The clinical spectrum of tubulointerstitial nephritis.

Tubules and interstitium make up approximately 80% of the renal volume, and occupy the compartment referred to as the tubulointerstitium. The interstitium space takes up 13% of rat and up to 17% of dog and rabbit kidneys, including 7 to 9% of renal cortex, 3 to 5% of outer medulla and 30 to 40% of inner medulla and papillary tip [1, 2]. It is made up of both cellular and matrix components. There are two main cell types. (a) Type I interstitial cells are fibroblast-like cells capable of producing and degrading extracellular matrix. The lipid-rich interstitial cells in the inner medulla, a possible source of prostaglandins, are also considered to be a form of type I interstitial cells. (b) Type II interstitial cells, found in all renal zones, include monocyte derived macrophages with capacity for phagocytosis and dendritic antigen-presenting cells found primarily in the cortex. The matrix is made up of a fibrillar net of interstitial and basement membrane collagens and associated proteoglycans, glycoproteins, and interstitial fluid. The interstitial compartment not only provides structural support for the individual nephrons, but also serves as a conduit for solute transport [2]. It is also the site of production of several hormones and cytokines such as erythropoietin and prostaglandins. Renal diseases can broadly be classified as glomerular, vascular, tubulointerstitial or obstructive in origin. Diseases of tubulointerstitial compartment may be the result of primary injury to this compartment or secondary to injury to other compartments. Several studies in patients with a variety of renal diseases have shown that changes in the tubulointerstitial compartment are a better predictor of the severity of renal dysfunction and long-term outcome than changes in other compartments [3–7]. Recent advances in our understanding of the process of injury and repair in general, and tubulointerstitial compartment in particular, have helped elucidate some of the important pathogenic events leading to tubulointerstitial nephritis (TIN). These advances have been summarized in several excellent reviews [8–12] and will only be discussed briefly here. This review focuses primarily on clinical aspect of the diseases where the tubulointerstitial compartment is the primary target of the pathogenic process rather than being secondarily involved by damage to the glomerular, vascular compartment or collecting system. The term acute interstitial nephritis was first used a century ago in 1898 by Councilman in describing a group of patients with systemic bacterial infection, primarily scarlet fever and diphtheria. This term was applied to acute inflammation of the kidney characterized by cellular and fluid exudation in the interstitial tissue that was not dependent on the presence of bacteria [13]. For many decades, the term chronic pyelonephritis was used to describe renal diseases associated with chronic injury to interstitum, despite the lack of evidence for the presence of active infection in a majority of the patients. Beginning in early 1950s, the work of Spuhler and Zollinger in Switzerland on the role of analgesics [14, 15], and Henderson and colleagues in Australia on the role of lead in the development of chronic tubulointerstitial nephritis (TIN) [16], provided strong evidence that the so-called chronic pyelonephrits was often not infectious in origin. It is now recognized that TIN represents a group of diseases that are due to a variety of etiologies and pathogenic mechanisms. Given the tight structure-function relationship between glomerular, vascular and tubulointerstitial compartments, a significant overlap exists between the clinical presentation of the diseases initiated in any compartment. In addition, the clinical presentation of TIN depends both on its etiology and the severity of renal dysfunction. Despite this factor, certain findings are more common in these patients than patients with glomerular disease. These include: (1) a lack of significant proteinuria and hypoalbuminemia; (2) the presence of sterile pyuria and white blood cell (WBC) casts rather than hematuria and red blood cell (RBC) casts; (3) the presence of a concentrating defect resulting in polyuria and nocturia; and (4) the presence of other tubular defects such as renal tubular acidosis, salt losing nephropathy and osteomalacia due to long-standing vitamin D