Histopathology

Histopathology of CIN is remarkably consistent despite the varied causes ( Box 44.1 ). In addition to tubular cell damage and predominantly mononuclear cell inflammation, CIN is characterized by the development of tubulointerstitial fibrosis and scarring ( Fig. 44.1 ). Interstitial granulomatous disease has also been observed in certain forms of CIN (e.g., sarcoidosis). Glomerular and vascular structures may be relatively preserved early in the course of disease but ultimately become involved in progressive fibrosis and sclerosis. Progressive development of tubulointerstitial fibrosis is a final common pathway to end-stage kidney disease (ESKD) observed in primary disorders of the tubulointerstitium, as well as in primary glomerular or vascular disorders. All forms of progressive kidney disease eventually result in chronic and progressive interstitial fibrosis.

Chronic interstitial nephritis.

Light microscopy findings demonstrate focal collections of lymphocytes and pronounced loss of normal tubulointerstitial architecture. There is evidence of tubular dilation and atrophy, as well as interstitial fibrosis and relative sparing of glomerular structures.

(Hematoxylin-eosin stain, courtesy Dr. James Balow, National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD.)

Mononuclear cell infiltrates generally accompany CIN, further suggesting a pathogenic immune-mediated mechanism for disease progression. One hypothesis concerning immune recognition of the interstitium suggests that portions of infectious particles or drug molecules may cross-react with or alter endogenous kidney antigens. An immune response directed against these inciting agents would therefore also target the interstitium. Intriguing results of a study examining a series of kidney biopsy samples obtained over 8 years at a single center suggest a prominent role of Epstein-Barr virus (EBV) in cases of CIN previously deemed idiopathic. Investigators detected EBV DNA and its receptor, CD21, primarily in proximal tubular cells of all 17 patients with primary idiopathic interstitial nephritis. These findings were not apparent in 10 control kidney biopsy specimens. Such observations imply a more prominent role than previously appreciated for EBV infections in eliciting chronic deleterious immune responses that target the interstitium.

Mechanisms of Tubulointerstitial Fibrosis

Observations from the experimental literature suggest that renal tubular epithelial-mesenchymal transition (EMT) may play a role in the initiation and progression of tubulointerstitial fibrosis. As the renal epithelium develops from the metanephric mesenchyme via a process of mesenchymal-epithelial transition, observations suggest a unique paradigm of tubulointerstitial response to injury whereby dedifferentiation pathways are activated within the epithelium, resulting in a transition to cells of more mesenchymal characteristics. Dysregulation of such processes in vivo could induce more fibrogenic responses ( Fig. 44.2 ). Renal EMT in this setting could thus facilitate accumulation of fibroblasts and myofibroblasts that are characteristic of CIN and other kidney diseases associated with tubulointerstitial fibrosis.

The development and progression of kidney fibrosis.

Fibroblasts and myofibroblasts (MF) originate from other cell types (as noted in the bottom box ) and play a significant role in the process of kidney fibrosis. The paradigm of tubular epithelial-mesenchymal transition suggests an additional pathway to kidney fibrosis, in that tubular epithelium undergoes profound phenotypic changes after exposure to fibrogenic stimuli (center box) . This results in loss of epithelial characteristics and gain of mesenchymal characteristics. The transitioning cells might remain in the tubular wall or migrate into the interstitium. Epithelial-derived fibroblasts contribute to the deposition of extracellular matrix (ECM), and a subpopulation may begin expressing α-smooth muscle actin (SMA), a hallmark of the MF phenotype. Activated fibroblasts and MF secrete elevated amounts of transforming growth factor-β (TGF-β), whereas the enhanced contractility of MFs contributes to activation of latent TGF-β through an integrin-mediated mechanochemical pathway. Increasing TGF-β levels along with ECM accumulation might facilitate transformation of previously intact tubules, thereby creating a positive feedback loop of epithelial injury. AJ , Adherens junction; EPI , epithelium; FIBRO , fibroblasts; L , lumen; TJ , tight junction.

(Reprinted by permission from Macmillan Publishers Ltd: Quaggin SE, Kapus A. Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int. 2011;80:41-50.)

The ability of renal tubular epithelial cells to transform in vitro to fibroblasts and myofibroblasts is well documented. Although the processes relevant for primary CIN in humans have not been elucidated, experimental models of injury and many in vitro studies have implicated a large role for transforming growth factor-β and other fibrogenic mediators, such as fibroblast growth factor-2, advanced glycation end products, and angiotensin II. These factors regulate the renal fibrogenic responses and renal tubular EMT ( Fig. 44.2 ). In addition, numerous human kidney biopsy studies have demonstrated the colocalization of epithelial and mesenchymal markers on tubular cells in areas of injury, supporting the notion that renal tubular EMT is associated with progressive tubulointerstitial fibrosis in a variety of kidney diseases. However, recent fate-mapping studies, which allow the tagging and tracking of renal epithelial cells in vivo in experimental models of disease, have generated apparently conflicting observations regarding the role of EMT in progressive kidney injury. Future studies will likely better characterize pathways that both initiate and propagate renal fibrogenic processes.

Clinical Features

As shown in Box 44.1 , CIN occurs in a variety of clinical settings, most commonly following exposure to drugs or toxins, or in settings of hereditary disorders, metabolic disorders, immune-mediated diseases, hematologic disturbances, infections, or obstruction. Because CIN tends to occur as a slowly progressive disease, most patients diagnosed with CIN present with systemic complaints of the primary underlying disease, if one exists, or with symptoms of CKD. Laboratory findings in these patients include low-grade (tubular) proteinuria, microscopic hematuria, and sterile pyuria. As listed in Table 44.1 , other frequently reported urinary abnormalities, such as glucosuria, phosphaturia, and sodium wasting, reflect tubular defects. Serologic studies in CIN, such as anti-DNA antibodies, antinuclear antibodies, and complement levels, are typically normal, except when CIN occurs in the setting of a systemic autoimmune disorder.

Table 44.1

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