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Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired hematological disease resulting from somatic PIGA gene mutations. These mutations cause a deficiency in glycosylphosphatidylinositol-anchored–anchored proteins such as CD55 and CD59 on blood cell surfaces, leading to uncontrolled complement-mediated hemolysis. Although this condition is typically identified in individuals in their third or fourth decades of life, diagnosis during late adolescence is rare. Renal complications are a known feature of PNH; however, they present more frequently as a gradual decline in function rather than as a severe acute insult. This report describes the unusual case of an 18-year-old male who presented with a 6-month history of intermittent dark urine followed by an acute illness. Laboratory evaluation revealed severe Coombsnegative hemolytic anemia, significantly elevated lactate dehydrogenase levels, and acute kidney injury requiring immediate hemodialysis. Renal biopsy-confirmed pigment nephropathy, and high-sensitivity flow cytometry detected a large PNH clone, establishing the diagnosis of classical PNH. The patient's renal function improved with supportive care, but hemolysis persisted. This case highlights the fact that PNH can manifest in young adults with acute kidney injury as the primary presenting symptom. Including PNH in the differential diagnosis of patients with unexplained hemolytic anemia and renal impairment is crucial, even in atypical age groups. Prompt diagnosis is vital for initiating appropriate management, including supportive measures and the consideration of complementary inhibitor therapy, to improve outcomes.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disorder of hematopoietic stem cells caused by somatic mutations in PIGA. This defect leads to a deficiency in glycosylphosphatidylinositol (GPI)-anchored proteins such as CD55 and CD59, resulting in complement-mediated intravascular hemolysis [1]. Clinically, it is characterized by hemolytic anemia, varying degrees of bone marrow failure, and a high risk of thrombosis [2]. The global prevalence is estimated at 1 to 1.5 cases per million, with chronic hemolytic anemia, recurrent hemoglobinuria, and nonspecific systemic symptoms being the most frequent presentations [3]. Data from the International PNH Registry indicate that approximately 10% of patients are diagnosed before the age of 25 years, making presentations during late adolescence particularly uncommon [4]. Hemolytic episodes may occur spontaneously or triggered by infection, exercise, transfusion, or medications [5].
Flow cytometry remains the diagnostic standard for detecting GPI-deficient clones in granulocytes, monocytes, and erythrocytes [6]. Although primarily regarded as a hematological disease, PNH can also cause renal complications. Intravascular hemolysis with hemoglobinuria may lead to pigment nephropathy and acute kidney injury (AKI), often associated with hemosiderin deposition in the renal tubules [7]. Based on the extent of the GPI deficiency, PNH is classified as type 1 (normal expression), type 2 (partial deficiency), or type 3 (complete deficiency) [8].
The treatment landscape for PNH has evolved significantly. Complement C5 inhibitors (eculizumab and ravulizumab) represent the standard of care, with newer agents, including the C3 inhibitor pegcetacoplan and the recently approved factor D inhibitor iptacopan [9]. We report the case of a young male with no prior comorbidities who presented with severe AKI and required dialysis as the initial manifestation of classical PNH. This presentation is unusual, as most cases are identified in older adults and renal involvement is typically chronic rather than acute.
Ethics statement and consent
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. The Institutional Review Board of Sindh Institute of Urology & Transplantation, Karachi, Pakistan deemed this case report exempt from formal review. All patient data were anonymized to protect privacy.
Case Report
An 18-year-old unmarried male farmer, a resident of Sajawal, with no prior comorbidities, presented to the emergency department with complaints of dark-colored urine for 6 months and fever, shortness of breath, and nausea/vomiting for the preceding 5 days. Dark urine episodes were gradual in onset, intermittent, lasting 2 to 3 days, and occasionally associated with bilateral flank pain. He denied having sore throat, hemoptysis, hematemesis, melena, mucosal bleeding, arthralgia, skin rashes, oral ulcers, alopecia, or weight loss. His medical history included two blood transfusions. The patient had no relevant family history.
Upon arrival, his vital signs were stable; blood pressure 115/76 mm Hg, pulse 82 beats/min, respiratory rate 20 breaths/min, oxygen saturation, normal; and afebrile. Examination revealed pallor without icterus, hepatosplenomegaly, or murmur. Respiratory and cardiovascular systems were unremarkable.
Laboratory investigations showed hemoglobin level of 4.3 g/dL, leukocyte count 3.0×109/L, and platelet count 155×109/L. Peripheral smear revealed anisocytosis, poikilocytosis, normochromic, and macrocytosis. Renal profile demonstrated levels of urea 242 mg/dL and creatinine 16.25 mg/dL with metabolic acidosis. Serum electrolytes revealed sodium 132 mEq/L, potassium 3.8 mEq/L, chloride 91 mEq/L, bicarbonate 17 mEq/L, calcium 7.8 mg/dL, phosphorus 14.4 mg/dL, and albumin 4.2 g/dL. Liver function tests showed total bilirubin 1.7 mg/dL (indirect 1.1 mg/dL), aspartate aminotransferase 125 U/L, and alanine aminotransferase 16 U/L. Hepatitis B, C, and human immunodeficiency virus serologies were negative. Urinalysis revealed proteinuria (3+) and blood positivity (3+) on a dipstick. However, microscopic examination revealed only 5 to 10 red blood cells per high-power field, indicating that the dipstick positivity was predominantly due to hemoglobinuria rather than hematuria. This discrepancy, along with the identification of granular casts, is a classic feature of pigment nephropathy. The protein/creatinine ratio was 2.6 g. Ultrasound revealed kidneys of normal size and echogenicity. Chest radiography and echocardiography findings were unremarkable. The patient was initiated on hemodialysis and received transfusion support.
The differential diagnosis of Coombs-negative hemolytic anemia with AKI has been extensively evaluated. Autoimmune hemolysis was ruled out based on a negative direct antiglobulin test. Thrombotic microangiopathy was considered unlikely because of normal platelet counts, the absence of schistocytes on peripheral smears, and normal coagulation studies. G6PD deficiency was excluded if the enzyme levels were normal. Infectious causes, such as malaria, were negative. Rhabdomyolysis was ruled out based on normal creatine kinase levels. Acute glomerulonephritis was excluded based on negative serology (antinuclear antibody [ANA], antineutrophil cytoplasmic antibody [ANCA], and antiglomerular basement membrane) and the absence of immune deposits on renal biopsy immunofluorescence. Gastrointestinal bleeding was excluded from the gastroenterological evaluation. Hematinic (vitamin B12, folate, and iron) levels were normal, while the autoimmune work-up (ANA, ANCA, and antiglioblastoma) and complement levels were negative. Hemolysis screening revealed elevated lactate dehydrogenase (4,135 U/L) with a negative Coombs test result.
Renal biopsy demonstrated pigment casts within the tubular lumina and golden-brown pigment within the tubular epithelial cells on Perls’ Prussian blue stain (400× magnification), consistent with hemosiderin deposition and pigment nephropathy (Figures 1, 2). Minimal focal tubular atrophy was observed, and immunofluorescence was negative. Crucially, biopsy showed no evidence of thrombotic microangiopathy (e.g., fibrin thrombi) or immune complex deposition. His renal function improved after two sessions of dialysis, with creatinine decreasing from a peak of 16.25 to 0.6 mg/dL by hospital day 10.
However, his hematological parameters failed to recover, and he developed recurrent anemia and pancytopenia despite transfusion. Bone marrow biopsy showed normoblastic erythropoiesis, normal granulopoiesis, megakaryopoiesis, and adequate iron stores (grade 2), reported as normocellular marrow. Considering the recurrent hemolysis, pigment nephropathy, and pancytopenia with negative Coombs test results, flow cytometry for PNH was performed. This revealed a deficiency in CD24/CD157 and fluorescent aerolysin in 51% of the cells, confirming the diagnosis of PNH.
The patient was started on low-dose prednisolone, with improvement in renal function and a partial hematological response. However, he experienced a relapse with recurrent dark urine and a drop in hemoglobin after 1 month. Complement inhibitor therapy (eculizumab or ravulizumab) was unavailable.
Discussion
PNH is predominantly observed in young adults, with a peak incidence between 30–40 years. Although childhood presentations have been reported, these are relatively rare [10]. Notably, our patient was an 18-year-old male, which made this case an unusual presentation with respect to age.
The clinical spectrum of PNH is highly variable and contributes to delayed diagnosis. Common manifestations include constitutional symptoms, such as fatigue and malaise, dyspnea, episodes of dark urine secondary to hemoglobinuria, and renal impairment due to hemosiderin deposition and tubulointerstitial inflammation. Additional features, such as abdominal pain, dysphagia, esophageal spasm, back pain, and erectile dysfunction, arise from smooth muscle dystonia related to nitric oxide depletion [2].
The mechanism of AKI involves complement-mediated intravascular hemolysis, which releases free hemoglobin into the plasma. This is filtered by the glomeruli and taken up by proximal tubular cells. Intracellular iron catalyzes the formation of reactive oxygen species, leading to direct tubular toxicity, inflammation, and cast formation, resulting in AKI.
Highly sensitive flow cytometry is the gold standard for detecting PNH [6]. In our patient, granulocytes carried the largest abnormal clone (51.02%), followed by red blood cells (18.45%), and monocytes (2.79%), reflecting a significant expansion of abnormal stem cell populations.
Renal complications represent a clinically important but sometimes underrecognized manifestation of PNH. Chronic hemolysis and recurrent hemoglobinuria can cause pigment nephropathy and AKI [7]. In line with published findings, a renal biopsy of our patient revealed hemosiderin-laden tubular epithelial cells and granular casts consistent with hemoglobinuria-induced nephropathy. Although recent individual case reports of biopsyconfirmed PNH-AKI are limited, the 2022 review continues to highlight the diagnostic importance of renal biopsy for such atypical presentations [9].
Clinically, PNH is categorized into three major subtypes: classical, PNH associated with bone marrow failure syndrome, and subclinical PNH [11]. Classical PNH is characterized by clinical and laboratory evidence of intravascular hemolysis, usually with large clones detected by flow cytometry. PNH is related to bone marrow disorders, such as aplastic anemia or myelodysplastic syndromes, which typically present with small clone sizes, and cytopenia dominates the clinical picture. Subclinical PNH, on the other hand, is characterized by very small clones in the absence of hemolysis or clinical manifestations and is often detected incidentally. In our case, flow cytometry showed both type II (2.99%) and type III (15.46%) red cell populations, with a combined clone size of 18.45% and a substantial granulocyte clone size of 51.02%. The clinical course, characterized by recurrent hemoglobinuria, AKI, and biochemical evidence of hemolysis, is most consistent with classical PNH with a predominance of type III clones.
The treatment landscape for PNH has evolved beyond supportive care. Complement C5 inhibitors (eculizumab and its long-acting successor, ravulizumab) are the standard of care for effectively controlling intravascular hemolysis and reducing thrombotic risk. More recently, targeted therapies have been approved, including the C3 inhibitor, pegcetacoplan (2021), for extravascular hemolysis and the factor D inhibitor, iptacopan (2023). The novel C5 inhibitor, crovalimab (2024), was administered subcutaneously. Critical to the initiation of any complement inhibitor treatment is appropriate prophylaxis, including vaccination against Neisseria meningitidis and consideration of antimicrobial prophylaxis, to mitigate the risk of meningococcal infections [9].
Our patient's laboratory profile closely mirrored the patterns described in the literature. Severe anemia (hemoglobin 4.3 g/dL), leukopenia, and preserved platelet counts reflect the variable extent of bone marrow involvement in PNH. A strikingly elevated LDH level and negative Coombs test confirmed intravascular hemolysis, consistent with the classical diagnostic criteria [1,2]. The presence of advanced renal dysfunction, with creatinine levels as high as 16.25 mg/dL requiring hemodialysis, parallels previous reports of pigment nephropathy and acute renal failure in patients [7]. Additional urinary findings of proteinuria and hematuria further substantiate the role of hemoglobinuria in renal injury. Flow cytometry confirmed the presence of type II and type III red blood cell populations with substantial granulocyte clones, reinforcing the diagnosis and alignment with international guidelines for PNH evaluation [6]. Laboratory investigations of the patient and their interpretation is added in Table 1. While Table 2 highlights the importance of awareness among primary care and when to suspect it.
In conclusion, PNH should be suspected in young patients presenting with recurrent dark urine, Coombs-negative hemolytic anemia, and unexplained AKI. Renal biopsy showing pigmented nephropathy and confirmatory flow cytometry are essential for the diagnosis. Early initiation of complement inhibition markedly improves prognosis; however, limited access in developing countries remains a major barrier.
Article Information
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Data availability
Data of this research are available from the corresponding author upon reasonable request.
Author contribution
Conceptualization: AR. Data curation: AR, TW. Formal analysis: AR, SG. Investigation: AR, HR, TW. Validation: SIB. Visualization: SG. Resources: HR. Supervision: SIB. Writing–originaldraft: HR, AR, SG, TW, SIB. Writing–review & editing: SIB, HR, SG, TW, AR. Final approval of the manuscript: all authors.
Figure 1
Renal biopsy histology demonstrating pigment nephropathy. (A) Hematoxylin and eosin (H&E) stain (400× magnification) showing granular, brown pigmented casts within tubular lumina (arrow). (B) Perls’ Prussian blue iron stain (400× magnification) revealing intense blue staining, confirming hemosiderin deposition within tubular epithelial cells (arrow). (C) High-power view (600× magnification) of H&E stain highlighting the characteristic golden-brown pigment in tubular cells (arrow). (D) High-power view (600× magnification) of Perls’ Prussian blue stain clearly demonstrating intracellular iron accumulation in renal tubules (arrow). All images include scale bars representing 50 micrometers. These findings are consistent with those of hemoglobinuria-induced acute tubular injuries.
Figure 2
Clinical timeline and laboratory trends. Clinical course: Day –30 to 0, symptom onset (recurrent dark urine); Day 0, emergency department (ED) presentation, acute kidney injury diagnosis, and hemodialysis initiation; Days 1 and 3, hemodialysis sessions; Day 7, renal biopsy; Day 10, creatinine normalized to 0.6 mg/dL, dialysis discontinued; Day 21, the diagnosis of paroxysmal nocturnal hemoglobinuria was confirmed using flow cytometry; Day 35, follow-up visit showing relapse (increased lactate dehydrogenase [LDH] and decreased hemoglobin). Laboratory trends: creatinine, peak 16.25 mg/dL (day 0) to 0.6 mg/dL (day 10) to 1.2 mg/dL (day 35); LDH, peak 4,135 U/L (day 0), 800 U/L (day 10), and 3,500 U/L (day 35); hemoglobin, 4.3 g/dL (day 0) to 8.5 g/dL (post-transfusion) to 5.8 g/dL (day 35).
Table 1
Laboratory investigations of the patient and their interpretation
Parameter
Patient value
Reference range
Interpretation
Hemoglobin (g/dL)
4.3
13–17
Severe anemia
Total leukocyte count (×109/L)
3.0
4.0–11.0
Leukopenia
Platelet count (×109/L)
155
150–450
Near normal
Lactate dehydrogenase (U/L)
4,135
140–280
Markedly elevated, evidence of intravascular hemolysis
Direct Coombs test
Negative
Negative
Rules out autoimmune hemolysis
Serum creatinine (mg/dL)
16.25
0.6–1.2
Severe renal dysfunction (acute kidney injury)
Urea (mg/dL)
242
10–50
Markedly elevated
Urinalysis
3+ proteinuria, numerous RBCs, protein/creatinine ratio 2.6 g
Negative
Hemoglobinuria and secondary proteinuria
Flow cytometry (RBCs)
Type II clone (2.99%), type III clone (15.46%), total (18.45%)
-
Significant abnormal clone population
RBC, red blood cell.
Table 2
Implications for primary care: when to suspect paroxysmal nocturnal hemoglobinuria
Category
Detail
Red flag signs & symptoms
Recurrent dark (cola- or tea-colored) urine, especially noted in the morning.
Severe fatigue, weakness, or shortness of breath that is disproportionate to the degree of anemia.
Unexplained episodes of abdominal pain, dysphagia (difficulty swallowing), or erectile dysfunction.
History of unexplained thrombotic events (e.g., venous thrombosis in unusual sites like hepatic or portal veins), particularly in young adults.
Immediate primary care work-up
Complete blood count with differential and reticulocyte count: to detect anemia, cytopenias, and assess bone marrow response.
Hemolysis panel: LDH, total and indirect bilirubin, haptoglobin.
Urinalysis with microscopy: to confirm hemoglobinuria (dipstick positive for blood with few red blood cells on microscopy) and check for proteinuria.
Direct antiglobulin test (Coombs test): to rule out autoimmune hemolytic anemia.
Same-day referral thresholds (to emergency department or specialist)
Refer immediately if any of the following are present:
Acute kidney injury: creatinine rising or ≥1.5–2× baseline.
Severe metabolic derangement: metabolic acidosis, hyperkalemia.
Signs of severe hemolysis: rapidly escalating LDH, rapidly falling hemoglobin, persistent dark urine.
Advise the patient to seek immediate medical attention if they develop: fever, severe headache, neck stiffness, or photophobia (potential signs of meningococcal infection, especially relevant if complement inhibitor therapy is started later).
A significant increase in fatigue or shortness of breath. Worsening or recurrence of dark urine. Any signs of thrombosis (e.g., painful/swollen limb, chest pain, neurological symptoms).
2. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. Diagnosis and management of paroxysmal nocturnal hemoglobin-uria. Blood 2005;106:3699-709.
4. Schrezenmeier H, Muus P, Socie G, Szer J, Urbano-Ispizua A, Maciejewski JP, et al. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica 2014;99:922-9.
5. Nishimura JI, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 2004;83:193-207.
6. Richards SJ, Rawstron AC, Hillmen P. Application of flow cytometry to the diagnosis of paroxysmal nocturnal hemoglobinuria. Cytometry 2000;42:223-33.
8. Rosse WF, Dacie JV. Immune lysis of normal human and paroxysmal nocturnal hemoglobinuria (PNH) red blood cells: I. the sensitivity of PNH red cells to lysis by complement and specific antibody. J Clin Invest 1966;45:736-48.
10. Borowitz MJ, Craig FE, Digiuseppe JA, Illingworth AJ, Rosse W, Sutherland DR, et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010;78:211-30.
11. de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008;112:3099-106.
Paroxysmal nocturnal hemoglobinuria presenting with acute kidney injury in an 18-year-old male: a case report
Figure 1
Renal biopsy histology demonstrating pigment nephropathy. (A) Hematoxylin and eosin (H&E) stain (400× magnification) showing granular, brown pigmented casts within tubular lumina (arrow). (B) Perls’ Prussian blue iron stain (400× magnification) revealing intense blue staining, confirming hemosiderin deposition within tubular epithelial cells (arrow). (C) High-power view (600× magnification) of H&E stain highlighting the characteristic golden-brown pigment in tubular cells (arrow). (D) High-power view (600× magnification) of Perls’ Prussian blue stain clearly demonstrating intracellular iron accumulation in renal tubules (arrow). All images include scale bars representing 50 micrometers. These findings are consistent with those of hemoglobinuria-induced acute tubular injuries.
Figure 2
Clinical timeline and laboratory trends. Clinical course: Day –30 to 0, symptom onset (recurrent dark urine); Day 0, emergency department (ED) presentation, acute kidney injury diagnosis, and hemodialysis initiation; Days 1 and 3, hemodialysis sessions; Day 7, renal biopsy; Day 10, creatinine normalized to 0.6 mg/dL, dialysis discontinued; Day 21, the diagnosis of paroxysmal nocturnal hemoglobinuria was confirmed using flow cytometry; Day 35, follow-up visit showing relapse (increased lactate dehydrogenase [LDH] and decreased hemoglobin). Laboratory trends: creatinine, peak 16.25 mg/dL (day 0) to 0.6 mg/dL (day 10) to 1.2 mg/dL (day 35); LDH, peak 4,135 U/L (day 0), 800 U/L (day 10), and 3,500 U/L (day 35); hemoglobin, 4.3 g/dL (day 0) to 8.5 g/dL (post-transfusion) to 5.8 g/dL (day 35).
Figure 1
Figure 2
Paroxysmal nocturnal hemoglobinuria presenting with acute kidney injury in an 18-year-old male: a case report
Laboratory investigations of the patient and their interpretation
Parameter
Patient value
Reference range
Interpretation
Hemoglobin (g/dL)
4.3
13–17
Severe anemia
Total leukocyte count (×109/L)
3.0
4.0–11.0
Leukopenia
Platelet count (×109/L)
155
150–450
Near normal
Lactate dehydrogenase (U/L)
4,135
140–280
Markedly elevated, evidence of intravascular hemolysis
Direct Coombs test
Negative
Negative
Rules out autoimmune hemolysis
Serum creatinine (mg/dL)
16.25
0.6–1.2
Severe renal dysfunction (acute kidney injury)
Urea (mg/dL)
242
10–50
Markedly elevated
Urinalysis
3+ proteinuria, numerous RBCs, protein/creatinine ratio 2.6 g
Negative
Hemoglobinuria and secondary proteinuria
Flow cytometry (RBCs)
Type II clone (2.99%), type III clone (15.46%), total (18.45%)
-
Significant abnormal clone population
RBC, red blood cell.
Implications for primary care: when to suspect paroxysmal nocturnal hemoglobinuria
Category
Detail
Red flag signs & symptoms
Recurrent dark (cola- or tea-colored) urine, especially noted in the morning.
Severe fatigue, weakness, or shortness of breath that is disproportionate to the degree of anemia.
Unexplained episodes of abdominal pain, dysphagia (difficulty swallowing), or erectile dysfunction.
History of unexplained thrombotic events (e.g., venous thrombosis in unusual sites like hepatic or portal veins), particularly in young adults.
Immediate primary care work-up
Complete blood count with differential and reticulocyte count: to detect anemia, cytopenias, and assess bone marrow response.
Hemolysis panel: LDH, total and indirect bilirubin, haptoglobin.
Urinalysis with microscopy: to confirm hemoglobinuria (dipstick positive for blood with few red blood cells on microscopy) and check for proteinuria.
Direct antiglobulin test (Coombs test): to rule out autoimmune hemolytic anemia.
Same-day referral thresholds (to emergency department or specialist)
Refer immediately if any of the following are present:
Acute kidney injury: creatinine rising or ≥1.5–2× baseline.
Severe metabolic derangement: metabolic acidosis, hyperkalemia.
Signs of severe hemolysis: rapidly escalating LDH, rapidly falling hemoglobin, persistent dark urine.
Advise the patient to seek immediate medical attention if they develop: fever, severe headache, neck stiffness, or photophobia (potential signs of meningococcal infection, especially relevant if complement inhibitor therapy is started later).
A significant increase in fatigue or shortness of breath. Worsening or recurrence of dark urine. Any signs of thrombosis (e.g., painful/swollen limb, chest pain, neurological symptoms).
LDH, lactate dehydrogenase.
Table 1
Laboratory investigations of the patient and their interpretation
RBC, red blood cell.
Table 2
Implications for primary care: when to suspect paroxysmal nocturnal hemoglobinuria
