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NDT Advance Access originally published online on August 5, 2006
Nephrology Dialysis Transplantation 2006 21(10):2953-2956; doi:10.1093/ndt/gfl197
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Albuminuria in acute tubular necrosis

Bradford Lee West1, Maria M. Picken2 and David J. Leehey1,

1Department of Medicine and 2Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA

Correspondence and offprint requests to: David J. Leehey, MD, Loyola University Medical Center, Bldg 102, Rm 3661, 2160 S 1st Ave, Maywood, IL 60153, USA. Email: dleehey{at}lumc.edu

Keywords: acute tubular necrosis; albuminuria; endocytosis



   Introduction
Top
 Introduction
Case report
 Discussion
 References
 
Acute renal failure (ARF) is defined as an abrupt decline in the glomerular filtration rate (GFR), as evidenced by rising serum levels of urea nitrogen and creatinine. Acute tubular necrosis (ATN) is the most common cause of ARF. ATN is an acute decline in glomerular filtration as a result of damage to the tubules in the kidney. Sepsis is the most common aetiology of ATN, causing ARF in 20–25% of normotensive patients and 50% of hypotensive patients [1].

The clinical diagnosis of ATN can be difficult as there are no uniform diagnostic criteria. Typical findings suggesting ATN are muddy brown granular or tubular epithelial cell casts, fractional excretion of sodium (FeNa) greater than 1%, and isosthenuria. ATN is not expected to affect the glomerulus, and thus should not cause glomerular proteinuria [2,3].

In this report, we describe a young woman with ARF and albuminuria who had biopsy-proven ATN but no glomerular pathology. The possible reasons for her albuminuria are discussed.



   Case report
Top
 Introduction
 Case report
Discussion
 References
 
A 31-year-old Hispanic woman presented at 17 weeks of gestation with spontaneous vaginal bleeding and threatened abortion. She had a history of poorly controlled tonic–clonic seizures secondary to head trauma 7 years previously, her most recent seizure occurring 1 month prior to admission. Three years prior to admission, she suffered a spontaneous abortion at 16 weeks after a car accident. One year before presentation, she had a 22-week spontaneous abortion due to premature rupture of membranes and chorioamnionitis. She had no history of diabetes, hypertension, non-steroidal anti-inflammatory drug (NSAID) use, or kidney disease. She had a negative urinalysis documented 4 months before admission. Medications included pre-natal vitamins, folic acid, carbamazepine 400 mg four times a day, and valproic acid 500 mg four times a day.

On admission, her temperature was 37.2°C, pulse 92/min, and blood pressure 126/68 mmHg. She was alert, oriented, and in no acute distress. Cardiac and lung examinations showed no abnormalities. Abdomen was gravid and non-tender. Extremities were warm, with no oedema, calf tenderness, or rashes. On vaginal examination, there was a 3-cm dilatation of the cervix with a yellow-green, foul discharge. The serum creatinine was 1.5 mg/dl (133 µmol/l), which was increased from her baseline 8 months prior of 0.6 mg/dl (53 µmol/l). An initial urinalysis was negative for proteinuria. Initial serum aspartate aminotransferase (AST) was 45 U/l (normal range 5–40), alanine aminotransferase (ALT) was 15 U/l (7–35), alkaline phosphatase was 166 U/l (30–110), albumin was 13 g/l (36–50) and total bilirubin was 1.3 mg/dl (22.3 µmol/l) (normal range 0–1.2 mg/dl). Sonogram demonstrated a twin pregnancy, with normal fetal heart tones.

She was diagnosed with chorioamnionitis and was treated empirically with ampicillin and gentamicin. Peak gentamicin level was 5.3 mg/l during the 4 days of treatment. On the second hospital day, she suffered two seizures and was found to have premature rupture of the placental membranes. Two non-viable twins were delivered on the third day. The placenta was not fully expelled and a dilation and curettage was performed. She subsequently developed septic shock and adult respiratory distress syndrome, and piperacillin–tazobactam was added to her dosage. She had persistent vaginal bleeding, and laboratory studies were consistent with disseminated intravascular coagulation (DIC). Mechanical ventilation was started and norepinephrine begun for hypotension. Escherichia coli was later identified on blood cultures. The organism was resistant to piperacillin; antibiotics were switched to imepenem and metronidazole.

On hospital day 7, renal replacement therapy was started for oliguric renal failure. Renal ultrasound and abdominal computed tomography (CT) revealed normal kidneys. She had no gross haematuria. A repeat urinalysis revealed 4+ proteinuria, pH 7, and specific gravity 1.020, with moderate blood, moderate bilirubin and 10 red blood cells per high-power field. The urinalysis was repeated 10 times over the course of her hospitalization, with all samples showing dipstick proteinuria. Two spot protein (mg/dl) to creatinine (mg/dl) ratios obtained on separate days were 376 to 30.1 (12.5), and 285 to 15.6 (18.3) (average 15.4 mg/mg) (Dade Behring pyrogallol red-molybdate assay). The urinary albumin to creatinine ratio was 7.2 (112 mg/dl to 15.6 mg/dl) (Beckman, rate nephelometry). The fractional excretion of sodium (FENa) was 40% [urineNa 151 meq/l/plasmaNa 140 meq/l]/[urinecr10 mg/dl/plasmacr 3.8 mg/dl]. Liver enzymes worsened (AST 119 U/l, ALT 36 U/l, alkaline phosphatase 329 U/l) and she became jaundiced [total bilirubin 12.1 mg/dl (207 µmol/l)]. Anti-nuclear antibody, hepatitis B and hepatitis C serum tests were negative. She continued to have fevers, but slowly improved on imepenem, vancomycin and fluconazole. An ultrasound of the pelvis showed evidence of retained products of conception and a repeat dilation and curettage was performed.

Although the clinical course suggested ATN, the presence of dipstick proteinuria and the markedly elevated protein-to-creatinine and albumin-to-creatinine ratios prompted a renal biopsy to confirm the diagnosis. A liver biopsy was also requested to investigate the cause of liver injury; therefore, a transjugular approach was used to perform simultaneous biopsies [4]. Liver biopsy showed centrilobar cholestasis with ductular cholestasis, acute cholangitis and microscopic abscess formation. Renal biopsy showed severe ATN with attenuation and degenerative changes of the tubular epithelium associated with the presence of proteinaceous casts (Figures 1 and 2). Proximal tubules contained irregular proteinaceous casts that were frequently admixed with cellular debris. On occasion, distal tubules showed rounded and condensed casts. However, at times it was difficult to distinguish between the involved segments (proximal vs distal) due to attenuation of the epithelial lining (Figures 1 and 2). No immune-complex deposits were seen by immunofluorescence (not shown) or electron microscopy (Figure 3). The glomerular epithelial cell foot processes were preserved (Figure 3).


Figure 1
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  		Fig. 1. Light microscopy of kidney biopsy tissue. The glomerulus is unremarkable. Irregular proteinaceous casts are seen in the tubular lumina. Original magnification 400x.

 

Figure 2
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  		Fig. 2. Light microscopy showing tubules containing proteinaceous casts admixed with degenerated epithelial cells. The irregular tubular casts appear to be seen predominantly in the proximal tubules. Occasional rounded and more condensed casts were seen in distal tubules. The epithelial lining of the affected tubules is frequently attenuated making the definite identification of the affected segment difficult. Original magnification 200x.

 

Figure 3
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  		Fig. 3. Electron micrograph showing preserved glomerular epithelial cell foot processes and lack of immune-complex deposits. Original magnification 7000x.

 
Over the next 3 months, she remained oliguric (average daily urine output of 50 ml). Cortical necrosis was considered, but two abdominal radiographs did not reveal renal calcifications. She was transferred to a long-term care facility and subsequently lost to follow-up.



   Discussion
Top
 Introduction
 Case report
 Discussion
References
 
Our patient had many clinical characteristics suggestive of ATN, including hypotension, oliguria, E. coli sepsis, nephrotoxin exposure, and a very high FENa. However, the presence of albuminuria was not expected with isolated ATN. A diagnostic renal biopsy was therefore performed. The biopsy revealed severe ATN (Figures 1–3GoGo). No glomerular pathology was identified.

Given the complex nature of this patient, other causes of albuminuria were considered. Pre-eclampsia seemed unlikely given a gestational age of only 17 weeks, and the absence of hypertension or glomerular endotheliosis on biopsy. The negative anti-nuclear antibody screen and the absence of immune deposits on biopsy excluded immune-mediated nephropathy. Cortical necrosis was considered based on her clinical presentation and associated DIC. However, radiographs performed 2 months after the onset of ARF did not demonstrate renal calcifications. She was not taking NSAIDs, which are known to cause ARF accompanied by marked albuminuria [5]. Renal function did not recover for at least 3 months, suggesting a severe ATN.

Urinary protein values measured with the pyrogallol red-molybdate assay may be falsely elevated in the presence of aminoglycosides. The overestimate is concentration-dependent, and is noted especially when the urine aminoglycoside concentration is >20 mg/dl [6]. Our patient received gentamicin for 4 days. However, the urinary protein concentration remained elevated 3 weeks after gentamicin was discontinued, suggesting that this does not explain the elevated urinary protein measurements. Moreover, there are no reports of interference with albumin measurements by aminoglycosides.

In healthy persons and patients with chronic kidney disease, urinary protein-to-creatinine and albumin-to-creatinine ratios have been widely used to quantify the degree of proteinuria and/or albuminuria, respectively. The rationale behind this procedure is that these substances are all normally excreted into the urine at a steady rate, and therefore a non-timed ratio will approximate the amount of protein (or albumin) in a timed urine specimen. In patients with ARF, there is failure to excrete creatinine due to decreased glomerular filtration and possibly also impaired tubular secretion. Thus, urinary protein- or albumin-to-creatinine ratios would be expected to be elevated due to a low value of the denominator, i.e. urinary creatinine concentration, if the numerator, i.e. urinary protein or albumin concentration, is not correspondingly decreased. However, we do not believe that this is the sole explanation for the markedly elevated albumin-to-creatinine ratio observed in our patient since a decrease in GFR should result in a decrease in filtered macromolecules as well as small molecular weight substances such as creatinine, unless there is increased permeability of the glomerular basement membrane.

Albuminuria can result from sepsis possibly as a part of the capillary leak syndrome [7]. The degree of albuminuria is thought to correlate with morbidity [8]. The degree of albuminuria in a diverse range of critically ill medical patients is variable with a range of albumin-to-creatinine ratios of 0–3.8 mg/mg (median of 0.6 mg/mg) reported. Patients without prior renal disease diabetes or other comorbidities tend to have less albuminuria [9]. The mechanism of albuminuria in sepsis is not known, but it does not appear to correlate with the systemic capillary permeability [10]. Our patient was not clinically septic at the time of the urinary albumin measurement, and her albumin-to-creatinine ratio was higher than those previously reported in septic patients.

Although albuminuria is generally believed to be a result of increased transit of albumin through the glomerular basement membrane, recent studies have suggested that it may also be attributed to altered proximal tubule receptor-mediated endocytosis (RME) of albumin [11]. The two pathways of RME, the retrieval pathway and the degradation pathway, both process albumin in the proximal tubule. Park and Maack [12] demonstrated two separate proximal tubule receptors with different affinities for albumin. These receptors are postulated to be megalin (low-affinity) and cubulin (high-affinity) [11]. The megalin and cubulin receptor systems bind albumin in clathrin-coated pits in the brush border of the proximal tubular epithelium [13,14]. After endocytosis, albumin can be directed to endocytic vesicles for transcytosis via the retrieval pathway or to lysosomes for degradation [15]. The retrieval pathway has been demonstrated to return albumin to the vascular space without degradation [16]. This retrieval pathway is proposed to be due to the low affinity, high-capacity pathway, and can process up to 400–500 g/day of albumin [17]. The teleological reason for a high-capacity RME in the proximal tubule could relate to the potential toxicity of albumin to the tubular epithelium [18]. Cubulin is postulated to be the receptor involved in the degradative pathway, with albumin fragments excreted into the urinary space [17] (Figure 4).


Figure 4
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  		Fig. 4. Schematic diagram depicting receptor-mediated endocytosis of albumin in the renal proximal tubule.

 
The sensitivity of immunochemical assays for albumin depends on whether the proteins are intact or in fragments. Healthy individuals excrete <25 mg/d of albumin as measured by immunochemical assays, but they may actually be excreting >1300 mg/d of albumin fragments [19]. Indeed, ~90–95% of urinary albumin is broken into fragments ranging from 1–15 kDa [11]. ATN could impair the retrieval and/or degradation pathway and result in more intact albumin in the urinary space, which would be measurable by conventional assays.

ATN has a variable impact on renal tubular epithelium depending on the severity. Profound and sustained ATN associated with marked histological changes would be expected to damage the proximal tubular machinery involved in RME. We hypothesize that in most cases of ATN, even if RME was markedly impaired, no albuminuria would be detectable due to the substantial reduction in GFR and filtered load of albumin associated with ARF. Albuminuria may have been present in our patient due to the severity of the tubular damage and resultant impairment of RME.

Acute kidney injury may result in fragmentation and/or oxidation of filtered albumin, leading to a loss of immunoreactivity [20]. Thus, when standard immune-based assays are utilized, the amount of intact albumin in the urine in patients with ATN could be underestimated, especially in those with higher protein excretion rates [20]. Thus, the amount of albumin excretion in our patient may have actually been greater than that measured in the clinical laboratory.

In conclusion, this case suggests that severe ATN may result in albuminuria, possibly due to a defect in receptor-mediated endocytosis resulting from damage to the proximal tubule. Such patients may masquerade as acute glomerulonephritis, and renal biopsy may be necessary to make the correct diagnosis.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Case report
 Discussion
 References
 

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  5. Ravsnskov U. (1999) Glomerular, tubular and interstitial nephritis associated with non-steroidal anti-inflammatory drugs: evidence of a common mechanism. Br J Clin Pharmacol 47:203–210.[CrossRef][Web of Science][Medline]
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  13. Kerjaschki D and Farquhar MG. (1982) The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci 79:5557–5561.[Abstract/Free Full Text]
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  16. Eppel GA, Osicka TM, Pratt LM, et al. (1999) The return of glomerular filtered albumin to the rat renal vein. Kidney Int 55:1861–1870.[CrossRef][Web of Science][Medline]
  17. Russo LM, Bakris GL, Comper WD. (2002) Renal handling of albumin: a critical review of basic concepts and perspective. Am J Kidney Dis 39:899–919.[CrossRef][Web of Science][Medline]
  18. Abbate M and Remuzzi G. (2001) Novel mechanism(s) implicated in tubular albumin reabsorption and handling. Am J Kidney Dis 38:196–204.[Web of Science][Medline]
  19. Greive KA, Balazs NDH, Comper WD. (2001) Protein fragments in urine have been considerably underestimated by various protein assays. Clin Chem 47:1717–1719.[Free Full Text]
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Received for publication: 17. 2.06
Accepted in revised form: 21. 3.06


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