INTRODUCTION

Structural abnormalities of the renal parenchyma that involve primarily the tubules and interstitium are called tubulointerstitial disease. In contrast to acute interstitial nephritis (AIN), diseases that cause tubulointerstitial disease, discussed in this section, are more often chronic processes (Table 18.1). Diseases of the tubulointerstitium are best thought of as either primary or secondary processes. Primary causes of tubulointerstitial nephritis typically occur as a result of systemic diseases or following exposure to environmental or therapeutic agents. In this circumstance, the glomeruli and vasculature are typically spared or have only minor structural changes until late in the course of disease. In general, approximately 10% to 20% of end-stage renal disease (ESRD) in the United States occurs from primary chronic tubulointerstitial disease. A secondary form of chronic tubulointerstitial disease may also result from progressive glomerular disease or vascular injury with associated renal parenchymal ischemia. A significant number of disease states cause this form of chronic tubulointerstitial injury, with diabetic nephropathy and hypertensive nephrosclerosis being most common. Tubulointerstitial disease with fibrosis and scarring significantly determine the progressive nature of these lesions and their ultimate outcome, which include chronic kidney disease (CKD) and ESRD requiring renal replacement therapy.

PATHOGENESIS OF TUBULOINTERSTITIAL DISEASE

The tubulointerstitium comprises the majority of renal parenchyma. Approximately 80% of total kidney volume is composed of tubular epithelial cells and cells within the interstitial space. The vast majority of nonepithelial cells are associated with the rich vascular network found within the kidney. The rest of the cells consist of a small number of resident mononuclear cells and fibroblasts. Recognizing that the tubulointerstitium is such a large component of the kidney makes it easy to understand why inflammation within this compartment, leading to fibrosis, is a major factor in progressive loss of renal function.

The basic model that underlies the development of chronic tubulointerstitial disease, regardless of the inciting disease or event, is one that involves cellular infiltration, fibroblast differentiation and proliferation, increased extracellular matrix protein deposition, and atrophy of tubular cells. The pathogenesis of tubulointerstitial injury is similar, whether the initiating process is a primary disease or injury to the tubulointerstitium or is secondary to a primary glomerular or vascular disease process. Examples of such secondary causes include primarily glomerular diseases like diabetic nephropathy and vascular diseases such as hypertension and calcineurin inhibitor toxicity. Activation of multiple proliferative pathways within the epithelial cells in an attempt to maintain integrity of this cell type occurs in response to tubular injury. Interplay between homeostatic proliferative and reparative forces and aberrant proinflammatory and overexuberant cell proliferation ensues. If the injurious factors overwhelm the normal cell processes, apoptotic pathways overrun the ability of tubular epithelial cells to survive. This results in tubular atrophy and interstitial fibrosis.

The initiating event that causes either primary or secondary injury to the tubulointerstitium promotes tubular atrophy and interstitial collagen deposition and fibrosis through various intrarenal and systemic factors. These include vasoactive substances such as angiotensin II (AII), endothelin, thromboxane A₂, and vasopressin. These compounds induce reductions in renal blood flow after 24 hours of ureteral obstruction and likely contribute to ischemic injury. In addition to hemodynamic effects, AII has profibrotic effects mediated by binding to the angiotensin type 1 (AT1) receptor. In fact, more than 50% of the fibrosis that develops in a mouse model of obstruction is dependent on expression of the angiotensinogen gene. This same process occurs in other forms of renal injury. AII upregulates the expression of factors such as transforming growth factor (TGF)-β, nuclear factor-κB, basic fibroblast growth factor, vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor (TNF)-α, and platelet-derived growth factor (PDGF). It is important, however, to recognize that increased expression of many of these chemoattractant compounds, adhesion molecules, and cytokines also occur independently of AII.

Other types of renal disease and injury induce these processes through other mechanisms including pressure-associated injury (obstructive uropathy), hyperglycemia (diabetic nephropathy), infiltrative diseases (sarcoidosis), and induction of oxidative stress. Resident nonepithelial cells, such as the fibroblast undergo proliferation/differentiation and produce interstitial fibrosis. Also, it is believed that renal epithelial cells undergo a process of dedifferentiation/redifferentiation into myofibroblastic cells expressing α-smooth muscle actin and collagen following exposure to the various factors noted above. This process has been termed epithelial-mesenchymal transition (EMT). Researchers believe that that there are 4 key events that occur in renal tubular EMT in renal fibrogenesis, namely: (a) loss of epithelial adhesion, (b) cytoskeletal reorganization and (c) de novo synthesis of α-SMA (smooth muscle actin), disruption of the tubular basement membrane (TBM), and (d) enhanced cell migration and invasion of the interstitium. It is thought that EMT is primarily an adaptive response of the tubular epithelial cells to an inimical milieu. Ultimately, the balance between homeostatic effects and harmful effects tips the balance in favor of the pathologic consequences, leading to collagen deposition, tubular atrophy, and interstitial fibrosis.

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HISTOPATHOLOGY OF TUBULOINTERSTITIAL DISEASE

In chronic tubulointerstitial disease, a cellular infiltrate and variable amounts of fibrosis are noted within the architecture of the interstitium. The characteristic lesion is an inflammatory cellular infiltrate composed of lymphocytes, usually T cells and, to a lesser degree, plasma cells. Early in the course of disease, the acute cellular infiltrate is accompanied by interstitial edema, tubulitis with TBM disruption, and dissolution of the normal tubulointerstitial architecture. Over time, the acute process transitions to a chronic tubulointerstitial lesion. The chronic histology is characterized by interstitial fibrosis with increased extracellular matrix, tubular ectasia and atrophy, and tubular dropout. The severity of this process typically advances over time until the entire tubulointerstitium is overtaken by fibrosis. In far advanced disease, glomerulosclerosis develops and blood vessels become involved by fibrosis and sclerosis. At this point in time, the patient often manifests clinically advanced CKD.

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CLINICAL PRESENTATION

More often than not, patients with tubulointerstitial disease have few clinical symptoms suggestive of CKD. In general, symptoms and signs reflect the extent of tubulointerstitial disease. For example, focal areas of injury are minimally symptomatic, whereas diffuse disease causes several tubular defects in electrolyte, acid–base, and mineral handling. Also, the area of the kidney involved by disease leads to disturbances characteristic of the loss of function of injured tubular segment. Injury to the proximal tubule is associated with impaired absorption of sodium, glucose, phosphorus, amino acids, potassium, uric acid, and several low-molecular-weight proteins. In contrast, disease of the loop of Henle and distal convoluted tubule causes sodium and potassium wasting (salt wasting, hypokalemia, and hypotension). Involvement of the cortical and medullary collecting ducts may be associated with hyperkalemia and metabolic acidosis (type 4 renal tubular acidosis) as a consequence of defects in potassium and ammonia (buffers acid) secretion by this segment. Another important determinate of the clinical manifestations of tubulointerstitial disease is the degree of compensation by the remaining normal (or less severely impaired) nephron segments. With mild-to-moderate disease, compensatory hypertrophy may eliminate or substantially reduce symptoms of renal disease.

Often times, chronic tubulointerstitial disease is discovered when blood testing reveals abnormal kidney function (increased blood urea nitrogen [BUN] and serum creatinine concentration) that is otherwise fairly asymptomatic. The presence of certain systemic diseases may also prompt investigation of kidney function and potential kidney disease. As is discussed later, several systemic diseases promote the development of chronic tubulointerstitial disease. The most common symptom associated with disease of the tubulointerstitium is polyuria. Two mechanisms account for this symptom, including salt wasting and the inability to maximally concentrate the urine. Dizziness from low blood pressure (salt wasting), weakness from either severe hypokalemia or hyperkalemia, and bone pain/fractures from osteopenia induced by metabolic acidosis. Advanced chronic tubulointerstitial disease results in the development of usual manifestations of CKD approaching ESRD. These include anorexia, nausea, vomiting, lethargy, somnolence, fatigue, restless legs, and other uremic manifestations.

Laboratory Findings

As noted in the previous section, tubulointerstitial disease often manifests with various renal tubular and urinary disorders (Table 18.2). Examination of blood and urine chemistries often provides insight into the disease. Proximal renal tubular acidosis (type 2 renal tubular acidosis [RTA]), as noted by a hypokalemic, nonanion gap metabolic acidosis, may occur in this setting. In this case, the urine is acid (pH <5.5) in steady-state acidosis, but becomes alkaline (pH >7) when therapy to correct the metabolic acidosis with bicarbonate is attempted. A full-blown Fanconi syndrome can develop with chronic tubulointerstitial disease involving the proximal tubule. This syndrome is characterized by the presence of a type 2 RTA that also demonstrates phosphaturia, aminoaciduria, glycosuria, enzymuria, and uricosuria. Salt wasting (urinary sodium >20 mEq/L) despite hypotension may indicate tubulointerstitial disease of the loop of Henle. Hypokalemia caused by urinary potassium wasting may also occur with a lesion in this segment. An acidification defect in the distal nephron may cause a type 1 RTA that is characterized by hypokalemia, nonanion gap metabolic acidosis, and alkaline urine (first morning void pH >5.5). A type 4 RTA (hyperkalemia with nonanion gap metabolic acidosis) may be seen with tubulointerstitial disease. Inability to concentrate the urine leads to a low urine osmolality and, if the patient is unable to gain free water access, may cause hypernatremia.

The urinalysis yields variable results in the setting of chronic tubulointerstitial disease. A couple of generalizations, however, can be made. Tubulointerstitial disease rarely has marked proteinuria; most often there is trace to 1+ protein on quantitative examination of the urine. A 24-hour urine collection or spot protein/creatinine usually contains less than 1 g of total protein. Examination of the urinary sediment under the microscope often reveals a preponderance of white blood cells (WBCs), occasionally with some WBC and granular casts. Red blood cells (RBCs) and RBC casts are extremely unusual. Urinary crystals may be present with certain disorders associated with chronic tubulointerstitial disease (calcium oxalate crystals with hyperoxaluria; uric acid crystals with uric acid nephropathy; calcium phosphate with acute/chronic phosphate nephropathy).

Examination of proteinuria (low-molecular-weight proteins) and enzymuria may provide insight into disease limited to the tubulointerstitium; however, they are not widely employed as clinical tools. High-molecular-weight proteins (>40,000 to 50,000 Da) in the urine are typically a marker of glomerular disease. Included in this group is albumin (69,000 Da), transferrin (77,000 Da), and immunoglobulin (Ig) G (146,000 Da). In contrast, small amounts of low-weight-molecular proteins are normally excreted in the urine. They are considered markers of “tubular” proteinuria (vs. glomerular proteinuria). Although there are several low-molecular-weight proteins, β₂-microglobulin (11,800 Da) and retinol-binding protein (21,400 Da) are the markers of tubular injury most commonly employed. Both substances are freely filtered; approximately 99.9% is reabsorbed in the proximal tubule where they are catabolized. When the reabsorptive capacity of the proximal tubular cells is impaired, increased amounts of various low-molecular-weight proteins can be demonstrated in the urine. Thus, levels increase in urine when disease injures proximal tubular cells. Although both β₂-microglobulin and retinol-binding protein are used to evaluate tubulointerstitial disease, the assay employed for retinol-binding protein is more stable in an acid urine and is preferred.

Urinary eosinophils greater than 1% eosinophils in a microscopic sample is a test that is commonly ordered when AIN is considered in the differential diagnosis of acute kidney injury, rather than a chronic tubulointerstitial process. A sensitivity of 63% to 91%, and a specificity of 85% to 93% are noted when using Hansel stain, thereby limiting its diagnostic value. Numerous diseases are associated with eosinophiluria, such as acute pyelonephritis, acute prostatitis, acute complicated cystitis, rapidly progressive glomerulonephritis, atheroembolic kidney disease, parasitic infections, and the presence of intraureteral stents.

Urinary enzymes also reflect tubular dysfunction and act as markers of tubulointerstitial disease. The basis for measuring high-molecular-weight enzymes in urine stems from the knowledge that the only source of enzymes is injured tubular cells. Despite this premise, however, the use of measuring enzymuria is hindered by a lack of correlation with specific disease states and the disconnect between severity of tubular injury and the magnitude of urine enzyme levels. Urinary enzyme activity is also affected by the presence of urinary enzyme inhibitors and activators, as well as urine pH and osmolarity. A few enzymes accepted as useful urinary biomarkers are used in clinical studies to assess tubular damage. They include N-acetyl-β-glucosaminidase, alanine aminopeptidase, and intestinal alkaline phosphatase. Enzymuria remains a valuable research tool, but has not gained widespread use in the clinical arena.

Diagnosis of Tubulointerstitial Disease

The clinical diagnosis of chronic tubulointerstitial disease is considered when other possible causes of kidney disease are excluded, in particular intrinsic renal disease such as glomerular lesions, as well as obstructive uropathy. An in-depth history of prescribed or nonprescription medications ingested by the patient and any at-risk occupational or environmental exposures suffered are keys to assess causes of tubulointerstitial disease. Evidence of systemic disease associated with this form of kidney disease helps support the diagnosis. In addition to the history, the laboratory findings described above, point to disease in the tubulointerstitium. In particular, evidence of tubular dysfunction is suggestive of chronic tubulointerstitial disease. These include a RTA, salt wasting, a urinary concentrating defect, and a urinalysis demonstrating pyuria with little or no protein. Ultrasonography of the kidney reveals normal-to-large-size kidneys with AIN, whereas small echogenic kidneys are present with chronic tubulointerstitial disease. The only exception to this caveat is certain infiltrative diseases. The kidneys are often large and echogenic. Examples include sarcoidosis, lymphomas and leukemias, amyloidosis, and cystic kidney disease. The kidney biopsy helps to establish the diagnosis. The classic lymphocytic infiltrate, the variable degrees of interstitial fibrosis, and tubular ectasia/atrophy characterize chronic tubulointerstitial nephritis. In the absence of a definable cause of chronic tubulointerstitial disease when the kidney biopsy supports this diagnosis, an idiopathic form of disease or presumed substance exposure (drug or toxin) is often implicated as the underlying cause.

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