by cellular and humoral mechanisms. We tried to induce DIAN in mice, where the mechanism depends on humoral immunity. The first attempt was made in mice actively producing antibodies against cephem antibiotics, i.e. cephalothin (CET). Acute interstitial nephritis (AIN), morphologically similar to human disease, was obtained by injection of a CET-protein conjugate into the renal cortex in mice producing anti-CET-IgE and IgG antibodies. AIN could also be induced when normal mice, passively given anti-CET IgG antibody, received a subsequent intrarenal challenge with CET-protein conjugate. These preliminary results indicate that IgG antibody has an important role in the genesis of DIAN. Further experiments were performed with monoclonal antibodies directed against haptens instead of antibiotics in order to clarify the Ig isotype concerned. In mice passively given anti-Dansyl-IgG2a or anti-NP-IgG2a monoclonal antibodies, a challenge with an appropriate hapten-protein conjugate into the renal cortex resulted in AIN. However, transfer of anti-Dansyl-IgE or anti-DNP-IgE monoclonal antibodies, followed by challenge, did not induce AIN. In the experimental systems described, the involvement of a cellular immune mechanism is excluded. The results suggest that IgG, but not IgE antibody, is essential for the induction of DIAN by humoral immune mechanism.

Mice immunized with rabbit renal basement membranes form autoantibodies to their kidney glomerular and tubular basement membranes (GBM/TBM). Development of renal tubular disease (RTD) consists of deposition of autoantibodies along the GBM/TBM with the inter- and intratubular accumulation of lymphocytes and macrophages and destruction of the TBM. Transfer of this disease in mice with either serum or monoclonal antibodies, however, has been difficult to demonstrate and, therefore, attempts were made to confirm a report that RTD is passively transferred by anti-TBM autoantibodies. Using the revised protocol in this later report, we found that 12 weeks after transfer autoantibodies were deposited along the GBM and/or TBM of the recipients, yet RTD was not observed. Although qualitative and quantitative characteristics of the antibody may play a role in the pathogenesis in the murine model of RTD, we could not obtain evidence to support and confirm this study.

The phagocytic activity of monocytes from 15 uremic patients was estimated by the superoxide anion test. There was a significant decrease in the ability of monocytes from these patients to produce superoxide anions in comparison with monocytes obtained from healthy subjects. Addition of urea to monocytes from healthy subjects caused a marked reduction in their ability to produce superoxide anions, while addition of creatinine did not cause any effect. Monocytes from patients with renal failure of glomerular origin were found to produce less superoxide anions than those from patients with other types of renal diseases.

The interrelationships between tubulointerstitial immune deposits (TID), interstitial inflammation, glomerular changes, renal function, and prognosis were assessed in the renal biopsies from 93 patients with lupus nephritis. The prevalence of TID was 33% by immunofluorescence and 23% by electron microscopy. Although predominantly detected along and within tubular basement membranes, extraglomerular immune deposits were also present in the wall of renal interstitial capillaries and small arteries as well as in Bowman's capsule. The prevalence of TID correlated with the activity of glomerular lesions and, to a lesser extent, with the severity of proliferative lupus nephritis (WHO classes II-IV). TID were much less common in the membranous form (WHO class V). The severity of interstitial inflammation correlated with the degree of renal insufficiency and was an accurate prognostic indicator of progressive deterioration of renal function. However, there was no correlation between prevalence of TID and prevalence and severity of interstitial inflammation, suggesting that the latter is not necessarily secondary to the presence of immune complexes and that other pathogenetic mechanisms may be involved.