Pathogenesis:
Immunopathological mechanisms are implicated in the pathogenesis of reactive TIN. Cytokines activated systemically in response to infection may be filtered and reabsorbed in the kidney with the subsequent localization of inflammatory cells to the kidney ¹. Pro-inflammatory cytokines can enhance the adhesion of lymphocytes to tubular epithelial cells. Infiltrating inflammatory cells may then release more pro-inflammatory molecules leading to further recruitment and amplification of the nephritis. In infectious TIN microbes may cause damage in several ways. The organism may release molecules that damage parenchymal elements including degradative enzymes, endotoxins, or exotoxins. Organisms may invade vessels and cause occlusion. Direct penetration of host cells by microbe such as rickettsiae and viruses may cause cytopathic change and cell lysis. Finally, host inflammatory responses including antibody mediated, cell mediated, or antibody dependent cell mediated pathways, activating the entire range of effector cascades, may damage the kidney.

Selected Specific Bacterial Infections:
Streptococci:
Before antibiotics, the rate of TIN secondary to streptoccal infection was reported to be 75-95% in autopsy series². Group A organisms cause immune complex mediated glomerulonephritis and reactive TIN with scarlet fever. The cellular infiltrate includes lymphocytes, plasma cells and occasional neutrophils and eosinophils. Group B organisms cause pyelonephritis and sepsis in immunosuppressed patients. Group D strep cause endocarditis and pyelonephritis. Microbial pathogenic factors include lipoteichoic acid, streptolysin O, peptidase, and M protein.

Staphylococcus:
Most renal staphylococcal infection is staph aureus which spreads to the kidney through a hematogenous route. Immunosupressed patients ,and in particular transplant patients, are at risk. Patients are acutely ill with fever, back pain, lower urinary tract symptoms, and renal failure. Abscess formation with many neutrophils is characteristic. Virulence factors include bacterial surface receptors which recognize adhesion molecules such as fibronectin and laminin and facilitate bacterial adherence; exotoxins such as pore forming protein³; and superantigens⁴.

Legionella:
Infection with Legionella pneumophilia is an unusual cause of TIN. Patients have hematuria, proteinuria, and leukocyturia with renal failure. On biopsy the infiltrate is an intense multifocal mixed inflammatory reaction with lymphocytes, plasma cells, macrophages, variable neutrophils and tubular necrosis. Bacteria have been identified in tissue⁵.

Mycobacteria:
Renal tuberculosis follows a primary pulmonary infection. Since the frequency of pulmonary tuberculosis is on the rise, an increase in renal mycobacterial infection is expected. Approximately 5% of tuberculosis is extrapulmonary and 20% of the extrapulmonary tuberculosis involves the genitourinary tract. Most mycobacterial infection is secondary to mycobacterium tuberculosis although other mycobacteria such as M bovis, M kansasii, M intracellulare can also cause renal infection. Renal tuberculosis comes in two forms; miliary and ulcerocaseous. Miliary tuberculosis results from hematogenous spread of a primary or reactivated active pulmonary tuberculous infection. The infection is often clinically silent. The kidneys are studded with small white nodules on the order of 1 mm. Nodules are more common in the cortex. Microscopically these tubercles are granulomas with epitheliod histiocytes and central necrosis. Organisms are found in the lesions. There is often an associated interstitial lympho-plasmacytic infiltrate. Granulomas may heal or progress both in the cortex and in the medulla.

In the ulcerocaseous form of renal tuberculosis lower urinary tract symptoms predominate. Sterile pyuria and microscopic hematuria are common. Renal involvement is usually unilateral. Lesions often begin in the medulla with subsequent pelvocalyceal caseation and necrosis. The kidneys show irregular scarring with pelvic deformity. Pelvic or ureteral stenosis may occur. When pelvic scarring occurs in association with caseous necrosis, pyonephrosis occurs and the kidneys are turned into bags of caseous material.

Macrophages will ingest bacteria but will not kill them unless they are activated. T cells activated by mycobacteria secrete ( interferon which activates macrophages to kill ingested organisms through active oxygen species. Non activated macrophages which have ingested mycobacteria can also be lysed by cytotoxic T cells.

Enterobacteria Causing Pyelonephritis:
Pyelonephritis implies inflammation of both the pelvocalyceal system and the renal parenchyma. Most pyelonephritis is associated with ascending infection from the lower urinary tract. Gram negative enteric organisms, and in particular E.coli, are the infectious agents. A selected number of O (polysaccharide), K(capsular polysaccharide) and H ( flagellar) serotypes are frequent in infection suggesting that these antigens as possible virulence factors⁶. Adhesion between bacteria and epithelial cells is effected by bacterial fimbriae or pili. P fimbriae ( so called because they attach to a digalactoside residues related to P blood group) are heavily represented in acute pyelonephritis ^{6, 7}. Uncomplicated acute pyelonephritis and non-obstructive acute pyelonephritis E coli stains show high levels of the pap ( pyelonephritis associated pili) gene and are antibiotic multisensitive ⁸.

Anatomically, pyelonephritis may be either obstructive ( tumor, stone, stricture) or non-obstructive and related to reflux ( reflux nephropathy). In both instances infected urine gains access to the kidney by intra-renal reflux, preferentially at the poles. In acute pyelonephritis there is acute pelvic inflammation and acute cortical interstitial inflammation which then ruptures into the tubular lumens. The glomeruli are spared. In chronic pyelonephritis the pelvic inflammation is lymphocytic with pelvocalyceal distortion. The cortical changes include chronic interstitial inflammation and fibrosis, tubular atrophy, glomerular obsolescence, and cortical thinning. Scarring is geographic and classically oriented towards the poles. Compound papillae at the poles may facilitate intarenal reflux and scarring at those sites⁹. Both infection and reflux are contributors to the scarring process and the relative contributions of each are debated¹⁰.

Selected Specific Viral Infections:
Immunocompromised hosts are known to be highly susceptible to viral infections. EBV associated PTLD, adenovirus, cytomegalovirus, herpes virus, and polyomavirus (BK or JC) have all been associated with renal disease in these patients.

EBV driven post-transplant lymphoproliferative disease (PTLD) occurs in 1-2% of renal allograft recipients. Morphologies may range form low grade polymorphous infiltrates to high grade non-Hodgkin's lymphoma. EBV infection is present in 98% of PTLD cases and can be recognized in tissue by performing in situ hybridization for either latent or lytic phase RNA. EBER is the most abundant latency species. PTLD may coexist with rejection. While no viral inclusions are found, clues to an EBV associated lymphoproliferation in a polymorphous infiltrate include the presence of immunoblastic atypia, excess plasma cells, and lymphoid mitoses.¹¹,¹². EBV has also been identified in some cases of idiopathic chronic interstitial nephritis including infection of tubular epithelial cells¹³.

Cytomegalovirus acute interstitial nephritis is well known in congenital and neonatal situations.¹⁴ CMV interstitial nephritis may also occur in immunosuppressed adults.¹⁵ The viral inclusions are characterized by cytomegaly, cytoplasmic inclusions, nuclear enlargement, and large lilac colored nuclear inclusions surrounded by a halo of chromatin clearing and peripheral condensation. CMV infections may lead to graft loss. Glomerulonephritis with CMV inclusions is rare.

HSV as a cause of kidney failure is very rare. Interstitial nephritis has been documented in renal allografts.¹⁶ The diagnosis is made by identifying the characteristic multinuclear inclusions.

Adenovirus produces a variety of clinical symptoms in the immunocompromised host. These include hemorrhagic cystitis, pneumonia, hepatitis, nephritis, enterocolitis and multiorgan failure. The frequency of adenovirus infection is probably underestimated since definitive diagnosis requires renal tissue. In marrow transplants, the frequency appears to be increasing. Shields¹⁷ in 1985 reported 4.9% infection rate with 0.9% invasive infection with virus present in tissue. More recently Flomberg¹⁸ has reported a positive culture rate of 20.9% with invasive disease of 3.5%. Hemmorhagic cystitis is most frequent in renal and bone marrow transplant patients. The B2 subgenus has tropism for the GU system and serotypes 7, 11, 34, and 35 are most frequent in GU infections. The symptoms of nephritis may be subtle¹⁹ and adenovirus cystitis may mask the nephritis. Hackman²⁰ characterized a group of 21 marrow recipients with kidney tissue positive for adenovirus. Symptoms and signs developed at a median of 50 days post engraftment and included gross hematuria (76%), flank pain (28%). Acute renal failure developed in 95% at a median of 75 days post transplant. The diagnosis of adenovirus infection was made by biopsy in 2 patients and at autopsy in 19 patients. Occasionally, adenovirus interstitial nephritis can be seen in immunocompetent patients²¹.

BK virus (BKV) is member of the polyomavirus family which includes JC virus (JCV), SV40, and many other animal viruses. Polyomaviruses are largely species specific and are classified in this category on the basis of size of the virion (dia 40-45 nm), naked icosahedral capsid, double-strand circular DNA genome of molecular weight 3.2X10⁶ , and sharing of sequence with other polyomavirus. All polyomaviruses multiply in the nucleus. Polyomaviruses have a large degree of host and tissue specificity. BKV and JCV do not naturally infect any other species other than humans. The sequence of events in infection with BKV very likely involves entry of the virus into the respiratory tract, multiplication at the site of entry, viremia with transport of the virus to the target organs which are kidney and bladder, and multiplication at the site of the target organ. In immunocompetent hosts following primary infection, BKV probably persists in the kidney for an indefinite period of time. Immunosuppression with impairment of T cell activity may lead to reactivation of BKV in the urinary tract. Patients at risk for reactivation infection with BKV may have one or more of the following conditions: bone marrow or kidney transplants; primary immune deficiency; cancer chemotherapy; pregnancy; diabetes; HIV; old age.

Respiratory infection in young children is almost always mild and a primary infection. Reactivation of BKV in pregnancy occurs in 3.2% of cases. Once established viral excretion persists intermittently through the pregnancy. Hemorrhagic cystitis is common in bone marrow transplant recipients. The onset of BKV infections occurs between 2-8 weeks post-transplant. The duration of viruria is usually 3-4 weeks. The onset and termination of viruria often corresponds to the timing of the hemorrhagic cystitis.

In renal transplant patients 25-44% excrete BKV or JCV in the urine.²² The duration of excretion varies from weeks to months. Infections may be primary or reactivation, and seropositive donors can infect recipients. Infections are associated with some cases of ureteral obstruction.²³ A multicenter study²⁴ found infection rates of 22% and 11% of BKV and JCV. This study failed to find an association with graft loss or death. Nickeleit et al²⁵ has described BKV infection in 5 allografts treated with tacrolimus. Infected epithelial cells were found along the entire length of the nephron and showed nuclear enlargement and pleomorphism. Viral inclusions were either irregular and eosinophilic or pale and without halos. Early changes were found in the medulla with secondary infection of the cortex. There was a mild interstitial infiltrate. "Decoy" cells, which are so-named because of their possible confusion with malignant transitional cells, were found in the urine. Creatinine levels deteriorated over months in these patients and there were two graft losses. Other case reports of renal failure associated with BKV infection have occurred in Hodgkin's lymphoma and immunodeficiency states.^{26 , 27} BKV has been found in islet cell tumors, glial brain tumors, renal cell carcinoma, Kaposi's sarcoma, and osteosarcoma although the carcinogenetic potential in these tumors has not been established.²⁸ Quantitative plasma PCR for BK has been used to detect infection in renal transplant recipients without resorting to biopsy²⁹,³⁰

HIV TIN
Acute and chronic tubulointerstitial inflammation in HIV patients is often related to the many drugs used in these patients, however, it may also be a feature of HIV infection. In one autopsy study of AIDS patients, 38% had tubulointerstitial inflammation³¹. The interstitum shows edema and collections of lymphs, plasma cells, neutrophils and macrophages. In areas of inflammation, degenerative and regenerative tubular changes, tubular , and interstitial fibrosis can be prominent. While the role of parenchymal infection has been debated in HIVN, some authors have documented HIV in tubular epithelium³².

Selected Fungal Infections:
Fungal infections are unusual in the kidney. Patients are often immunosuppressed. Candida, Torulopsis and Aspergillus are the most frequent agents. Most infection is hematogenously carried to the kidney. Tissue reaction may be necrotizing with acute inflammation or it may be absent, depending on the host.

Tubulointerstial Nephritis Secondary to Allogeneic Reaction
Acute tubulointerstitial rejection is categorized under the revised Banff Classification of 1997 as either "suspicious " or "Type I" depending on the extent of infiltrate and the presence of lymphocytic tubulitis. Biopsies "suspicious" for rejection have an interstitial infiltrate involving 10-25% of the parenchyma with minimal tubulitis ( less than 4 lymphs per tubular cross section).

"Type 1A" tubulointerstitial rejection have an interstitial infiltrate which involves more than 25% of the parenchyma with moderate tubulitis ( >4 lymphs per tubular cross section). "Type IB" rejection have an interstitial infiltrate which involves more than 25% of parenchyma but also has severe tubulitis ( > 10 lymphs per tubular cross section)³³.

There are three fundamental immunological considerations when considering the pathogenesis of acute tubulionterstitial rejection i.e. the antigenic targets and targeting mechanisms, the cells and molecules which effect damage , and the mechanisms for the induction of tolerance.

The Major Histocompatibility Complex (MHC) antigens ( Class I and II) are the fundamental targets of alloreactive T cells in graft rejection. The cell surface expression of MHC is regulated by inflammatory mediators including cytokines such as the interferons (IFN) and tumor necrosis factor (TNF). IFN "/ $ produced by macrophages and fibroblasts and induces MHC I on a variety of cells and most especially on glomerular endothelium³⁴. IFN( produced by activated T cells and upregulates both MHC I and II on many cells and in particular on the tubular epithelium³⁵. This increased MHC density might facilitate targeting by alloreactive T cells however, the hypothesis that such upregulation of MHC facilitates rejection is debated. Minor tissue specific antigens may also be allogeneic targets. In the kidney we know little about these minor antigens. A monocyte-endothelial antigen system has been associated with some cases of hyperacute rejection³⁶. Graft infiltrating lymphocytes which react with tubular epithelial cells can be found³⁷. Cytokines may facilitate the adhesion of T cells to epithelial target surface ( conjugate formation) through the upregulation of adhesion molecules. In combination IFN ( , TNF and IL-1 are efficient in enhancing conjugate formation³⁸. Tubular epithelial cells may also make chemokines in response to cytokine stimulation including IL 8 in response to IL-1 and TNF- ". . This may facilitate the entrance of more inflammatory cells into the microenvironment of the allogeneic reaction. Some have suggested that the primary target of tubulointerstitial rejection is not the tubular epithelial cell but rather the peritubular capillary endothelium³⁹.

The immunophenotype of grafts with acute tubulointerstitial rejection and the minor infiltrates which can be seen in stable grafts overlap, however, certain differences are recognized. The infiltrates of active rejection have been reported to have increased numbers of CD8+ cells⁴⁰, invasion of tubules by CD57+ cells⁴¹, and an increased ratio of CD45RO/CD45RA isoforms⁴².

The induction and maintenance of tolerance is largely not understood. Functioning allografts may have a decrease in donor specific cytotoxic lymphocytes⁴³ but this decrease does not always correlate with the absence of rejection. Tubular epithelial cells stimulated with IFN ( and TNF will upregulate MHC, ICAM and LFA-3 and have enhanced binding of lymphs, this conjugate formation fails to stimulate a significant proliferative response to donor antigen and may result in an effete allogeneic reaction⁴⁴, thus promoting tolerance. Microchimerism with donor derived cells in the circulation has also been proposed as a mechanism of long term tolerance ⁴⁵.

Tubulointerstitial Nephritis Secondary to Autoimmune Disease
Antibody Tubular Basement Membrane Antibody Mediated TIN is an unusual cause for interstitial nephritis. Primary anti-TBM antibody mediated TIN is exquisitely rare with just a handful of cases in the literature. Linear deposits of IgG and C3 are seen along the TBM's in association with a dense mixed interstitial inflammatory infiltrate. The glomeruli are negative for immunoreactants. Circulating antibodies to 48-58 kd TBM protein are found in the serum⁴⁶. Secondary anti-TBM antibody mediated TIN is found in 50-70% of patients with anti-GBM antibody mediated GN. The TBM linear deposits are generally more focal and less intense that the GBM labels. Anti-TBM antibodies have also been found is several patients with membranous glomerulonephritis, particularly in children. Some cases are associated with other autoantibodies.

Immune Complex Mediated TIN
Interstitial nephritis associated with immune complex deposition is for the most part secondary to other known infectious or autoimmune diseases, or associated with other primary glomerulonephridites. Primary idiopathic immune complex associated interstitial nephritis has been reported with granular deposits of IgE along the TBM's. The most common instance with granular immune deposits along the TBM's is secondary to SLE. Overall, approximately 50% of biopsies from patients with SLE have granular TBM deposits. The frequency of TIN varies from 12-69%. TBM deposits are most frequent with WHO class IV nephritis and least common with class V. Deposits usually contain IgG, C3, and C1q. Some patients with mixed cryoglobulinemia can have granular TBM deposts. In occasional cases of membranous glomerulonephritis there is an associated TIN and granular immune deposits along the TBM's⁴⁷. In rare instances, reactivity with antiserum to FX1A ( Heyman nephritis) has be demonstrated.

Specific Categories of Cell Mediated TIN
TubuloInterstitial Nephritis with Uveitis (TINU)
In 1975 Dobrin⁴⁸ described a syndrome of tubulointerstitial nephritis with uveitis (TINU). Patients with TINU may present with renal failure, proximal tubular dysfunction (Fanconi's syndrome), or renal insufficiency and proteinuria. Ocular symptoms may precede or follow the renal dysfunction. Histology shows a brisk tubulointerstial nephritis with mostly mononuclear cells and variable eosinophilia. Occasional microganulomas without necrosis can be seen in kidney and bone marrow. The process is thought to be a T-cell mediated reaction. Occasional TINU cases may be associated with EBV⁴⁹ or reduced complement⁵⁰.

Sarcoidosis
Renal failure secondary to sarcoidosis is unusual being seen in about 1% of patients with sarcoid. The frequency of asymptomatic renal involvement is higher, in the range of 9-25%⁵¹. Histology shows an infiltration of the interstitium with lymphs and macrophages and numerous well formed non-caseating granulomas.

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