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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 1  |  Page : 105-108
Acute tubular necrosis in a patient with paroxysmal nocturnal hemoglobinuria

1 University Medical Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka
2 Department of Pathology, Faculty of Medicine, Colombo, Sri Lanka
3 Department of Medicine, Faculty of Medicine, Colombo, Sri Lanka

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Date of Web Publication22-Jan-2013


Acute renal failure (ARF) is a well-recognized complication of paroxysmal nocturnal hemoglobinuria (PNH). The predominant mechanism is intravascular hemolysis resulting in massive hemoglobinuria ARF. We report a case of acute tubular necrosis (ATN) developed in the absence of overwhelming evidence of intravascular hemolysis in a 21-year-old man with anemia, who was eventually diagnosed to have PNH. The patient presented with rapidly deteriorating renal functions in the background of iron deficiency anemia, which was attributed to reflux esophagitis. There was no clinical or laboratory evidence of intravascular hemolysis. Renal biopsy revealed ATN with deposition of hemosiderin in the proximal tubular epithelial cells. Diagnosis of PNH was confirmed with a positive Ham's test and flow cytometry. Our case emphasizes the need to consider ATN as a possible cause for ARF in patients suspected to have PNH even in the absence of overwhelming evidence of intravascular hemolysis.

How to cite this article:
Wijewickrama ES, Gooneratne L, De Silva C, Lanarolle RL. Acute tubular necrosis in a patient with paroxysmal nocturnal hemoglobinuria. Saudi J Kidney Dis Transpl 2013;24:105-8

How to cite this URL:
Wijewickrama ES, Gooneratne L, De Silva C, Lanarolle RL. Acute tubular necrosis in a patient with paroxysmal nocturnal hemoglobinuria. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 Sep 28];24:105-8. Available from: https://www.sjkdt.org/text.asp?2013/24/1/105/106302

   Introduction Top

Acute renal failure (ARF) is a well-recognized complication of paroxysmal nocturnal hemoglobinuria (PNH). The predominant mechanism is intravascular hemolysis leading to massive hemoglobinuria, resulting in acute tubular necrosis (ATN). The patients classically have evidence of intravascular hemolysis and overt hemoglobinuria by the time they develop ARF. [1],[2],[3] We report a patient with PNH who developed ATN in the absence of over-whelming evidence of intravascular hemolysis.

   Case Report Top

A 21-year-old man presented with facial swelling and reduced urine output, which had developed over four days. This was associated with fever, dysuria and frequency. There was no hematuria or frothy urine. The patient was detected to have hypochromic microcytic anemia associated with low serum ferritin, raising a diagnosis of iron deficiency anemia the previous month when he presented with fever and oral ulcers to the same unit. He required several blood transfusions, and subsequent investigations revealed grade 4 reflux esophagitis for which he was started on omeprazole.

On examination, the patient was pale, anicteric with mild periorbital edema. Blood pressure was 120/70 mmHg and the pulse rate was 80. His heart, lungs, abdomen and nervous system were normal. Investigations revealed a serum creatinine level of 944 μmol/L (normal range 60-120 μmol/L) and blood urea of 31 mmol/L (normal range 2.9-8.2 mmol/L). Serum potassium was 6.7 mmol/L (normal range 3.5-5.l mmol/L). Urinalysis showed a pH of 5.5, specific gravity of 1.026, protein 75 mg/dL, five to 10 pus cells and two to four red cells per high-power field. There were no glucose, ketones or bilirubin in the urine, and urobilinogen were present in normal amounts. Urine culture yielded no growth. Full blood count revealed a hemoglobin level of 5.7 g/dL (normal range 12-15 g/dL), white cell count of 6.9 × 10 9 /L (normal range 4.5-11.0 × 10 9 /L) and a platelet count of 162 × 10 9 /L (normal range 150-400 × 10 9 /L). A peripheral blood smear revealed normochromic normocytic anemia with few acanthocytes. There was no evidence of hemolysis and the white cell and platelet lines were within normal limits. Reticular cell count was 332 × 10 3 /mm 3 . Serum bilirubin level was 14 μmol/L (normal range 5-17 μmol/L). His serum ferritin level was 18.6 ng/mL (normal range 28-397 ng/mL) with normal serum B12 and folate levels.

Urgent hemodialysis was performed and the patient was subsequently investigated to identify the cause for the rapidly progressive renal failure (RPRF). He had no significant past medical history, except for the brief febrile illness that was not complicated with severe sepsis or septic shock, one month prior to admission. He had not been exposed to any nephrotoxic substances including nephrotoxic drugs. Serum antinuclear antibodies, anti-double stranded DNA antibodies, c and p anti-neutrophil cytoplasmic antibodies and anti-glomerular basement membrane antibodies were negative. Serum anti-streptolysin "O" titer was less than 200 IU/mL. An ultrasound image revealed enlarged and globular kidneys with increased parenchymal echogenicity and prominent pyramids.

A renal biopsy was performed, which revealed evidence of tubular degeneration and regeneration, with most of the tubular epithelial cells containing hemosiderin pigment [Figure 1]. There was marked interstitial edema, focal interstitial fibrosis and few scattered collections of chronic inflammatory cells. Glomeruli and blood vessels were histlogically unremarkable. There was no evidence of microvascular thrombosis. These features were suggestive of a recovery stage of ATN. Subsequent urinalysis was positive for hemosiderin and the Ham's test was positive. On flow cytometry, 88% of the neutrophils were negative for CD55 and CD59, confirming the diagnosis of PNH.
Figure 1a: Histopathology of the renal biopsy obtained from the patient. Tubular epithelial cells with intracellular hemosidderin deposits (a) hemotoxyllin and eosin stain; magnification ×100, (b) Pearl stain; magnification ×100.

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The patient had to be transfused with three units of packed red cells. Subsequently, he was started on prednisolone, folic acid and alendronate. He was anuric for 11 days and required four sessions of hemodialysis before starting to produce some urine. He was discharged from the ward 16 days after admission, at which point his creatinine was 476 μmol/L. Five months after the initial presentation, his level of serum creatinine dropped to 63 μmol/L and his level of hemoglobin improved to 11.2 g/dL.

   Discussion Top

PNH is an acquired clonal disorder due to a stem cell mutation that results in a partial or complete absence of glycosylphosphatidylinositol anchor, which is involved in the attachment of several proteins to the external cell membrane surface: CD55 (delay accelerating factor); CD59; and, possibly, C8-binding protein. These proteins block complement activation on the cell surface. Hence, their absence accounts for the increased sensitivity of red blood cells to complement lysis in PNH.

According to the quantity of the glycoproteins present on their surface, PNH cells are classified as class I, II and III. Class III cells show complete absence of glycoproteins, whereas class I cells have normal amounts of glycoproteins and class II cells show partial absence of glycoproteins. The most sensitive cells to complement lysis are those most deficient in glycoproteins (class III).

The degree of hemolysis seen in a patient with PNH is related to several factors. Firstly, it depends on the proportion of cells that are abnormal. Patients with fewer than 20% abnormal cells usually have evidence of hemolysis and hemosiderinuria, but rarely have hemoglobinuria. In contrast, patients with more than 60% of abnormal cells often have frequent episodes of hemolytic crises and hemoglobinuria. However, due to unclear reasons, some patients do not develop acute hemolytic episodes despite having very high percentages of abnormal cells. Secondly, as described above, the severity of hemolysis depends on the degree of abnormality of the red cells. Patients having PNH class III red cells develop greater hemolysis than those having PNH class II red cells. Thirdly, it depends on the degree to which the complement is activated. Certain viral and bacterial infections are well-known activators of the complement cascade, leading to profound hemolysis in the affected patients.

Renal disease in PNH is mainly related to intravascular hemolysis, which can result in two forms of renal disease. Firstly, an acute hemolytic episode associated with massive hemoglobinuria can cause acute renal failure. [4],[5] The proposed mechanisms include: (a) hypovolemia and renal ischemia, (b) direct tubular toxicity of hemoglobin, (c) tubular obstruction from heme pigment casts or uric acid crystals and (d) glomerular fibrin deposition. [6] Secondly, chronic hemolysis can cause iron deposition in the kidneys and proximal tubular dysfunction. [7],[8] In addition, chronic renal failure due to hemosiderosis can occur in patients with long-standing PNH. [7],[9] Furthermore, rarely, renal vein thrombosis can occur in PNH leading to flank pain, hematuria, with or without acute renal failure.

In our patient, the history, examination and initial investigations were not suggestive of ongoing intravascular hemolysis. Therefore, hemoglobinuria was not considered a possible cause for the renal failure at presentation. At the same time, the patient was found to have reflux esophagitis, which could have caused the anemia as a result of occult upper gastrointestinal bleeding. It was only after the biopsy, which revealed evidence of hemosiderin deposition in the renal tubular epithelial cells, that the diagnosis of PNH was considered. The patient could have been having a long-standing low level intravascular hemolysis sufficient to cause hemoglobinuria and hemosiderin deposition in the renal tubules. The reason for the sudden deterioration of renal function in this patient is not clear.

This case highlights the need for the nephrologists to consider the diagnosis of PNH in a patient presenting with RPRF associated with severe anemia even in the absence of overwhelming evidence of intravascular hemolysis.

   References Top

1.Chow KM, Lai FM, Wang AY, Chan YL, Tang NL, Li PK. Rversible renal failure in paroxysmal nocturnal haemoglobinuria. Am J Kidney Dis 2001;37:E17.  Back to cited text no. 1
2.Jose MD, Lynn KL. Acute renal failure in a patient with paroxysmal nocturnal haemoglobinuria. Clin Nephrol 2001;56:172-4.  Back to cited text no. 2
3.Chen SC, Hung CC, Hsu CP, et al. Recurrent acute renal failure in a patient with aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome: A case report. Kaohsiung J Med Sci 2007;23:579-83.  Back to cited text no. 3
4.Jackson GH, Noble RS, Maung ZT, Main J, Smith SR, Reid MM. Severe haemolysis and renal failure in a patient with paroxysmal nocturnal haemoglobinuria. J Clin Pathol 1992;45: 176-7.   Back to cited text no. 4
5.Mooraki A, Boroumand B, Mohommad Zadeh F, Ahamed SH, Bastini B. Acute reversible renal failure in a patient with paroxysmal nocturnal hemoglobinuria. Clin Nephrol 1998; 50:255-7.  Back to cited text no. 5
6.Zager RA, Burkhart KM, Conrad DS, Gmur DJ. Iron, heme oxygenase, and glutathione: effects on myohemoglobinuric proximal tubular injury. Kidney Int 1995;48:1624-34.   Back to cited text no. 6
7.Clark DA, Butler SA, Braren V, Hartmann RC, Jenkins DE Jr. The kidneys in paroxysmal nocturnal hemoglobinuria. Blood 1981;57:83-9.   Back to cited text no. 7
8.Riley AL, Ryan LM, Roth DA. Renal proximal tubular dysfunction and paroxysmal nocturnal hemoglobinuria. Am J Med 1977;62:125-9.   Back to cited text no. 8
9.Zachee P, Henckens M, Van Damme B, Boogaerts MA, Rigauts H, Veberckmoes RK. Chronic renal failure due to renal hemosiderosis in a patient with paroxysmal nocturnal hemoglobinuria. Clin Nephrol 1993;39:28-31.  Back to cited text no. 9

Correspondence Address:
Eranga S Wijewickrama
University Medical Unit, National Hospital of Sri Lanka, Colombo
Sri Lanka
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DOI: 10.4103/1319-2442.106302

PMID: 23354203

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