Cytokines accumulated in acquired renal cysts in long-term hemodialysis patients

BACKGROUND: Cytokines play a pivotal role in growth, differentiation, and apoptosis. In this study, we measured cytokine content in the renal cyst fluid of patients with acquired cystic disease of the kidney (ACDK) in order to elucidate the possibility that cytokines are related to the development of ACDK. PATIENTS AND METHODS: All or some of 15 cytokines, IL-1a, -1b, -2, -4, -5, -6, -8, -10, IFN-alpha, -gamma, G-, M-, GM-CSF, TNF-alpha, and vascular endothelial growth factor (VEGF) were analyzed in cyst fluid and serum of 12 patients on hemodialysis (HD) including 8 with ACDK and 8 with normally functioning kidneys by sandwich enzyme-linked immunosorbent assay. RESULTS: Out of these cytokines, only IL-6, -8, M-CSF, and VEGF were detected in the cyst fluid of patients with ACDK. Moreover, IL-6, -8, and VEGF showed significantly higher concentrations in the cyst fluid than in the blood (194.9 +/- 90.9 vs. 0.0 +/- 0.0 pg/ml, 2,377. 5 +/- 602.9 vs. 0.0 +/- 0.0 pg/ml, 5,167.8 +/- 1,316.9 vs. 41.1 +/- 14.7 pg/ml, respectively), while M-CSF showed comparable concentrations in the cyst fluid with those in the blood (3,519.4 +/- 730.0 vs. 3,250.3 +/- 319.1 pg/ml, p = 0.69). Additionally, IL-6, -8, and VEGF accumulated more abundantly in the cyst fluid of patients with ACDK than in that of patients with other cystic nephropathies including ADPKD patients on HD (194.9 +/- 90.0 vs. 4.6 +/- 3.2 pg/ml, 2,377.5 +/- 602.9 vs. 76.8 +/- 46.5 pg/ml, 5,167.8 +/- 1,316.9 vs. 131.1 +/- 63.1 pg/ml, respectively). However, there was no significant correlation between the intracystic concentrations of these cytokines and the corresponding cyst diameters. CONCLUSION: These results showed that in ACDK patients a local environment exists in which production or accumulation of certain cytokines is selectively enhanced compared with patients with other cystic nephropathies. They imply that these cytokines are closely related to pathogenesis particular to ACDK.     

Severity of acquired renal cysts in native kidneys and renal allograft with long-standing poor function

To identify factors related to the development of uremic acquired cystic disease of the kidney, native and grafted kidneys were examined in four men and three women after kidney transplantation. The incidence and severity of cystic transformation of native kidneys and grafts were compared by plain computed tomographic scans. In a uremic environment (serum creatinine level of greater than or equal to 265 mumol/L [3 mg/dL] for an average of 5.0 years; range, 2.8 to 8.2 years), acquired renal cysts were formed in both the native kidneys and the graft in three of the male and one of the female patients. Cysts were extensive in the native kidneys but relatively infrequent in the grafts in three of the men. One male subject was found to have acquired cysts only in the native kidney. Acquired renal cysts developed even in grafts undergoing chronic rejection, and increased numbers were found in native kidneys that were in uremic conditions for long periods, both before and after renal transplantation. These results suggest that the duration of uremia is the most important factor in the development of acquired renal cysts.     

Histological alterations in implant and one-year protocol biopsy specimens of renal allografts

BACKGROUND: The natural course of histological changes and their correlations with clinical parameters have not been studied in large numbers in renal allograft specimens. The aim of this study was to determine whether any histological alterations developed during the first posttransplantation year. Immunological and nonimmunological factors possibly associated with subsequent histopathological changes and development of chronic rejection were also assessed. METHODS: We studied 102 cadaveric kidney allografts for which both implant and 1-year protocol biopsy specimens were available. The chronic allograft damage index (CADI) was used to quantify the extent of histological changes that developed during the first year. RESULTS: Overall, an increase in histological alterations were seen during the first posttransplantation year, and the CADI increased significantly. The mean CADI was 0.7 in relation to implant biopsy samples and 2.9 in relation to 1-year biopsy samples (P<0.05). Although the degree of changes increased during the first posttransplantation year, they were seldom severe. Significant increases in incidences of interstitial inflammation and fibrosis, tubular atrophy, and basement-membrane thickening were seen. Vascular intimal proliferation and glomerular mesangial matrix increase and glomerular sclerosis were also noted. In contrast, anisometric vacuolization in the tubular epithelium decreased significantly in incidence during the first year. CADI values 1 year after transplantation were significantly affected by donor age, occurrence of acute rejection episodes, and prevalence of HLA-DR mismatches. CADIs were also significantly higher in grafts with decreased function. CONCLUSIONS: Histopathological alterations increased in almost every graft, even well-functioning grafts, during the first year. The CADIs relating to alterations seen in cases of chronic rejection increased significantly and were strongly affected by both immunological and nonimmunological factors.     

Prognostic value of simple measurement of chronic damage in renal biopsy specimens.

BACKGROUND: A simple method of measurement of chronic damage in renal biopsy specimens would be useful in clinical management, prognosis, comparisons between different centres and trials. METHODS: An interactive image analysis system was used to outline and measure areas of chronic damage in 247 renal biopsy specimens to give an index of chronic damage, expressed as a percentage of cortical cross-sectional area. Prognostic value was analysed by the Kaplan-Meier method to study time between biopsy and onset of permanent dialysis. RESULTS: There was no significant bias between measurements by the same observer or different observers. The index of chronic damage ranged from 0 to 90%. Increasing severity of chronic damage was associated with shortened renal survival. Each increase of 10% in the index increased the hazard ratio of risk of permanent dialysis by 1.5 times (95% confidence interval 1.4-1.7, P<0.001). CONCLUSIONS: A simple measure of chronic damage was a powerful indicator of prognosis. This is likely to be clinically useful in routine practice and trials.     

Detection of B lymphocytes (CD20+) in renal allograft biopsy specimens

Acute allograft rejection represents an important complication after transplantation with significant impact on long-term graft survival. The involvement and relevance of B lymphocytes in this process is still not clear. The aim of this study was to quantify in renal allograft biopsy specimens the number of cells positive for CD20, a specific marker for B lymphocytes. Immunohistochemical techniques using monoclonal anti-CD20 antibody was used on paraffin sections from 38 renal allograft biopsy specimens. The biopsy specimens were classified into 3 groups, according to clinical and histological criteria: normal kidney, acute rejection, and chronic allograft nephropathy (CAN). In the normal kidney, no CD20(+) cells were detected. In contrast, in all cases of acute rejection and CAN, there were CD20(+) cells. The CD20(+) cells occurred in the infiltrate in 2 distinct patterns: scattered or nodular. In cases of acute rejection, the number of CD20(+) cells was significantly higher than in CAN cases (137.0 +/- 57.2 vs 45.4 +/- 9.8 cells/mm(2); P < 0.05). The nodular pattern was observed in 4 of 11 cases (36%) in the acute rejection group, and in 4 of 20 cases (20%) in the CAN cohort. In the acute rejection group, the presence of B-cell clusters tender to be associated with a higher level of serum creatinine (3.7 +/- 1.8 mg/dL vs 2.8 +/- 0.1 mg/dL in the scattered pattern group; not significant [ns]). In conclusion, these preliminary results demonstrated B lymphocytes in cases of renal allograft dysfunction, which were more pronounced in acute allograft rejection. Further analyses are required to determine whether the detection of CD20(+) cells in renal allograft biopsy specimens can be used as a prognostic marker.     

Subclinical rejection and borderline changes in early protocol biopsy specimens after renal transplantation

BACKGROUND: To determine the significance of early subclinical rejection, we reviewed protocol biopsies performed on days 7 and 28 during a 4-year period. METHODS: The study was confined to patients (n=115) with stable graft function at the time of biopsy; 76 adequate biopsies at day 7 and 79 at day 28 were performed. RESULTS: At day 7, 10 biopsy specimens (13%) showed acute rejection (AR) and 9 (12%) showed borderline changes. Eight of 10 patients with AR received immediate pulsed methylprednisolone (MP) and one untreated patient developed clinical rejection (CR) within 3 days. Four of nine patients whose biopsy specimens showed borderline changes received MP and three untreated patients developed CR within 3 days. At day 28, six biopsy specimens (8%) showed AR and 13 (16%) showed borderline changes. Three of six patients with AR received immediate pulsed MP and one untreated patient developed CR within 6 days. Ten of 13 patients with borderline changes had been treated for AR in the previous 3 weeks. Twelve patients with subclinical rejection or borderline changes at day 28 were never subsequently treated for rejection, and outcome at 6 years did not differ from those patients whose biopsy specimens showed no rejection. CONCLUSIONS: Compared with some units, the incidence of subclinical rejection is low. The majority of untreated subclinical borderline changes and rejection at day 7 behaved as early clinical rejections and at day 28 as resolving clinical rejections. Untreated subclinical rejection or borderline change at day 28 was not an adverse prognostic factor for long-term outcome.     

Diagnosis of renal tumors on needle biopsy specimens by histological and molecular analysis

PURPOSE: We diagnosed the subtypes of renal cell carcinoma on needle core biopsies using a combination of histopathology and a molecular diagnostic algorithm. MATERIALS AND METHODS: Core biopsies were taken of renal tumors following nephrectomy. RNA was extracted and quantitative real-time polymerase chain reaction was performed for 4 gene products to differentiate among renal cell carcinoma subtypes. Histopathological diagnosis was achieved on a second core before and after obtaining the molecular diagnostic algorithm results. RESULTS: Based on the nephrectomy diagnosis 6 of 77 renal masses were nonneoplastic and 71 were tumors, including 65 renal cell carcinoma/oncocytomas. The overall diagnostic accuracy using histology and our molecular diagnostic algorithm combined was 90.0% (70 of 77). Side by side comparison of histology vs molecular diagnostic algorithm was feasible for 60 classifiable renal cell carcinoma/oncocytomas (31 clear cell, 14 papillary renal cell carcinoma, 6 chromophobe renal cell carcinoma, 2 mucinous tubular and spindle cell carcinoma, and 7 oncocytoma). In this group histology correctly predicted the final histological subtype in 83.3% (50 of 60) of cores. Addition of the molecular diagnostic algorithm to histology improved the subtyping accuracy to 95% (57 of 60), whereas the molecular diagnostic algorithm alone was accurate in 50 of 60 cases (83.3%). Dividing these 60 specimens into clear cell and nonclear cell neoplasms, the addition of the molecular diagnostic algorithm improved the sensitivity for the diagnosis of clear cell carcinoma from 87.1% (27 of 31) to 100% and the negative predictive value from 87.5% to 100%. CONCLUSIONS: Core biopsies of renal tumors provide adequate material for diagnosing and subtyping renal cell carcinoma. The addition of our molecular diagnostic algorithm to histology improved the diagnostic accuracy of core biopsies of renal masses.     

Assessment of extracellular matrix components in renal biopsy specimens showing various degrees of mesangial expansion

Background. Compositional changes in the extracellular matrix (ECM) and the role of transforming growth factor β₁ (TGF-β₁) in the process of mesangial expansion have been widely investigated in experimental animals, but much less attention has been focused on such changes in human renal biopsy specimens, particularly in regard to quantitative studies. Methods. In 28 biopsy specimens with varying degrees of mesangial expansion, we performed conventional ECM staining and immunohistochemical staining for ECM components, including cellular fibronectin containing extra domain A (EDA(+)cFn), tenascin, and type IV collagen, as well as investigating mRNA and protein expression of TGF-β₁. Results for ECM components stained were evaluated quantitatively. Results. By multiple regression analyses, mesangial expansion, as quantitated by conventional silver, but not by periodic acid Schiff (PAS) staining, correlated well with EDA(+)cFn accumulation. In specimens with increased mesangial expansion estimated by silver staining, the ratio of the EDA(+)cFn-positive area to the silver-positive area was greater than the ratio of the type IV collagen-positive area to the silver-positive area; the type IV collagen-positive area, however, was always larger than the EDA(+)cFn-positve area. In glomeruli with moderate mesangial expansion, expression of TGF-β₁ mRNA and protein was enhanced. Where mesangial expansion was severe, TGF-β₁ protein and mRNA expression was decreased in the mesangial area but increased in neighboring epithelium and endothelium. Conclusion. Our results indicate that silver staining, but not PAS, reflects the accumulation of mesangial ECM proteins and that while the proportion of EDA(+)cFn is altered in the course of ECM expansion, type IV collagen remains the major ECM component. Expression of TGF-β₁ was suppressed at sites of massive mesangial ECM accumulation. Received: May 12, 1999 / Accepted: June 7, 1999     

Cystic renal cell carcinoma,suspected because of lack of regression of renal cysts after renal transplantation in a dialysis patient with acquired renal cystic disease

A 34-year-old man who had been on dialysis for about 6 years, and had acquired renal cystic disease, received a renal transplantation. However, in spite of the success of the transplantation, one area without cyst regression was observed in the original kidney. Therefore, carcinoma was suspected and nephrectomy was performed. Histology revealed cystic renal cell carcinoma (RCC). No case of cystic RCC occurring in a dialysis patient has previously been reported. Cystic RCC should be suspected in a cystic mass in the original kidney which does not regress after successful renal transplantation. Received: August 23, 2002 / Accepted: November 25, 2002 Acknowledgments We thank Dr. Shigehiko Sato, Department of Internal Medicine, Tonami General Hospital, who referred this patient to us. Correspondence to:I. Ishikawa     

Obstructive renal cysts

Renal cysts usually are asymptomatic, produce no harm to the kidney and require no treatment once diagnosed. However, an occasional expanding cyst causes progressive obstruction to caliceal or pelvic outflow. Herein is reported observations on 4 patients in whom cysts produced significant obstruction to the pelvic or major caliceal outflow. In 3 cases treatment was by decompression, with resolution of the obstruction. Two requirements must be met for a cyst to obstruct: 1) it must lie at or near the hilus and 2) it must have turgor sufficient to overcome the pressure of the intrapelvic urine. In contrast to most renal cysts those producing significant obstruction require operation.