Kidney biopsy in patients with antineutrophil cytoplasmic antibody-associated vasculitis with mild renal abnormality.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic inflammation of small or medium blood vessels that includes microscopic polyangiitis. A diagnosis of ANCA-associated vasculitis can be aided by histological identification of vasculitis, and identification of renal impairment can help predict outcomes. However, kidney biopsy is not generally indicated in the absence of renal findings. We report two cases of ANCA-associated vasculitis diagnosed by kidney biopsy despite the absence of remarkable urinary abnormality and renal impairment. These patients had fever of unknown origin and were positive for myeloperoxidase (MPO)-ANCA but showed few findings that would suggest small-vessel vasculitis in the kidney. Nevertheless, kidney biopsies revealed small-vessel arteritis, necrotizing glomerulonephritis, and interstitial nephritis. Immunofluorescent antibody tests performed using samples of glomeruli were all negative, suggesting microscopic polyangiitis. Therefore, kidney biopsy may be useful in confirming the diagnosis, even if patients have completely normal urinary findings in the absence of other organ lesions.

Syphilis-associated membranous nephropathy successfully treated with amoxicillin.

A 33-year-old Japanese man with no significant past medical history was admitted to our hospital for evaluation of weight gain and pitting edema. A laboratory test confirmed nephrotic-range proteinuria. Renal biopsy showed subepithelial deposits, and membranous nephropathy (MN) was diagnosed. Closer examination clarified an active syphilis infection. After renal biopsy, we prescribed amoxicillin for 8 weeks to treat the syphilis infection. Three weeks later, the patient's proteinuria dramatically decreased. This case is of interest because syphilis can become a cause of acute-onset MN in younger adults, and the incidence of syphilis is increasing in Japan.
.

Cyst infection in autosomal dominant polycystic kidney disease: penetration of meropenem into infected cysts.

BACKGROUND: Cyst infection is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD) that is often refractory. Carbapenems are frequently needed to treat to patients with refractory cyst infection, but little is known about the penetration of newer water-soluble carbapenems into cysts. This study investigated the penetration of meropenem (MEPM) into infected cysts in patients with ADPKD. METHODS: Between August 2013 and January 2014, 10 ADPKD patients (14 infected cysts) receiving MEPM at Toranomon Hospital underwent drainage of infected cysts and definite cyst infection was confirmed through detection of neutrophils by cyst fluid analysis. The serum concentration of MEPM was measured just after intravenous administration and was compared with that in fluid aspirated from infected cysts. RESULTS: In the patients undergoing cyst drainage, the mean serum MEPM concentration was 35.2 ± 12.2 µg/mL (range: 19.7 to 59.2 µg/mL, while the mean cyst fluid concentration of MEPM in the drained liver cysts (n = 12) or kidney cysts (n = 2) was 3.03 ± 2.6 µg/mL (range: 0 to 7.3 µg/mL). In addition, the mean cyst fluid/serum MEPM concentration ratio was 9.46 ± 7.19% (range: 0 to 18.8%). There was no relationship between the cyst fluid concentration of MEPM and the time until drainage after MEPM administration or between the cyst fluid/serum MEPM concentration ratio and the time until drainage. CONCLUSION: These findings suggest that MEPM shows poor penetration into infected cysts in ADPKD patients. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (UMIN) as "Penetration of meropenem into cysts in patients with autosomal dominant polycystic kidney disease (ADPKD)", UMIN ID 000011292 on July 26th, 2013.

Clinical and histological features of antineutrophil cytoplasmic antibody-associated vasculitis related to antithyroid drugs
.

BACKGROUND: Antithyroid drugs such as propylthiouracil and methimazole have been reported to cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but little is known about long-term outcomes. MATERIALS AND METHODS: We identified AAV patients who underwent renal biopsy and retrospectively assessed their clinical and histological findings. Patients with AAV who had received propylthiouracil or methimazole were defined as having antithyroid drug-associated AAV (ATD-AAV), and the other patients were defined as having primary AAV. RESULTS: Seven patients with ATD-AAV and 83 patients with primary AAV were identified. Compared with the primary AAV group, the patients with ATD-AAV were significantly younger (mean ± standard deviation; 45.4 ± 21.4 years vs. 65.9 ± 13.8 years, p < 0.01), and had lower serum creatinine (median [interquartile range]; 0.7 mg/dL [0.6 - 1.5] vs. 2.3 mg/dL [1.0 - 4.0], p = 0.02), as well as a higher frequency of positivity for MPO--ANCA/PR3-ANCA (42.9 vs. 4.8%, p < 0.01). While glomerular crescents varied, interstitial fibrosis and tubular atrophy were milder in ATD-AAV patients. Kaplan-Meier analysis showed a significantly higher kidney survival rate in patients with ATD-AAV than in those with primary AAV (p = 0.05). CONCLUSION: Patients with ATD-AAV were younger and had milder kidney involvement, resulting in a better long-term outcome compared with primary AAV.
.

Clinical and pathological features of anti-neutrophil cytoplasmic antibody-associated vasculitis in patients with minor urinary abnormalities.

AIM: Kidney biopsy is the gold standard for diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but it is unknown whether vasculitis can be detected from AAV patients with minor urinary abnormalities. METHODS: Ninety ANCA-positive patients undergoing kidney biopsy were evaluated retrospectively after being divided into two groups, which were group A (minor urinary abnormalities with both proteinuria <0.5 g/day and red blood cells ≤5/high power field) and group B (major urinary abnormalities except group A). RESULTS: Thirteen patients were included in group A and 77 patients were in group B. Crescentic glomeruli were detected less frequently in group A than in group B (61.5% vs. 92.2%, P < 0.01). The percentage of crescentic glomeruli relative to total glomeruli was significantly lower in group A than in group B (median [interquartile range]; 2.7% [0-5.2%] vs. 27.3% [8.1-56.1%], P < 0.01). Vasculitis of the small renal arteries was detected more frequently in group A than in group B without significant difference (30.8% vs. 19.5%, P = 0.46). Overall renal vasculitis (crescentic glomeruli and/or small renal artery vasculitis) was detected less frequently in group A than in group B (69.2% vs. 92.2%, P = 0.03). CONCLUSIONS: These findings indicate that renal biopsy can be a useful tool for histological diagnosis of ANCA-associated vasculitis in ANCA-positive patients with minor urinary abnormalities, even though the rate of renal vasculitis to the total number of glomeruli sampled is lower in patients with minor urinary abnormalities than patients with major abnormalities.

IgA nephropathy featuring massive wire loop-like deposits in two patients with alcoholic cirrhosis.

BACKGROUND: Various renal manifestations are known to develop in patients with liver disease, including chronic hepatitis and cirrhosis. CASE PRESENTATION: We evaluated renal disease in two 47-year-old Japanese men with liver cirrhosis and chronic alcoholism for 34 years and 27 years, respectively. Renal biopsy demonstrated massive wire loop-like deposits in the subendothelial space of the glomerular basement membrane and in the mesangium. However, immunofluorescence was only positive for IgA and C3, and electron microscopy did not reveal any organized structures in the electron-dense deposits. IgA nephropathy was diagnosed, although the features were different from primary IgA nephropathy. Both patients had portosystemic shunts associated with liver cirrhosis. Their renal deposits and proteinuria resolved completely after 1 year of steroid therapy. CONCLUSION: Alcohol abuse may have contributed to development of secondary IgA nephropathy in these two patients, probably via their portosystemic shunts.

Nodular lesions in diabetic nephropathy: Collagen staining and renal prognosis.

AIMS: Nodular lesions are one of the most characteristic pathological changes of advanced diabetic nephropathy (DN). Previous studies have demonstrated that the pattern of both routine and collagen staining of nodular lesions changes during their development. However, the association between such changes of staining and the renal prognosis remains unclear. METHODS: Among 252 patients with biopsy-proven DN, 67 met the selection criteria and were enrolled to investigate this relationship. In all patients, nodular lesions were stained with periodic acid Schiff, periodic acid methenamine silver, and Masson trichrome stains, and immunostaining was done for type I, III, IV, V, and VI collagen. The endpoint was commencement of dialysis due to end-stage renal disease. RESULTS: At least one mesangiolytic nodular lesion (MNL) that showed faint staining for PAS and PAM was found in 61% of the patients. MNLs were negative for type IV collagen staining, unlike the strong positivity of non-MNLs, while type V and VI collagen staining were strongly positive in all nodular lesions. Cox proportional hazards regression analysis revealed that the hazard ratio (HR) for the endpoint was significantly higher in patients with at least one MNL than in patients with no MNLs after adjustment for known promoters of renal progression (HR: 2.94; 95% confidence interval: 1.24-7.07). CONCLUSIONS: MNLs may reflect characteristic differences of collagen production and could be a useful prognostic indicator in patients with nodular lesions. Further investigation of the mechanism underlying these differences of collagen production could contribute to finding new therapeutic targets for DN.

Five Sequential Evaluations of Renal Histology in a Patient with Light Chain Deposition Disease.

A 58-year-old man was referred to our institution for an evaluation of nephrotic range proteinuria. Renal biopsy showed a marked expansion of the mesangial matrix and thickening of glomerular basement membrane (GBM) in periodic acid-silver methenamine (PAM). Immunofluorescence (IF) revealed strong staining for the monoclonal kappa light chain. EM demonstrated massive subendothelial and mesangial dense deposits. As a result, light chain deposition disease (LCDD) was diagnosed. Melphalan and prednisolone (MP) therapy was started, which was continued for 10 years with minimal complications. Serial evaluations of renal histology revealed the resolution of nodular lesions and the glomeruli became nearly normal. MP therapy can therefore be an effective therapeutic option for LCDD if it is continued over the long term.

AA-negative and Kappa-positive Amyloidosis in a Patient with Rheumatoid Arthritis.

A 57-year-old Japanese woman with a 5-year history of rheumatoid arthritis (RA) was admitted to our hospital for an evaluation of nephrotic range proteinuria (4.8 g/day). A renal biopsy led to the diagnosis of amyloidosis according to strong positivity for Congo red staining and the detection of microfibrillar structures on electron microscopy that were negative for AA and positive for kappa light chain. Combination therapy with high-dose melphalan and autologous stem cell transplantation was performed according to the regimen for AL amyloidosis. Her proteinuria and RA subsided, but relapsed after 3 years. This is the first report regarding kappa light chain amyloidosis in an RA patient.

Phospholipase A2 Receptor-Positive Idiopathic Membranous Glomerulonephritis with Onset at 95 Years: Case Report.

A 95-year-old woman was admitted to our hospital for evaluation of bilateral lower-limb edema persisting for 3 months. Serum creatinine was 1.55 mg/dl, and urinary protein excretion was 9.1 g/day. Renal biopsy revealed stage 1 membranous glomerulonephritis (MGN) with immunoglobulin G4-dominant staining. This patient did not have any underlying disease such as infection with hepatitis B or C virus or malignancy, and anti-phospholipase A2 receptor (PLA2R) antibody was detected in the serum. Accordingly, idiopathic MGN was diagnosed. Corticosteroid therapy was avoided, but hemodialysis was required to treat generalized edema. The patient is currently doing well. This is the oldest reported case of idiopathic MGN with positivity for anti-PLA2R antibody.

Prognostic Value of Tubulointerstitial Lesions, Urinary N-Acetyl-ß-d-Glucosaminidase, and Urinary ß2-Microglobulin in Patients with Type 2 Diabetes and Biopsy-Proven Diabetic Nephropathy.

BACKGROUND AND OBJECTIVES: Some biomarkers of renal tubular injury are reported to be useful for predicting renal prognosis in the early stage of diabetic nephropathy (DN). Our study compared predictions of the renal prognosis by such biomarkers and by histologic tubulointerstitial damage. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 210 patients with type 2 diabetes and biopsy-proven DN managed from 1985 to 2011, 149 patients with urinary N-acetyl-ß-d-glucosaminidase (NAG) and urinary ß2-microglobulin (ß2-MG) data at the time of renal biopsy were enrolled. The primary outcome was a decline in eGFR of ≥50% from baseline or commencement of dialysis for ESRD. RESULTS: The median follow-up period was 2.3 years (interquartile range, 1.1-5.3), and the primary outcome was noted in 94 patients. Mean eGFR was 46.3±23.2 ml/min per 1.73 m(2), and 132 patients (89%) had overt proteinuria at baseline. Cox proportional hazards analysis revealed that the association of urinary NAG and ß2-MG with the outcome was attenuated after adjustment for known promoters of progression (+1 SD for log NAG: hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 0.84 to 1.55; +1 SD for log ß2-MG: HR, 1.23; 95% CI, 0.94 to 1.62). In contrast, the interstitial fibrosis and tubular atrophy (IFTA) score was still significantly correlated with the outcome after adjustment for the same covariates (+1 for IFTA score: HR, 2.31; 95% CI, 1.56 to 3.43). Moreover, adding the IFTA score to a model containing known progression indicators improved prediction of the outcome (increase of concordance index by 0.02; 95% CI, 0.00 to 0.05; category-free net reclassification improvement by 0.54; 95% CI, 0.03 to 1.05; and relative integrated discrimination improvement by 0.07; 95% CI, -0.08 to 0.22). CONCLUSIONS: Adding urinary NAG and ß2-MG excretion to known promoters of progression did not improve prognostication, whereas adding the IFTA score did. The IFTA score may be superior to these tubulointerstitial markers for predicting the renal prognosis in advanced DN.

ANCA-Associated Vasculitis in a Patient with Systematic Sclerosis and Sjögren's Syndrome: A Case Report.

A 65-year-old woman with a limited form of systematic sclerosis (SSc) and Sjögren's syndrome (SS) was admitted to our hospital for the evaluation of renal dysfunction. Her serum creatinine was 1.6 mg/dl, proteinuria was 1.6 g/day, and the urine sediment contained 20-29 erythrocytes/high-power field. Myeloperoxidase anti-neutrophil cytoplasmic antibodies, anti-SS-A/SS-B antibodies and anti-centromere antibodies were positive. A renal biopsy showed focal necrotizing glomerulonephritis with focal interstitial lymphoplasmacytic infiltration. A diagnosis of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) was made. A steroid therapy was initiated and AAV subsided. This is a rare case of AAV in a patient with anti-centromere-positive limited SSc and SS.

Peritoneal Dialysis is Limited by Kidney and Liver Volume in Autosomal Dominant Polycystic Kidney Disease.

We evaluated the influence of kidney volume (KV) and liver volume (LV) on continuation of peritoneal dialysis (PD) in patients with autosomal dominant polycystic kidney disease (PKD). Twenty-two PKD patients on PD were retrospectively investigated after being divided into two groups. Group 1 comprised 15 patients who started PD at our hospital and group 2 was composed of seven patients referred from other hospitals for treatment of renomegaly by transcatheter arterial embolization (TAE) at 47.1 ± 21.8 months after commencing PD. In group 1, KV for both kidneys (mean ± SD) was 2787 ± 1945 mL (range: 1043 to 6816 mL), LV was 2198 ± 1139 mL (1005 to 4116 mL), and the total organ volume (TV=KV+LV) was 4985 ± 1815 mL (2320 to 8912 mL). In the patient with the largest TV from group 1 (KV of 6816 mL, TV of 8912 mL, and TV/BMI ratio of 426, PD was stopped due to dialysate leakage. However, dialysate leakage did not occur in the other 14 patients (TV ≦ 7963 mL and TV/BMI ratio of 353 at the start of PD). In group 2, KV was 5822 ± 1597 mL (3832 to 8862 mL), LV was 1776 ± 519 mL (1271 to 2671 mL), and TV was 7597 ± 1431 mL (5505 to 10358) before TAE. Leakage of dialysate did not occur with a mean infusion volume of 1530 ± 370 mL (1000 mL to 2000 mL), even after renomegaly and hepatomegaly progressed to the maximum TV/BMI ratio of 359. Six patients from the two groups developed new abdominal hernias at 36 ± 5 months (6-55 months) after starting PD. These findings suggest that performance of PD may be limited by renomegaly and hepatomegaly in patients with PKD.

Clinical and pathological predictors of estimated GFR decline in patients with type 2 diabetes and overt proteinuric diabetic nephropathy.

BACKGROUND: The effect of clinical and pathological parameters on the estimated glomerular filtration rate (eGFR) decline has not been investigated in patients with type 2 diabetes and overt proteinuric biopsy-proven diabetic nephropathy. METHODS: Among 198 patients with type 2 diabetes who underwent renal biopsy and were confirmed to have pure diabetic nephropathy according to the recent classification, 128 patients with overt proteinuria were enrolled. Receiver operating characteristic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were performed using models adjusted for various clinical and pathological covariates to determine the best predictors of rapid eGFR decline [defined as >14.9%/year (median eGFR decline)]. RESULTS: A model that incorporated proteinuria showed the largest area under the curve (AUC) among clinical models, which suggested that proteinuria was the best clinical predictor. Although a model incorporating interstitial fibrosis and tubular atrophy (IFTA) score did not display a significantly larger AUC than the model with proteinuria (0.843 vs 0.812, respectively, p = 0.47), a model with both IFTA score and proteinuria had a significantly larger AUC than the model with proteinuria alone (0.875 vs 0.812, respectively, p = 0.014). Similarly, the addition of IFTA score resulted in a significantly greater net reclassification improvement and integrated discrimination improvement than the model with proteinuria alone [NRI: 0.78 (95% CI: 0.43-1.13; p < 0.001), IDI: 0.13 (95% CI: 0.07-0.19; p < 0.001)]. CONCLUSIONS: Our results suggest that not only proteinuria but also tubulointerstitial lesions should be assessed to predict rapid eGFR decline in patients with type 2 diabetes who have overt proteinuria and biopsy-proven diabetic nephropathy.