Elderly Man with Anorexia and Acute Renal Failure


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A 75-year-old man presented to the emergency department with weakness, anorexia, and nausea, and was found to have acute renal failure with a creatinine of 7.9 mg/dL.

Past medical history included non-insulin dependent diabetes, hypertension, coronary artery disease with prior stenting and a more recent bypass graft placement, and low-grade bladder cancer in remission after recent intravesical chemotherapy. Six months earlier, his serum creatinine level was 1.2 mg/dL. He denied use of non-steroidal agents, herbal treatment, or prior known renal disease.

Physical examination revealed a blood pressure of 154/80 mm Hg and morbid obesity, without other significant findings. In addition to a creatinine level of 7.9, laboratory results showed BUN 62, K 5.9, Na 128, Hgb 12.0, and hct 35. Liver function tests were normal and serologic studies were pending. Urinalysis revealed 1+ protein, 3+ blood, negative leukocyte esterase, 10-20 RBCs, and no WBCs or eosinophils. The urine protein to creatinine ratio was 0.6. What’s your diagnosis?

This clinical case was prepared by Cynthia C. Nast, MD, Professor of Pathology at the David Geffen School of Medicine at the University of California in Los Angeles.

Acute tubular necrosis — or as it is currently termed, acute tubular injury, as frank necrosis often is not present — clinically presents as acute renal failure. The most frequent cause is ischemic-hypoxic tubular damage, although toxic tubular injury is...

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Acute tubular necrosis — or as it is currently termed, acute tubular injury, as frank necrosis often is not present — clinically presents as acute renal failure. The most frequent cause is ischemic-hypoxic tubular damage, although toxic tubular injury is not uncommon. In the setting of severe systemic disease, an inflammatory milieu may induce renal cell dysfunction and tubular injury. Morphologically, tubular cell injury/necrosis is characterized by loss of proximal cell brush border staining, loss of tubular epithelial cell volume, and epithelial cell degeneration or necrosis and sloughing of cells into the tubular lumina. In severe cases, tubules may rupture with the contents spilling into the adjacent interstitium or into veins. This can be identified by the presence of extra-tubular Tamm-Horsfall protein, a large glycoprotein (mucoprotein) produced by epithelium of the thick ascending limb of the loop of Henle, and which is the fundamental constituent of renal casts.

Tamm-Horsfall protein is PAS positive and stains blue on Masson’s trichrome stain. When Tamm-Horsfall protein is admixed with fibrin (red on Masson’s trichrome stain) within a vein lumen, it indicates there has been tubular rupture into a vein, also known as tubulo-venous herniation. As a consequence, intravascular contents cross into the tubular lumen, resulting in hematuria. In these uncommon instances, acute renal failure with 4+ microscopic or gross hematuria may be the presenting features of acute tubular injury/necrosis without accompanying glomerular damage.

Pauci-immune crescentic glomerulonephritis, the renal manifestation of small vessel vasculitis, presents clinically with rapidly progressive glomerulonephritis, with an active urinary sediment, including hematuria and usually red cell casts. 

The predominant light microscopic feature is necrotizing and crescentic glomerulonephritis, which represents a nonspecific response to severe injury of the glomerular capillary wall.  Capillary injury occurs, causing disruption of the wall with leukocytes and fibrin extruding into the urinary space. This produces a cellular (fresh and active) crescent. During active crescent formation there may be disruption of Bowman’s capsule with extension of fibrin and cells into the adjacent interstitium, with associated tubular cell injury and interstitial inflammation.  However, the hallmark of this lesion morphologically is glomerular crescents without significant immune complex deposition. These patients most often have positive ANCA serologic tests, c-ANCA (anti-proteinase 3) generally in Wegener’s granulomatosis and p-ANCA  (anti-myeloperoxidase) in microscopic polyangiitis, associated with underlying systemic vasculitis.

IgA nephropathy is the most common immune complex glomerulonephritis in the world. It has protean clinical presentations, from asymptomatic hematuria and proteinuria to nephrotic syndrome, acute renal failure, rapidly progressive glomerulonephritis and chronic renal failure.  The diagnostic feature is dominant or co-dominant IgA deposition in the glomerular mesangium, with mesangial immune complex deposits. IgA often is exacerbated by upper respiratory tract infections, and gross hematuria not infrequently occurs in this setting. In the setting of hematuria and renal failure, the differential diagnosis includes crescentic IgA nephropathy. However, gross hematuria itself may induce acute tubular injury/necrosis and renal failure due to a direct toxic effect of hemoglobin or iron on the tubular epithelium, or by tubular obstruction due to luminal erythocytes. In this setting, renal biopsy will demonstrate erythrocytes in tubular lumina in addition to glomerular mesangial IgA deposition without glomerular crescents.   

The kidneys are the organ most affected by atheroembolic vascular disease, being injured approximately 75% of the time when atheroemboli occur. The 150-200m vessels (interlobular arteries) are most often involved. Patients have a wide variety of presentations including acute, subacute or chronic renal failure, often with microscopic hematuria. Eosinophilia and/or hypocomplementemia are often present, clinically mimicking hypersensitivity allergic reactions or acute glomerulonephritis. The majority of cases have a history of recent intravascular manipulation or radiographic procedures of the vasculature, although atheroemboli may occur spontaneously. If there is extensive embolization, there are palpable purpura and other symptoms which mimic vasculitis. With extensive renal vascular impairment, ischemic acute tubular injury ensues resulting in acute renal failure. This has an ischemic morphologic appearance, usually with early chronic damage and the intravascular cholesterol crystals often can be found with careful examination of the renal biopsy.

Patients with acute interstitial nephritis present with varying degrees of acute renal failure. There also may be microscopic or macroscopic hematuria, low-grade proteinuria, and granular, hyaline and/or white blood cell casts. In patients with associated glomerular lesions, such as minimal change disease induced by non-steroidal anti-inflammatory agents, nephrotic syndrome may be the presenting symptom. While allergic symptoms including fever, rash, arthralgias, eosinophilia, and eosinophiluria may occur, these are the exception and are becoming less common.  Etiologic factors are diverse, including drugs, reaction to systemic infections, direct renal infection (viral and selected bacteria), antibody immune responses (anti-tubular basement membrane disease), hereditary and metabolic disorders, and obstruction and reflux in the acute stages. Most cases are due to drug-induced, cell-mediated, delayed-type hypersensitivity reactions. Less commonly, immune complex deposition may occur with systemic diseases such as lupus erythematosus, and there is variable interstitial nephritis in association with active glomerulonephritis. Morphologically, the primary findings are interstitial edema and an inflammatory infiltrate, with variable degrees of acute tubular cell injury. There may be tubular inflammation, and tubular rupture may occur as a consequence of tubulitis. However, in cases of tubular rupture due to acute tubular injury/necrosis, no significant interstitial or tubular inflammation is present.

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