Saudi Journal of Kidney Diseases and Transplantation

: 2018  |  Volume : 29  |  Issue : 5  |  Page : 1232--1236

Hemosiderin tubulopathy-induced acute kidney injury - A rare initial manifestation of paroxysmal nocturnal hemoglobinuria

Srikanth Prasad Rao1, Sindhura Lakshmi Koulmane Laxminarayana2, Shankar Prasad Nagaraju1, Mahesha Vankalakunti3, Ravindra Prabhu Attur1, Chethan Manohar2,  
1 Department of Nephrology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India
2 Department of Pathology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India
3 Department of Pathology and Lab Medicine, Manipal Hospital, Bengaluru, Karnataka, India

Correspondence Address:
Dr. Sindhura Lakshmi Koulmane Laxminarayana
Department of Pathology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal - 576 104, Udupi


Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by episodes of intravascular hemolysis, infections, and thromboembolic complications. Renal abnormalities are rare which occur either due to hemolytic crisis or repeated thrombotic episodes involving small venules. Acute kidney injury (AKI) requiring hemodialysis due to toxic effects of hemoglobinuria, with a stable disease is exceptional. We describe a case of an elderly gentleman presenting with features of severe AKI requiring hemodialysis due to hemosiderin tubulotoxicity as the first manifestation of PNH. The diagnosis was challenging because of the rarity and unfamiliarity with this entity. The outcome was complete recovery of renal function with hemodialysis.

How to cite this article:
Rao SP, Laxminarayana SL, Nagaraju SP, Vankalakunti M, Attur RP, Manohar C. Hemosiderin tubulopathy-induced acute kidney injury - A rare initial manifestation of paroxysmal nocturnal hemoglobinuria.Saudi J Kidney Dis Transpl 2018;29:1232-1236

How to cite this URL:
Rao SP, Laxminarayana SL, Nagaraju SP, Vankalakunti M, Attur RP, Manohar C. Hemosiderin tubulopathy-induced acute kidney injury - A rare initial manifestation of paroxysmal nocturnal hemoglobinuria. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Sep 15 ];29:1232-1236
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Full Text


Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by episodes of intravascular hemolysis, infections and thromboembolic complications, associated with bone marrow failure syndromes such as aplastic anemia. Renal abnormalities are rare which either result from hemolytic crisis or repeated thrombotic episodes involving small venules. Severe acute kidney injury (AKI) requiring hemodialysis (HD) as initial manifestation is exceptional. Conversely, testing for PNH must be done when a patient presents with AKI and hemosiderinuria. We describe a challenging case of severe AKI requiring HD due to hemosiderin tubulotoxicity as the first manifestation of PNH.

 Case Report

A 62-year-old male with no comorbid illness presented with a history of vomiting and decreased urine output with dark colored urine since four days. He had no history of fever, chest pain, or any drug intake.

On clinical examination, he was afebrile with regular pulse rate at 90 beats/min and blood pressure of 150/90 mm Hg. He had moderate pallor and bilateral pedal edema up to the ankles. Review of his systems was normal.

Laboratory investigations are summarized in [Table 1]. Peripheral smear did not show schistocytes, and Coombs test was negative. Bone marrow was hypercellular with myeloid to erythroid ratio of 1:1 and 3+ iron stores. Ultrasonography of the abdomen, cardiac evaluation including electrocardiogram and echocardiogram were normal. Antinuclear antibody profile, antineutrophil cytoplasmic antibodies, and markers for human immunodeficiency virus, hepatitis B surface antigen as well as anti-hepatitis C virus antibody were negative.{Table 1}

In view of advanced renal failure, hyperkalemia and oliguria; he underwent HD through a double lumen uncuffed right internal jugular vein HD catheter.

His kidney biopsy showed 21 normal glomeruli. The tubular epithelial cytoplasm showed brown-colored pigment which stained positive for iron [Figure 1] and [Figure 2]. Immunofluorescence was negative. Biopsy findings were suggestive of hemosiderin-induced tubulotoxicity. There was no evidence of vascular thrombosis.{Figure 1}{Figure 2}

Flow cytometry was performed using gating antibodies cluster differentiation (CD) 45, CD15, CD64 and glycosyl phosphatidylinositol (GPI) linked proteins such as CD24 for neutrophils, CD14 for monocytes, CD59 for red blood cells (gated using CD235a) and fluorescein labeled aerolysin (FLAER) for both neutrophils and monocytes. Complete CD59 deficient (type III PNH) erythrocytes were 16.1%, partial CD59 deficient (type II PNH) erythrocytes were 74.3%. FLAER and CD24 deficient neutrophils (gated using CD15 and CD45) were 40.1%. FLAER, and CD14 deficient monocytes (gated using CD64 and CD45) were 82.6% [Figure 3]. Thus, a diagnosis of PNH was made. {Figure 3}

The patient was managed with hemodialysis. He showed improvement over nine days and became dialysis-independent. His serum creatinine came down to 1.1 mg/dL and he had good diuresis at 2.5 L/day.


PNH is an intrinsic erythrocyte disorder characterized by acquired stem cell somatic mutation of an X-linked gene, phosphatidylinositol glycan complementation Group A (PIGA).[1] This gene is required for the synthesis of GPI anchor moiety. The deficient clonal progeny coexists with that of the normal stem cells which are not PIGA deficient, creating a phenotypic mosaic. The abnormal erythrocytes, granulocytes, and platelets are deficient in complement regulatory proteins such as CD59, CD55, and C8 binding protein and highly sensitive to complement-mediated lysis.[2] Visibly apparent constant hemoglobinnuria is present only when type III PNH population is >50% of erythrocytes.[3]

The International PNH Interest Group classifies PNH into three categories.[1] Patients with classic PNH have clinical evidence of intravascular hemolysis in the form of reticulocytosis, elevated serum LDH, and indirect bilirubin along with cellular marrow possessing erythroid hyperplasia as was the case in our patient. The other types are PNH with a history of specified bone marrow abnormality and PNH-sc associated with bone marrow failure syndromes.

It should be noted that all proteins that are deficient in PNH are GPI anchored and all GPI anchored proteins which are expressed by hematopoietic cells are deficient in PNH.[4] In the present case, GPI anchored proteins CD24, CD14 and FLAER were demonstrated to be deficient in neutrophils and monocytes. Dim expression of CD59 was shown in erythrocytes (type II PNH cells).

FLAER is an Alexa 488-labeled inactive variant of aerolysin (a 52-kDa protein secreted by Aeromonas hydrophila) that does not cause lysis of cells but binds to the GPI moiety of cell surface GPI-linked molecules. FLAER is more sensitive than CD59 at detecting small abnormal granulocyte populations in patients to a level of approximately 0.5%.[5]

The spectrum of kidney involvement in PNH ranges from reversible AKI to irreversible chronic kidney disease (CKD) but is generally benign, resulting in mild impairment in urinary concentration. Only about 25% of PNH patients show abrupt onset of visible hemoglobinuria.[6] Patients may present with symptoms of chronic hemolysis such as weakness, jaundice and iron deficiency anemia if there is long-standing hemosiderinuria. Our patient had moderate anemia and chronic hemosiderinuria along with other features of chronic hemolysis although total leukocyte count and platelet counts were normal. Type III PNH red cell population was also <20% which explains the absence of constant visible hemoglobinuria. The unusual presentation of PNH with AKI and absence of visible hemoglobinuria posed difficulty in diagnosis.

AKI in PNH is usually associated with acute hemolytic crisis and is reversible depending on renal epithelial hemoglobin-mediated toxicity, contraction of renal blood vessels and intratubular obstruction.[7],[8] In the present case, there were no features of acute hemolysis, but tubular hemosiderin deposition was noted. An intense renal hemosiderin deposition is also seen in PNH patients with normal renal function.[7] Hence, the role of hemosiderinuria in causing AKI in PNH patients is uncertain. In intravascular hemolysis, the free plasma hemoglobin (Hb) binds to haptoglobin (Hp), forming Hp–Hb complex.[8] Normally, this large complex is not filtered by glomerulus but it is catabolized in liver, spleen, and bone marrow. In chronic episodic intravascular hemolysis, plasma Hp levels decrease due to increased consumption and free Hb accumulates in the plasma where tetrameric Hb dissociates to dimeric Hb. Dimeric Hb is filtered more easily by the glomerulus and incorporated into proximal tubules, leading to accumulation of ferric ions (hemosiderin) in these cells.[9] Cytotoxic effect of Hb includes the generation of oxygen reactive species, apoptosis and inflammation.[10] This may cause acute tubular necrosis (ATN), severe tubular atrophy and interstitial fibrosis along with papillary necrosis, kidney infarction as a result of renal artery thrombosis and cortical thinning. Recurrent microvascular thrombosis, one of the most significant pathological findings, may cause cortical necrosis leading to loss of concentrating ability.[11],[12] Our patient did not have microvascular thrombosis but had ATN. Thus, the case in question was an uncommon presentation of AKI without acute hemolysis or venous thrombosis in a patient with PNH.

Early diagnosis and treatment of AKI in PNH is crucial as it is the cause of death in up to 18% of PNH patients.[13] More than half of the patients with AKI tend to develop CKD secondary to tubular hemosiderin deposition and microvascular thrombosis.[14] A vast majority of reported cases of AKI in PNH were treated with HD although a few researchers have attempted alkaline diuresis with success.[15] AKI of our patient was successfully treated with hemodialysis. The only curative option for PNH patients is bone marrow transplantation which our patient could not afford. Eculizumab therapy which prevents the cascade of events leading to chronic hemolysis may reduce the incidence of renal manifestations. Corticosteroids may also be used to reduce the severity and duration of the acute hemolytic crisis, but are unsuitable for long-term use.[15]

In conclusion, we suggest that even in the absence of visible hemoglobinuria PNH is an important cause of reversible AKI.

Conflict of interest: None declared.


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