|Year : 2019 | Volume
| Issue : 3 | Page : 177-179
A case of paroxysmal nocturnal hemoglobinuria with renal hemosiderosis
Parimal B Patel, Jayant Hota
Transplant Critical Care, Indraprastha Apollo Hospital, New Delhi, India
|Date of Submission||14-Jun-2019|
|Date of Acceptance||27-Aug-2019|
|Date of Web Publication||11-Sep-2019|
Indraprastha Apollo Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder of bone marrow. It is characterized by blood cells lacking membrane proteins that are normally attached by the glycosylphosphatidylinositol anchor. It usually presents with intravascular hemolysis, cytopenias, frequent infections, bone marrow hypoplasia, and a high incidence of life-threatening venous thrombosis. Kidney involvement is usually benign and secondary to chronic tubular deposition of hemosiderin. Acute kidney injury may occur in association with a hemolytic crisis. Here, we report a case of a 50-year-old male with hematuria, pancytopenia, and acute renal failure due to PNH. Renal biopsy demonstrated acute tubular necrosis with considerable hemosiderin deposition (hemosiderosis), but no evidence of vascular thrombosis.
Keywords: Acute kidney injury, hemolysis, hemosiderosis, pancytopenia, paroxysmal nocturnal hemoglobinuria
|How to cite this article:|
Patel PB, Hota J. A case of paroxysmal nocturnal hemoglobinuria with renal hemosiderosis. Apollo Med 2019;16:177-9
| Introduction|| |
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired chronic disorder characterized by a triad of clinical features - hemolytic anemia, pancytopenia, and thrombosis. However, even in the absence of one or more of these manifestations a conclusive diagnosis can be made by appropriate laboratory investigations. PNH has an estimated prevalence of 1–1.5 patients per million population. The diagnosis is often made in East Asian countries, but it is not certain whether the incidence is greater in this region. There is a tendency to male preponderance.PNH arises from a somatic mutation involving a gene on the X chromosome which codes for a protein involved in the assembly of phosphatidylinositol glycan (PIG), which anchors many proteins to the surface of cell membranes. Due to shortage of PIG, the two protective proteins which inactivate complement complexes, decay accelerating factor (DAF; CD55) and membrane inhibitor of reactive lysis (MIRL; CD59) are absent in PNH red cells, which then become sensitive to lysis by complement.
The association of PNH and kidney disease was first recognized in the early 1970s. Subsequently, a high incidence of functional and anatomic renal abnormalities among PNH patients was documented. While these renal abnormalities in PNH are prevalent, they appeared to be generally mild and may not be brought to medical attention, apart from a few patients presenting with acute kidney injury.
| Case Report|| |
A 50-year-old chronic alcoholic and smoker male from Uttar Pradesh was admitted in our hospital with the complaints of generalized weakness for the past 4 years with black-colored urine following consumption of some herbal drugs with febrile illness 10 days back. On evaluation, he was found to be conscious, oriented, presently afebrile, and grossly pale with mild pedal edema. His initial laboratory parameters revealed hemoglobin 4 gm%, total leukocyte counts 1000/cmm, and platelet counts 55,000/cmm; peripheral smear showed normocytic normochromic anemia without any fragmented red blood cells (RBCs), blood urea 186 mg%, serum creatinine 14.4 mg%, serum sodium 145 mg%, serum potassium 5.8 mg%, serum lactate dehydrogenase (LDH) 3784 IU/L, plasma hemoglobin 6%, reticulocyte counts 6%, serum haptoglobins (Hp) 0.2%, serum total bilirubin 5 mg% (direct 1 mg% and indirect 4 mg%), alanine dehydrogenase 451 U/L, aspartate dehydrogenase 1781 U/L, normal serum Vitamin B 12, and folate levels normal coagulation parameters; urine microscopy revealed 2 + protein, 2–4 white blood cells/high-power field (HPF), and 4–6 RBCs/HPF without any cast or crystals. In view of the rapidly progressive renal failure, few more tests were done. He had normal complements; antinuclear antibodies were negative, serum protein electrophoresis was negative, and viral markers, including hepatitis B surface antigen, anti-hepatitis C virus, and HIV, were negative. Ultrasound whole abdomen revealed mild splenomegaly with normal size kidneys. Since he was chronic alcoholic, a possibility of chronic liver disease was thought and fibroscan was done which was normal. Upper gastrointestinal endoscopy ruled out the possibility of portal hypertension. To find out the cause of pancytopenia, bone marrow biopsy was done which showed cellular marrow with erythroid hyperplasia and deficient iron store, but there was no evidence of aplastic anemia or myelodysplastic features. After stabilizing the patient with few sessions of hemodialysis and packed cell transfusion, the renal biopsy was done. Light microscopy of the kidney biopsy revealed 12 unremarkable and 3 globally sclerosed glomeruli. The tubules showed diffuse deposition of brown-colored pigment, which gave a positive blue-colored reaction on Perls' stain, consistent with deposition of ferric ions (hemosiderin). There were structural changes indicative of tubular damage such as distention of tubules and cell debris in the lumen. There was neither interstitial fibrosis nor vascular changes.
Immunofluorescence (anti-IgG, anti-IgA, anti-IgM, anti-C3, and anti-C1q) was negative. There were diffuse hemosiderin deposits with chronic tubulointerstitial changes. Urine was sent for hemosiderin which came out to be positive. In view of pancytopenia with erythroid marrow, evidence of intravascular hemolysis (as we had no fragmentation with high LDH without any false positives, direct Coomb's test was not done), renal hemosiderin deposits, and urine hemosiderin positivity, a provisional diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) was made and Ham's test was done which was positive. He was managed with pulse steroid to control hemolysis, intravenous iron, erythropoietin, folic acid, sodium bicarbonate, diuretics, and dialytic support. Gradually, he started improving and was advised the need of stem cell transplantation, but the family refused and was discharged in a stable condition.
| Discussion|| |
PNH is an acquired clonal disorder associated with somatic mutations of the X-linked glycosylphosphatidylinositol biosynthesis Class A gene in hematopoietic stem cells, which results in the absence of the phosphatidylinositol-linked proteins necessary to protect cells from complement-mediated lysis. The primary clinical manifestations of PNH include intravascular hemolytic anemia and thrombosis in vessels (mostly cerebral and abdominal commonly splenic and hepatic veins) with or without evident bone marrow failure, which can cause pancytopenia. Renal involvement in PNH is usually not clinically apparent, but essentially all patients with classic PNH report gross hemoglobinuria at some point during the course of their illness (though nocturnal periodicity is uncommon). However, when the renal disease is significant, it usually manifests as acute kidney injury (AKI) and rarely as chronic kidney disease (CKD). Like in our case, few others have also reported AKI following ingestion of herbal drugs which are probably due to the severe hemolysis induced by these drugs. The repetitive exposure of the kidney to cell-free hemoglobin can cause renal hemosiderin accumulation, tubule-interstitial inflammation, and chronic kidney damage. In these cases, eculizumab, preventing the cascade of events that lead to recurrent and chronic hemolysis, may improve CKD. In India it is not available. Acute tubulonecrosis and acute renal failure usually occur after a major hemolytic attack and are due to hemoglobinuria and the toxicity of heme and iron, decreased renal perfusion, and tubular obstruction with pigment casts. Reversible AKI in PNH is thought to depend on renal epithelial hemoglobin-mediated toxicity due to hemolysis, contraction of renal blood vessels, and intratubular obstruction., Intravascular hemolysis releases Hb into plasma, where Hb is bound quickly to Hp, forming a Hp-Hb complex. Under normal conditions, this large complex is not filtered by glomerulus and is further degraded by the liver, spleen, and bone marrow and degraded. In persistent intravascular hemolysis, plasma Hp is consumed and free Hb accumulates in plasma and dissociates from its usual tetrameric form to dimeric Hb. Dimeric Hb is filtered more easily by the glomerulus and incorporated into proximal tubules, leading to the accumulation of ferric ions (hemosiderin) in these cells. The renal biopsy in our case showed hemosiderin deposits in tubular cells, most prominent in the proximal tubules. Although hemosiderin accumulates quite rapidly in tubules, its role in AKI remains controversial since intense renal hemosiderosis can be found in PNH patients with normal renal function. The treatment of PNH has been largely symptomatic but as the hemolysis of PNH is a consequence of complement-mediated cytolysis, inhibition of complement is a logical approach to therapy. Eculizumab is a humanized monoclonal antibody that targets C5 convertase preventing C5b-9 membrane attack complex formation. Data from treated patients demonstrated a reduction in hemolysis and a reduction in thrombotic events. Eculizumab in renal dysfunction was well tolerated and usually associated with clinical improvement. In certain cases of severe hemolysis, as in the case of our patient, the concentration of hemoglobin in the tubular filtrate becomes sufficiently high to impair renal function and acute renal failure results. In these patients, conservative treatment, with fluid administration and urinary alkalinization improves renal function whereas corticosteroids, attenuates acute hemolytic exacerbations and may reduce the severity and duration of the crisis. However, their efficacy is limited and is not recommended for long-term treatment. In our case, splenomegaly was due to splenic vein thrombosis being PNH hypercoagulable state. Prophylactic herinization has not shown promising results. In conclusion, AKI due to PNH is associated with tubular hemosiderin deposits, local inflammation, oxidative stress, and activation of the anti-inflammatory response. Conservative management usually suffices to ameliorate the acute crisis through hematopoietic stem cell transplant early indicated if associated with aplastic anemia or myelodysplastic syndrome.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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| References|| |
Rosse WF. Paroxysmal nocturnal hemoglobinuria as a molecular disease. Medicine (Baltimore) 1997;76:63-93.
Nair RK, Khaira A, Sharma A, Mahajan S, Dinda AK. Spectrum of renal involvement in paroxysmal nocturnal hemoglobinuria: Report of three cases and a brief review of the literature. Int Urol Nephrol 2008;40:471-5.
Tsai CW, Wu VC, Lin WC, Huang JW, Wu MS. Acute renal failure in a patient with paroxysmal nocturnal hemoglobinuria. Kidney Int 2007;71:1187.
Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et al.
Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111:1840-7.
Bessler M, Hiken J. The pathophysiology of disease in patients with paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program 2008;104-10. doi: 10.1182/asheducation-2008.1.104.
Chow KM, Lai FM, Wang AY, Chan YL, Tang NL, Li PK, et al.
Reversible renal failure in paroxysmal nocturnal hemoglobinuria. Am J Kidney Dis 2001;37:E17.
Tracz MJ, Alam J, Nath KA. Physiology and pathophysiology of heme: Implications for kidney disease. J Am Soc Nephrol 2007;18:414-20.
Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995;333:1253-8.