Rare renal proximal tubular dysfunctions in primary biliary cholangitis

Figures & data

Table 1. Summary of the clinical characteristics of the 11 PBC-PT patients.

Indicators	All cases (n = 11)	Indicators	All cases (n = 11)
Demographic characteristics		Renal involvement
Gender, female, n (%)	9 (81.8)	Proteinuria, g/d, median (n, range)	0.50 (10, 0.10–1.81)
Age at diagnosis, years, mean ± SD	57.8 ± 5.2	Sterile leukocyturia, n (%)	5 (45.5)
Disease duration, months, median (range)	36 (2–163)	Hematuria, n (%)	3 (27.3)
Dx of TI injuries before Dx of PBC, n (%)	7 (63.6)	Serum creatinine, μmol/L, median (range)	118 (66–396)
Immunological findings		eGFR, ml/min/1.73m^2, mean ± SD	46.54 ± 23.03
Elevated serum IgG^a, n (%)	6 (54.5)	eGFR < 60 ml/min/1.73m^2, n (%)	9 (81.8)
Elevated serum IgM^b, n (%)	9 (81.8)	Tubular dysfunction
Positive rheumatoid factor, n (%)	6/7 (85.7)	Renal potassium loss with hypokalemia, n (%)	10 (90.9)
Hypocomplementemia, n (%)	1 (9.1)	Serum potassium^h, mmol/L, mean ± SD	3.15 ± 0.37
Positive antinuclear antibody, n (%)	11 (100.0)	Renal tubular acidosis, n (%)	8 (72.7)
Positive AMA-M2 antibody, n (%)	11 (100.0)	Renal-origin metabolic alkalosis, n (%)	2 (18.2)
Positive anti-Ro/SSA antibody, n (%)	3 (27.3)	Arterial blood pH^i, mean ± SD	7.374 ± 0.078
Positive anti-La/SSB antibody, n (%)	3 (27.3)	Arterial blood [HCO3^-] ^j, mmol/L, mean ± SD	20.50 ± 5.88
Accompanying pSS, n (%)	7 (63.6)	Hyperuricosuria, n (%)	4/5 (80.0)
Liver involvement		Hypouricemia, n (%)	7 (63.6)
Jaundice, n (%)	2 (18.2)	Serum uric acid^k, μmol/L, mean ± SD	177 ± 98
Pruritus, n (%)	1 (9.1)	Normoglycemic glycosuria, n (%)	7 (63.6)
Elevated ALT^c, n (%)	7 (63.6)	Generalized aminoaciduria, n (%)	5/8 (62.5)
Elevated AST^d, n (%)	8 (72.7)	Hyperphosphaturia, n (%)	3/5 (60.0)
Elevated ALP^e, n (%)	9 (81.8)	Hypophosphatemia, n (%)	6 (54.5)
Elevated GGT^f, n (%)	10 (90.9)	Serum phosphorus^l, mmol/L, mean ± SD	0.96 ± 0.37
Elevated serum total bilirubin^g, n (%)	5 (45.5)

Normal ranges of the indicators: ^aserum IgG 7.00–17.00 g/L; ^bserum IgM 0.40–2.30 g/L; ^cALT 7–40 U/L; ^dAST 13–35 U/L; ^eALP 35–100 U/L; ^fGGT 7–45 U/L; ^gserum total bilirubin 5.1–22.2 μmol/L; ^hserum potassium 3.5–5.5 mmol/L; ⁱarterial blood pH 7.350–7.450; ^jarterial blood [HCO₃^-] 22.0–26.0 mmol/L; ^kserum uric acid 210–416 μmol/L (male)/150–357 μmol/L (female); ^lserum phosphorus 0.81–1.45 mmol/L.

PBC-PT, primary biliary cholangitis with proximal tubular dysfunctions; SD, standard deviation; Dx, diagnosis; TI, tubulointerstitial; IgG, Immunoglobulin G; IgM, Immunoglobulin M; AMA-M2, anti-mitochondrial antibody M2 subtype; SSA, Sjӧgren-syndrome-related antigen A; SSB, Sjӧgren-syndrome-related antigen B; pSS, primary Sjӧgren’s Syndrome; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ-glutamyltransferase; eGFR, estimated glomerular filtration rate.

Table 2. Detailed clinicopathological features and renal prognosis of the 11 PBC-PT patients.

No	Age/Sex	AMA-M2 (RU/ml)	Other AID	sIgG^a(g/L)	sIgM^b(g/L)	ALT^c(U/L)	AST^d(U/L)	ALP^e(U/L)	GGT^f(U/L)	PBC clinical staging	Scr (μmol/L)	Tubular dysfunction	Renal Histology	Treatment of primary disease	F/U time (m)	Outcome of kidney, liver, and immunology
1	59/F	117	pSS	21.23↑	3.70↑	207	254	146	57	Asymptomatic	185	Glycosuria, hypophosphatemia*, hypouricemia*, RTA	Diffuse TIN, tubulitis, focal TIF	GCs 55 mg/d, Aza 50 mg/d, UDCA	216	Improved (K/Tu/Im); Stable (L)
2	57/F	>800	pSS	22.46↑	1.83	54	107	443	494	Decompensated	66	Aminoaciduria, hypouricemia, hyperuricosuria	/	UDCA	27	Stable (K/Tu/L); NA (Im)
3	55/F	>800	pSS	12.44	14.53↑	42	41	375	129	Asymptomatic	118	Glycosuria, aminoaciduria, hypophosphatemia*, hypouricemia*, RTA	Diffuse TIN, tubulitis, focal TIF	GCs 50 mg/d, UDCA	36	Improved (K/Tu/Im); Stable (L)
4	66/F	154	(-)	13.23	3.42↑	15	25	151	30	Asymptomatic	107	Glycosuria, aminoaciduria, hypophosphatemia*, RTA hypouricemia, hyperuricosuria	/	UDCA	49	Stable (K/Tu/L); NA (Im)
5	59/F	115	(-)	10.46	1.20	694	480	154	340	Asymptomatic	111	Aminoaciduria, hyperphosphaturia, RTA	Diffuse TIN, tubulitis, focal TIF	GCs 40 mg/d, UDCA	NA	NA
6	53/F	91	pSS	26.28↑	3.75↑	35	67	238	200	Decompensated	177	Glycosuria, RTA	/	GCs 40 mg/d, UDCA	15	Improved (Im); Stable (K/L); NA (Tu)
7	63/F	>800	pSS	29.10↑	3.55↑	289	133	411	808	Symptomatic	70	Glycosuria, RTA	/	GCs 15 mg/d, UDCA	36	Improved (K/Im); Stable (L); NA (Tu)
8	62/M	103	(-)	18.82↑	7.66↑	24	22	85	68	Asymptomatic	165	Hyperphosphaturia, hyperuricosuria, metabolic alkalosis, renal loss of potassium, hypokalemia, hypocalciuria	Diffuse TIN, tubulitis, focal TIF	GCs 40 mg/d, CTX 50 mg/d, UDCA	25	Improved (K/Im); Stable (L); NA (Tu)
9	59/F	>200	pSS	10.20	17.30↑	63	65	989	272	Decompensated	396	Glycosuria, aminoaciduria, hypophosphatemia*, hypouricemia*, RTA	/	UDCA	108	Progressed (K/L) to Death^#; NA (Tu/Im)
10	53/F	NA	pSS	25.60↑	5.69↑	32	56	138	163	Asymptomatic	95	Glycosuria, hypophosphatemia*, hypouricemia*, RTA	/	GCs 50 mg/d, CTX 0.6 g IV Q2W, UDCA	NA	NA
11	51/M	>400	(-)	12.71	2.62↑	58	27	95	113	Asymptomatic	155	Hyperphosphaturia, hypophosphatemia, hyperuricosuria, hypouricemia, metabolic alkalosis, renal loss of potassium, hypokalemia, hypocalciuria	Diffuse TIN, diffuse TIF	GCs 30 mg/d, CTX 50 mg/d, UDCA	8	Improved (K/Tu/Im); Stable (L)

Normal ranges of the indicators: ^aserum IgG 7.00–17.00 g/L; ^bserum IgM 0.40–2.30 g/L; ^cALT 7–40 U/L; ^dAST 13–35 U/L; ^eALP 35–100 U/L; ^fGGT 7–45 U/L.

PBC, primary biliary cholangitis; PBC-PT, PBC with proximal tubular dysfunctions; AMA-M2, anti-mitochondrial antibody M2 subtype; AID, autoimmune diseases; sIgG, serum immunoglobulin G; sIgM, serum immunoglobulin M; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, γ-glutamyltransferase; Scr, serum creatinine; F/U, follow-up; pSS, primary Sjӧgren’s Syndrome; RTA, renal tubular acidosis; TIN, tubulointerstitial nephritis; TIF, tubulointerstitial fibrosis; GCs, glucocorticoids equivalent to prednisone; Aza, azathioprine; UDCA, ursodeoxycholic acid; K, kidney function reflected by estimated glomerular function rate; Tu, tubular functions; L, liver functions; Im, immunological indicators (including sIgG and sIgM); NA, not available; CTX, cyclophosphamide; IV, intravenous; Q2W, every 2 weeks.

*Probable proximal tubular dysfunction, which needed synchronous urinary tests to confirm the existence of hyperphosphaturia or hyperuricosuria.

^#The death cause was liver failure.

Figure 1. PBC-PT patients presented with tubulointerstitial nephritis in kidney biopsy. (a) Focal interstitial inflammatory infiltrates with major components of lymphocytes and plasma cells were shown by HE staining (×100). (b) Enlarged boxed area in (a) (×400). (c) Proximal tubulitis characterized as inflammatory cell infiltration in proximal tubular epithelium (asterisks) was revealed by HE staining (×400). (d) Focal tubular atrophy was shown by periodic acid-silver metheramine staining (×100). (e) Focal interstitial fibrosis was indicated by masson trichrome staining (×100). (f) Swollen mitochondria with destroyed or disappeared cristae (arrows) in proximal tubular epithelium were shown by transmission electron microscopy (×5000). Abbreviations: PBC-PT, primary biliary cholangitis with proximal tubular dysfunctions; HE, hematoxylin and eosin staining.

Figure 2. Long-term renal prognosis and eGFR improvements after GCs treatment in PBC-PT patients. Patients who had follow-up time less than three months (n = 2) and insufficient eGFR follow-up data (n = 1) were excluded. (a) Evolution of eGFR in the whole population of PBC-PT patients (n = 8 at baseline). (b–d) After receiving GCs treatment, PBC-PT patients (n = 6) showed improvements in serum IgM (p = 0.019), eGFR (p = 0.028) and Scr (p = 0.052) during follow-up. Abbreviations: IgM, immunoglobulin M; eGFR, estimated glomerular filtration rate; GCs, glucocorticoids; PBC-PT, primary biliary cholangitis with proximal tubular dysfunctions; mo, months; Scr, serum creatinine.

Table 3. Improvements of PT functions after GCs treatment in PBC-PT patients.

No.	Gender	Clinical indicators*	Baseline	1^st month	3^rd month	Final follow-up
Patient 1	Female	Serum phosphorus, mmol/L	0.77↓	1.01	0.90	0.98
		Serum uric acid, μmol/L	126↓	169	265	214
		Urine glucose	(+)	(-)	(-)	(-)
		Serum IgG, g/L	21.23↑	NA	NA	7.65
		Serum IgM, g/L	3.70↑	NA	NA	0.50
Patient 3	Female	Serum phosphorus, mmol/L	0.73↓	0.99	0.90	0.90
		Serum uric acid, μmol/L	73↓	167	215	215
		Urine glucose	(+++)	(++)	(+)	(+)
		Serum IgG, g/L	12.44	7.60	7.60	NA
		Serum IgM, g/L	14.53↑	7.70↑	4.91↑	NA
Patient 11	Male	Serum phosphorus, mmol/L	0.79↓	1.09	1.09	0.95
		Serum uric acid, μmol/L	207↓	214	276	249
		Arterial blood [HCO3^-], mmol/L	26.5↑	24.3	NA	NA
		Serum IgG, g/L	12.71	NA	NA	13.42
		Serum IgM, g/L	2.62↑	NA	NA	1.52

Abbreviations: PT, proximal tubular; GCs, glucocorticoids; PBC-PT, primary biliary cholangitis with proximal tubular dysfunctions; IgG, immunoglobulin G; IgM, immunoglobulin M; NA, not available.

* The lower limits of normal for serum phosphorus and serum uric acid were 0.81 mmol/L and 150 (female)/210 (male) μmol/L, respectively. The normal range for arterial blood [HCO₃^-] was 22–26 mmol/L.

Data availability statement

The data underlying this article are available in the article and in its online supplementary material.