Abstract and Introduction
Abstract
Background
Tubulointerstitial lesions (TIL) adversely affect the prognosis of various glomerulonephritis. The aim of this study is to evaluate the significance of TIL in the cortical area of renal biopsy specimens.
Methods
A clinicopathologic prospective study was performed on patients with idiopathic nephrotic syndrome (NS). The presence of TIL was assessed qualitatively by light microscopic observation and was correlated with several histopathologic and clinical parameters at biopsy time, as well as with status at final follow-up.
Results
The total number of patients was 136 with a mean duration of follow-up of 23.8 ± 11.9 months. In all patients with idiopathic NS, the presence of TIL in the cortical area was correlated significantly with hypertension at presentation, response to treatment, and outcome. Histopathologically, TIL correlated with glomerular lesions.
Conclusion
It was concluded that qualitative evaluation of TIL in the cortex could reflect glomerular injury and could contribute to the assessment of prognosis in patients with idiopathic NS.
Introduction
It is well known that tubulointerstitial lesions (TIL), such as interstitial cell infiltration, interstitial fibrosis (IF), and tubular atrophy (TA), can be observed in renal biopsy specimens of primary glomerulonephritis (GN), especially when specimens contain sclerosed glomeruli.[1–4]
According to many investigators, IF and TA usually reflect glomerular obsolescence.[1,3,4] If this were true, an evaluation of such lesions would provide helpful information in estimating the severity and prognosis of primary GN on biopsy specimen, even when the biopsy material includes only a small number of glomeruli. However, the body of literature that focuses on the importance of TIL in examining renal biopsy specimens is small, and such lesions may have been overlooked and regarded as minimally significant, in contrast to the glomerular and vascular lesions.[1–10]
Therefore, we carried out a prospective study to evaluate the significance of TIL in assessing the severity and the prognosis of the most common type of adult primary GN presented as nephrotic syndrome (NS).
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Methods
This study included 136 patients with idiopathic NS. Those patients were referred to Al-Rasheed Military Hospital, Baghdad, Iraq – renal unit – from November 1991 to June 1994 for diagnosis, evaluation, treatment, and follow-up.
Definitions
NS was diagnosed on clinical ground with proteinuria > 3.5 g/day, serum total protein concentrations < 6 g/dL, and serum albumin < 3 g/dL.
Hypertension was defined as blood pressure ≥ 140/90 mm Hg on 2 occasions.
Heavy proteinuria was considered when proteinuria was > 10 g/day during any time in the course of the disease.
Renal impairment was considered when the serum creatinine concentration was > 1.5 mg/dL.
Complete remission was defined as proteinuria < 200 mg/day.
Partial remission was defined as proteinuria < 2 g/day but > 200 mg/day, as defined by others.[4]
Unremitting disease was defined as persistent nephrotic range proteinuria.
Chronic renal failure was defined as a persistent and irreversibly low glomerular filtration rate below 30-40 mL/minute, regardless of the need for dialysis with a serum creatinine concentration always > 2.5 mg/dL.
Steroid responsiveness was defined as complete remission following a course of prednisolone 40-60 mg/day initially, according to body weight.
Steroid dependency was defined as 2 or more relapses within a year, when corticosteroid treatment was reduced or discontinued.
Steroid resistance was defined as persistent nephrotic range proteinuria despite 4-6 months of treatment.
Only cases of idiopathic NS were included. Patients with clinical, laboratory, or histologic evidence of underlying disease were excluded.
Exclusion Criteria
The exclusion criteria include patients who have been known to be nephrotic, patients who have been known to be hypertensive, patients with diabetes mellitus, patients who are taking drugs that are known to cause NS, patients with positive antinuclear antibodies, hepatitis B surface antigen-positive patients, VDRL-positive patients, patients with clinical features that are suggestive of vasculitis, and patients with sickle cell anemia.
For all patients, percutaneous kidney biopsy was done with a modified Menghini (Sure cut) needle after stabilizing the patient's general condition. Two pieces of kidney tissue were sent to 2 histopathologists. All specimen slides were stained with hematoxylin and eosin, periodic acid-Schiff and silver, whereas Congo red staining was used only if there was a suspicion of amyloidosis. Only light microscopy was used. Immunofluorescence and electron microscopy were not available.
In evaluating the significance of TIL, interstitial inflammation (II), IF, TA, and blood vessel wall thickening (BT) in the interstitium were assessed qualitatively; II was defined as any degree of mononuclear cell infiltration, whether focal or diffuse and scored as present or not; IF whether focal or diffuse was also scored as present or not; TA was reported as positive when seen; and, again, BT in the interstitium was reported positive when seen. Specimens in which no TIL were seen were reported as an intact interstitium.
Glomerular lesions that were taken in comparison with TIL included mesangial expansion of any degree; mesangial cell proliferation, whether diffuse or focal; polymorphonuclear leukocytes in the glomerular capillary lumen; epithelial crescents of any number; and global glomerulosclerosis, regardless of the number of glomeruli examined and the number of glomeruli sclerosed.
Biopsy specimens, which showed amyloidosis, inadequate tissues, or inconsistent results between the 2 histopathologists, were excluded. The time of biopsy was taken as the date of diagnosis and used as an objective point in the calculation of progress.
For statistical analysis, the chi-square test was used when indicated, and a P value of < .05 was considered to be significant.
Results
Characteristics of patients at presentation, outcome, and response to treatment as well as TIL and glomerular lesions are indicated in Tables 1 and 2.
Table 1.
Characteristics of 136 Patients With Primary Glomerulonephritis
| Characteristic | Number (%) |
|---|---|
| Total | 136 (100) |
| Men | 126 |
| Women | 10 |
| Age (years) (24.7 ± 6.4)(mean +SD) | (24.7 ± 6.4) |
| Duration of follow-up (23.8 ± 11.9)(months) (mean ± SD) | (23.8 ± 11.9) |
| Hypertension | 50 (36) |
| Heavy proteinuria | 45 (33) |
| Renal impairment at presentation | 26 (19) |
| Complete remission | 42 (30.8) |
| Partial remission | 21 (15.4) |
| Unremitting | 73 (53.6) |
| Chronic renal failure | 20 (14) |
| *Death | 7 (5) |
(Cause of death: 2 sepsis, 2 pulmonary embolism, 2 end-stage renal disease, and 1 hypokalemia)
Table 2.
Tubulointerstitial Lesions and Glomerular Lesions in Biopsy Specimens of 136 Patients With Primary Glomerulonephritis
| Characteristic | Number (%) |
|---|---|
| Interstitial inflammation | 94 (69.1) |
| Interstitial fibrosis | 70 (51.4) |
| Tubular atrophy | 26 (l 9.1) |
| Blood vessel wall thickening | 16 (11.7) |
| Intact interstitium | 25 (18.3) |
| Mesangial expansion | 110 (80.8) |
| Mesangial cell proliferation | 75 (55.1) |
| Fusion to Bowman's capsule | 23 (18.9) |
| Periglomerular fibrosis | 33 (24.2) |
| Polymorphonuclear leukocytes in the glomerular capillary lumen | 42 (30.8) |
| Epithelial crescent | 13 (9.5) |
| Glomerulosclerosis | 56 (41.1) |
Table 3 shows that patients presenting with hypertension had more II, IF, TA, and BT, and each of these lesions was statistically significant (P < .05). Only 2% of hypertensive patients had an intact interstitium. In patients presenting with heavy proteinuria, the only statistically significant association was with IF and II. Regarding renal impairment at presentation, there was no statistically significant association with TIL; 33.3% of those patients who achieved complete remission had an intact interstitium, whereas only 14.2% had IF and 4.7% had TA (P < .05). Of those with unremitting diseases, only 10.9% had an intact interstitium, whereas 78% had II; 61.6% had IF; and 24.6% had TA (P < .05). Only 5% of those who progressed to chronic renal failure had an intact interstitium, whereas 85% had II; 45% had TA; and 35% had BT (P < .05). Concerning steroid responsiveness or dependence, 37.8% of patients had an intact interstitum; 48.6% had II; 29.7% had IF; and 8.1% had TA (P < .05). For steroid-resistant patients, 11.8% had an intact interstitium, whereas 88.1% had II and 71.1% had IF (P < .05).
Table 3.
Correlation Between Clinical Presentation, Outcome, and Tubulointerstitial Lesions in 136 Patients
| Clinical Presentation and Outcome Number | Interstitial Inflammation Number (%) | Interstitial Fibrosis Number (%) | Tubular Atrophy Number (%) | Blood Vessel Wall Thickening Number (%) | Intact Interstitial Number (%) |
|---|---|---|---|---|---|
| Hypertension 50 | 43 (86)* | 31 (62)* | 15 (30)* | 10 (20)* | 1 (2)* |
| Heavy proteinuria 45 | 36 (80)* | 29 (64.4)* | 11 (24.4)** | 5 (11.1)** | 7 (15.5)** |
| Renal impairment 26 | 15 (57.6)** | 13 (50)** | 6 (23)* | 3 (11.8)** | 0* |
| Complete remission 42 | 21 (50)** | 6 (14.2)* | 2 (4.76)* | 5 (11.8)** | 14 (33.3)* |
| Unremitting disease 73 | 57 (78)* | 45 (61.6)* | 18 (24.6)* | 8 (10.9)** | 8 (10.9)* |
| Chronic renal failure 20 | 17 (85)* | 13 (65)** | 9 (45)* | 7 (35)* | 1 (5)* |
| Steroid-responsive or -dependent 37 | 18 (48.6)* | 11 (29.7)* | 3 (8.1)* | 4 (10.8)** | 14 (37.8)* |
| Steroid-resistant 59 | 52(88.1)* | 42(71.1%)* | 14 (23.7%)** | 5 (8.4%)** | 7 (11.8%)* |
Statistically significant (P < .05)
Statistically not significant (P > .05)
Table 4 shows the correlation between TIL and glomerular lesions. Mesangial expansion was associated with II in 80%, IF in 59%, TA in 22.7%, and BT in 14.5% in decreasing frequency. Mesangial cell proliferation correlated significantly with II (77.3%), and only 12% had an intact interstitium. None of those with fusion to Bowman's capsule and periglomerular fibrosis had an intact interstitum, and the association with TIL was significant in both of these glomerular lesions. The association between polymorphonuclear leukocytes in the glomerular capillary lumen and TIL was not statistically significant except for II in 85.7% of patients. None of those with epithelial crescents had an intact interstitium, and there was a significant association with II, IF, and TA. Global glomerulosclerosis, regardless of the number, was significantly associated with TIL, except for BT, and only 5.3% had an intact interstitium.
Table 4.
Correlation Between Glomerular Lesions and Tubulointerstitial Lesions in 136 Patients With Primary Glomerulonephritis
| Glomerular Lesion Number | Interstitial Inflammation Number (%) | Interstitial Fibrosis Number (%) | Tubular Atrophy Number (%) | Blood Vessel Wall Thickening Number (%) | Intact Interstitial Number (%) |
|---|---|---|---|---|---|
| Mesangial expansion 110 | 88 (80)* | 65 (59)* | 25 (22.7)* | 16 (14.5)* | 14 (12.7)** |
| Mesangial cells proliferation 75 | 58 (77.3)* | 41 (54.6)** | 16 (21.3)** | 9 (12)** | 9 (12)* |
| Fusion to Bowman's capsule 23 | 21 (91.3)* | 18 (78.2)* | 8 (34.7)* | 6 (27.2)* | 0* |
| Periglomerular fibrosis 33 | 30 (90.9)* | 29 (87.8)* | 12 (36.3)* | 9 (27.2)* | 0* |
| Polymorphonuclear leukocytes in the glomerular capillary lumen 42 | 36 (85.7)* | 19 (45.2)** | 7 (16.6)** | 3 (7.1)** | 5 (11.9)** |
| Epithelial crescents 13 | 13 (100)* | 11 (84.6)* | 5 (38.4)** | 3 (23)** | 0* |
| Glomerulosclerosis 56 | 46 (82.1)* | 33 (58.9)* | 15 (26.7)** | 12 (21.4)** | 3 (5.3)* |
P < .05
P > .05
Table 5 shows the prevalence of hypertension, response to treatment, progression to chronic renal failure, and the absence of TIL among different types of primary GN in 136 patients presenting with NS.
Table 5.
Prevlance of Hypertension, Response to Treatment, Progression to Chronic Renal Failure, and Intact Interstitium in Different Types of Glomerulonephritis
| Type of Glomerulonephritis Number | Hypertension Number (%) | Received Corticosteroid Number (%) | Steroid-Responsive or -Dependant Number (%) | Progression to Chronic Renal Failure Number (%) | Intact Interstitium number (%) |
|---|---|---|---|---|---|
| MCN 27 | 2 (7) | 27 (100) | 16 (59.2) | 1 (3.7) | 19 (70) |
| FSGS 24 | 8 (33) | 18 (75) | 6 (25) | 4 (16.6) | 1 (4.1) |
| MSPGN 23 | 11 (47) | 12 (52) | 5 (21.7) | 3 (13) | 1 (4.3) |
| MN 21 | 6 (28) | 15 (71) | 6 (28.5) | 0 | 2 (9.5) |
| MPGN 19 | 15 (78) | 13 (68) | 1 (5.2) | 3 (15.7) | 1 (5) |
| FSPGN 12 | 0 | 8 (66) | 3 (25) | 0 | 1 (8) |
| GS 5 | 4 (80) | 2 (40) | 0 | 4 (80) | 0 |
| RPGN 3 | 2 (66) | 0 | 0 | 3 (100) | 0 |
| DPGN 2 | 2 (100) | 1 (50) | 0 | 2 (100) | 0 |
MCN = minimal change nephropathy; FSGS = focal segmental glomerulosclerosis; MSPGN = mesangial proliferative glomerulonephritis; MN = membranous nephropathy; MPGN = membranoproliferative glomerulonephritis; FSPGN = focal segmental proliferative glomerulonephritis; GS = glomerulosclerosis; RPGN = rapidly progressive glomerulonephritis; DPGN = diffuse proliferative glomerulonephritis
Discussion
TIL adversely affect the prognosis of various types of GN-like focal segmental glomerulosclerosis, membranoproliferative GN, membranous nephropathy, minimal change nephropathy, and immunoglobulin (Ig)A nephropathy.[1–4,9–17] These lesions are often observed in various types of chronic progressive GN. The cause of such lesions has not yet been clarified.
It is impossible to conclude which lesions, glomerular or tubulointerstitial, initially occur and lead to the decline of renal function. Additional studies are needed to clarify this point.[1,18]
Glomerular lesions rather than interstitial damage may be affected by sample errors because the glomerular lesions occur individually in which the interstitial damage is zonal in nature.[1]
From our study, a statistically significant correlation existed between TIL and hypertension, response to treatment, and outcome in patients with primary GN. Moreover, TIL were clearly associated with glomerular lesions. These findings seem to suggest that the lesions may be secondary to ischemia, which occurs due to glomerular damage, and TIL reflect the degree of glomerular obsolescence. In any case, TIL are very important in estimating nephron injuries, especially when a sample of renal tissue obtained by needle biopsy contains a limited number of glomeruli.
Although it is known that TIL accompany GN, the body of literature that stresses their importance in evaluating biopsy specimens is rather small. This may be due to the difficulty of assessing the lesion quantitatively. This problem may be partly solved by a computer-assisted image-analysis device that has come into use in the field of laboratory medicine.[1]
In conclusion, to assess the prognosis of GN from renal biopsy specimens, TIL are one of the most important indexes. And attention should be focused not only on the glomerular and vascular changes, but also on the TIL in examining renal biopsy specimens of patients with primary GN. TIL at the time of biopsy provide the only decisive morphologic parameter that can be used to predict whether the disease will follow a favorable course, even in the same type of GN. In addition, pathologists, when examining renal biopsy material, can give relevant information concerning the prognosis of GN.
Contributor Information
Abbas Ali Mansour, Department of Medicine, Basrah College of Medicine, Basrah, Iraq. Email: aambaam@yahoo.com.
Ihsan Al-Shamma, Medical City, Baghdad, Iraq.
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