B-cell activating factor, a predictor of antibody mediated rejection in kidney transplantation recipients.

AIM: Donor-specific antibody (DSA) is a widely-used biomarker for antibody-mediated rejection (ABMR) but correctly indicates only 30-40% of patients with ABMR. Additional biomarkers of ABMR in kidney transplant recipients are needed. METHODS: All 68 kidney transplanted-recipients enrolled in this study were negative for graft rejection as determined by surveillance-biopsy ELISA at day 7 post-transplantation. Allograft biopsy was then performed at 6 months post-transplantation for subclinical-ABMR detection. Recipients were stratified by pre-transplant DSA and BAFF at day 7 into four groups. RESULTS: During the study period, 13.2% of the recipients demonstrated subclinical-ABMR at 6 months, without patient with clinical ABMR presentations. Overall mean BAFF at day 7 was 393 pg/mL (95% CI = 316-471 pg/mL). The optimal cut-off value for low vs. high BAFF level was 573 pg/mL, with sensitivity and specificity at 77.8% and 88.1%, respectively. Fifty percent of recipients with high BAFF at day 7 (14 patients) and only 3.7% of patients with low BAFF demonstrated ABMR (P < 0.05). Indeed, ABMR was more common in patients high BAFF level (hazard ratio = 7.30; 95% CI = 3.77-14.15). The prevalence of ABMR among negative pre-transplant DSA/low BAFF, positive DSA/low BAFF, negative DSA/high BAFF, and positive DSA/ high BAFF recipients were 4.4, 0, 37.5 and 66.7%, respectively (P < 0.05). CONCLUSIONS: Post-transplant ABMR can be predicted by perioperative serum BAFF level. Together with DSA testing, BAFF provides additional predictive value for ABMR.

Increased oxidative DNA damage seen in renal biopsies adjacent stones in patients with nephrolithiasis.

Urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, is significantly higher in nephrolithiasis patients than in healthy individuals, indicating that these patients have higher degree of oxidative stress. In the present study, we investigated 8-OHdG expression in renal biopsies of patients with nephrolithiasis and in renal tubular cells (HK-2 cells) exposed to calcium oxalate monohydrate (COM). We performed immunohistochemical staining for 8-OHdG in renal biopsies adjacent stones obtained from 28 patients with nephrolithiasis. Controls were noncancerous renal tissues from nephrectomies of patients with renal cancer. 8-OHdG was overexpressed in the nucleus of renal tubular cells in patients with nephrolithiasis compared with controls. Only one nephrolithiasis biopsy was negative for 8-OHdG, whereas in 19 cases 8-OHdG was highly expressed. The level of expression of 8-OHdG among patients with calcium oxalate (mostly mixed with calcium phosphate) and uric acid stones was not significantly different. Increased leukocyte infiltration was observed in renal tissues from patients with nephrolithiasis. Exposure of HK-2 cells to COM caused increased intracellular reactive oxygen species and nuclear expression of 8-OHdG. To our knowledge, this is the first report of increased 8-OHdG expression in renal tubular cells of patients with nephrolithiasis. In vitro, COM crystals were capable of inducing oxidative damage of DNA in the proximal renal tubular cells.

APRIL, a proliferation-inducing ligand, as a potential marker of lupus nephritis.

INTRODUCTION: BLyS and APRIL are cytokines from the tumor necrosis factor family which play an important role in systemic lupus erythematosus (SLE). Previous works suggested an association between both molecules and SLE disease activity although their correlation with lupus nephritis is not known. We therefore assessed serum BLyS and APRIL in active lupus nephritis patients. METHODS: Serum samples from active lupus nephritis and at 6 months post-treatment were obtained. Serum levels of BLyS and APRIL (n = 47) as well as renal mRNA expression were measured. Serum levels of both molecules and clinical data (n = 27) were available at 6 months follow-up. All biopsy-proven lupus nephritis patients were treated with similar immunosuppressive drugs. RESULTS: Serum levels of APRIL were associated with proteinuria (Rs = 0.44, P value < 0.01) and degree of histological activity (Rs = 0.34; P value < 0.05) whereas BLyS levels were associated with complement levels (Rs = 0.46; P value < 0.01) and dosage of immunosuppressant. Interestingly, serum APRIL as well as its intrarenal mRNA levels were associated with resistance to treatment. From the receiver operating characteristic (ROC) analysis, high levels (> 4 ng/mL) of serum APRIL predicted treatment failure with a positive predictive value of 93 percent. CONCLUSION: APRIL could be a potential biomarker for predicting difficult-to-treat cases of lupus nephritis.

Epithelioid sarcoma of the parotid gland of a child.

Epithelioid sarcoma is a rare soft-tissue tumor that usually occurs in young adults, with a median age of 26 years. This malignancy has been divided into distal and proximal types. The latter is found in proximal body sites including the head and neck region. We present a rare case of parotid proximal-type epithelioid sarcoma in a 1-year-old male child; this is the 4th reported case in the literature and the youngest in a pediatric patient to date. The tumor showed prominent rhabdoid features by light microscopy. Immunohistochemical studies revealed positive staining to cytokeratin (AE1/AE3), epithelial membrane antigen, vimentin, and BAF47. Thus, while the tumor resembled a malignant rhabdoid tumor, the positive staining for BAF47 supported instead a diagnosis of epithelioid sarcoma, according to our current understanding of these 2 tumor types. Also, the clinical course was not the typical aggressive behavior of a rhabdoid tumor. The patient underwent radical parotidectomy without adjuvant therapy and remained disease-free at follow-up, 14 months after surgery.

An update on acute postinfectious glomerulonephritis worldwide.

Postinfectious glomerulonephritis is an immunologic response of the kidney to infection, commonly triggered by streptococci, although many other organisms can cause the condition. In recent decades, the prevalence of postinfectious glomerulonephritis has tended to decline in most industrialized countries, but high rates persist in some developing communities. Nowadays, patients in developed countries are usually adult and male, and those with comorbidities such as diabetes and alcoholism are at increased risk of developing the disease. The acute presentation ranges from nephritic syndrome to asymptomatic glomerulonephritis. The exact pathophysiology of postinfectious glomerulonephritis is still unknown; however, several possible pathologic antigens are under investigation. The majority of children and patients with the epidemic form of postinfectious glomerulonephritis have an excellent prognosis, which contrasts with the poor long-term outcome of sporadic cases. Therapy is largely supportive unless renal function fails to recover after eradication of the causative organism. This Review focuses on acute postinfectious glomerulonephritis, and covers its epidemiology, presentation, pathology, pathogenesis, treatment and outcomes.

Mixed embryonal/alveolar rhabdomyosarcoma of the prostate: report of a case with molecular genetic studies and literature review.

Alveolar rhabdomyosarcoma (RMS) is 1 of 2 main subtypes of RMS in the pediatric age group and tends to occur in the extremities. The urogenital tract is another common site for RMS, but this typically involves the embryonal subtype including sarcoma botryoides. We report a 28-year-old male with a prostatic tumor that was excised en bloc and showed a RMS with separate areas of embryonal and solid alveolar morphologies at the light microscopic level. Both areas showed diffuse nuclear expression for myogenin, and both areas expressed the PAX3-FKHR fusion gene, a genetic change associated with alveolar but not embryonal RMS. A review of the literature documented only 5 cases of RMS primary to the prostate showing alveolar or mixed histology. Ours is the 6th case and the 1st with molecular findings. Although the diagnostic category of mixed embryonal/alveolar RMS remains in use, the nature of this type of RMS is incompletely understood. In our case, although the morphology was mixed embryonal/alveolar, at the genetic level this tumor was alveolar in nature.

Primary hyperoxaluria.

A 5-month-old female infant who had chronic diarrhea and acute renal failure was referred to Chulalongkorn Hospital for further investigation and management. Laboratory investigation revealed elevated blood urea nitrogen and creatinine level, hypocalcemia, hyperphosphatemia, and hyponatremia. Ultrasonography of the kidneys showed normal size with bilateral hyperechoic kidneys. Eyes examination was compatible with oxalosis maculopathy. Urine organic acid analysis revealed peak of oxalate and glycolate. Clinical impression concluded acute renal failure from hyperoxaluria. The patient underwent continuous venovenous hemodiafiltration (CVVH-DF) with regional citrate anticoagulation and expired on day 13 after admission. Pathological examination of kidney necropsy revealed diffuse intraluminal deposition of oxalate crystals within the renal parenchyma. Primary hyperoxaluria is a very rare disease and has rarely been reported in Thailand. In the presented case, the diagnosis was delayed due to uncommon presentation and unavailability of diagnostic laboratory.

Lipid peroxidation and renal injury in renal ischemic reperfusion: effect ofangiotensin inhibition.

OBJECTIVES: To investigate the role of angiotensin inhibition on lipid peroxidation (LPO) and renal pathology in ischemic reperfusion (IR). MATERIAL AND METHOD: Male Wistar rats were subjected to 15-, 30-, 45- or 60- minutes ofrenal ischemia (I) by left renal artery occlusion. In the 30-minute I group, reperfusion (R) for I day (13,R) was performed in additional animals that had been treated with water, angiotensin converting enzyme inhibitor (ACE]; enalapril 5 mg/kg/d), or angiotensin receptor type 1 blocker (ARB; losartan 10 mg/kg/d) one day before I and were continued for 1 day after R. Renal tissue malondialdehyde (MDA), an indicator of LPO, was examined during I and IR periods. Renal pathology was also determined. RESULTS: During ischemia, renal tissue MDA levels were increased throughout the 60-minute ischemic period and was maximum at 30 minutes of ischemia (p < 0.01). Histological changes in 30-minutes I group showed slight tubular cell congestion and mild interstitial edema. One day after reperfusion, MDA levels were still elevated (p < 0. 01) when compared with sham. Progression of renal pathology was observed after I day of reperfusion. Both ACEI and ARB could attenuate the heightened MDA levels (p < 0.01). IR-induced renal injury was markedly diminished by administration ofACEI as well as by ARB. CONCLUSION: These results indicate that inhibition of angiotensin could reduce lipid peroxidation and ameliorate renal injury during IR condition.

Alleviation of renal and pulmonary injury by immunomodulation in leptospirosis: hamster model.

OBJECTIVE: Severe leptospirosis manifestations include acute renal failure, caused by acute interstitial nephritis and pulmonary hemorrohage. Spirochete invasion and toxicity of outer membrane cause robust inflammatory host responses. These responses lead to the generation of cytokines, chemokines, and inflammatory cell infiltrations which result in severe organ dysfunctions. The immunomodulation by the modulation of host immune response may alleviate the renal and pulmonary injury. The authors determined whether the current immunosuppressive agents could alleviate the inflammation and minimize the organ injury in hamster model. MATERIAL AND METHOD: The animal experiments were conducted with the approval of The Ethical Research Committee of Chulalongkorn University Hospital. The leptospira interrogan serovar pyrogenese was isolated from a wild rat. The spirochete was grown in Fletcher's semisolid media and after subcultures were transferred to the Fletcher's liquid media. An amount of 0.5 ml of the spirochete culture media containing 1 x 10(8) leptospires/ml was intraperitoneally injected to golden Syrian hamsters (Mesocrietus auratus), age 4-6 weeks, weighing 60-80 grams. The hamsters were randomed into 5 groups (n = 4 in each group) namely, 1) Normal group (Control group), 2) Leptospira group, 3) CsA group (leptospira with cyclosporine feeding, 100 mg/kg/ day), 4) Rapa group (leptospira with rapamicin feeding, 0.6 mg/kg/day), and 5) Irra group (leptospira with irradiation). Cyclosporine and rapamicin were started at day 0 after the spirochete injection. Gamma ray dose 200 cGy was irradiated to the hamster 3 days before the spirochete inoculation. The animals were autopsied or euthanized if expired or at day 5 post inoculation. The blood samples for BUN, and creatinine were drawn before the inoculation and at autopsy or euthanasia. RESULTS: The inoculation of L Interrogan 0.5 ml (1 x 10(8) leptospires/ml) without immunomodulation cause mortality of all animals at day 4 or day 5 post inoculation. The blood chemistry showed acute severe azotemia. The autopsy findings revealed severe interstitial nephritis and severe pulmonary hemorrhage. The hamsters in the Rapa group had only minimal pulmonary hemorrhage and minimal focal interstitial inflammation of kidney. There were cytoadherance of inflammatory cells to the endothelial cells in lungs and kidneys without the intrusion into the interstitium. The blood chemistry in Rapa group showed mild elevation of BUN and Cr. The immunomodulation by cyclosporine and irradiation did not alleviate the disease. On the contrary, cyclosporine and irradiation caused more severe histopathology. CONCLUSION: The immunomodulation by rapamicin in leptospirosis in hamsters could alleviate the kidney and pulmonary injuries. The up-regulation of IL-2 in peripheral blood lymphocytes did not result in the kidney and pulmonary injuries.

Reduced endothelial factor VIII staining in renal microcirculation correlates with hemodynamic alteration in nephrosis.

Endothelial factor VIII staining in renal microcirculation was performed in eight nephrotic patients associated with mesangial proliferation (MesP) and six nephrotic patients associated with focal segmental glomerulosclerosis (FSGS). The result in MesP revealed a greater staining for glomerular endothelial factor VIII (35 +/- 15%) and for postglomerular capillary endothelial factor VIII (65 +/- 21%) than that observed in FSGS, which revealed a 11 +/- 8% staining for glomerular endothelial factor VIII and 19 +/- 15% staining for postglomerular capillary endothelial factor VIII. This finding implies that there is a greater loss of endothelial cell in renal microcirculation in FSGS. Such a finding correlates with the intrarenal hemodynamics which illustrated (Futrakul, P.; Sitprija, V.; Yenrusi, S. Glomerular endothelial dysfunction determines disease progression: a hypothesis. Am. J. Nephrol. 1997, 17, 533-540.) a mild reduction in renal plasma flow (535 +/- 106 mL/min/1.73 m2, normal 600 mL/min/1.73 m2) and in peritubular capillary flow (422 +/- 80 mL/min/1.73 m2, normal 480 mL/min/1.73 m2) in MesP and (Futrakul, P. Coagulation in glomerulonephritis and nephrotic symdrome: Its therapeutic intervention. In Asian Manual of Nephrology, Takeuchi, T.; Sugino, N.; Ota, K., Eds.; SEAMIC Publication, Tokyo, 1981; pp. 89-95.) a greater reduction in renal plasma flow (108 +/- 50 mL/min/1.73 m2) and in peritubular capillary flow (87 +/- 42 mL/min/1.78 m2) in FSGS. Therefore the study has emphasized both the structural and functional defects of endothelium in renal microcirculation in particular in FSGS.

Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening.

BACKGROUND: Somatic cells in vitro have a finite life expectancy before entering a state of senescence, but it is unclear whether this state occurs in vivo in kidney development, growth, and aging. We previously showed that human kidney cortex displays telomere shortening with age. In this study, we compared the structural and functional changes in rat kidney with age to phenomena associated with cellular senescence in vitro. METHODS: We assessed the changes in Fischer 344 rat kidneys from age 1 to 9 months to define growth and development and from age 9 to 24 months to define aging. RESULTS: Rat kidney telomeres were approximately 35 to 40 kb long and did not shorten significantly. Expression of mRNA for p16INK4a, a characteristic senescence gene in vitro, was undetectable in most young rats but rose 27 fold during growth and a further 72-fold during aging. p16INK4a protein was localized to the nucleus and increased with age. p16INK4a mRNA also increased in other tissues. Lipofuscin and senescence-associated beta-galactosidase increased in epithelium with growth and aging and their occurrence was significantly associated with each other. Lipofuscin was particularly found in atrophic nephrons. CONCLUSION: We conclude that cell senescence occurs in both growth and aging in rat kidney and may contribute to the age-related pathology. These changes are not due to telomere shortening, but may reflect cumulative environmental stress.