Table 1.

Comparison of Histopathological Findings of the Studies^a

Study (Country of origin; N)	Mean age (SD), years M : F ratio	Histological Analysis	Glomeruli	Tubules	Interstitium	Vessels	Immunofluorescence	Electron Microscopy	Main Conclusions
Athuraliya et al.26 2011	45.05b (14.79)	No scoring or grading method used.	Normal to severe GS. GS was proportionate to IF and TA.	TA distribution included varying levels ranging from mild to severe.	IF was mild to severe.	Not mentioned.	Negative	Not done	Primary lesion was tubulointerstitial disease.
(SL; 26)	1.5:1b			Tubulitis not mentioned.	II showed active inflammation accompanying fibrotic lesions.
Nanayakkara et al.27 2012	45 (10.5)	% scoring of glomeruli.	Mean GS = 37.1% ± 4	TA distribution was not quantified.	IF distribution:	Fibrous intimal thickening distribution:	Negative	Not done	Primary lesion was tubulointerstitial nephritis which is unlikely to be from tubular inflammation.
					ci0 - 7.0%
(SL; 57)	2.8:1	IF, II, and vessels graded using Banff.	Collapsed glomeruli scorea was	Tubulitis was not seen.	ci1 - 31.6 % ci2 - 35.1 % ci3 - 26.3%	cv0 - 50.0% cv1 - 40.5% cv2 - 9.5%			Glomerular lesions are due to ischemia and progressive chronic loss of nephrons.
			17.6 ± 3.7%.
			Glomerular enlargement was 36.8%.
			Perihilar FSGS was 3.5%.		II distribution:	AH distribution:
					i0 - 40.4%
			No proliferative changes.		i1 - 36.8%	ah0 - 41.5%
					i2 - 21.0%	ah1 - 39.6%
					i3 - 1.8%	ah2 - 18.9%
					IF more prominent than II.
Wijetunge et al.28 2013	36.8 (14)	GS as %.	Mean GS:	TA distribution:	IF distribution:	Hypertensive changes seen in 14.2% but none in early stages	Negative	Not done	Earliest detectable pathology is IF even with normal GFR.
(SL; 211)	2.6:1	SQ grading for IF, II, and TA (not Banff).	Cat. 1 = 27.7%	Absent – 19.9%	<10% - 35.8%				II is more likely a factor in disease progression rather than initiation.
		Vascular changes were not graded.	Cat. 2 = 35.2%	<10% - 26.1%	10-50% - 39.2%				Pathogenesis: Either; a) many episodic exposures to toxins causing acute TIN & healing by IF or b) chronic low grade exposure to toxin causing progressive IF or c) both
		Cases grouped into 7 categories based on biopsy findings.	Cat. 6 = 77.7%	10% to 50% - 49.3%	>50% - 25%
			GS absent at 35.8%.	>50%-17.1%	II distribution:
				Wide-spread tubulitis - 2 cases.	Absent - 44.1%
					<10% - 19.1%
					10-50% - 22.1%
					>50% - 16.7%
					IF more prominent than II.
Wijetunge et al.29 2015	37.3 (12.5)	GS as %.	GS absent - 29.9% GS ≤50% - 53.4%	TA distribution: Absent - 13.9% <10% - 20.3% 10-50%- 37.1% >50% - 28.7%	IF distribution:<10% - 25.1% 10-50% - 43.8% >50% - 31.1% II distribution: Absent - 29.5% <10% - 16.7% 10-50% - 27.9% >50% - 25.9%	Hypertension associated vascular changes - 14.3%	Negative	Not done	A significant proportion in all clinical stages are asymptomatic.
(SL; 251)	3.3:1	SQ grading for IF, II, and TA (not Banff).							There was significant correlation between the advancing histopathological parameters (IF, II, TA, and GS) and the mean GFR
		Vascular changes were not graded.							Pathogenesis: a) Noninflammatory process →IF and TA; b) Vicious cycle of IF → ischemia → further IF
		Pathology compared with clinical staging.
Badurdeen et al.30 2016	44 (9)	SQ scoring not Banff.	GS absent - 22.6% GS <30% - 50% PGF - 41.9%.	TA distribution: Absent – 8.1% <30% - 35.5% 30-60% - 51.6% >60% - 4.8%	IF distribution: Absent – 12.9% <10% – 35.5% 10-50%– 46.8% >50% – 4.8%	Not mentioned	Negative	Not done	Pathology in acute symptomatic CKDu is significant II and wide-spread tubulitis in the background of IF and TA.
(SL; 46)	13.75:1	AI and CI calculated.							Pathogenesis: Multiple acute episodes of interstitial nephritis progressing to residual scarring.
				Tubulitis:	II distribution:
				Absent – 19.4%	Absent - 3.3%
				<30% - 33.9%	<10% - 43.5%
				30-60% -24.2%	10-50% -35.5%
				>60% - 22.6%	>50% - 17.7%
Selvarajah et al.31 2016	46.21 (11.64)	No scoring or grading system.	Mean GS = 42.2% ± 29.19	TA present in 70.4%.	IF present in 71.2%	AH - 12.8%	Negative	Not done	Pathological changes supersede the clinical markers.
(SL; 125)	2.8:1	GS as %.	GS absent - 5.2%		II present in 76.0% (lymphocytic infiltrate - 74.4% neutrophilic infiltrate - 1.6%)				Progression of CKDu mainly due to II.
		Others present or absent.	GS >50% - 48%
			PGF - 16%
			Mesangial hypercellularity - 10.4%
Wijkström et al.32 2018	48 (11)	SQ scoring similar to Banff.	Mean GS = 43% ± 20	TA distribution:	IF distribution:	Intimal thickening:	Negative	No immune complexes.	Sri Lankan CKDu showed a more mixed morphological pattern than MeN, which may represent different stages of same disease or different diseases.
(SL;11)	All male		All had GS	<6% – 0%	<6% – 0	Mild - 20%		Segmental podocytic foot process effacement – 18%.	Glomerular ischemia may not be due to arterial disease alone.
(Large blood vessels present in only 10 cases)			GS >50% - 45%	6-25%% - 91%	6-25%% - 55%	Moderate - 30%		Podocytic cytoplasmic inclusions – 82%
			Glomerular hypertrophy - 100%	26-50% - 9%	26-50% - 36%	Mild smooth muscle hyperplasia 40%
			Glomerular ischemia - 63.6%	>50% - 0%	>50% - 9%	AH:
			Endocapillary proliferation – Absent	Tubulitis - 3 cases	II distribution:	Mild - 63.6%
				Intratubular granulocytes - 2 cases	<6% – 18% 6-25%% - 45% 26-50% - 18% >50% - 18%	Moderate - 27.3%
Anand et al.33 2019 (SL;87) (Histology described only in the PTKD group; N = 43)	48 (11) 6.2:1	SQ scoring not Banff. AI and CI calculated.	GS >25% - 15% Coexistent glomerular disease - 10%	TA distribution: <25% - 85% ≥26% - 15% Tubulitis Foci with 5-10 cells/tubular cross section – 30%	IF distribution: <25% - 85% >=26% - 15% II distribution: >=26% - 30%	Arteriosclerosis – only mild changes.	IMF used to exclude cases of GN. Coexisting glomerular disease - 4.	Not done.	Young or middle-aged CKD patients with negative dipstick proteinuria and normal serum albumin were more likely to have CKDu. Diabetes should not be an exclusion criterion for CKDu.
Vervaet et al.38 2020	SL– 48.61	Experimental exploration for specific lysosomal lesion in the proximal tubules.	GS absent - 38.9%.	IFTA distribution:	IFTA distribution:	Arterial intimal fibrosis in 33.3%	A subset of the proximal tubular granules that were autofluorescent and agyrophylic on silver stain were positive for lysosomal associated membrane protein 1 (LAMP1) and cathepsin B.	Electron dense lysosomal inclusion bodies were identified in proximal tubular epithelium.	A proximal tubular cell (lysosomal) lesion identical to that found in calcineurin inhibitor nephrotoxicity was identified in CINAC in different geographic regions.
(SL;18)	3.5:1	SQ scoring not Banff.	PGF - 27.8%.	0-5% - 22.2%	0-5% - 22.2%	Vascular muscular hypertrophy:			Pathogenesis: CINAC occurs due to a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.
						Mild – 44.4%
			Glomerulomegaly - 22.2%.	6-25% - 38.9%	6-25% - 38.9%	Moderate – Severe - 38.9%
				26-50% - 28%	26-50% - 28%	AH in 22.2%
				>50 – 11.1% Tubular inflammation - 1 case Tubular luminal neutrophils - 1case Jones silver stain - light brown - black cytoplasmic granules in cortical tubular cells.	>50 – 11.1%
					II distribution: 0-5% - 33.3% 6-25% – 33.3% 26-50% - 22.2% >50% - 11.1%
Wijkström et al.36 2017	33 (8)	SQ scoring similar to Banff.	Mean GS = 38%± 21.	TA distribution:	IF distribution:	Intimal thickening:	Negative	No immune deposits.	Ratio between glomerular and tubulointerstitial damages suggest that glomerular changes cannot be explained by tubulointerstitial damage alone.
(NCG;19)				Absent – 6%
(Histology evaluated in 16 biopsies. Large blood vessels were present in only 15 cases)	All male.		All had GS;	<25%% - 81%	Absent – 6%	Mild - 20%		Mild thickening of GBM- 31.25%.	Findings compatible with the hypothesis of heat stress.
			25-50% grade – 44%	26-50% - 13% >50% - 0	<25%% - 50%	Moderate–7%		Podocytic foot process effacement – 56.25%.
			Glomerular hypertrophy - 100%.		26-50% - 44% >50% - 0	Smooth muscle hyperplasia:		Inclusion-like vacuoles in podocytic cytoplasm.
			Wrinkled GBM and PGF - 94%.	Few granulocytes in tubules – 2 cases		Mild - 40%		.
					II distribution:	Moderate - 27%
					Absent – 13%	AH:
					<25%% - 75%	Mild – 18.75%
					26-50% - 13%	Moderate – 12.5%
					>50% - 0
Fischer et al.37 2017	26	Chronic TIN and GS as a %.	Mean GS = 13.37% (0-50)	All showed TIN with a predominantly mononuclear cell infiltrate (confirmed to be T cells and macrophages on IHC). Some had a mild neutrophilic infiltrate with neutrophils casts in tubules.		Mild intimal fibrosis – 27.3%	Focal segmental mesangial staining for IgA - 5	Nonspecific, mild, focal segmental changes of podocyte effacement, mesangial sclerosis, and changes of chronic ischemic injury – 36.4%.	Renal histopathology in MeN reveals primary interstitial disease with intact glomeruli.
(NCG;11)	All male.		GS absent - 54.5%	Acute TIN – 18.2%			IgG - negative	No immune-type electron-dense deposits.
			Ischemic changes and mild glomerular enlargement – few cases	Acute and chronic TIN – 36.4%			IgM (mesangial) - all cases
				Chronic TIN – 45.5%
				Chronic TINdistribution:
				Absent – 18.2% <10% - 9.1% 10-25% - 36.4% 25 - 50% - 27.3%% >50% - 9.1%
Wijkström et al.34 2013	44.25	SQ scoring for IF, II, and TA (not Banff).	Mean GS = 51.75% (29-78).	TA distribution:	IF distribution:	Mild intimal thickening -25%	Small amounts of IgG-1 (postulated to be a previous episode of GN).	Segmental foot process effacement - 37.5%.	GS and glomerular ischemia were more advanced than tubulointerstitial changes suggesting possible primary injury to glomeruli in addition to tubulointerstitial damage.
(ES; 8)	All male		All had GS; majority (62.5%) within 25-50% grade.	<25% - 50%	<25% - 50%	Mild smooth muscle hyperplasia - 87.5%		Podocyte vacuolations - 75%.
			Glomerular hypertrophy -100%.	26-50% - 50%	26-50% - 50%	AH - 37.5%		Electron dense deposits - 12.5%.
			Wrinkled GBM & PGF - 87.5%.	Tubulitis - 1 case	II distribution:
				No crystals on polarized light	Absent - 12.5%
					<25% - 50%
					26-50% - 37.5%
Lopez-Marin et al.35 2014	45.4	SQ scoring for IF, II, and TA stated as Banff 97.	GS >25% - 58.7%.	TA distribution:	IF distribution:	Intimal proliferation - 19.6%	One case with IgG deposition (coexistent early membranous nephropathy).	Not done	Pathology is chronic TIN.
(ES; 46)	3.6:1		Glomerulomegaly≥10% - 47.8%.	Absent - 10.9%	≤5% - 37%	Tunica media thickening - 52.2%			Severity increased with CKD stage.
				<25% - 76.1%	6-50% - 37 %				Consistent with a multifactorial etiology.
				≥25% - 13%	>50% - 26.1 % II distribution: ≤25% - 89.1% 26-50% - 10.9%
Vervaet et al.38 2020	ES – 43.73		GS absent - 9.1%	IFTA distribution:	IFTA distribution:	Arterial intimal fibrosis in 36.7%
(ES; 11)	4.5:1		PGF - 63.6%	0-5% - 45.4%	0-5% - 45.4%	Vascular muscular hypertrophy:
						Mild - 63.6%
			Glomerulomegaly - 72.7%	6-25% - 45.4%	6-25% - 45.4%	Moderate - severe - 27.3%
				26-50% - 9.1%	26-50% - 9.1%	AH in 27.3%
				>50 - 0% Tubular inflammation - 2 cases Tubular luminal neutrophils – 1 case	>50 - 0% II distribution: 0-5% - 45.4% 6-25% – 45.4% 26-50% - 9.1% >50% - 0%

TA distribution refers to the percentage of Tubular atrophy seen. It is graded as Absent, <10%, 10-50% and >50%.

^aAH, arteriolar hyalinosis; ah#, arteriolar hyalinosis grading according to BANFF ; AI, activity index; Banff, Banff classification for kidney transplant pathology; Cat., category; CINAC, chronic interstitial nephritis in agricultural communities; CI, chronicity index; ci#, interstitial fibrosis grading according to BANFF ; CKD, chronic kidney disease; CKDu, chronic kidney disease of unknown origin; cv#, vascular fibrous intimal thickening grading according to BANFF; ES, El Salvador; FSGS, focal segmental glomerulosclerosis ; GBM, glomerular basement membrane; GFR, glomerular filtration rate; GN, glomerulonephritis; GS, glomerulosclerosis; i#, interstitial inflammation grading according to BANFF; Ig, immunoglobulin; IF, interstitial fibrosis; IFTA, interstitial fibrosis and tubular atrophy combined; IHC, immunohistochemistry; II, interstitial inflammation; IMF, immunofluorescence; MeN, Mesoamerican nephropathy; NCG, Nicaragua; PGF, periglomerular fibrosis; PTKD, primary tubulointerstitial kidney disease; SL, Sri Lanka; SQ, semiquantitative; TA, tubular atrophy; TIN, tubulointerstitial nephritis.

^bTotal screened population.