Clinical and pathological analyses of interstitial fibrosis and tubular atrophy cases after kidney transplantation.

AIM: We carried out a clinicopathological analysis of cases presenting with interstitial fibrosis and tubular atrophy (IF/TA) after renal transplantation in an attempt to clarify the mechanisms underlying the development and prognostic significance of IF/TA. METHODS: IF/TA was diagnosed in 35 renal allograft biopsy specimens (BS) obtained from 35 renal transplant recipients under follow up at the Department of Transplant Surgery, Kidney Center, Toda Chuo General Hospital, between January 2014 and March 2015. RESULTS: IF/TA was diagnosed at a median of 39.9 months after the transplantation. Among the 35 patients with IF/TA, 19 (54%) had a history of acute rejection. Among the 35 BS showing evidence of IF/TA, the IF/TA was grade I in 25, grade II in 9, and grade III in 1. Arteriosclerosis of the middle-sized arteries was observed in 30 BS (86%). We then classified the 35 BS showing evidence of IF/TA according to their overall histopathological features, as follows; IF/TA alone (6 BS; 17%), IF/TA + medullary ray injury (12 BS; 34%), and IF/TA + rejection (12 BS; 34%). Loss of the renal allograft occurred during the observation period in one of the patients (3%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 15 patients (43%). CONCLUSIONS: The results of our study suggests that rejection contributes to IF/TA in 30-40% of cases, medullary ray injury in 30-40% of cases, and nonspecific injury in 20% of cases. IF/TA contributes significantly to deterioration of renal allograft function.

Clinical and pathological analyses of chronic vascular rejection after kidney transplantation.

AIM: We discuss the clinicopathological analysis of cases of chronic vascular rejection (CVR) cases after renal transplantation and clarify the mechanisms underlying the development and prognostic significance of CVR. PATIENTS: CVR was diagnosed in 46 renal allograft biopsy specimens (BS) obtained from 34 renal transplant patients being followed up at the Department of Urology, Tokyo Women's Medical University, between January 2009 and December 2013. RESULTS: CVR was diagnosed at a median of 47.4 months post-transplant. Among the 36 patients, 23 had a history of acute rejection. Among the 46 BS showing evidence of CVR, the CVR was mild (cv1 in Banff's classification) in 23, moderate (cv2) in 17, and severe (cv3) in 6. Of the 40 samples obtained at the time of the biopsy and assayed with plastic beads coated with HLA antigen, 31 (78%) showed circulating ant-HLA alloantibody, and 15 (38%) showed donor-specific antibodies. We then classified the 46 BS showing evidence of CVR by their overall histopathological features, as follows; cv alone was seen in 16 (35%) BS, cv + antibody-mediated rejection (AMR) in 26 (56%), and cv + T-cell-mediated rejection in 9 (19%). Loss of the renal allograft occurred during the observation period in nine of the patients (26%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 11 patients (32%). CONCLUSION: The results of our study suggest that AMR may underlie CVR in many cases, while T cell-mediated rejection may play an important role in some cases.

How the Bladder Senses? A Five-Grade Measure.

OBJECTIVES: During bladder filling, the bladder starts to sense it and the sensation steadily increases. However, little is known concerning volume-sensory correlation in normal bladder and pressure-sensory correlation during detrusor overactivity (DO). We aimed to real-time assess bladder sensation in normal bladder and DO using a five-grade measure. METHODS: We enrolled 74 normal individuals and 87 patients with DO (51 terminal, 36 phasic). During slow bladder filling, we instructed individuals to indicate sensation in five grades: 1, first sensation; 2, obviously greater than 1 but less than 3; 3, first desire to void when he or she usually goes to toilet; 4, obviously greater than 3 but less than 5; and 5, strong desire to void. We also instructed individuals to report other sensations, such as pain. RESULTS: The five-grade measure is feasible in all participants, showing a volume and pressure- sensory correlation. Among the five grades, grade 0 to 1 was the longest, followed by grade 4 to 5, in all participants. Grade 0 to 1 in phasic DO and grade 4 to 5 in terminal and phasic DO were shorter than those in normal bladder (P < 0.05). Eighty-six percent of patients with DO reported that the rapidly increased sensory grade is akin to urinary urgency in daily life. CONCLUSION: The five-grade measure is feasible to assess a volume and pressure-sensory correlation. Using this measure the sensory grade rapidly increased during DO compared with normal bladder, and 86% of the patients with DO reported that it is akin to urinary urgency in daily life.

Brain metastasis in a patient with a sarcomatoid variant RCC with well-controlled extracerebral metastases by temsirolimus.

BACKGROUND: The sarcomatoid variant of metastatic renal cell carcinoma (RCC) has often an aggressive course and a poor prognosis, particularly when accompanied with brain metastasis. CASE REPORT: We describe the case of a patient with sarcomatoid variant RCC in whom brain metastasis was observed as a new lesion during treatment with temsirolimus, despite other extracerebral metastatic lesions being well-controlled and progression-free. RESULTS: This discrepancy between the effectiveness of temsirolimus for extracerebral metastases and the simultaneous progression of brain metastases of RCC raises a concern that while vascular endothelial growth factor (VEGF)-targeted therapy may have clinical efficacy, it may also carry a risk for new brain metastases due to weakening of the structure of the blood brain barrier. CONCLUSION: This case indicates that computed tomography monitoring of the brain should be regularly performed during VEGF-targeted therapy in patients with sarcomatoid variant RCC, even if brain metastases are absent and extracerebral metastatic lesions are well controlled.

Improvement of urinary dysfunction after kidney transplantation by administration of the antimuscarinic agent--prospective randomized controlled study.

BACKGROUND: Bladder dysfunction after kidney transplantation (KTx) impairs the patients' quality of life. We examined the bladder function status perioperatively in patients undergoing KTx and performed a randomized prospective study to determine the efficacy of an antimuscarinic agent, solifenacin, in ameliorating the bladder dysfunction after KTx. METHODS: The subjects in this study were 33 patients who underwent KTx at our institution. The patients were divided into two groups: group 1 (n=18), composed of patients who were not treated with any antimuscarinic agent, and group 2 (n=15), composed of patients treated with an antimuscarinic agent. We investigated the actual bladder function status of these patients before and after KTx by the following two methods: (1) video water cystometry and (2) questionnaire study using the Overactive Bladder Symptom Score and King's Health Questionnaire. RESULTS: The cystometry study revealed a significantly greater increase of the maximum cystometric capacity in group 2 than in group 1 (173.0±60.7 mL in group 1 and 260.1±51.0 mL in group 2 [P=0.005]) after KTx. In the questionnaire surveys, the decreases in the scores for all domains were observed 6 weeks after KTx. The scores in group 2 tended to be lower than those in group 1. CONCLUSION: In all of our patients, the bladder dysfunction status improved dramatically after KTx. In addition, our results suggest that administration of the antimuscarinic agent, solifenacin, may contribute to improvement of the quality of life of patients undergoing KTx.

Do Sacral/Peripheral Lesions Contribute to Detrusor-Sphincter Dyssynergia?

OBJECTIVES: While detrusor-sphincter dyssynergia (DSD) occurs in conjunction with lesions between the brainstem and the sacral cord, it is not well known whether sacral/peripheral lesions contribute to DSD. We studied the relationship between DSD and sacral/peripheral lesions. METHODS: One hundred and forty-four patients with diverse neurologic etiologies underwent urodynamic study and analysis of motor unit potentials in the external sphincter muscles, 117 of whom were able to void during a urodynamic test. Sacral/peripheral lesion (SPL) is defined as neurogenic change in motor unit potentials. Detrusor overactivity (DO) is defined as involuntary detrusor contractions during the filling phase, which commonly occurs in lesions above the sacral cord. We considered DO as a putative indicator of supra-sacral lesion. RESULTS: DSD was found in 44 (30.6%), SPL in 71 (49.3%), and DO in 83 (57.6%) of 144 patients, respectively. The incidence of DSD was the same in the SPL positive group (31%) and the SPL negative group (30.1%). By contrast, within the subgroup of patients without DO, the incidence of DSD was significantly more common in the SPL positive group (41.4%) than in the SPL negative group (25.0%) (P < 0.05). In 53 of the SPL positive group who were able to void, postvoid residual >100 mL was more common in patients with DSD (not statistically significant). CONCLUSION: The results of the present study suggest that not only suprasacral pathology, but also sacral/peripheral lesions can produce DSD. In light of the previous reports, DSD might also result from partial lesions in peripheral branches of the sphincter circuit.

Pathogenesis of reduced or increased bladder sensation.

OBJECTIVE: Pathogenesis of reduced or increased bladder sensation is not well known. Hence, we systematically investigated the frequency of reduced or increased bladder sensation in neurologic/mental diseases. METHODS: We analyzed 911 patients who were referred from within our hospital. Data registries included a diagnosis, a lower urinary tract symptom questionnaire, a urodynamic study, and neurological examinations. Reduced bladder sensation is defined as bladder volume at the first sensation >300 ml. Increased bladder sensation is defined as bladder volume at the first sensation <100 ml. These patients were stratified into those with and without DO. RESULTS: Neuropathies are the most common cause of reduced bladder sensation (33.3-43.8% in diabetic neuropathy, etc.). Myelopathies are the second most common cause (17.4-25.0% in multiple sclerosis, etc.). Less common is brain diseases (9.6% in multiple system atrophy, etc.). In contrast, myelopathies are the most common cause of increased bladder sensation without DO (25.0-40.0% in spinal forms of systemic lupus erythematosus, Sjogren's syndrome, etc.). Neuropathies are the second most common (17.3-22.2% in post-pelvic organ surgery, diabetic neuropathy, etc.). Less common is brain/mental diseases (20.0% in psychogenic bladder dysfunction, 8.1% in Parkinson's disease, etc.). CONCLUSION: The present study revealed that neuropathies are the most common cause of reduced bladder sensation in neurologic/mental diseases. Increased bladder sensation without DO occurs mainly in peripheral and central sensory pathway lesions, as well as in basal ganglia lesions and psychogenic bladder dysfunction. Reduced and increased bladder sensation should be a major treatment target for maximizing patients' quality of life.

Clinicopathological analysis of acute vascular rejection cases after renal transplantation.

UNLABELLED: Histopathological change of acute vascular rejection (AVR) is characterized by intimal arteritis and transmural arteritis. In this report, we discuss the clinicopathological analysis of AVR cases after renal transplantation (RTX). PATIENTS: AVR was diagnosed in 17 patients from 17 renal transplant patients followed in our institute between January 2003 and September 2008. We retrospectively reviewed these 17 patients. RESULTS: Among 17 cases of AVR, 10 cases were mild (v1 in Banff 07 classification), five were moderate (v2), and two were severe (v3). Interstitial inflammation (i1-i3) was present in all 17 biopsies. Moderate to severe tubulitis (t2-t3) was present in seven biopsies, and transplant glomerulitis (g1-g3) was present in 11, peritubular capillaritis (ptc1-ptc3) was in 15 of 17 biopsies. C4d deposition in peritubular capillary (PTC) was observed in 6 of 17 cases. By assaying with plastic beads coated with anti-human leukocyte antigen (HLA) antigen performed in 17 cases, the circulating ant-HLA alloantibody was detected in 10 patients, of which 5/10 were donor-specific antibodies (DSA). Acute antibody-mediated rejection (AAMR) was diagnosed in three cases. Many of v1 cases, steroid pulse therapy (SP) were effective. In v2 and v3 cases, six of seven were steroid-resistant rejection and were need more anti-rejection therapy (ART), such as muromonab CD3 (OKT3) injection, gusperimus (DSG) injection, plasmapheresis, intravenous immune globulin, and injection of rituximab. Ten of 17 patients recovered their renal allograft functions by ART, and 16 of 17 patients' grafts are functioning. Deterioration of renal allografts' function after biopsies was seen in seven patients with one of them lost their graft. CONCLUSIONS: In some cases, AVR might be provoked by anti-donor antibodies. The prognosis of the graft exhibiting AVR was relatively good in present immunosuppression and ART.

Real-time measurement of oxyhemoglobin concentration changes in the frontal micturition area: an fNIRS study.

OBJECTIVE: To explore brain activity in the frontal micturition area during natural bladder behavior. METHODS: Five control subjects (one man and four women; mean age 61 years [38-70]) and four subjects with detrusor overactivity (all men; mean age 55 years [33-65]) were enrolled in the study. We performed real-time measurements of oxyhemoglobin concentration (oxy-Hb) changes in the frontal micturition area using functional near-infrared spectroscopy (fNIRS) in response to quasi-natural, continuous bladder filling, and voiding in a sitting position. RESULTS: In the control group the following results were obtained: (1) a slight increase of oxy-Hb before first sensation occurred, (2) there was a continuous increase of oxy-Hb during bladder filling to the point just after voiding began, (3) there was a continuous decrease of oxy-Hb after voiding, (4) in subjects who were unable to urinate, oxy-Hb also decreased after attempting to void, and (5) the area activated was the bilateral lateral prefrontal area, particularly Brodmann's areas 8, 10, and 46. In the detrusor overactivity group, (6) an increase of oxy-Hb before first sensation was rare and frontal cortical activation was weak, (7) at the moment detrusor overactivity appeared, fNIRS brain activity in the frontal cortex did not change significantly; and otherwise the results were almost the same as those in the control group. CONCLUSIONS: This study shows that the frontal micturition area is activated during natural bladder filling and voiding using fNIRS.

Bladder function of end-stage renal disease patients.

OBJECTIVES: To evaluate the bladder function of end-stage renal disease (ESRD) patients by using video H(2)O cystometry (CM) before renal transplantation (RTx). METHODS: A total of 92 patients (57 men and 35 women; mean age 45.4 years; mean period of renal replacement therapy (RRT) 60.2 months) were divided in two groups based on the presence of detrusor overactivity (DO). In each group the following parameters were recorded during CM: first sensation (FS), maximum cystometric capacity (MC) and compliance. The effect of the duration of RRT on the H(2)O cystometric results was also assessed. RESULTS: There were 25 patients (27.2%) who had DO before their operation, this ratio being higher than the general Japanese population. Subjects with DO were observed independently for the duration of RRT and there was no difference in the prevalence of DO based on this variable. In contrast, 50 patients kept their bladder compliance in the normal range. The numerical value of FS, MC and compliance decreased proportionally for the duration of RRT. CONCLUSIONS: Patients undergoing RTx frequently present with bladder dysfunction in terms of low capacity, low compliance and also DO. This bladder dysfunction has a negative impact on patients' quality of life. Thus, bladder function and its related symptoms require specific attention during the management of transplant patients.

Influence of Body Position on Defecation in Humans.

OBJECTIVES: To compare three positions for defecation by measuring abdominal pressure and the anorectal angle simultaneously. METHODS: We recruited six healthy volunteers. The videomanometric measures included simultaneous fluoroscopic images, abdominal pressures, subtracted rectal pressures and anal sphincter pressures. Three positions were used: sitting, sitting with the hip flexing at 60 ° with respect to the rest of the body, and squatting with the hip flexing at 22.5 ° with respect to the rest of the body. RESULTS: Basal abdominal pressure before defecation on hip-flex sitting was lower than that with normal sitting, although the difference did not reach statistical significance. Basal abdominal pressure before defecation on squatting (26 cmH2 O) was lower than that with normal sitting (P < 0.01). Abdominal pressure increase (strain) on hip-flex sitting was lower than that with normal sitting, although this difference did not reach statistical significance. Similarly, the abdominal pressure increase on squatting was smaller than that with normal sitting, and yet the difference did not reach statistical significance. The rectoanal angle on defecation on hip-flex sitting did not differ from that with normal sitting. The rectoanal angle on defecation on squatting (126 °) was larger than that with normal sitting (100 °) (P < 0.05), and was also larger than that with hip-flex sitting (99 °) (P < 0.01). CONCLUSION: The results of the present study suggest that the greater the hip flexion achieved by squatting, the straighter the rectoanal canal will be, and accordingly, less strain will be required for defecation.

Clinicopathological analysis of transplant glomerulopathy cases.

INTRODUCTION: Transplant glomerulopathy (TG) is involved in the criteria of chronic active antibody-mediated rejection (c-AMR) in Banff 07 classification. In this report, we discuss the clinico-pathological analysis of TG cases after renal transplantation, and analysis of whether all TG cases are applied to c-AMR. PATIENTS: Transplant glomerulopathy, defined by double contours of glomerular basement membranes, was diagnosed in 13 patients from 13 renal transplant patients followed-up in our institute between January 2007 and April 2008. We retrospectively reviewed these 13 patients. RESULTS: Among 13 cases of TG, three cases were mild (cg1 in Banff classification), four were moderate (cg2), and six were severe (cg3). Transplant glomerulitis and interstitial inflammation were present in all 13 biopsies, and peritubular capillaritis was present in 12 of 13 biopsies, interstitial fibrosis/tubular atrophy in 13, and the thickening of the peritubular capillary (PTC) basement membrane in 11. PTC C4d deposition was presented in six cases, three out of six cases had diffuse C4d deposits in PTC, and the remainder had focal deposits. By assaying with plastic beads coated with human leukocyte antigen (HLA) in 12 cases, the circulating anti-HLA alloantibody was detected in all 12 patients of which only 3 of 12 were donor-specific antibodies (DSA). In our cases, there was no patient who fully met criteria for c-AMR in Banff classification, which included TG, C4d deposition in PTC, and existence of DSA, but seven patients were diagnosed suspicious for c-AMR. Seven cases (54%) had proteinuria at the time of the biopsies and the severity of proteinuria was associated with the severity of TG. Deterioration of renal allografts' function after biopsies was seen in seven (54%), and two of them lost their graft. CONCLUSIONS: We suggest that histopathological changes of TG accompanied by transplant glomerulitis, peritubular capillaritis, the thickening of the peritubular capillaries basement membrane, and circulating anti-HLA antibodies may indicate c-AMR, even if C4d deposition in PTC is negative. The severity of TG may be associated with proteinuria, reduced graft function, and reduced graft survival.

Cerebellar Ataxia and Overactive Bladder after Encephalitis Affecting the Cerebellum.

The cerebellum is one of the regions that contribute to urinary dysfunction in humans. A 43-year-old woman at age 35 had an acute onset of encephalitis that led to fever, generalized convulsion and coma. Six months after the disease onset, she regained consciousness and developed generalized myoclonus, cerebellar ataxia and overactive bladder, e.g., urinary urgency, daytime urinary frequency, and urinary incontinence. Eight years after the disease onset, she was revealed to have cerebellar atrophy on MRI, cerebellar hypoperfusion on SPECT, and detrusor overactivity on urodynamic study. Selective inflammation in the cerebellum seemed to produce cerebellar ataxia and overactive bladder in our case.

A case of acute humoral rejection with various depositions of C4d, IgG, IgM, and C3c in peritubular capillaries and/or glomerular capillaries.

A 41-year-old Japanese male patient with end-stage renal disease received ABO compatible living related kidney transplantation from his sister on April 2003. The kidney functioned immediately after kidney transplantation. Protocol allograft biopsy at 1 yr after kidney transplantation was performed on April 2004. His serological data was not particular and he did not suffer with chronic inflammation. The allograft biopsy specimen revealed moderate accumulations of polymorphonuclear leukocytes in peritubular capillaries (PTCs), dilatation of PTCs and moderate infiltrations of polymorphonuclear and/or mononuclear cell in glomeruli (Transplant glomerulitis, moderate). Immunofluorescent study (IF) of a frozen section of the allograft biopsy specimen showed a strong, diffusely distributed endothelial-staining pattern in PTCs for C4d. The C4d was also strongly detected in a linear glomerular basement membrane (GBM) pattern. And widespread moderate C3c deposits, weak IgM, and IgG deposits were also seen in PTCs. Immunofluorescent study also showed granularly peripheral and mesangial deposits of strong IgM, C1q, and moderate IgG in glomeruli, IgA and C3c were faintly positive. The panel reactive antibody, which had been negative before transplantation, was positive for both HLA classes I and II at that time. We diagnosed as acute humoral rejection (AHR) and he was treated with course of steroid pulses and 5 d of gusperimus (DSG); and a total of three times Plasma exchange (PE) treatment was added. The level of serum creatinine, once increased to 1.7 mg/dL, decreased gradually to 1.4 mg/dL. He has a stable graft function. This is the only case of various depositions of immunoglobulins and complements in PTC and/or glomerular capillaries during AHR.