Hyaline vascular type of unicentric Castleman's disease with proliferation of glomerular endothelial cells.

Castleman’s disease (CD) is a lymphoproliferative disorder of uncertain etiology. It can be classified histopathologically as hyaline vascular (HV) or plasma cell (PC) type; and clinically as unicentric or multicentric. Multicentric CD mostly manifests as the PC type and is often associated with a variety of systemic complications, although renal complications are uncommon. We present here a case of HV type, unicentric CD with a variety of systemic and renal complications, including the proliferation of glomerular endothelial cells. Various cytokines are thought to be involved in the etiology of this disease, especially interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), which are the main cytokines inducing systemic complications. It has been reported that most PC types and/or multicentric types of CD show increasing levels of serum IL-6 and VEGF, as well as systemic symptoms. Although the current case showed high serum IL-6 and VEGF levels as well as systemic symptoms, the pathological and clinical type were of the HV type and unicentric type, respectively. After immunosuppressive therapy, the serum levels of IL-6 and VEGF returned to the normal range, and systemic complications, including renal involvement, also improved. We report the possibility of pathogenesis via the serum and the pathology of this rare case.

Translocation of dendrin to the podocyte nucleus in acute glomerular injury in patients with IgA nephropathy.

BACKGROUND: It has been reported that podocytopenia has been occurring with increasing disease severity in patients with IgA nephropathy (IgAN). Dendrin is localized at the slit diaphragm (SD) in podocytes. We showed that dendrin translocates to the nucleus of injured podocytes in experimental nephritis and the nuclear dendrin promotes podocyte apoptosis. It is still unknown whether dendrin translocates from the SD to podocyte nucleus in IgAN. We investigated the presence of nuclear dendrin in patients with IgAN and the association between the translocated dendrin to the podocyte nucleus and disease activity. METHODS: Fourteen adult patients with IgAN were enrolled. The pathological parameters were analyzed. Immunostaining of renal biopsy specimens and urinary sediments from IgAN or minimal change nephrotic syndrome (MCNS) as the control was performed. RESULTS: A positive correlation was observed between an acute extracapillary change and the number of dendrin-positive nuclei. The location of dendrin in the nuclei was found in urinary podocytes of IgAN. The number of dendrin-positive nuclei in urinary podocytes of IgAN was significantly higher than that of MCNS. Urinary podocytes, which expressed the apoptosis marker annexin V, were also detected in IgAN. The translocation of dendrin to the podocyte nucleus as well as strong cathepsin L staining were detected in the glomeruli of IgAN. CONCLUSION: An increasing number of dendrin-positive nuclei in the glomeruli suggest acute glomerular injury in IgAN. Apoptotic podocytes were detectable in the urine of IgAN. It appears that the translocation of dendrin to the podocyte nuclei enhances podocyte apoptosis in acute glomerular injury and leads to podocytopenia in patients with IgAN.

Risk of overestimation of kidney function using GFR-estimating equations in patients with low inulin clearance.

BACKGROUND: Accurate estimation of the glomerular filtration rate (GFR) is very important in clinical practice. Although renal inulin clearance (Cin) is the gold standard for measuring GFR, the procedure for Cin measurement is complicated. Use of GFR-estimating equations has been increasing recently due to their simplicity. The objectives of the present study are to analyze the correlation between Cin and other GFR-estimating parameters and to investigate their clinical usefulness and limitation. METHODS: Seventy-two Japanese patients were enrolled in this study. Cin was measured by the continuous infusion method. Serum creatinine (s-Cr), cystatin C, uric acid (UA), and hemoglobin (Hb) were measured. The Japanese formula of estimated GFR (eGFR) was as follows: eGFR (ml/min/1.73m(2) ) = 194 × s-Cr(-1.094) × Age(-0.287) × 0.739 (if female). The endogenous creatinine clearance test was also performed. RESULTS: Levels of Cin were highly correlated with those of endogenous creatinine clearance (Ccr) (R(2) = 0.7585) and eGFR (R(2) = 0.5659). However, patients with lower Cin showed unexpectedly elevated levels of endogenous Ccr and eGFR. Moreover, the levels of eGFR tended to be unexpectedly increased in patients with low body surface area. CONCLUSION: Although GFR-estimating equations are useful for estimating GFR accurately, they pose a risk of overestimation of kidney function in patients with decreased GFRor a poor physique.

Clinicoepidemiological manifestations of RPGN and ANCA-associated vasculitides: an 11-year retrospective hospital-based study in Japan.

Antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitides are major causes of rapidly progressive glomerulonephritis (RPGN). Although recent papers suggest differences in clinicoepidemiological manifestations of ANCA-associated vasculitis between Japan [microscopic polyangiitis (MPA) " Wegener's granulomatosis (WG)] and Europe (WG"MPA), little is known about the prevalence and serological pattern. We retrospectively analyzed 27 RPGN patients who were admitted in our hospital over the past 11 years and who could be basically followed for more than 1 year, concerning the incidence of ANCA-related vasculitis, the presence of (MPO)/proteinase 3 (PR3)-ANCA and their clinical outcomes. As there were no PR3-ANCA single positive and/or WG patients, all patients were serologically divided into four groups; Groups I: MPO-ANCA single-positive patients (N = 11), II: MPO-ANCA and PR3-ANCA double-positive patients (N = 3), III: antiglomerular basement membrane antibody (anti-GBM Ab)-positive patients (N = 6), and IV: all negative patients (N = 7). Patients in Groups II/III showed more severe manifestation at admission. However, in Group I, only 36.3% patients avoided death and/or dialysis-dependent end-stage renal disease. Most patients in Group IV were women (85.7%), and 50% of these patients was diagnosed as having rheumatic diseases. Every patient in Groups I-III was treated with oral corticosteroid and/or methylprednisolone pulse therapy. Most patients treated with immunosuppressants showed severe prognosis because of frequent recurrences of vasculitis and infectious episodes after repeated and prolonged treatments with immunosuppressants. Present analysis further confirms the epidemiological and serological differences in ANCA-related RPGN between Japan and Europe, and reinforced the fact that ANCA-associated vasculitis is the most serious causal disease for RPGN.

Validation of the Simplified Palliative Prognostic Index Using a Single Item From the Communication Capacity Scale.

CONTEXT: Although the Palliative Prognostic Index (PPI) is a reliable and validated tool to predict the survival of terminally ill cancer patients, all clinicians cannot always precisely diagnose delirium. OBJECTIVES: The primary aim of this study was to examine the predictive value of a simplified PPI. In the simplified PPI, a single item from the Communication Capacity Scale was substituted for the delirium item of the original. METHODS: This multicenter prospective cohort study was conducted in Japan from September 2012 through April 2014 and involved 16 palliative care units, 19 hospital-based palliative care teams, and 23 home-based palliative care services. Palliative care physicians recorded clinical variables at the first assessment and followed up patients six months later. RESULTS: A total of 2425 subjects were recruited; 2343 had analyzable data. The C-statistics of the original and simplified PPIs were 0.801 and 0.800 for three week and 0.800 and 0.781 for six-week survival predictions, respectively. The sensitivity and specificity for survival predictions using the simplified PPI were 72.9% and 67.6% (for three week) and 80.3% and 61.8% (for six week), respectively. CONCLUSION: The simplified PPI showed essentially the same predictive value as the original PPI and is an alternative when clinicians have difficulties in diagnosing delirium.

Tensin is expressed in glomerular mesangial cells and is related to their attachment to surrounding extracellular matrix.

Glomerular expression of tensin was immunohistochemically studied in normal and diseased rat kidneys to determine whether tensin might be related to specific binding in individual glomerular cells. Normal rat kidneys displayed an intense immunofluorescence reaction for tensin along the basal aspects of proximal and distal tubule cells and parietal epithelial cells of Bowman's capsules. In glomeruli, a positive reaction for tensin was detected only in the mesangial areas. Immunoelectron microscopy revealed a positive reaction in the mesangial cell (MC) processes. RT-PCR and immunoprecipitation demonstrated mRNA and protein levels of tensin in cultured rat MCs. Mesangial tensin expression was decreased when the mesangium was injured by Habu snake venom. During the regenerative process after mesangiolysis, tensin expression was not detected in early-phase proliferating MCs that did not have extracellular matrix (ECM). The expression of tensin recovered in late-phase proliferating MCs, which became attached to regenerated ECM. It appears that tensin is related to MC attachment to surrounding ECM, which suggests that signal transduction regulated by tensin may be related to a specific mechanism of MC matrix regeneration. Furthermore, tensin can act as a marker for rat MCs because the expression of tensin was detected only in MCs in glomeruli.

[Immunosuppressive therapy for nephrotic syndrome and strategy for adverse side effects from that therapy].

The nephrotic syndrome is commonly caused by various glomerulonephritides, i.e. minimal change nephrotic syndrome, focal segmental glomerulosclerosis and membranous nephropathy. A long term corticosteroid therapy is a first therapeutic approach for patients with nephrotic syndrome. In patients who have contraindication to steroids or in those who do not respond to steroids, immunosuppressive agents such as cyclosporine, mizoribine, azathioprine and cyclophosphamide are the next therapeutic approach for inducing the remission of the nephrotic syndrome. In this review, we described an appropriate use of systemic immunosuppressive agents for steroid resistant nephrotic syndrome, and the toxicity and side effects of each agent. And currently the clinical trials with new immunosuppressants like tacrolimus (FK 506) and mycophenolate mofetil are also described.

Relationships between levels of urinary podocalyxin, number of urinary podocytes, and histologic injury in adult patients with IgA nephropathy.

BACKGROUND AND OBJECTIVES: Podocalyxin (PCX) is present on the apical cell membrane of podocytes and is shed in urine from injured podocytes. Urinary podocalyxin (u-PCX) is associated with severity of active glomerular injury in patients with glomerular diseases. This study examined the relationship between number of urinary podocytes, levels of u-PCX, and glomerular injury in adults with IgA nephropathy (IgAN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urine samples voided in the morning on the day of biopsy were obtained from 51 patients with IgAN (18 men and 33 women; mean age, 31 years). All renal biopsy specimens were analyzed histologically. Pathologic variables of IgAN were analyzed per Shigematsu classification, the Oxford classification of IgAN, and the Clinical Guidelines of IgAN in Japan. Levels of u-PCX were measured by sandwich ELISA. RESULTS: Histologic analysis based on Shigematsu classification revealed a significant correlation between levels of u-PCX and severity of acute extracapillary abnormalities (r=0.72; P<0.001), but levels of urinary protein excretion did not correlate with acute glomerular abnormalities. Levels of urinary protein excretion in patients with segmental sclerosis (n=19) were higher than in patients without (n=22) (0.49 [interquartile range (IQR), 0.20-0.88] g/g creatinine versus 0.20 [IQR, 0.10-0.33] g/g creatinine; P<0.01). The number of urinary podocytes in patients with segmental sclerosis was higher than in patients without (1.05 [IQR, 0.41-1.67] per mg creatinine versus 0.28 [IQR, 0.10-0.66] per mg creatinine; P<0.01). CONCLUSIONS: Levels of u-PCX and the number of urinary podocytes are associated with histologic abnormalities in adults with IgAN.

Marked improvement by high-dose chemotherapy and autologous stem cell transplantation in a case of light chain deposition disease.

A 55-year-old woman presented with heavy proteinuria (6.2 g/day) in April 2007. Because monoclonal IgG-k was detected in serum and urine samples, bone marrow aspiration and renal biopsy were performed. She was diagnosed with plasma cell dyscrasia because a bone marrow aspiration specimen showed plasma cells at 6.1%. Renal tissues revealed the formation of nodular glomerulosclerosis which was negative for Congo-red staining. Renal immunohistochemistry showed positive staining for kappa light chains in the nodular lesions, proximal tubules and part of Bowman's capsules. Her renal involvement was diagnosed as light chain deposition disease. Proteinuria disappeared and renal function stabilized after high-dose chemotherapy and autologous stem cell transplantation. It appears that an early initiation of active therapy such as high-dose chemotherapy and autologous stem cell transplantation may be beneficial for patients with light chain deposition disease.

Immune Complex-Mediated Complement Activation in a Patient with IgG4-Related Tubulointerstitial Nephritis.

A 59-year-old man was diagnosed with IgG4-related tubulointerstitial nephritis. His symptoms as well as laboratory and imaging findings were improved after initiation of steroid therapy. Serologically, he showed hypocomplementemia (C3 23 mg/dl, C4 <2 mg/dl, CH50 <7 U/ml) with high levels of IgG (IgG4 1,970 mg/dl) and immune complexes (C1q assay 8.1 µg/ml) and a low level of C1q (<2.0 mg/dl). Histologically, he also showed linear depositions of IgG, IgM, C3, C4d, C1q, membrane attack complex and all IgG subclasses (IgG1, IgG2, IgG3 and IgG4) along the tubular basement membrane, as well as granular depositions of these components in the renal interstitium. However, mannose-binding lectin and L-ficolin were not detected in these tissues. Homogeneous electron-dense deposits were observed by electron microscopy in the tubular basement membrane. It appears that the immune complexes might activate the classical pathway of the complement in both blood and local tissues in a patient with IgG4-related tubulointerstitial nephritis.

One-year results of an open-label study on antiproteinuric effect of benidipine in elderly patients with chronic kidney disease.

BACKGROUND: The long-term antiproteinuric effects of benidipine, a calcium channel blocker (CCB), have not been evaluated in detail in hypertensive patients with chronic kidney disease (CKD). METHODS: Benidipine (4 mg/day) was administered to previously untreated hypertensive patients with CKD, or hypertensive patients with CKD not achieving target blood pressure (BP) despite taking an angiotensin II receptor blocker (ARB). The patients were followed up for 1 year. If target BP was not achieved by 2 weeks after the start of benidipine treatment, the dosage was increased to 8 mg/day. The urinary protein to creatinine (UP/cre) ratio was evaluated before and after benidipine treatment. RESULTS: This study evaluated 65 hypertensive patients with CKD. BP (systolic/diastolic) decreased from 154 ± 19 / 91 ± 12 mm Hg before treatment to 134 ± 16 / 78 ± 10 mm Hg at 1 year after treatment (p<0.001). The UP/cre ratio decreased significantly from 2.21 ± 2.47 g/g creatinine (g/g cre) before treatment to 1.43 ± 2.21 g/g cre after treatment (p<0.001). In both the untreated and ARB-treated groups, the BP and UP/cre ratio decreased significantly at 1 year after treatment. The percentage change in the UP/cre ratio was significantly greater in patients aged 65 years or older than in those less than 65 years (79.1% vs. 48.7%, p=0.038). CONCLUSIONS: Benidipine treatment reduced the UP/cre ratio in hypertensive patients with CKD, and the percentage decrease of the UP/cre ratio was greater in elderly patients, suggesting that benidipine may have more potent antiproteinuric effects in elderly hypertensive patients with CKD.

Protein gene product 9.5 is selectively localized in parietal epithelial cells of Bowman's capsule in the rat kidney.

Parietal epithelial cells (PEC) of Bowman's capsules cover the inner aspect of Bowman's capsules and are believed to contribute to extracapillary lesions of glomerulonephritis such as crescent formation. In glomerular research including cell culture experiments and pathology, differentiation between PEC and podocytes has frequently been a major problem. Immunohistochemistry of the adult rat kidney for protein gene product 9.5 (PGP 9.5), a neuron-specific ubiquitin C-terminal hydrolase, demonstrated selective localization of the immunoreactivity in PEC. At the urinary pole of the glomerulus, immunoreactive PEC were clearly differentiated from proximal tubular cells that were negative for PGP 9.5. In the subcapsular nephrogenic zone of newborn rat kidney, immunoreactivity was observed in almost all cells in the commashaped body and early S-shaped body and selectively in PEC in the late S-shaped body and capillary-stage glomerulus. In rat glomerular disease models (Masugi-nephritis and puromycin aminonucleoside nephrosis), cells that consisted of cellular crescents or adhered to glomerular tufts were positive for PGP 9.5. The selective localization of PGP 9.5 in PEC in rat kidney provides a new cytochemical marker for identifying the cells. Development expression of the protein suggests that PGP 9. 5 is involved in the processes of nephrogenesis of rat kidney.