Renal salt-wasting syndrome with tubular copper deposition in a heterozygous ATP7B carrier: a case report

Abstract

Background

ATP7B mutations classically lead to Wilson’s disease, characterized by hepatic and neurological involvement due to systemic copper overload. However, renal-limited phenotypes are extremely rare, easily overlooked and clinically diverse. Here, we report a woman carrying a heterozygous ATP7B variant who presented with isolated salt-wasting syndrome, marked renal copper deposition.

Case presentation

We report a 30-year-old Chinese woman with renal salt-wasting syndrome and chronic kidney disease, without hepatic, neurological, or ophthalmologic abnormalities. Laboratory tests, including ceruloplasmin (0.20 g/L), 24-h urinary copper (20.8 µg/24 h), and liver function were within normal or borderline ranges, not fulfilling Wilson’s disease diagnostic criteria (Leipzig score < 4). Renal biopsy revealed marked copper accumulation within tubular epithelial cells, and immunohistochemistry showed reduced ATP7B expression. Whole-exome sequencing identified a heterozygous ATP7B mutation (c.2621 C > T, p.Ala874Val). Given the absence of systemic copper overload, the patient was treated with corticosteroids and electrolyte replacement rather than copper-chelating agents, leading to partial clinical improvement.

Conclusion

This case suggests a possible renal-limited phenotype in an ATP7B carrier, underscoring the importance of integrating genetic testing and histopathology in unexplained tubulointerstitial nephritis. Long-term follow-up is essential to monitor for potential systemic manifestations.

Background

Wilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene, resulting in impaired copper excretion and systemic copper accumulation. The classical phenotype includes progressive hepatic dysfunction, neuropsychiatric symptoms, and ophthalmological signs such as Kayser-Fleischer rings.

Heterozygous ATP7B variants usually indicate asymptomatic carrier status and do not meet Wilson’s disease diagnostic criteria. Nonetheless, isolated organ manifestations have been sporadically reported, though their pathogenic link remains uncertain. Renal involvement in confirmed Wilson’s disease is uncommon and typically secondary to systemic copper overload, presenting as acute kidney injury, nephrolithiasis, or tubular dysfunction.

Here, we report a unique case of a woman carrying a heterozygous ATP7B variant who presented with isolated salt-wasting syndrome, marked renal copper deposition, but no systemic features of Wilson’s disease. This case highlights the importance of considering copper dysregulation as a potential mechanism in unexplained tubulointerstitial nephritis, even in ATP7B carriers.

Case presentation

A 30-year-old Chinese woman was referred for evaluation of chronic kidney dysfunction and recurrent electrolyte disturbances.

Timeline of illness:

• 4 years before admission: Onset of recurrent joint swelling, erythema, and pain; diagnosed with gouty arthritis, self-managed with non-steroidal anti-inflammatory drugs(NSAIDs, Non-steroidal anti-inflammatory drugs) and colchicine; labs showed hypokalemia (K⁺ 2.5 mmol/L), hypochloremia (Cl^- 92mmol/L), hyperuricemia (Uric acid 475 µmol/L) and normal kidney function.

• 1 year before admission: Hypokalemia, hypochloremia and first documented mild renal insufficiency (creatinine 174 µmol/L); ultrasound normal.

• 2 months before admission: Progressive renal impairment (creatinine 468 µmol/L) with metabolic alkalosis; labs showed 24 h urine K⁺ 33 mmol/d, K⁺ 2.7 mmol/L, CO2 49.6mmol/L, pH 7.504.

• 1 week before admission: Episode of transient vision loss, limb convulsions, and vomiting; labs showed Na⁺ 124.5 mmol/L, Cl^- 67 mmol/L, K⁺ 2.56 mmol/L, creatinine 688 µmol/L.

• After admission: Fatigue, nausea, and poor appetite; labs showed Na⁺ 128 mmol/L (oral sodium chloride supplementation at a dose of 1 g/d), Cl^- 67 mmol/L, K⁺ 4.5 mmol/L (oral potassium chloride supplementation at a dose of 1.5 g/d), 24 h urine Na⁺ 43 mmol/L, 24 h urine Cl^- 28 mmol/L, 24 h urine K⁺ 49.7 mmol/L, pH 7.61, HCO3^- 60 mmol/L, creatinine 784 µmol/L.

She had low daily fluid intake, nocturia (2–3 times/night), and a history of left ureteral stone treated with shock wave lithotripsy 5 years earlier. She denied hypertension, diabetes, or family history of kidney disease.

Physical examination: BP 82/65 mmHg, temperature 36.5℃, pulse rate 96 bpm, and BMI 14.6 kg/m².

Laboratory and imaging findings

The laboratory profile was characterized by hyponatremia, hypochloremia, metabolic alkalosis, mild hypermagnesemia, and inappropriately high urinary sodium and chloride excretion despite low serum concentration (Table 1). To differentiate from inherited salt-wasting syndromes such as Bartter and Gitelman syndromes, hydrochlorothiazide and furosemide challenge tests were performed (Table 2). Results showed that the patient responded to both drugs. These findings argue against inherited tubular salt reabsorption defects and are consistent with acquired tubular salt-wasting secondary to tubulointerstitial injury.

Table 1.

Baseline Laboratory findings of the patient

Variables	Value	Reference range	Variables	Value	Reference range
Urinary tests			Complement C3(g/L)	1.11	0.90–1.80
pH	9	5.0–8.0	Complement C4(g/L)	0.35	0.10–0.40
U-specific gravity	1.007	1.003–1.030	Total complement (IU/mL)	56.4	50.0-100.0
U-protein	(+)	(-)	Ceruloplasmin(g/L)	0.2	0.2–0.6
U-red blood cell(/µL)	44	0–25	Immunoglobulin A(g/L)	4.15	0.7-4.0
U-white blood cell(/µL)	9	0–25	Immunoglobulin G(g/L)	14.65	7.0–16.0
U-glucose	(-)	(-)	Immunoglobulin M (g/L)	0.99	0.40–2.30
Bence-Jones protein	(-)	(-)	Immunoglobulin E (IU/mL)	21	< 100
U-albumintocreatinine ratio (µg/mg Cr)	127.8	< 30.0	Immunoglobulin G4 (g/L)	2.11	0.03–2.01
U-β2 microglobulin(mg/L)	> 6.65	0-0.220	Arterial blood gas analysis
24 h urinary protein(g)	0.68	0-0.14	pH	7.61	7.35–7.45
24 h urinary uric acid (µmol/L)	276.8	/	Actual bicarbonate (mmol/L)	60	21.3–24.8
24 h urine sodium (mmol/L)	43	/	Parathyroid hormone (pg/ml)	632.3	15.0–65.0
24 h urine potassium (mmol/L)	49.7	/	Transferrin saturation(%)	12.15	16–45
24 h urine chloride (mmol/L)	28	/	Ferritin(ng/ml)	88.9	13.0-150.0
24 h urine calcium (mmol/L)	0.49	/	Immunofixation electrophoresis	(-)	(-)
24 h urine glucose (mmol/L)	0.4	/	Hepatitis B surface antigen (COI)	0.352	< 1.0
24 h urine copper (µg/24 h)	20.8	15.0–60.0	Hepatitis C antibody (COI)	0.031	< 1.0
Blood tests			HIV antibody(COI)	(-)	(-)
Leukocyte(*10^9/L)	5.68	3.5–9.5	Treponema pallidum antibody(COI)	(-)	(-)
Hemoglobin(g/L)	79	115–150	Tuberculin test	(-)	(-)
Platelet(*10^9/L)	178	125–350	Antinuclear antibodies	(-)	(-)
Alanine aminotransferase (U/L)	7	7–40	Anti-dsDNA antibody(IU/mL)	< 10.0	< 100
Aspartate aminotransferase(U/L)	8	13–35	Anti-Sm antibody	(-)	/
Urea nitrogen(mmol/L)	14.5	2.6–7.5	Anti-SSA antibody	(-)	/
Creatinine(µmol/L)	784	41–73	Anti-SSB antibody	(-)	/
Uric acid(µmol/L)	484	155–357	PRO-ANCA(RU/ml)	< 2.0	< 20
Cystatin C (mg/L)	5.74	0.61–0.95	MPO-ANCA(RU/ml)	< 2.0	< 20
Carbon dioxide(mmol/L)	44	23–29	Anti-GBM antibody	(-)	/
Sodium(mmo/L)	128	137–147	Carcino-embryonic antigen(ng/mL)	1.9	< 5.0
Potassium(mmol/L)	4.5	3.5–5.3	Alpha fetoprotein (ng/mL)	1.9	< 20.0
Chloride(mmol/L)	67	99–110	CA125(U/mL)	8.3	< 47.0
Calcium(mmol/L)	2.21	2.11–2.52	Epididymis protein (pmol/L)	2390	< 150
Phosphorus(mmol/L)	3.14	0.85–1.51	Renin(ng/ml/hr)	4.84	0.25–5.82
Magnesium(mmol/L)	1.47	0.75–1.02	Angiotensin II(pg/ml)	31.14	5.0–40.0
Copper(µg/L)	764	800–1550	Aldosterone(ng/dL)	25.71	≤ 28.0

Table 2.

Diuretic challenge test

	Urine Chloride (mmol/L)	Urine Creatinine (µmol/L)	Serum Chloride (mmol/L)	Serum Creatinine (µmol/L)	FECl (%)
Hydrochlorothiazide test
30 min	66	2000			10.28
60 min	62	1838	95	296	10.51
90 min	59	1686			10.24
120 min	56	1323			12.39
150 min	58	1123			15.11
180 min	60	1082			16.23
210 min	58	1072			15.83
240 min	55	1027	95	278	15.67
Furosemide test
30 min	56	2653			7.67
60 min	56	2370	96	349	8.59
90 min	54	2112			9.42
120 min	46	1468			11.54
150 min	52	1482			12.93
180 min	54	1538			12.94
210 min	47	1266			13.68
240 min	46	1092	95	350	15.52

FECl = fractional excretion of chloride, calculated using urine and serum creatinine concentrations

One day prior to the hydrochlorothiazide/furosemide test, all potassium supplementation was discontinued (the patient had previously received 4.5 g of potassium chloride daily), and normokalemia was confirmed before the test. Before the test, the patient received oral water at a dose of 10 mL/kg, followed by 150 mL of water every hour thereafter. Hydrochlorothiazide (50 mg)/furosemide (1 mg/kg) was administered at the first hour. During the test, urine samples were collected every 30 min, and blood samples were drawn at the first and fourth hours for testing. During the test, vital signs were closely monitored, and electrolyte supplementation was resumed immediately after the test

Chest CT, ECG, abdominal and renal ultrasound, and Doppler studies of adrenal glands and renal vessels were normal. Slit-lamp examination showed no Kayser-Fleischer rings.

Renal pathology and genetic findings

Renal biopsy showed global glomerulosclerosis in 2 of 11 glomeruli, mild mesangial proliferation, and 55% cortical tubular atrophy with epithelial degeneration, proteinaceous casts, and focal calcifications. Interstitial edema, lymphoplasmacytic infiltration, and fibrosis were present (Fig. 1). Immunofluorescence microscopy showed no immune complex deposits, consistent with non-immune-mediated tubulointerstitial injury. Electron microscopy revealed focal GBM thickening and podocyte foot process effacement, without electron-dense deposits. Renal biopsy subsequently revealed chronic tubulointerstitial injury with marked tubular atrophy and interstitial fibrosis, accompanied by copper deposition in tubular epithelial cells.

Fig. 1.

Renal histological staining of the patient showing tubulointerstitial injury and glomerular changes. (A) Hematoxylin and eosin (HE) staining reveals patchy tubular epithelial degeneration, interstitial edema, and lymphoplasmacytic infiltration. (B) Periodic acid-Schiff (PAS) staining highlights mild mesangial matrix proliferation and irregular tubular basement membranes. (C) Periodic acid-silver methenamine (PASM) staining shows representative segmental glomerulosclerosis. (D) Masson’s trichrome staining demonstrates interstitial fibrosis involving approximately 55% of the cortical area. Scale bar = 200 μm

Whole-exome sequencing identified heterozygous ATP7B c.2621 C > T (p.Ala874Val) and heterozygous FN1 c.5173 C > T (p.Arg1725Cys) (Table 3). Copper staining revealed marked perinuclear and cytoplasmic copper accumulation in tubular epithelial cells compared with three controls (matched for age and tubulointerstitial lesions) (Fig. 2). Immunohistochemical analysis demonstrated reduced ATP7B expression predominantly on the luminal membrane of renal tubules (Fig. 3). The FN1 mutation, typically associated with fibronectin glomerulopathy, was not consistent with the observed histopathological findings.

Table 3.

Genetic variants identified by whole-exome sequencing

Gene	Transcription	Nucleotide alterations	Amino acid alterations	Chromosomal location	MAF
ATP7B	NM_000053.4	c.2621 C > T	p.Ala874Val	chr13:52524252	0.000068
FN1	NM_212482.4	c.5173 C > T	p.Arg1725Cys	chr2:216245795	0.000032

Fig. 2.

Renal copper accumulation in the patient compared to controls. (A) Copper staining shows increased perinuclear and cytoplasmic copper deposition in tubular epithelial cells of the patient compared to three controls with similar tubulointerstitial lesions. All staining procedures were performed in the same batch under identical conditions. (B) Quantitative analysis demonstrates a significantly higher copper-positive area (%) in the patient compared with controls. *P < 0.05; *** P < 0.001; **** P < 0.0001. Scale bar = 200 μm

Fig. 3.

Reduced ATP7B expression in renal tubules. (A) Immunohistochemistry reveals markedly decreased ATP7B expression in the patient’s tubular epithelial cells, predominantly localized to the luminal membrane. All staining procedures were performed in the same batch under identical conditions. (B) Quantitative analysis shows a significantly reduced ATP7B-positive area (%) in the patient compared with controls. **** P < 0.0001. Scale bar = 100 μm

Genetic analysis of the ATP7B variant

The ATP7B c.2621 C > T (p.Ala874Val) variant was identified in the patient. Its clinical significance was assessed using public databases, in silico prediction tools, and the ACMG/AMP guidelines.

Database status. In ClinVar, this variant (RCV000004055.46) is reported as Pathogenic/Likely pathogenic by 19 submissions, with multiple laboratories classifying it as pathogenic for Wilson disease. No conflicting interpretations are present.

Population frequency. The variant is extremely rare in the general population. The overall allele frequency in gnomAD is 0.00001 (gnomAD exomes: 0.00006; ExAC: 0.00007), meeting the ACMG PM2 criterion.

In silico prediction. Using established thresholds, all applied in silico tools predicted a deleterious effect. SIFT (Damaging, score 0.003), PolyPhen-2 (HumVar model, Probably Damaging, score 0.937), MutationTaster (Disease causing, probability 1.0), and REVEL (Deleterious, score 0.78) all supported a damaging effect (ACMG PP3).

ACMG classification. According to the ACMG/AMP guidelines, this variant meets the following evidence criteria: PM2 (extremely low allele frequency in population databases); PM3 (reported in trans with a pathogenic variant in multiple individuals with Wilson disease, as documented in ClinVar and literature); PP3 (multiple in silico tools predict a deleterious effect); PS3_Supporting (functional studies demonstrate reduced copper transport activity [1]). Based on these criteria, the variant is classified as Pathogenic.

Clinical correlation. Although the patient did not meet full clinical criteria for Wilson disease, the presence of a pathogenic ATP7B variant and copper deposition in renal tissue suggests that the variant may contribute to the renal phenotype.

Diagnosis and clinical course

Given the renal copper deposition, Wilson disease was considered in the differential diagnosis. However, there was no evidence for hepatic or neurological involvement, and 24-hour urinary copper excretion was within the normal range. We evaluated the patient using the Leipzig diagnostic score for Wilson disease. Her score was 1 point: low-normal serum ceruloplasmin (0.20 g/L) [1 point], no Kayser-Fleischer rings [0 point], normal 24-hour urinary copper excretion (20.8 µg/24 h) [0 point], and only a single heterozygous ATP7B variant [0]. A total score < 4 does not support a diagnosis of Wilson disease. Therefore, the final diagnosis was renal salt-wasting with chronic interstitial nephritis in an ATP7B carrier, with histological evidence of copper accumulation in renal tubules but no systemic copper overload.

The patient was treated with oral prednisone (0.5 mg/kg/day), intravenous fluid, electrolyte supplementation, and anemia correction. Serum creatinine improved from 784 to 301 µmol/L. After discharge, steroids were gradually tapered and the patient remained on chronic kidney disease management. Over 6 months of follow-up, renal function and electrolytes remained stable without hepatic or neurological involvement.

Discussion and conclusions

The patient presented with chronic hypotension, recurrent electrolyte disturbances, and progressive renal dysfunction, characterized by hyponatraemia, hypokalemia, hypochloremia with metabolic alkalosis, and mild hypermagnesaemia. Common causes of chloride depletion were carefully excluded, and diuretic challenge tests supported a renal origin. Notably, renin and aldosterone levels were not markedly elevated, which may be explained by prior fluid and electrolyte replacement as well as potential suppression related to chronic NSAID use and malnutrition. Renal biopsy further demonstrated chronic tubulointerstitial injury with tubular atrophy, interstitial fibrosis, and focal copper deposition in tubular epithelial cells.

The biochemical profile suggested primary renal salt loss. Common causes of hypochloremic metabolic alkalosis, including vomiting, eating disorders, and diuretic or laxative use, were carefully evaluated and were not supported by repeated clinical assessment. In addition, hydrochlorothiazide and furosemide challenge tests both produced an increase in urinary chloride excretion above baseline, effectively excluding classical inherited salt-reabsorption defects such as Bartter or Gitelman syndromes. ATP7B encodes a copper-transporting ATPase primarily responsible for exporting excess intracellular copper, predominantly in hepatocytes, but it is also expressed in renal tubular epithelial cells. In the kidney, ATP7B contributes to copper homeostasis by mediating its excretion or intracellular sequestration. Mutations in ATP7B may impair this process, potentially leading to local copper accumulation and tissue injury, even in the absence of systemic copper overload. Ye et al. [2] described siblings with heterozygous ATP7B mutations (c.2621 C > T and c.2790_2792del) who initially presented with osteoarthritis before developing classical Wilson’s disease features after 20 years. Similarly, Dang et al. [3] reported that approximately 5% of patients with Wilson’s disease initially present with renal tubular dysfunction, including hypokalemia and metabolic alkalosis. In the present case, immunohistochemistry and copper staining confirmed reduced ATP7B expression and intracellular copper accumulation in renal tubules, indicating localized copper metabolism dysfunction. Despite evidence of localized copper accumulation, the patient’s ceruloplasmin level was only borderline (0.2 g/L), 24-hour urinary copper excretion was within normal range, and liver function remained normal. Therefore, diagnostic criteria for classical Wilson’s disease requiring chelation therapy were not met. Experimental studies further support this observation: ATP7B-deficient mice develop renal copper accumulation without significant hepatic injury [4], suggesting enhanced renal sensitivity to ATP7B dysfunction, possibly due to differential transporter expression and tissue-specific copper handling.

Copper is a critical cofactor involved in numerous physiological processes, including enzymatic activity and mitochondrial function [5]. In patients with Wilson’s disease, renal copper content may reach up to 60 times the normal levels. Excess copper causes a variety of renal complications, including tubular dysfunction [3, 6–10], nephrolithiasis, bone metabolism disorders [11–13], and even acute kidney injury [4, 14–16]. Normal renal copper homeostasis relies on the coordinated action of ATP7A and ATP7B copper transporters. When serum copper levels rise, ATP7A facilitates copper efflux from renal tubular cells, offering protection. However, ATP7B serves as a crucial compensatory mechanism, and its dysfunction may lead to intracellular copper accumulation, triggering oxidative stress [17], autophagy and epithelial-mesenchymal transition [18], inflammatory responses, and apoptosis [19]. This cascade of events damages tubular epithelial cells, impairing sodium, potassium, and chloride reabsorption, ultimately leading to a clinical picture of renal salt-wasting syndrome. In our patient, immunohistochemistry demonstrated reduced ATP7B protein expression in renal tubules, while copper staining revealed focal perinuclear accumulation, suggesting a defect in copper efflux. These findings are consistent with the hypothesis that ATP7B dysfunction may contribute to localized renal copper accumulation and tubular injury; however, causality is not proven. Notably, chronic NSAIDs use likely exacerbated renal ischemia by inhibiting prostaglandin synthesis, compounding copper-induced damage. The relative contribution of chronic NSAID exposure versus genetic predisposition remains uncertain, and NSAID-related tubulointerstitial injury alone could potentially account for part of the observed findings. Additionally, the patient’s low body mass index (BMI 14.6 kg/m²) and malnutrition may have further impaired tubular repair mechanisms. A “multiple-hit” model, involving genetic susceptibility together with environmental and nutritional factors, may best explain the observed phenotype. Clinically, this case must be distinguished from other inherited salt-wasting syndromes, such as Bartter or Gitelman syndromes, and drug-induced nephrotoxicity. The combination of genetic findings, copper-specific histological changes, and the absence of systemic Wilson’s disease features points to an organ-limited ATP7B-related phenotype. However, the potential risk of progression to systemic disease warrants continued monitoring. To date, there are no established guidelines for managing localized renal copper deposition in the absence of systemic Wilson’s disease. Whether chelation or zinc therapy can benefit such patients is an open question. In this case, treatment was directed at suppressing tubular interstitial inflammation and correcting electrolyte imbalances. The patient responded to corticosteroids and supportive therapy with partial improvement in renal function, suggesting that inflammation and copper-induced tubular stress may be partially reversible. Long-term monitoring for liver function and neurologic symptoms remains essential due to the risk of phenotypic progression. However, in cases of persistent or relapsing renal dysfunction, individualized consideration of zinc therapy or low-dose chelation may be warranted despite the absence of systemic Wilson’s disease criteria.

This case report has several limitations. First, only a single heterozygous ATP7B variant was identified and segregation/functional studies were not available; therefore causality can not be established. Second, quantitative hepatic copper measurement (by liver biopsy) or non-invasive MRI copper assessment were not performed, limiting assessment of occult hepatic copper load. Third, although copper staining and ATP7B immunohistochemistry showed localized renal changes, functional proof that the p.Ala874Val variant causes impaired ATP7B activity in renal tubular cells is lacking. Finally, the small number of control samples for histological quantification (n = 3) limits statistical power. These limitations temper causal conclusions and highlight the need for further genetic and functional studies.

In conclusion, this case challenges the classical phenotype boundaries of ATP7B-related disease by presenting with renal-limited manifestations and localized copper deposition, in the absence of systemic features. It underscores the diagnostic value of integrating genetic testing with copper-specific histopathology in patients with unexplained tubulointerstitial injury. Moreover, it raises important questions regarding the threshold of copper nephrotoxicity and the potential role of chelation therapy in non-cirrhotic ATP7B-related renal disease.

Author contributions

L.L. and J.Z. prepared the initial manuscript draft. J.Z., Q.X, C.L were responsible for data collection and figures/tables. J.T and J.W were involved with review and editing. All authors edited the manuscript, and reviewed and approved the final version of the manuscript.

Funding

This work was supported by Fujian Provincial Natural Science Foundation of China (grant number: 2024D032, 2022J011419). This case report was prepared in accordance with the Care guidelines.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

All procedures were conducted in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments. Ethics approval was not required for this case report in accordance with the policy of our institution. The patient provided written informed consent for publication of the clinical details and associated images in this case report.

Consent for publication

Written informed consent was obtained from the patients for publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.