Tubulointerstitial and Vascular Diseases of the Kidney
Section 3 -
Chronic Tubulointerstitial Nephritis
Donna J. Lager, M.D.
Matthew Lewin, M.D.
Case 2: Chronic Tubulointerstitial Nephritis
A 34 year old man with a history of ulcerative colitis presented with renal
failure and a serum creatinine of 8.7 mg/dl.
Chronic structural alterations of the tubules and interstitium can develop as a primary lesion after
prolonged exposure to various therapeutic or environmental agents or in association with a number of
systemic illnesses, or as a result of progressive glomerular or vascular injury. Primary chronic
tubulointerstitial nephritis accounts for 15-30% of cases of end stage renal disease.
As discussed earlier, the morphologic features of acute TIN include infiltration of the tubules and
interstitium by an inflammatory infiltrate containing lymphocytes, mostly T cells, and occasional plasma
cells accompanied by interstitial edema and disruption of the tubular basement membrane. The transition
to a chronic process occurs with the development of interstitial fibrosis, which is accompanied by
tubular ectasia, tubular atrophy and a marked increase in extracellular matrix. Eventually glomerular
and vascular structures are involved, with fibrotic and sclerotic changes throughout the kidney.
Etiology of Chronic Tubulointerstitial Nephritis:
There is no universally accepted classification of tubulointerstitial nephritis, however the most
comprehensive, the WHO classification uses a pathogenic and etiologic approach. A simpler system
proposed in 1998 classifies TIN into primary and secondary causes independent of acuity or chronicity of
- Infection - Bacterial pyelonephritis, Hantavirus, Leptospirosis
- Immune-mediated - Sjogren syndrome, anti-TBM disease, IgG4 TIN
- Drug-induced - Analgesics, lithium, cyclosporine, Chinese herbs
- Toxins - Lead
- Metabolic disorders - Gout, hypercalcemia, hypokalemia
- Hematologic disorders - Sickle cell disease, paraproteinemias
- Miscellaneous - Balkan nephropathy
A review of 1068 renal biopsies from 1968 to 1997 found acute tubulointerstitial nephritis in 6.5%.
The cause was infection induced in 10%, idiopathic in 4% and drug induced in 85% (antibiotics in 13
cases, analgesics in 17, NSAID's in 16, diuretics in 5 and various other drugs in 7). Renal
insufficiency was reversible in 69% and permanent in 31%. The infection induced and idiopathic types of
ATIN were reversible, whereas drug induced ATIN caused permanent renal insufficiency in 36% with a
maximum of 56% in NSAID induced cases. In drug-induced cases, ingestion of the suspected drug for more
than one month prior to diagnosis caused permanent renal injury in 88% and interstitial granulomata in
- Glomerular disease
- Vascular disease
- Structural disease - Cystic disease, obstruction, reflux
Other features useful in separating permanent from reversible renal insuffiency included: more
tubular atrophy on biopsy, more chronic use of mixed analgesics and/or NSAID's, less oliguria or anuria
as an acute symptom, fewer antibiotics as causative agents, more interstitial granulomata, more
pronounced interstitial inflammation and greater evidence of renal shrinkage radiographically.
IgG4 Immune-complex Tubulointerstitial Nephritis:
A recently described form of chronic tubulointerstitial nephritis associated with IgG4 positive plasma
cell infiltrates has been demonstrated in a subset of patients with autoimmune or sclerosing
pancreatitis. There is often a clinical suspicion of a renal malignancy and on biopsy the renal
parenchyma is involved by a localized, destructive interstitial infiltrate composed of plasma cells,
numerous eosinophils and variable numbers of lymphocytes and macrophages with associated interstitial
fibrosis and tubular injury. The plasma cells express IgG4 which is often also present along tubular
basement membranes. Described cases have occurred in older men who present with renal failure or a renal
mass. They may also have a history of other inflammatory or autoimmune diseases, and often have elevated
serum levels of IgG4. In addition to pancreatic and renal involvement, inflammatory lesions of the
salivary gland, liver and biliary system and inflammatory pseudotumors of breast, lung, liver and orbit
have been described. Autoimmune pancreatitis has also been associated with inflammatory bowel disease
and retroperitoneal fibrosis. This type of tubulointerstitial nephritis is part of a systemic
IgG4-related disease termed "IgG4-associated immune complex multiorgan autoimmune disease (IMAD).
Non-narcotic analgesics are among the most commonly used medications in the world. These drugs
include salicylates such as aspirin, pyrazolones such as antipyrine, anilides such as phenacetin and
acetoaminophen. These drugs became popular as single or mixed agents in the late nineteenth century as
pain relievers. The historical prevalence of analgesic-induced TIN varies geographically and ranges from
0% in Queenscliff, Australia, 10-35% in Switzerland, 33-41% in Scandinavia and Wales to 49% in Brisbane,
Australia. The prevalence of analgesic-induced TIN in end-stage renal disease patients varies from 1.7%
in Philadelphia, 10% in North Carolina, 18% in Belgium and 30% in Queensland, Australia.
Analgesic-induced TIN has a significant female predominance and is closely associated with papillary
necrosis. The average quantity of analgesics consumed by patients with papillary necrosis in Australia
was 25.3 kg, while the average in all ESRD patients in Germany was 3.6 kg. The difference between the
incidence of analgesic-induced TIN geographically reflects the overall incidence of regular use of
combination analgesics. The heaviest users develop classical findings of analgesic-induced TIN.
Morphologic features: The earliest lesion described in analgesic
nephropathy is capillary sclerosis of the urinary tract mucosa and peritubular capillary sclerosis in the
inner medulla, which eventually leads to papillary necrosis followed by interstitial fibrosis. In the
cortex, the fibrosis is relatively bland with few inflammatory cells and extensive tubular atrophy.
Secondary glomerulosclerosis occurs and often the glomeruli are not damaged but become crowded due to
Non-steroidal Anti-inflammatory Drugs (NSAID) and TIN:
Non-steroidal anti-inflammatory drugs may induce a variety of renal lesions including oliguric and
non-oliguric acute renal failure with or without associated nephrotic syndrome and chronic renal
insufficiency as well as effects on electrolyte and water homeostasis. Acute ischemic renal
insufficiency occurs within hours of the initial doses of NSAIDs in susceptible individuals and is
readily reversible upon withdrawal of the offending agent.
Renal lesions occurring in patients taking NSAIDs include acute tubular necrosis, acute
tubulointerstitial nephritis, minimal change disease without interstitial nephritis, membranous
nephropathy and chronic renal insufficiency and end-stage renal failure.
Inflammatory Bowel Disease, Mesalazine and TIN:
5-Aminosalicylic acid (5-ASA) or mesalazine, is a first line therapy for mild to moderately active
inflammatory bowel disease and a number of reports have linked oral 5-ASA therapy to chronic TIN. The
causal relationship is supported by reports of patients with inflammatory bowel disease and normal
baseline serum creatinine levels who developed deterioration in renal function following treatment with
5-ASA and subsequent partial reversal of deterioration upon drug withdrawal. The mechanism of induction
of TIN by 5-ASA is not known and is a systemic type-1 hypersensitivity reaction in only a minority of
patients. In the acute stage there is a mixed inflammatory cell infiltrate associated with edema in the
interstitium. In more chronic stages the cellular infiltrate is accompanied by interstitial fibrosis and
Mesalazine is structurally related to salicyclic acid and phenacetin, both of which are associated
with analgesic nephropathy. Salicylates inhibit the synthesis of intra-renal prostaglandins, which are
vasoactive mediators of intra-renal blood flow and uncouple oxidative phosphorylation in mitochondria.
These effects cause a regional disturbance of intra-renal blood flow and local tissue hypoxia.
Diagnosis of Chronic TIN:
Interstitial fibrosis and inflammation on a kidney biopsy is often non-specific and it may be
difficult to determine if the cause is glomerular, vascular or primary tubulointerstitial. Primary
tubulointerstitial diseases tend to spare glomeruli and vessels, and if the glomeruli and vessels appear
normal, the interstitial damage is more likely primary. With advanced tubulointerstitial nephritis,
however, the glomeruli may be sclerotic and the arteries may show changes of secondary hypertension. If
the degree of interstitial inflammation exceeds the degree of interstitial fibrois, then a diagnosis of
chronic tubulointerstitial nephritis should be suggested.
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