Acute Interstitial Nephritis: Infection, Rejection, and Autoimmune
University of Pennsylvania Medical Center
Infection is a cause of tubulointerstitial nephritis which damages the kidney in one of two ways. In
"reactive TIN" secondary to infection, organisms are not identified in the
kidney. The systemic immune reaction to infection is presumed to favor the renal accumulation of
pro-inflammatory molecules in the kidney leading to TIN. On the other hand, some infections localize
infectious particles to the kidney and the inflammation is a response to kidney-trophic pathogens. This
process is termed "infectious TIN". These categories are generally useful but
may not always be so neatly separated.
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:
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.
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.
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.
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
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
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
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
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
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
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.
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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