KDIGO stage 3 acute kidney injury in children with severe Plasmodium falciparum malaria including blackwater fever: a case series from a resource-limited setting in Southwest Ethiopia

Abstract

Background

Acute kidney injury (AKI) is a frequent complication of severe Plasmodium falciparum malaria in children, and blackwater fever (BWF) can precipitate severe renal injury. Evidence on management when renal replacement therapy (RRT) is unavailable remains limited.

Methods

We describe four pediatric patients with confirmed P. falciparum malaria and KDIGO stage 3 AKI managed at Mizan-Tepi University Teaching Hospital (MTUTH), Southwest Ethiopia, between November and December 2025. Two cases met the operational definition of BWF, while two had severe malaria-associated AKI without documented hemoglobinuria. All met standard indications for RRT, which was not available. Management included intravenous artesunate, careful fluid titration, electrolyte correction, blood transfusion when indicated, and avoidance of nephrotoxic agents.

Results

Peak serum creatinine ranged from 10.77 to 17.23 mg/dL. Two of four patients (50%) achieved complete clinical and renal recovery. One patient had partial recovery, the remaining patient died after presenting with anuria, pulmonary edema, and multi-organ failure. In the two BWF cases, renal recovery was preceded by a prolonged oliguric phase followed by polyuric recovery and a biphasic potassium pattern from hyperkalemia to hypokalemia. One surviving patient was discharged with residual renal dysfunction and persistent proteinuria.

Conclusions

In this small case series from a resource-limited setting without dialysis, conservative management of severe malaria-associated KDIGO stage 3 AKI was associated with renal recovery in three of four children. These findings are hypothesis-generating and highlight the need for dialysis access, closer electrolyte monitoring, and prospective studies of phase-specific renal recovery in malaria-associated AKI.

Introduction

Malaria remains a major cause of childhood morbidity and mortality in sub-Saharan Africa, with Plasmodium falciparum accounting for the majority of severe disease and malaria-related deaths in the region [1, 2]. Despite substantial progress in malaria control, severe malaria continues to impose a significant burden on health systems in endemic regions, particularly among children younger than five years of age [1, 3]. Acute kidney injury (AKI) has emerged as an increasingly recognized complication of severe malaria and is associated with prolonged hospitalization, increased mortality, and long-term renal sequelae, including progression to chronic kidney disease (CKD) [3–6].

Recent studies from Africa have reported that AKI affects 24–59% of hospitalized children with severe P. falciparum malaria, with KDIGO stage 3 disease linked to mortality rates of 11.7% versus 1.8% in those without AKI [3, 6, 7]. The pathogenesis of malaria-associated AKI (MAKI) is multifactorial and involves intravascular hemolysis, endothelial dysfunction, microvascular obstruction by parasitized erythrocytes, inflammatory activation, and renal tubular injury [8–10]. These mechanisms may occur alone or in combination, resulting in a spectrum of renal manifestations ranging from transient creatinine elevation to severe Kidney Disease: Improving Global Outcomes (KDIGO) stage 3 AKI requiring renal replacement therapy (RRT) [11]. Electrolyte disturbances, including hyponatremia, hyperphosphatemia, hypocalcemia, and potassium abnormalities, frequently complicate the clinical course and evolve dynamically across the oliguric and recovery phases of AKI [8, 12].

Blackwater fever (BWF) represents one of the most severe manifestation of P. falciparum infection and is characterized by massive intravascular hemolysis leading into hemoglobinuria, severe anemia, and dark or cola-colored urine [10]. Increasing evidence suggests that hemolysis-mediated nephrotoxicity plays a central role in the development of severe AKI in affected patients [3, 10, 13]. When circulating haptoglobin and hemopexin scavenging systems become saturated, free hemoglobin and heme are released into the circulation, promoting oxidative stress, endothelial injury, and acute tubular necrosis [13]. Pediatric studies from East Africa have demonstrated a strong association between hemoglobinuria and severe AKI, highlighting BWF as an important predictor of poor renal outcomes [3].

Management of severe malaria-associated AKI (MAKI) is primarily supportive and includes prompt administration of parenteral artesunate, careful fluid management, correction of electrolyte disturbances, avoidance of nephrotoxic agents, and initiation of RRT when indicated [11, 14, 15]. Current international guidelines recommend dialysis for patients with severe azotemia, refractory electrolyte disturbances, pulmonary edema, severe metabolic complications, or persistent oliguria/anuria [11, 14]. However, access to pediatric dialysis remains extremely limited across many malaria-endemic regions of sub-Saharan Africa. Consequently, clinicians are frequently required to manage children with dialysis-indicated AKI using conservative measures alone.

Although the epidemiology and prognostic significance of MAKI have been increasingly described [3, 5, 7], published reports detailing the clinical course, electrolyte evolution, and renal recovery patterns of children managed without access to RRT remain scarce. Furthermore, few studies have specifically examined the differences between BWF-associated AKI and severe MAKI without documented hemoglobinuria. Understanding these trajectories is important for clinicians practicing in resource-constrained settings where referral for RRT may be delayed or impossible.

Southwest Ethiopia is a region of intense P. falciparum transmission where severe malaria remains a common cause of pediatric hospitalization [1, 16]. Mizan-Tepi University Teaching Hospital serves as a major referral center for this population but lacks on-site dialysis services. This setting provides a unique opportunity to describe the presentation and short-term outcomes of children with advanced malaria-associated kidney injury managed under substantial resource constraints.

We therefore report a retrospective case series of four children with severe P. falciparum malaria complicated by KDIGO stage 3 AKI, including two cases of blackwater fever. All patients met accepted indications for RRT, yet dialysis was unavailable. The objectives of this study were to describe their clinical presentation, laboratory characteristics, electrolyte disturbances, management strategies, and short-term renal outcomes, and to highlight key challenges encountered in the care of severe malaria-associated AKI in a dialysis-limited setting.

Methods

Study design and setting

This retrospective descriptive case series was conducted at Mizan-Tepi University Teaching Hospital (MTUTH), a tertiary referral hospital in Southwest Ethiopia serving a population in a malaria-endemic region where Plasmodium falciparum is the predominant malaria species. MTUTH provides inpatient pediatric and critical care services but does not have on-site RRT facilities. The study included all eligible patients admitted between November and December 2025.

Case identification and data collection

Cases were identified retrospectively through review of pediatric inpatient records, admission and discharge registers, laboratory records, nursing charts, and outpatient follow-up documentation. All consecutive patients meeting the predefined eligibility criteria during the study period were included. Data extracted included demographic characteristics, clinical presentation, laboratory findings, malaria severity indicators, AKI characteristics, treatment interventions, electrolyte abnormalities, and short-term outcomes.

Inclusion criteria

Pediatric patients aged < 18 years with: (1) confirmed P. falciparum malaria by blood film or RDT; (2) KDIGO stage 3 AKI; and (3) conservative management (i.e., no RRT available) during the study period.

Inclusion criteria

No eligible patients were excluded and defining non-eligible patients.

Definitions

Severe malaria

Defined per WHO 2024 criteria, including impaired consciousness, severe anaemia (hemoglobin < 5 g/dL), AKI, pulmonary oedema, abnormal bleeding, hyperparasitaemia (> 10%), hypoglycaemia, circulatory collapse, or prostration [15].

Blackwater fever (BWF)

Defined by the co-occurrence of (1) confirmed P. falciparum malaria; (2) parental or patient report of dark, cola-colored, reddish, or black urine; and (3) urine dipstick positive for blood with absent or few red blood cells on urine microscopy (where performed), supporting hemoglobinuria rather than hematuria. This clinical definition and its limitations are acknowledged [3, 10].

KDIGO stage 3 AKI

Serum creatinine >3x baseline or > = 4.0 mg/dL, or urine output < 0.3 mL/kg/hour for > = 24 h, or anuria for > = 12 h [11].

Renal recovery

was defined as sustained reversal of AKI, i.e., no longer meeting KDIGO AKI criteria by serum creatinine and/or urine output for ≥ 48 h [17].

Conservative management

All AKI management strategies that do not include RRT, encompassing fluid titration, electrolyte correction, nutritional support, antimalarial therapy, and avoidance of nephrotoxic agents [8, 15].

Institutional AKI management protocol

The MTUTH conservative AKI bundle was applied in all cases and is based on WHO severe malaria management and KDIGO-aligned AKI supportive-care principles adapted to a resource-limited setting. It comprised: (1) early parenteral artesunate 2.4 mg/kg/dose for children > 20 kg and 3 mg/kg/dose for children ≤ 20 kg at 0, 12, and 24 h, then every 24 h until oral therapy is tolerated, followed by a full oral artemether–lumefantrine completion course; (2) meticulous isotonic crystalloid management (e.g., 0.9% saline), titrated to perfusion/hydration assessment, respiratory findings, and urine output with explicit emphasis on avoiding fluid overload, and avoidance of non-indicated fluid boluses; (3) electrolyte management with protocolized correction of life-threatening abnormalities, including IV calcium gluconate 10%: 0.5 ml/kg (max 10-20 ml) IV over 5–10 min for severe/symptomatic hypocalcemia and/or for ECG-threatening hyperkalemia, with transition to oral calcium 50 mg/kg/day when indicated; aluminium hydroxide 30 mg/kg/day in divided doses with meals as a short-term phosphate binder when sevelamer was unavailable; and potassium supplementation 0.3 mEq/kg/dose IV during the polyuric recovery phase, titrated to ECG monitoring and serial serum potassium (with concurrent attention to magnesium where feasible); (4) strict avoidance of nephrotoxic agents; (5) blood transfusion using severe-malaria restrictive thresholds Hb ≤ 5 g/dL, or Hb < 6 g/dL with respiratory distress/hemodynamic compromise to limit unnecessary transfusion-related volume/viscosity burden while ensuring timely treatment of life-threatening anemia; and (6) nasogastric nutritional support when indicated. All patients meeting formal RRT indications were managed conservatively solely due to structural unavailability of dialysis. The authors do not advocate conservative management as equivalent to RRT in children with formal dialysis indications.

Ethics

Ethical approval was obtained from the Research and Ethics Review Committee, College of Medicine and Health Sciences, Mizan-Tepi University (Approval reference: MTU-IR/03/18). Written informed consent was obtained from parents or guardians of all patients. Patient assent was sought from patients aged > = 7 years (applicable to Cases 3 and 4). Patient identifiers have been anonymized.

Case presentations

Case 1 (BWF-associated AKI)

Demographics and presentation

A previously healthy 6-year-old male (weight 18 kg) presented with a 3-week history of progressive fatigue and anorexia, followed by high-grade fever, chills, rigors, and repeated vomiting for 5 days. Three days before admission, his mother observed reddish to dark cola-colored urine accompanied by reduced urine output and increasing lethargy. There was no prior history of renal disease, hemoglobinopathy, or nephrotoxic medication use.

Examination and initial investigations (referring hospital): Physical examination revealed pallor, tachycardia (HR 121 bpm), RR 34/min, temperature 38 degrees C, Blood pressure 90/60 mmHg (below the 75th percentile for age/sex), SpO2 87% on room air, with features of high-output cardiac failure in the context of severe anemia. There was no jaundice. Lung fields were clear. Initial investigations showed: hemoglobin 3.6 g/dL; platelet count 21,600/mcL; serum creatinine rising from 0.81 to 2.56 mg/dL within 48 h; blood film: +3 Plasmodium falciparum parasitemia; liver function tests within normal limits. Urine dipstick: blood 3+; no red cell casts, consistent with hemoglobinuria. These findings were consistent with severe P. falciparum malaria complicated by BWF and evolving AKI. Parenteral artesunate (3 mg/kg at 0, 12, and 24 h) and ceftriaxone (100 mg/kg/day IV) were initiated, and the patient was referred to MTUTH.

MTUTH course On arrival, the patient was alert but toxic. Two units of whole blood (20 mL/kg each, administered sequentially over 3 h each) were transfused for severe anemia; furosemide 1 mg/kg IV was co-administered with each transfusion to mitigate volume accumulation in the setting of oliguria. Hemodynamics were monitored throughout transfusion; no pulmonary edema or hemodynamic instability resulted. Blood pressure was within normal limits. Despite transfusion, renal function continued to deteriorate: serum creatinine peaked at 12.73 mg/dL and blood urea nitrogen at 285 mg/dL (KDIGO stage 3 AKI). The patient developed progressive lethargy and irritability consistent with uremic encephalopathy, and urine output declined further (‘<0.3 mL/kg/hour) for > 24 h. Peripheral blood film showed a leukemoid reaction.

Parasitological response

Blood film was negative by day 3 of artesunate therapy, confirming satisfactory parasitological clearance.

Electrolyte disturbances and management

Marked electrolyte derangements were documented and managed with close clinical and laboratory monitoring. Hyponatremia (nadir 123 mmol/L) managed with an individualized fluid plan targeting euvolemia, with restriction and clinical monitoring. Severe hyperphosphatemia (peak 5.33 mmol/L [16.4 mg/dL]) managed with short term aluminium hydroxide 30 mg/kg/day and dietary phosphate restriction (sevelamer unavailable). Hypocalcemia (total calcium 1.55–1.60 mmol/L) was treated with IV 10% calcium gluconate bolus dosing with ECG monitoring followed by oral calcium supplementation once stable. Hyperkalemia (serum potassium 5.1–5.7 mmol/L) during the oliguric phase was treated medically with ECG-guided therapy (including potassium-shifting measures and cardiac membrane stabilization when indicated). Hypokalemia during polyuric recovery (serum potassium 2.9–3.2 mmol/L) was corrected with cautious IV and oral potassium supplementation (0.3 mEq/kg/dose) titrated against ECG monitoring and daily serum potassium. Ceftriaxone was discontinued by day 4 as clinical parameters were inconsistent with bacterial sepsis. Nephrotoxic agents were avoided throughout.

Nutritional support

Nasogastric feeding was initiated due to poor oral intake. Strict fluid input/output monitoring, regular repositioning, and head elevation were maintained.

Recovery and outcome The patient showed gradual clinical and biochemical improvement over subsequent days. Mental status normalized, urine output increased to 1.5–2.0 mL/kg/hr, and serum creatinine declined from the peak of 12.73 mg/dL to 7.89 mg/dL, then 1.79 mg/dL, and eventually normalized to 0.63 mg/dL. Electrolyte abnormalities resolved; mild hypokalemia during recovery continued to improve with supplementation. Platelet count recovered to 420,000/µL. Hemoglobin improved to 7.2 g/dL; oral iron was prescribed at discharge. At 4-week outpatient follow-up: creatinine 0.58 mg/dL (normal), blood pressure normal, urinalysis normal. RRT was indicated (uremic encephalopathy, severe electrolyte disturbances) but was structurally unavailable.

Case 2 (BWF-associated AKI)

Demographics and presentation

A previously healthy 14-year-old female (weight 35 kg) presented with a 3-day history of high-grade fever, chills, and rigors. Reddish discoloration of the urine was noted from symptom onset. There was no prior history of renal disease, hemoglobinopathy, chronic illness, vomiting, diarrhea, facial or peripheral edema, dysuria, cough, skin rash, or bleeding.

Examination and investigations Conscious but toxic; HR 128 bpm, RR 36/min, temperature 38.9 degrees C, SpO2 82% on room air; moderate to severe respiratory distress. Blood pressure: 100/60 mmHg (below the 90th percentile for age/sex). Blood film: +2 Plasmodium falciparum parasitemia. Hemoglobin 6.0 g/dL on admission, declining to 5.7 g/dL on day 2. Platelet remained normal (190,000-203,000/µL). Kidney indices worsened rapidly: Serum creatinine 3.12 mg/dL on admission, rising to 3.93 mg/dL (day 2), 10.22 mg/dL (day 4), and 10.77 mg/dL (day 5), consistent with KDIGO stage AKI. Serum sodium 131.6 mmol/L and Serum potassium 4.8 mmol/L on admission. Urine dipstick was blood 3 + with gross discoloration, supporting hemoglobinuria in the clinical context of falciparum malaria. Objective urine output monitoring documented oliguria (0.36 mL/kg/hr).

Management

Intravenous artesunate 2.4 mg/kg (> 20 kg) at 0, 12, and 24 h, then every 24 h until oral therapy was tolerated. Furosemide 1 mg/kg IV was administered in the early oliguric phase to assess residual tubular function and facilitate fluid management; this was not for treatment of fluid overload (which was absent on clinical assessment) but as a pragmatic measure used in resource-limited settings, acknowledging the lack of evidence for mortality benefit. One unit of packed red blood cells (10 mL/kg) was transfused at admission; hemodynamics were stable throughout. Fluid management, electrolyte monitoring, avoidance of nephrotoxins, and strict input/output monitoring continued throughout.

Parasitological response

Blood film was negative by day 3 of artesunate therapy.

Recovery and outcome

By day 7 the patient’s urine output had increased to 2.14 mL/kg/hr (24 h), with a serum creatinine of 8.7 mg/dL. On day 8 creatinine fell to 6.2 mg/dL and urine output was 1.91 mL/kg/hr (24 h). By day 10 creatinine had decreased to 2.62 mg/dL. The patient was discharged on oral ferrous sulfate with outpatient follow-up arranged. At the 4-week follow-up the serum creatinine was 0.70 mg/dL and urinalysis was normal, indicating complete renal recovery. Renal replacement therapy had been indicated for uremic encephalopathy and severe azotemia but was not available locally.

Case 3 (severe malaria-associated AKI without confirmed hemoglobinuria)

Demographics and presentation

A 7-year-old female (weight 20 kg) presented with a 3-day history of high-grade fever, repeated episodes of bloody vomiting, fast breathing, and progressive oliguria culminating in anuria for > 24 h. One month prior, she had been hospitalized at a tertiary hospital (Addis Ababa) for severe P. falciparum malaria complicated by KDIGO stage 3 AKI and stage 2 hypertension, during which dialysis was performed. She was discharged with creatinine 0.9 mg/dL, and continued on nifedipine. No history of dark or cola-colored urine was documented at the current presentation or at the prior admission.

Examination and investigations On arrival she was critically ill, pale, lethargic, and with altered mental status. Moderate-to-severe respiratory distress with bilateral coarse crackles across both lung fields, requiring immediate CPAP support. Blood pressure: 120/70 mmHg (above the 95th percentile for age/sex). Anuria for > 24 h. Blood film: +2 Plasmodium falciparum parasitemia. Urine dipstick: blood 2+; urine microscopy demonstrated red blood cell casts and dysmorphic red cells, raising the possibility of glomerular involvement. Serial laboratory results showed rapidly progressive renal dysfunction and severe metabolic derangements (Table 1).

Table 1.

Serial laboratory parameters during acute kidney injury progression in case 3

Parameter	Day one	Day 2	Day three
Sodium (mmol/L)	124	131	135
Potassium (mmol/L)	5.6	6.6	5.7
Calcium (mmol/L)*	1.43	1.55	1.85
Phosphate (mmol/L)	2.42	3.52	4.42
Creatinine (mg/dL)	5.98	14.98	16.24
BUN (mg/dL)	31	129	148
Hb (g/dl)	4.7	-	5.1
WBC (/µL)	14,000	-	12,000
Platelets (/µL)	100,200	-	40,000
AST (U/L)	16
ALT (U/L)	20

*Calcium reported in mmol/L (conversion: mmol/L x 4.01 = mg/dL). Normal range: 2.1–2.6 mmol/L

Management Working diagnoses: severe P. falciparum malaria; pulmonary edema; KDIGO stage 3 AKI; hypertension; uremic encephalopathy; upper gastrointestinal bleeding; severe electrolyte derangement. RRT was formally indicated but structurally unavailable. Intravenous artesunate 3 mg/kg (weight 20 kg) at 0, 12, and 24 h, then once daily. Broad-spectrum antibiotics (ceftriaxone 100 mg/kg/day IV) initiated empirically due to inability to exclude bacterial co-infection in the context of severe illness, leukocytosis, and clinical deterioration (blood cultures unavailable at our facility). One unit of whole blood 20 mL/kg over 3 h transfused for severe anemia (hemoglobin 4.7 g/dL); CPAP was continued throughout transfusion with close monitoring for pulmonary edema exacerbation; hemodynamics remained stable during transfusion. Electrolyte management included aluminium hydroxide for severe hyperphosphatemia (13.7 mg/dL). Severe hyperkalemia (K 6.6 mmol/L) was treated with continuous ECG monitoring and IV calcium gluconate for cardiac membrane stabilization plus insulin–dextrose for potassium shifting, consistent with severe malaria supportive-care pathways. Upper GI bleeding was managed with omeprazole, antiemetic therapy, and vitamin K. Supportive measures included CPAP for pulmonary edema, strict input/output monitoring, head elevation, regular repositioning, and temporary nil-by-mouth with reassessment for early enteral nutrition as tolerated.

Parasitological response

Blood film positive (+ 2) on admission; +1 on day 2; negative by day 3, confirming parasitological clearance. The fatal outcome was driven by established multi-organ failure rather than persistent parasitemia.

Outcome

Despite maximal conservative therapy, the patient succumbed to multi-organ failure on day 3 (refractory AKI with anuria, pulmonary edema/respiratory failure, uremic encephalopathy, and upper GI hemorrhage). This case demonstrates the lethal potential of recurrent severe malaria-AKI when compounded by respiratory failure, anuria, and established end-organ damage [7].

Case 4 (severe malaria-associated AKI without confirmed hemoglobinuria)

Demographics and presentation

A 10-year-old male (weight 28 kg) presented with a 3-week history of progressive periorbital and bilateral lower-limb puffiness, fatigue, poor appetite, and decreased urine output. Swelling was initially periorbital, more pronounced in the morning, subsequently involving the lower extremities. There was no history of dark or cola-colored urine, gross hematuria, dysuria, frothy urine, or sore throat. He had three prior episodes of severe P. falciparum malaria, two complicated by KDIGO stage 3 AKI managed conservatively with apparent renal recovery; however, his most recent documented baseline creatinine was 2.7 mg/dL, indicating likely pre-existing chronic kidney disease (CKD) from prior malarial AKI-to-CKD progression rather than a true healthy baseline. The most recent febrile illness preceded the edema by days, consistent with a malarial precipitant. Family history was unremarkable.

Examination and investigations Acutely ill, markedly pale; conscious and oriented; severe pallor, periorbital edema, mild bilateral pitting pedal edema. Blood pressure: 100/65 mmHg (below the 90th percentile for age/sex). Investigations: Hb 5.1 g/dL; WBC 7,960/µL; platelets 151,000/µL; CRP 112 mg/L; ESR 25 mm/h; serum creatinine 17.23 mg/dL; BUN 311.99 mg/dL; blood film + 2 P. falciparum parasitemia. Serum albumin 15 g/L (markedly low; consistent with severe hypoalbuminemia in the context of heavy proteinuria and systemic illness). Urine dipstick: protein 3+, blood 1+; urine microscopy showed granular and hyaline casts without dysmorphic red blood cells or RBC casts a pattern consistent with acute tubular necrosis (ATN) rather than active glomerulonephritis. Renal ultrasound revealed bilaterally enlarged kidneys with increased cortical echogenicity, consistent with AKI. Day 3 labs: creatinine 16.9 mg/dL; BUN 289 mg/dL; potassium 4.7 mmol/L; sodium 125 mmol/L; calcium 8.2 mg/dL. An immunological evaluation was partially performed. HIV serology, hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV) antibody testing, and antistreptolysin O (ASO) titre were negative. However, complement levels (C3/C4), antinuclear antibody (ANA) testing, and other advanced immunological investigations were unavailable because of resource limitations, representing an important diagnostic constraint. Consequently, immune-mediated glomerular disease could not be definitively excluded. This patient did not meet the clinical definition of blackwater fever because hemoglobinuria was not documented and was therefore classified as severe MAKI without blackwater fever.

Management

Intravenous artesunate 2.4 mg/kg (weight > 20 kg) at 0, 12, and 24 h, then every 24 h, with transition to a full oral ACT completion course once tolerated. Empirical broad-spectrum antibiotics (ceftriaxone 100 mg/kg/day IV) were initiated given inability to exclude bacterial co-infection (blood culture unavailable), with intent to reassess upon clinical response. For severe anemia (Hb 5.1 g/dL), one unit of cross-matched packed red blood cells (10 mL/kg) was transfused at admission; hemodynamics remained stable without fluid overload. Furosemide was administered during the oliguric phase as a pragmatic diuretic challenge to assess residual tubular function and facilitate fluid management not for treatment of clinical fluid overload, and without proven mortality benefit in this context. Electrolyte correction included IV calcium gluconate (bolus dosing with ECG monitoring) for hypocalcemia and aluminium hydroxide as a short-term phosphate binder. Meticulous input/output monitoring and strict avoidance of nephrotoxic agents were maintained throughout.

On prednisolone use

After confirmed parasitological clearance (blood film negative day 3), prednisolone 1 mg/kg/day was initiated empirically for suspected malaria-associated nephrotic syndrome given nephrotic-range proteinuria (3+) and hypoalbuminemia (15 g/L). This decision is acknowledged as not guideline-concordant; KDIGO 2021 Practice Point explicitly states there are no indications for immunosuppressive agents in malarial nephropathy, and treatment should focus on malarial eradication [18]. Critically, the urinary sediment pattern (granular/hyaline casts, absent dysmorphic RBCs/RBC casts) is more consistent with ATN with heavy proteinuria than primary glomerular disease. ATN is the dominant histological lesion in malaria associated AKI [18]. Heavy proteinuria and hypoalbuminemia are recognized in severe malaria-associated ATN and do not establish primary nephrotic syndrome without histopathological or immunological confirmation. The decision was made in the absence of renal biopsy, immunological workup, and nephrologist input, reflecting the resource-limited context; this represents a significant management limitation of Case 4. Whether clinical improvement reflects steroid responsiveness or natural recovery of malarial AKI cannot be determined from this case alone.

Parasitological response

Blood film negative by day 3 of artesunate therapy. Prednisolone was initiated only after this confirmed clearance.

Recovery and outcome Gradual improvement followed parasitological clearance. Mental status normalized, urine output recovered, and edema diminished. Serum creatinine declined from 17.23 → 12.8 → 5.79 → 4.32 mg/dL at discharge; Hb improved to 7.2 g/dL. The patient was discharged on oral ferrous sulfate and prednisolone (with planned taper) with outpatient follow-up arranged. At 4-week review: creatinine 2.1 mg/dL (improved below pre-admission baseline of 2.7 mg/dL), proteinuria 2+, periorbital edema resolved, BP 110/70 mmHg. Incomplete renal recovery and persistent proteinuria are acknowledged; importantly, the pre-existing CKD baseline (creatinine 2.7 mg/dL) makes interpretation of 4-week creatinine 2.1 mg/dL complex, the trajectory is encouraging but recovery relative to the true healthy baseline (before recurrent malarial AKI) cannot be determined. A summary of all four cases, including key clinical variables, dialysis indications, and outcomes, is provided in Table 2.

Table 2.

Summary of pediatric severe malaria-AKI series

Variable	Case 1	Case 2	Case 3	Case 4
BWF classification	Yes	Yes	No	No
Age (years)	6	14	7	10
Sex	Male	Female	Female	Male
Weight (kg)	18	35	20	28
Hemoglobin on admission (g/dL)	3.6	6.0	4.7	5.1
Admission creatinine (mg/dL)	2.56*	3.12	5.98	17.23
Peak creatinine (mg/dL)	12.73	10.77	16.24	17.23
Discharge creatinine (mg/dL)	0.63	2.62	N/A	4.32
4-week follow-up creatinine	0.58	0.70	N/A	2.1
Hemoglobinuria	Yes	Yes	No	No
Oliguria/anuria	Oliguria	Oliguria	Anuria > 24 h	Oliguria
Lowest sodium (mmol/L)	123	131.6	124	125
Highest potassium (mmol/L)	5.7	4.8	6.6	4.7
Highest phosphate (mg/dL)	16.4	Not recorded	13.7	Not recorded
Lowest calcium (mg/dL)	6.2	Not recorded	5.7	8.2
Pulmonary edema	No	No	Yes	No
Uremic encephalopathy	Yes	Yes	Yes	Yes
Dialysis indication	Yes	Yes	Yes	Yes
Artesunate	3 mg/kg IV	2.4 mg/kg IV	3 mg/kg IV	2.4 mg/kg IV
Parasitemia clearance	Negative day 3	Negative day 3	Negative day 3	Negative day 3
Transfusion	2 units whole blood 20 mL/kg each)	1 unit PRBC (10 mL/kg)	1 unit whole blood (20 mL/kg)	1 unit PRBC (10 mL/kg)
Outcome	Complete renal recovery	Complete renal recovery	Death (day 3)	Partial recovery

*Creatinine at referring hospital on admission. PRBC = packed red blood cells. BWF = blackwater fever. All patients had at least one formal indication for RRT; conservative management was employed solely due to structural unavailability of dialysis at MTUTH

Discussion

This case series describes four children with severe Plasmodium falciparum malaria complicated by KDIGO stage 3 AKI, including two presentations consistent with blackwater fever (BWF), managed in a tertiary hospital without access to RRT. All children developed life-threatening complications commonly considered indications for urgent dialysis; severe azotemia with uremic manifestations, prolonged oliguria/anuria, refractory electrolyte abnormalities, and/or pulmonary edema: yet none could receive RRT because of structural and financial barriers. Despite this constraint, three children survived with substantial renal recovery, while one died with fulminant multiorgan failure. Among survivors, recovery followed a typical trajectory from oliguric AKI to a polyuric phase with prominent and rapidly changing electrolyte disturbances, underscoring both the potential reversibility of malaria-associated AKI (MAKI) and the clinical hazards of severe renal involvement when laboratory surveillance and dialysis are limited. Importantly, these outcomes should not be interpreted as evidence that conservative management is equivalent to dialysis; rather, they represent outcomes achieved under conditions where RRT was unavailable.

Comparison with contemporary pediatric malaria-associated AKI studies

Our findings align with prospective data demonstrating that AKI is common among African children hospitalized with severe malaria and is strongly severity-dependent in its prognostic implications. In a large prospective cohort of children with severe malaria in Uganda (n = 598), AKI occurred in 45.3%, and in-hospital mortality increased from 1.8% in children without AKI to 26.5% in those with KDIGO stage 3 AKI [19]. Earlier work by Conroy et al. similarly demonstrated that AKI affects nearly half of children hospitalized with severe malaria and is independently associated with increased mortality and neurological complications [3]. Similarly, Oshomah-Bello et al. demonstrated that severe AKI was associated with prolonged hospitalization and increased risk of adverse outcomes among children with severe malaria [5]. The 25% mortality observed in our small series is therefore consistent with the high-risk phenotype represented by KDIGO stage 3 AKI, while also highlighting that survival and renal recovery remain possible even in the absence of dialysis, provided that intensive supportive care can be sustained.

A key contribution of our series is the documentation of outcomes in children who met indications for RRT but could not receive it. In a prospective pediatric severe-malaria cohort (n = 600), 14.4% met clinical indications for dialysis and this was associated with markedly higher odds of death (OR 6.56, 95% CI 3.41–12.59) [7]. In the parallel Ugandan cohort, none of the children who met indications for RRT received dialysis [19], emphasizing that the “dialysis gap” is not an exceptional circumstance but a recurrent feature of pediatric MAKI care in endemic regions.

The fatal case in our cohort presented with anuria, pulmonary edema, hyperkalemia, severe anemia, and uremic encephalopathy, features typical of severe malaria-associated multiorgan dysfunction. Contemporary pediatric analyses demonstrate that the effect of AKI on mortality is amplified by coexisting coma, acidosis, and impaired perfusion; in one prospective cohort, AKI significantly interacted with these severe-malaria features to increase mortality risk (interaction p < 0.001) [7]. This interaction framework helps interpret the divergent outcomes in our patients: renal failure severity alone is not the sole determinant of survival, but rather its convergence with neurologic, respiratory, and circulatory compromise.

Blackwater fever and hemolysis-associated AKI

The two cases of BWF in our series support the growing recognition of hemoglobinuria-associated AKI as an important contributor to severe malaria morbidity. Once considered relatively uncommon, BWF is increasingly reported in pediatric falciparum malaria and has been strongly associated with severe AKI, prolonged hospitalization, and adverse renal outcomes [10, 19]. In a prospective Ugandan cohort, BWF was identified as a risk factor for acute kidney disease (AKD) following AKI, suggesting that hemolysis-related kidney injury may persist beyond the acute illness in some children [19]. Both children with BWF in our series developed KDIGO stage 3 AKI accompanied by marked electrolyte disturbances, yet subsequently achieved complete renal recovery. This observation is consistent with a predominantly tubular pattern of injury in which renal function may recover following resolution of hemolysis, restoration of renal perfusion, and effective antimalarial treatment. Nevertheless, our findings should be interpreted cautiously, as larger cohorts indicate that BWF may also increase the risk of incomplete renal recovery and persistent kidney dysfunction after discharge [19].

Pathophysiological Interpretation

The clinical trajectories observed in this series are consistent with current understanding of malaria associated-AKI. In patients with BWF, massive intravascular hemolysis results in release of free hemoglobin and heme into the circulation. Once the scavenging capacity of haptoglobin and hemopexin is exceeded, these molecules accumulate within renal tubular epithelial cells and promote oxidative stress, mitochondrial dysfunction, inflammation, and acute tubular necrosis [13]. In addition to hemolysis-mediated injury, severe malaria contributes to renal dysfunction through microvascular sequestration of parasitized erythrocytes, endothelial activation, impaired tissue perfusion, and systemic inflammatory responses [8, 13]. These overlapping mechanisms likely explain the occurrence of severe AKI among the two patients without documented hemoglobinuria. Case 3, in particular, demonstrated a fulminant phenotype characterized by pulmonary edema, refractory anuria, severe electrolyte disturbances, and multiorgan failure, emphasizing the multifactorial nature of kidney injury in severe malaria.

Electrolyte evolution and phase-specific monitoring

A notable finding in the above case series was the dynamic evolution of electrolyte abnormalities throughout the course of AKI. Hyponatremia was observed in all patients and likely reflected a combination of impaired free-water excretion, non-osmotic antidiuretic hormone release, and systemic inflammation [12]. Hyperphosphatemia and hypocalcemia were most pronounced during the oliguric phase, reflecting markedly reduced glomerular filtration, intracellular phosphate release, and secondary disturbances in calcium homeostasis [5, 10]. As renal function improved and diuresis was established, phosphate concentrations progressively declined and calcium levels normalized. In our setting, aluminium hydroxide was used as a phosphate binder because newer agents such as sevelamer and calcium acetate were unavailable; however, evidence supporting phosphate-binding therapy specifically in malaria-associated AKI remains limited [10].

Particularly noteworthy was the characteristic biphasic potassium pattern observed during recovery. Hyperkalemia predominated during severe oliguria owing to impaired renal potassium excretion, whereas hypokalemia emerged during the polyuric recovery phase, likely reflecting urinary potassium wasting associated with tubular regeneration and transient defects in tubular potassium handling [11]. Although this phenomenon is well recognized in AKI, it has received relatively little attention in the pediatric malaria literature. Failure to recognize this transition may result in life-threatening cardiac arrhythmias, neuromuscular complications, or other adverse events. Consequently, serial electrolyte monitoring, electrocardiographic surveillance, and timely potassium supplementation were essential components of patient management during the recovery phase. These observations highlight the importance of phase-specific electrolyte management in children recovering from severe malaria-associated AKI.

Clinical implication in resource-limited settings

Several practical lessons emerge from this case series. First, clinicians should maintain a high index of suspicion for AKI in any child with severe malaria, particularly in the presence of hemoglobinuria, oliguria, severe anemia, altered mental status, or respiratory compromise. Early measurement of serum creatinine and close monitoring of urine output should be incorporated into routine management whenever feasible, as AKI is common in severe malaria and is independently associated with increased mortality and adverse hospital outcomes [3, 5, 7, 11].

Second, blackwater fever should be recognized as a high-risk syndrome requiring intensive monitoring. In our series, both children with BWF developed severe AKI despite rapid initiation of antimalarial therapy. These observations are consistent with previous studies identifying hemoglobinuria and massive intravascular hemolysis as important risk factors for severe AKI in falciparum malaria [3, 10, 13].

Third, electrolyte monitoring should continue throughout both the oliguric and recovery phases of AKI. The transition from hyperkalemia to hypokalemia may occur rapidly and can easily be overlooked in settings where laboratory testing is infrequent. Daily electrolyte assessment and electrocardiographic monitoring, when available, may help prevent potentially life-threatening complications associated with potassium disturbances [9–11].

Finally, the absence of dialysis represented the most important systems-level challenge encountered in this series. All patients met accepted indications for RRT according to KDIGO criteria, yet transfer to a dialysis-capable facility was not feasible because of limited local availability and financial constraints. Although renal recovery occurred in several patients, one child died and another demonstrated persistent renal dysfunction at follow-up. These observations highlight the urgent need to expand pediatric nephrology services and improve access to renal replacement therapy in malaria-endemic regions of Sub-Saharan Africa [3, 4, 7, 8].

Case 4 and corticosteroid exposure in the setting of heavy proteinuria

Case 4 required special consideration because prednisolone was initiated after parasite clearance in the context of nephrotic-range proteinuria and severe hypoalbuminemia. Without kidney biopsy, immunologic workup, or nephrology consultation, the mechanism of proteinuria could not be determined, and the overall presentation remained dominated by severe AKI in the setting of malaria. Current KDIGO guidance for malaria-associated glomerular disease emphasizes eradication of the malarial infection and explicitly states that there is no indication for immunosuppressive agents in malarial nephropathy [20]. Therefore, improvement in renal function in this child should not be attributed to corticosteroid efficacy; instead, it should be interpreted as renal recovery following resolution of the acute infectious and hemodynamic insult. This case highlights an evidence gap regarding glomerular presentations during/after severe malaria and supports future efforts to incorporate kidney biopsy where feasible and safe when heavy proteinuria persists or the clinical course is atypical, to guide diagnosis and avoid empiric immunosuppression [21].

Strengths and limitations

This study has several strengths. To our knowledge, it represents one of the few detailed pediatric case series from Ethiopia describing severe Plasmodium falciparum malaria complicated by KDIGO stage 3 AKI, including cases of blackwater fever, in a setting without access to RRT. The detailed clinical and laboratory characterization of each case enabled description of the temporal evolution of kidney injury, electrolyte disturbances, and short-term renal recovery. Serial biochemical monitoring further allowed documentation of phase-specific electrolyte changes, including the transition from oliguric hyperkalemia to recovery-phase hypokalemia, a clinically important but infrequently reported feature of pediatric malaria associated AKI.

Several limitations should also be acknowledged. First, the retrospective design is subject to incomplete documentation, missing data, and information bias. Second, the small sample size precludes statistical inference and limits the generalizability of the findings. Third, important biomarkers of hemolysis and tubular injury, including lactate dehydrogenase, haptoglobin, plasma free hemoglobin, cystatin C, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin, were unavailable. Fourth, renal biopsy was not performed, limiting diagnostic certainty regarding the underlying renal pathology, particularly in Case 4, where nephrotic-range proteinuria prompted empirical corticosteroid therapy. Fifth, follow-up was limited to four weeks, preventing assessment of long-term renal outcomes, AKI-to-CKD transition, and late mortality. Sixth, referral bias may have influenced case selection because only the most severe patients were admitted to the tertiary referral center. Finally, the absence of dialysis services precluded comparison between conservative management and outcomes achievable in centers with access to RRT. Consequently, the observed recovery among survivors should not be interpreted as evidence that conservative management is equivalent to dialysis when standard indication for RRT are present.

Recommendations

Children with severe Plasmodium falciparum malaria should have early assessment of renal function and urine output, with particular vigilance for blackwater fever as a marker of high risk for severe AKI. Serial monitoring of electrolytes is essential across both the oliguric and recovery phases, especially for hyperkalemia during oliguria and hypokalemia during polyuric recovery. Health systems in malaria-endemic regions should strengthen referral pathways, laboratory monitoring capacity, and access to pediatric RRT. Further prospective studies are needed to define predictors, outcomes, and long-term renal sequelae of malaria-associated AKI.

Conclusion

In this series of four children with severe P. falciparum malaria complicated by KDIGO stage 3 AKI, including two with blackwater fever, three survived with substantial renal recovery despite the absence of RRT, whereas one died with multiorgan failure. These cases show that recovery is possible even when dialysis is unavailable, but they should not be interpreted as evidence that conservative care is an adequate substitute for kidney replacement therapy in advanced AKI. The transition from hyperkalemia during the oliguric phase to hypokalemia during polyuric recovery highlights the importance of phase-specific electrolyte surveillance. Persistent renal dysfunction in one survivor supports structured post-discharge kidney follow-up, and the BWF cases reinforce hemolysis-associated kidney injury as a high-risk phenotype. Prospective studies are needed to evaluate supportive-care bundles and long-term kidney outcomes, alongside urgent expansion of pediatric RRT capacity in endemic regions.

Author contributions

T.Y.G.: Conceptualization, writing, supervision; A.A.G & H.A.G.: data curation, validation; H.H.H. & T.G.G: Writing review, methodology; all authors approved final manuscript.

Funding

No funding was received for this study.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Ethical approval for this case series was obtained from the Research and Ethics Review Committee, College of Medicine and Health Sciences, Mizan-Tepi University (Approval reference: MTU-IR/03/18), and was conducted in accordance with the Declaration of Helsinki.

Consent for publication

Parents were informed of the case series and agreed to the publication of this case series. Written informed consent obtained from parents for publication of anonymised case details.

Competing interests

The authors declare no competing interests.