Global Sclerosis Research Articles

MON-023 HYPOKALEMIC NEPHROPATHY IN NEPHROTIC SYNDROME PATIENT

Hypokalemic nephropathy (HN) caused by prolonged K+ deficiency is associated with metabolic alkalosis, polydipsia, polyuria, growth retardation, hypertension, and progressive tubulointerstitial injury. Histopahologic report of HN in nephrotic syndrome (NS) patient is rare. A 27 year male suffered from weakness, especially lower leg, since two weeks prior to admission. The patients had a history of NS since childhood and cared by nephrologist. Recent condition was hemodynamically stable, laboratory examination showed potassium serum 1.85 mmol/L, albumin plasma 1.8 g/dL, serum creatinine 2.45 mg/dL, and marked dyslipidemia. The patient was clinically assesed with hypokalemia, relapse nephrotic syndrome and renal insufficiency. Intravenous potassium was given and renal biopsy was performed. Histopathologic findings showed global sclerosis. The specific findings may related to HN were mesangial proliferation and specific lesions on tubules including athrophy, vacuolization, intratubular deposition of amorphous and laminated hyaline materials and colloidisation of tubular epithelial, and interstitial nephritis. The patient was discharged at 10th day of hospitalization with potassium level 2.93 mmol/L, and serum creatinine 1.95 mg/dL. The patient was treated with oral methylprednisolone, mychophenolate mofetil, ACE-inhibitor, simvastatin and oral potassium Hypokalemic nephropathy may associate with chronic hypokalemia. Hypokalemia, especially if persistently occurs, can induce a variety of changes in renal tissue, impairing tubular transport and possibly inducing chronic tubulointerstitial disease and cyst formation. HN also associated with alterations in intrarenal vasoactive substances, leading to vasoconstriction, salt-sensitivity, and progression of interstitial fibrosis. Histopathological changes in HN, including severe tubular dilatation, intratubular deposition of amorphous and laminated hyaline materials, intratubular cellular casts, and tubular atrophy is found. More attention is paid to athrophy and vacuolar changes in renal tubular epithelium accompanied by inflammatory interstitial changes in patients with potassium losses. One function that is not impaired is the ability to appropriately conserve potassium, which can be important in distinguishing between extrarenal and renal sources of potassium losses when the cause of hypokalemia is not clear.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) A case with nephrotic syndrome associated with HN is reported. Chronic hypokalemia may involve in the development of hypokalemic nephropathy. Hallmark of histopathologic finding are tubular epithel athrophy, intratubular amorphous deposition and vacuolization of tubular cells, and interstitial nephritis to fibrosis.

MON-013 A CASE OF MEMBRANOUS NEPHROPATHY THAT DEVELOPPED AFTER USE OF NIVOLUMAB

Immune checkpoint inhibitors (ICIs) are novel medicines for cancer immunotherapy that have increasingly been used in recent years.Nivolumab is a human anti-programmed cell death 1(PD-1) monoclonal antibody that serves as an ICI. It activates anti-tumor immunity by interfering with the interaction between PD-1 and PD-1 ligand. However, by activating the immune system, ICIs also cause unique side effects, termed immune-related adverse events (irAE). Although renal irAEs are considered less common, case reports related to renal irAEs are becoming more frequent with the increasing use of ICIs. Most renal irAEs involve acute interstitial nephropathy, and glomerulonephritis is rarely reported. Here, we present the first case of membranous nephropathy (MN) that developed after use of nivolumab. ［HPI］ A 69-year-old man was referred to our hospital with nephrotic syndrome. Sixteen months previously, he commenced chemotherapy with docetaxel for stage IV non-small cell lung carcinoma. However, docetaxel was discontinued because of drug-induced lung injury and immunotherapy with nivolumab was initiated 5 months previously. He subsequently developed leg edema and increasing proteinuria. Despite discontinuation of nivolumab after the seventh course, his symptoms did not improve. He was admitted and underwent renal biopsy. ［Investigations］ His urine protein/creatinine ratio was 19 g/g Cre and serum albumin was 2.3 g/dL. Light microscopic examination of the biopsy specimen, which contained 19 glomeruli, showed global sclerosis in one of the glomeruli. The remaining glomeruli demonstrated diffuse thickening and spikes in the glomerular basement membrane. There was no evidence of acute interstitial nephritis. Immunofluorescence staining showed IgG and C3 deposition on the capillary walls. IgA, IgM, C4, and Ciq were not stained. These observations led to the diagnosis of MN. Staining for IgG subclasses and phospholipase A2 receptor (PLA2R), a membrane protein expressed on podocytes, indicated only IgG1 deposition on the capillary wall. ［In-hospital course］ Glucocorticoid therapy was started with 50 mg/day prednisolone as the standard treatment for irAEs, with recovery of proteinuria from the nephrotic range in 4 weeks. During tapering of glucocorticoids, proteinuria decreased and he attained incomplete remission in 7 months. Thereafter, chemotherapy was resumed with pemetrexed, anantimetabolic drug, which maintained the lung carcinoma at a steady disease state. ［Discussion］ It is well-documented that about 10% of MN cases are associated with malignancy. In previous studies, the absence of IgG4 and PLA2R deposition was a common finding in malignancy-associated MN (M-MN) and was useful for distinguishing M-MN from idiopathic MN. Our case was considered as M-MN because of the staining pattern. Although previous reports show that M-MN improves after successful treatment of malignancy, our patient’s proteinuria increased even though his lung carcinoma remained stable during chemotherapy with nivolumab. This suggests that his M-MN was induced by immune activation caused by nivolumab. Additionally, the favorable response to glucocorticoid therapy supports the association between nivolumab and MN. With the increasing use of ICIs, renal irAEs will likely increase. Our case report demonstrates that ICIs can cause M-MN, which can be successfully treated with glucocorticoids.

Prediction and Risk Stratification of Kidney Outcomes in IgA Nephropathy

Immunoglobulin A nephropathy (IgAN) is common worldwide and has heterogeneous phenotypes. Predicting long-term outcomes and stratifying risk are important for clinical decision making and designing future clinical trials. Multicenter retrospective cohort study of 2,047 patients with IgAN. Derivation and validation cohorts composed of 1,022 Chinese patients with IgAN from a single center and 1,025 patientswith IgAN from 18 renal centers, respectively. 36 characteristics, including demographic, clinical, and pathologic variables. Combined event of end-stage kidney disease or 50% reduction in estimated glomerular filtration rate within 5 years after diagnostic kidney biopsy. A gradient tree boosting method implemented in the eXtreme Gradient Boosting (XGBoost) system was used to select the 10 most important variables from 36 candidate variables. Stepwise Cox regression analysis was used to derive a simplified scoring scale model (SSM) based on these 10 variables. Model discrimination and calibration were assessed using the C statistic and Hosmer-Lemeshow test. Risk stratification of the SSM was evaluated using Kaplan-Meier analysis. In the derivation and validation cohorts, 74 and 114 patients reached the outcome, respectively. XGBoost predicted the outcome with a C statistic of 0.84 (95% CI, 0.80-0.88) for the validation cohort. The SSM included 3 variables: urine protein excretion, global sclerosis, and tubular atrophy/interstitial fibrosis. Using Kaplan-Meier analysis, the SSM identified significant risk stratification (P< 0.001). Retrospective study design, application for other ethnic groups needs to be verified. A prediction model using routinely available characteristics and based on the combination of a machine learning algorithm and survival analysis can stratify risk for kidney disease progression in the setting of IgAN. An online calculator, the Nanjing IgAN Risk Stratification System, permits easy implementation of this model.

SAT-058 Histopathological Analysis of Kidneys and Adrenal Glands in the Same Primary Aldosteronism (PA) Patients: Exploring the Mechanisms of Aldosterone Specific Renal Injuries

Primary aldosteronism (PA) is a major cause of secondary hypertension, accounting for 5 to 10% of all of the patients with hypertension. PA is also well known to harbor relatively higher incidence of cardiovascular complications than essential hypertension (EH) despite similar blood pressure levels. Among these complications, renal injuries are considered clinically important because up to 15% of APA (Aldosterone-producing adenoma) patients had already been chronic kidney disease at the time of its initial diagnosis (Iwakura et al., JCEM, 2014). In addition, PA patients are relatively younger than EH, which makes early clinical intervention pivotal. Many pathways of aldosterone-induced renal injuries have been proposed but the actual mechanism of aldosterone related injuries in human kidney has remained virtually unknown. Therefore, in this study, we performed the detailed histopathological analysis for kidneys and adrenal glands of the same PA patients and compared with those of EH. We analyzed 7 APA cases undergoing renal biopsy or nephrectomy with adrenalectomy. As a control group, 40 age-matched EH cases (31 autopsy, 9 biopsy) were examined. Digital image software (HALO, Indica Labs) was employed to perform quantitative histological analysis. There were no significant differences of eGFR between EH and PA before adrenalectomy (p=0.8111), but eGFR become lower in post-operative PA than in EH (p=0.0511). The prevalence of global glomerular sclerosis (GGS) and focal glomerular sclerosis (FGS) was significantly higher in PA than in EH (p=0.0031, 0.0035). Mesenchymal fibrosis was also more marked in PA than in EH (p=0.0091). Among the increased GGS groups (over 10%), the ratio of GGS/mesenchymal fibrosis tended to be lower in PA than in EH(p=0.0653). CYP11B2 positive area in adrenal cortex was more extended in autopsy EH than in adjacent cortex of PA (p=0.0209), and a significant correlation was also detected between CYP11B2 and renin immunoreactivity in autopsy EH adrenals (p=0.0067). In PA, CYP11B2 immunoreactivity in adenomas tended to be correlated with glomerular swelling (p=0.0539), probably reflecting the status of glomerular hyperfiltration. 11βHSD2 immunoreactivity of cortical tubules was significantly higher in PA than in EH (p=0.0001) and significantly correlated with the degree of renal arteriole hyalinization in PA (p<.0001). The renal injuries in PA demonstrated not only glomerular sclerosis but also mesenchymal fibrosis in contrast to kidneys of EH which predominantly demonstrated glomerular sclerosis. Higher 11βHSD2 expression in the tubules of PA kidneys could also enhance topical effects of aldosterone, resulting in renal arteriole hyalinization in PA. We firstly demonstrated the markedly different patterns of renal injuries between PA and EH patients and could contribute to the management of renal functions of these two different hypertensive disorders.

The beneficial effects of renin-angiotensin system inhibitors (RASI) on IgA nephropathy with tubulointerstitial lesions categorized by Oxford classification.

Global sclerosis has been reported as the risk factor of IgAN. In Oxford classification, global sclerosis was correlated with tubulointerstitial (T) lesions. Therefore, in patients with T lesions, renin-angiotensin system inhibitors (RASI) might be effective by decreasing glomerular hyperfiltration and hypertension. However, these beneficial effects of RASI have not been reported. In this retrospective cohort study, we divided 87 IgAN patients with T1/2 lesions into two groups: RASI group (n = 47, treated with RASI) and APA group (n = 40, treated with anti-platelet agents). We analyzed the background of each group, the serial changes of blood pressure and the amount of proteinuria (U-Prot), progression to end-stage renal disease, and the risk factors for progression. After propensity score matching, 22 cases from each group were selected, and clinical and histological characteristics were similar. Serial changes of blood pressure had been significantly decreased in RASI group (p = 0.0029), but not in the APA group. Proteinuria was tended to decrease in RASI group, though it was not significant (1.14-0.47g/gCre) and it was similar in APA group (0.95-0.85g/gCre). 20year renal survival rate was 59.5% in RASI group, whereas 21.3% in APA group (p = 0.0119). In multivariate Cox regression analysis, RASI was an independent factor to prevent from progression to ESRD (HR 5.91, p = 0.0039). RASI has shown a significant beneficial effect on histologically advanced IgAN patients with T lesions. These results are compatible with the previous studies that reported the beneficial effects of RASI on clinically advanced IgAN patients.

Estimating the Change in Renal Function During the First Year of Therapy in ANCA-Associated Vasculitis

IntroductionStudies in antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) consistently show that the months following diagnosis have the greatest impact on the long-term renal function. Yet, it remains uncertain how much early gain should be expected with treatment. We sought to determine the factors associated with the change in glomerular filtration rate (GFR) throughout the first year.MethodsWe retrospectively reviewed patients from 3 university hospitals who received treatments. We assessed the proportions of glomeruli with crescents, with global sclerosis, the AAV glomerulonephritis classification, the severity of chronic vascular and tubulo-interstitial disease, and the presence of acute tubular injury (ATI). We used repeated-measures analyses of variance (ANOVAs) to determine factors associated with the change in GFR throughout the first year.ResultsThere were 162 individuals with AAV identified, 96 with a valid renal biopsy and 82 with at least 12 months of follow-up. The initial GFR of 30 ± 25 ml/min per 1.73 m2 rose by 15 ± 20 during the first year. The severity of pathology findings, myeloperoxidase positivity, and those with kidney- and lung-limited disease presented with a lower GFR. Younger patients with a lower initial GFR and the presence of ATI correlated with a greater increase in GFR by 12 months. A higher proportion of crescents did not predict the change in GFR, contrary to global glomerulosclerosis, where each 10% increase added a loss of 2.7 ± 1.3 ml/min per 1.73 m2 per year (P = 0.03). These factors remained independent of each other.ConclusionMultiple factors influence renal recovery during the first year of therapy. Estimating the change in GFR early on will help identify and reassess outliers.

IgM nephropathy – Successful treatment with rituximab

Immunoglobulin M nephropathy (IgMN) is a primary glomerulonephritis which is characterized by variable degrees of morphological features ranging from minimal glomerular involvement to segmental or global sclerosis. No specific treatment is known to date for this disease because of uncertainties in etiopathogenesis. The mainstay treatment for this disease has been corticosteroids, which has varying degrees of resistance ranging from 0% to 50%. We present the case of a 59-year-old Caucasian male who was referred to the outpatient nephrology clinic for the evaluation of proteinuria and was diagnosed with IgMN. We successfully treated the patient with rituximab with resolution of his proteinuria.

Renal ultrasound and Doppler parameters as markers of renal function and histopathological damage in children with chronic kidney disease.

Doppler ultrasonography can be used to assess the progression of vascular (arterial sclerosis) and parenchymal (glomerular sclerosis and crescents) renal damage. The aim of this study was to evaluate the significance of some sonographic and Doppler parameters as non-invasive markers of glomerular filtration rate (GFR) and renal histopathological damage in children. A cohort of 84 children were enrolled in a case-control study (42 with CKD stages 2-5 and 42 healthy children). GFR was assessed using new improved equation using serum creatinine and cystatin C. Sonar guided renal specimen was obtained and evaluated for the severity of global sclerosis (GS), segmental sclerosis (SS), tubular atrophy (TA), interstitial fibrosis (IF), arterial sclerosis (AS) and arteriolar hyalinosis (AH). The following sonographic and Doppler parameters were assessed in both patients and control group: resistivity index (RI), pulsatility index (PI), atrophic index (AI), mean renal volume, mean renal density, time average velocity (TAV) and body surface area related volume perfusion (BSARVP). There was significant difference in renal density (P < 0.001), RI (P < 0.001), PI (P = 0.021), TAV (P < 0.001) and BSARVP (P < 0.001) between patients and control group. The cutoff value of RI was 63.5% (sensitivity 83% and specificity 64%). Multivariate analysis revealed that renal density and RI were significant predictors of worsening of estimated GFR (eGFR) in CKD patients. Any increase in the RI and PI values must arouse alarm to the possibility of advancing renal damage. Moreover, RI and PI could fairly predict the degree of glomerular sclerosis and interstitial fibrosis.

Complement deposition on renal histopathology of patients with diabetic nephropathy

AimsAs the potential role of the complement system in diabetic nephropathy (DN) is increasingly reported, this study aimed to investigate C1q and C3c deposition as seen on renal histopathology, as well as its association with clinical and pathological parameters, in DN patients. MethodsRenal biopsy specimens from 161 DN patients were investigated using direct immunofluorescence, light, and electron microscopy. For direct immunofluorescence, staining for C1q and C3c on fresh-frozen renal tissue was performed immediately after biopsy. Complement deposition was defined as the presence of C1q or C3c of at least 1 + on a 0–4 + Scale. The association between complement deposition and clinicopathological data was also analyzed. ResultsOn direct immunofluorescence microscopy, C1q and C3c were detected in specimens from 44/161 (27.3%) and 89/161 (55.3%) patients, respectively. Regarding clinical data, patients with C1q deposition had a significantly higher level of urinary protein (7.25 ± 4.20 g/24 h vs. 4.97 ± 3.76 g/24 h; P < 0.01) and significantly lower estimated glomerular filtration rate (eGFR; 34.16 ± 25.21 mL/min/1.73 m2 vs. 51.17 ± 31.56 mL/min/1.73 m2, respectively; P < 0.01), whereas patients with vs. without C3c deposition had a significantly lower eGFR (40.09 ± 27.97 mL/min/1.73 m2 vs. 54.48 ± 32.49 mL/min/1.73 m2, respectively; P < 0.01). On renal histopathology, patients with C1q deposition had significantly higher Scores for interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation and vascular lesions (P < 0.01, P < 0.05 and P < 0.05, respectively), whereas patients with C3c deposition had significantly higher IFTA Scores and proportions of global sclerosis (P < 0.01 and P < 0.01, respectively). ConclusionComplement deposition of C1q and C3c on renal histopathology is associated with more severe kidney damage in patients with DN.

Combination therapy with or without warfarin and dipyridamole for severe childhood IgA nephropathy: an RCT

Two previous randomized controlled trials showed that treatment of severe childhood immunoglobulin A (IgA) nephropathy using prednisolone with azathioprine, heparin-warfarin, or dipyridamole prevented the increase of sclerosed glomeruli. Prednisolone alone, however, did not prevent further increase. These studies indicated the importance of immunosuppressants in the treatment. An additional pilot study using mizoribine instead of azathioprine enabled us to complete 2years of combined regimen. It showed non-numerical inferior effectiveness compared with the azathioprine regimen. Further examination of the additional efficacy of warfarin and dipyridamole was required. A randomized control trial of prednisolone and mizoribine with (group 1) or without (group 2) warfarin and dipyridamole was administered for treatment of 71 children with severe IgA nephropathy to evaluate the efficacy of additional warfarin and dipyridamole. Thirty of 34 patients (88.2%) in group 1, and 27 of 36 patients (75.0%) showed the disappearance of proteinuria as defined by early morning urinary protein to creatinine ratio of < 0.2 during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by the Kaplan-Meier method showed that the disappearance rate of proteinuria was significantly higher in group 1 than in group 2 (log-rank P= 0.04). There was no significant difference in pathological findings, but there was a tendency of increase of global sclerosis in group1 which might be related to warfarin. Most of the adverse effects were related to prednisolone, but fortunately transient. The balance between minimal benefits of warfarin/dipyridamole and potential adverse effects may be in favor of avoiding them in children with IgA nephropathy.

Histological predictors of renal outcome in lupus nephritis: the importance of tubulointerstitial lesions and scoring of glomerular lesions.

Introduction Lupus nephritis (LN) affects nearly 60% of patients with systemic lupus erythematosus and up to 30% of them will progress to end-stage renal disease (ESRD), despite receiving aggressive immunosuppressive therapy. The prognostic value of ISN/RPS classification is controversial. Therefore, we aimed to identify clinical and pathological predictors of outcome in LN patients independent of this classification. Material and methods Thirty-seven patients with LN who underwent percutaneous kidney biopsy between 1997 and 2016 were included in this study. Twenty clinical and twenty histological variables were tested for their association with a composite end-point of doubling of serum creatinine, ESRD and death. Univariate and multivariate Cox proportional hazard regression analysis were performed to identify independent predictors of outcome. Results During a median follow-up period of 48 months (IQR: 17.5-120 months), 21.6% of patients reached the composite end-point. The overall survival rate of our cohort was 89% at one year, 86% at five years, 74% at 10 years and 64% at 20 years. Patients with Class IV LN showed the worst prognosis with 44% survival at 10 years, while those who additionally showed crescents and global sclerosis on kidney biopsy had an even lower survival of 21% and 0% at 10 years, respectively. After multivariate adjustment, we identified estimated glomerular filtration rate at baseline (HR, 0.91 per ml/min /1.73 m2; 95% CI, 0.84 to 0.99), 24-hour proteinuria at baseline (HR, 2.04 per g/d; 95% CI, 1.19 to 3.5), crescents (HR, 1.068 per %; 95% CI, 1.003 to 1.091), global sclerosis (HR, 1.036 per %; 95% CI, 0.984 to 1.091), presence of adhesions (HR, 9.2; 95% CI, 1.38 to 61.2) and tubulitis (HR, 13.1; 95% CI; 1.3 to 131) as independent predictors of outcome in our cohort of LN. Conclusions Our study identified glomerular (crescents, global sclerosis, adhesions) and tubulointerstitial (tubulitis) lesions, in addition to clinical variables (renal function, 24-hour proteinuria), as important predictors of renal outcome, independent of the ISN/RPS classification. We suggest that the ISN/RPS classification could be improved by a quantitative assessment of glomeruli with active and chronic lesions and by a greater emphasis given to tubulointerstitial lesions.

The features in IgA-dominant infection-related glomerulonephritis distinct from IgA nephropathy: a single-center study.

IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN). Thirteen patients with IgA-IRGN (IgA-IRGN group) and 122 with IgAN (IgAN group) were selected from 1788 patients who underwent kidney biopsy between 2000 and 2015 in Kitano Hospital. Data selected included clinical and serological parameters; light and electron microscope findings; immunofluorescence findings; and prognostic parameters like renal and overall survival and creatinine increase by > 50%. In addition, a 26-patient IgAN cohort (matching-IgAN), matching with IgA-IRGN group with respect to age, sex, estimated glomerular filtration rate (eGFR), and proteinuria was segregated for comparison. Compared to IgAN group, IgA-IRGN group were older, had lower hemoglobin, higher CRP, lower eGFR, heavier proteinuria, lower serum albumin, and higher serum IgG and IgA levels (p < 0.05). Endocapillary hypercellularity, deposition of immune complexes along the glomerular capillary wall, and subendothelial and subepithelial electron dense deposits were more frequently observed (p < 0.05); and they were more susceptible to renal dysfunction and poorer prognosis. After propensity score-matching, serum albumin was significantly lower in the IgA-IRGN group. Significantly subendothelial and subepithelial deposits were frequently observed in this group. Matching-IgAN group showed relatively advanced sclerotic lesions with more global sclerosis and fibrous crescent. Local inflammation involved glomerular capillary wall in IgA-IRGN, in contrast to relatively chronic and sclerotic renal lesion in IgAN, might result in poorer prognosis in former, even under indistinguishable condition of deteriorated renal function and proteinuria.

Role of Kidney Biopsies for Biomarker Discovery in Diabetic Kidney Disease.

Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of diabetic kidney disease (DKD), additional biomarkers are needed, especially for the early stages of the disease when both albuminuria and estimated glomerular filtration rate may still be in the normal range and are less helpful for identifying those at risk of progression. Traditional biomarker studies for early DKD are challenging because of a lack of good early clinical end points, and most rely on changes in existing imprecise biomarkers to assess the value of new biomarkers. There are well-characterized changes in kidney structure, however, that are highly correlated with kidney function, always precede the clinical findings of DKD and, at preclinical stages, predict DKD progression. These structural parameters may thus serve as clinically useful end points for identifying new biomarkers of early DKD. In addition, investigators are analyzing tissue transcriptomic data to identify pathways involved in early DKD which may have associated candidate biomarkers measurable in blood or urine, and differentially expressed microRNAs and epigenetic modifications in kidney tissue are beginning to yield important observations which may be useful in identifying new clinically useful biomarkers. This review examines the emerging literature on the use of kidney tissue in biomarker discovery in DKD.

Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine and reproductive disorder in premenopausal women, characterized by hyperandrogenemia, metabolic syndrome, and inflammation. Women who had PCOS during their reproductive years remain hyperandrogenemic after menopause. The consequence of chronic hyperandrogenemia with advanced aging has not been studied to our knowledge. We have characterized a model of hyperandrogenemia in female rats and have aged them to 22–25 months to mimic advanced aging in hyperandrogenemic women, and tested the hypothesis that chronic exposure to hyperandrogenemia with aging has a deleterious effect on renal function. Female rats were chronically implanted with dihydrotestosterone pellets (DHT 7.5 mg/90 days) that were changed every 85 days or placebo pellets, and renal function was measured by clearance methods. Aging DHT‐treated females had a threefold higher level of DHT with significantly higher body weight, mean arterial pressure, left kidney weight, proteinuria, and kidney injury molecule‐1 (KIM‐1), than did age‐matched controls. In addition, DHT‐treated‐old females had a 60% reduction in glomerular filtration rate, 40% reduction in renal plasma flow, and significant reduction in urinary nitrate and nitrite excretion (UNOxV), an index of nitric oxide production. Morphological examination of kidneys showed that old DHT‐treated females had significant focal segmental glomerulosclerosis, global sclerosis, and interstitial fibrosis compared to controls. Thus chronic hyperandrogenemia that persists into old age in females is associated with renal injury. These data suggest that women with chronic hyperandrogenemia such as in PCOS may be at increased risk for development of chronic kidney disease with advanced age.

The Histomorphological Spectrum of Renal Lesions in an Autopsy Study

Background: Autopsy provides normal as well as diseased human tissue for morphologic studies, for establishment of cell and organ culture as well for xenotransplantation. It provides the opportunity to discover new diseases, to evaluate toxic effects of drugs and therapies. The kidneys are often affected by chronic inflammatory lesions, neoplasms , toxic effects of various drugs and metabolic disorders. Methods : This was a five year study from January 2011 to December 2015 in our department of pathology. The kidneys of medico legal autopsies performed during these years were subjected to our study. After excluding 30 cases of severely damaged tissue, 120 cases of well preserved renal medico legal autopsies were included in our study. The stained microscopic sections were examined by two histopathologists independently. Results: Seventy five of the 120 autopsies were males, while 45 were females. In 27 (22.5%) cases, the microscopic morphology was close to normal histology. Remaining 93(77.5%) cases had a nephropathological findings The percentage of non glomerular nephropathies (60.8%) was higher as compared to that of glomerular lesions (16%). 20 (16% ) cases exhibited glomerular alterations such focal global glomerular sclerosis, segmental glomerular sclerosis, nodular mesangial sclerosis, basement thickening and mesangial cellular proliferation. Tubular and interestium lesions were observed in 34.16% which included acute tubular necrosis, chronic pyelonephritis and tubercular pyelonephritis. Renal arteriosclerosis was observed in 25% cases. Renal cell carcinoma was incidentally detected in1.6% Conclusion :Our study provided satisfactory data in respect to morphological spectrum of various renal lesions in autopsy. DOI: 10.21276/APALM.1455

111 A LUPUS NEPHRITIS PATIENT WITH BREATHLESSNESS FOLLOWING PLASMA EXCHANGE

Category: Other Presenter: Dr WAN HASNUL HALIMI WAN HASSAN Keywords: SLE, lupus nephritis, plasma exchange, fluid overload A 17 years old girl, diagnosed with Lupus nephritis since 2014. She had Lupus Nephritis class III , in partial remission following treatment with t.mycophenolate mofetil (MMF). She was transferred to high dependency ward requiring non invasive ventilation after 4th cycle of plasmapharesis. This is due to fluid overload and her condition improves after hemodialysis and ultrafiltration. She initially presented with symptoms of facial puffiness and leg swelling for 2 weeks. She was admitted was started on high dose prednisolone (60mg OD) and t.MMF 1g BD. Progressive worsening renal function was noted (urea 29/creat 190; baseline renal function was normal urea/creat) Renal biopsy results shows Crescentric Lupus Nephritis, ISN/RPS class IV-G (A/C). activity index 15/24, chronicity index 4/12. (57% cellular crescent, 15% global sclerosis). IV cyclophosphamide induction and plasma exchange was initiated. She completed total of 10 plasmapheresis cycle and is currently still ongoing 3rd cyclophosphamide induction. Her renal profile shows improvement (urea 15.7/creatinine 116). Plasma Exchange is a recognized modality of treatment in more severe and/or resistant lupus nephritis, moreover for crescentic glomerulonephritis. The complication rate of is not high. The Swedish registry reported no fatalities during 20,485 procedures, and an overall adverse incidence rate of only 4.3% of all exchanges (0.9% for severe adverse events) of which 27% were paresthesias, 19% transient hypotension, 13% urticaria, and 8% nausea. An overall complication rate of 1.4% has been reported in more than 15,000 treatments in patients receiving albumin, and 20% in patients receiving FFP. There's increases the risk of bleeding as a result of depletion of coagulation factors in patients receiving albumin as sole replacement colloid. A study in Japan looking at 53 kidney transplant recipients receiving plasma exchange for desensitization, recorded the were no severe adverse event, milder events were pruritus 53%, numbness 40% and mild dyspnea 5%. The incidence of numbness during plasma exchange was less in patients receiving combined hemodialysis. In our case, fluid overload was noted as a major complication requiring non invasive ventilation and hemodialysis. This is due to the large volume exchange and associated renal impairment. Although uncommon, fluid overload and other complication related to large volume plasma exchange is needed to be taken under account in a renal impaired patient.

Nephron development and extrarenal features in a child with congenital nephrotic syndrome caused by null LAMB2 mutations

BackgroundCongenital nephrotic syndrome (CNS) is a rare disorder caused by various structural and developmental defects of glomeruli. It occurs typically as an isolated kidney disorder but associates sometimes with other systemic, extrarenal manifestations.Case PresentationsAn infant presented with severe CNS, which progressed rapidly to renal failure at age of 3 months and death at 27 months. The clinical phenotypes and genetic causes were studied, including the renal pathology at autopsy.Besides the CNS, the affected child had remarkable right-side predominant eye-ball hypoplasia with bilateral anterior chamber dysgenesis (microcoria). Brain MRI revealed grossly normal development in the cerebrum, cerebellum, and brain stem. Auditory brainstem responses were bilaterally blunted, suggesting a defective auditory system. At autopsy, both kidneys were mildly atrophied with persistent fetal lobulation. Microscopic examination showed a diffuse global sclerosis. However, despite of the smaller size of glomeruli, the nephron number remained similar to that of the age-matched control. Whole-exome sequencing revealed that the affected child was compound heterozygous for novel truncating LAMB2 mutations: a 4-bp insertion (p.Gly1693Alafs*8) and a splicing donor-site substitution (c.1225 + 1G > A), presumably deleting the coiled-coil domains that form the laminin 5–2-1 heterotrimer complex.ConclusionsOur case represents a variation of Pierson syndrome that accompanies CNS with unilateral ocular hypoplasia. The average number but smaller glomeruli could reflect either mal-development or glomerulosclerosis. Heterogeneous clinical expression of LAMB2 defects may associate with the difference in fetal β1 subtype compensation among affected tissues. Further study is necessary to evaluate incidence and features of auditory defect under LAMB2 deficiency.

Renal Allograft Dysfunction Possibly Caused by Amiodarone Nephrotoxicity: a Case-Report

Abstract Amiodarone is a potent inhibitor of CYP3A4 and can increase serum concentrations of drugs that are substrates of this enzyme system. Immunosuppressive drugs are also metabolized through the cytochrome metabolic pathway what may lead to important drug-drug interactions. A 60-year-old female received her second allograft from the deceased donor and was treated with tacrolimus, mycophenolate mofetil and steroids. Amiodarone was introduced for treatment of paroxysmal atrial fibrillation four days after the transplantation. One month after the discharge she was readmitted to hospital for evaluation of the creeping creatinine. Biopsy showed borderline acute rejection. She received 3 boluses of 6- methilprednisolone but creatinine continued to rise. Repeated biopsy was without signs of rejection with mild interstitial fibrosis/tubular atrophy, mild global glomerulosclerosis and moderate arterial sclerosis. However, tubular vacuolization was prominent. After careful revision of her therapy we decided to replace amiodarone with sotalol. One week later her creatinine fell from 350 to 220 μmol/l and remained stable. This case illustrates possible amiodarone nephrotoxicity in a renal transplant recipient. We suggest that patients who need amiodarone in combination with tacrolimus be closely monitored by both cardiologists and nephrologists, with frequent determinations of tacrolimus trough levels and serum creatinine measurements.

Glomerular Density and Volume in Renal Biopsy Specimens of Children with Proteinuria Relative to Preterm Birth and Gestational Age.

A low total nephron number, which is associated with low birth weight (LBW), may indicate increased susceptibility to early-onset renal diseases in children. However, few studies have assessed renal biopsy findings in LBW children. We examined the relationship between LBW and glomerular density (GD) and/or glomerular volume (GV) in renal biopsy samples as a surrogate for total nephron number. Renal biopsy findings of children of LBW were compared with those of age-matched control subjects of normal birth weight (NBW) who were histopathologically diagnosed with FSGS or minimal change nephrotic syndrome (MCNS) from 1995 to 2011. The GD and GV were estimated on the basis of measurements obtained by computerized image analysis. A total of 31 subjects (mean age 11 years; eight with low birth weight-FSGS [LBW-FSGS], 10 with normal birth weight-FSGS [NBW-FSGS], and 13 with normal birth weight-minimal change nephrotic syndrome [NBW-MCNS]) were analyzed. The mean birth weight of each group was 777 g (629-1000), 3110 g (2888-3358), and 3120 g (2748-3398), respectively (median [25th-75th percentile]). Age, body mass index, BP, and degrees of globally sclerotic glomeruli at biopsy were comparable between the groups. The GD was lower (LBW-FSGS, 1.4±0.6/mm2; NBW-FSGS, 3.3±1.2/mm2; and NBW-MCNS, 3.6±1.1/mm2; P<0.05) and the GV was greater (LBW-FSGS, 4.1 [3.1-5.1]×106µm3; NBW-FSGS, 1.6 [1.5-2.1]×106µm3; and NBW-MCNS, 1.3 [1.1-1.8]×106µm3 [median, (25th-75th percentile)]; P<0.05) in patients with LBW-FSGS than in the other patient groups. The GD showed close positive correlations with birth weight (r=0.48) and gestational age (r=0.54), independent of renal function and degree of global glomerular sclerosis. A low GD together with marked glomerular enlargement characterizes renal biopsy samples of children born with a LBW at an early stage of gestation.

Deficiency of the Angiotensinase Aminopeptidase A Increases Susceptibility to Glomerular Injury.

Aminopeptidase A (APA) is expressed in glomerular podocytes and tubular epithelia and metabolizes angiotensin II (AngII), a peptide known to promote glomerulosclerosis. In this study, we tested whether APA expression changes in response to progressive nephron loss or whether APA exerts a protective role against glomerular damage and during AngII-mediated hypertensive kidney injury. At advanced stages of FSGS, fawn-hooded hypertensive rat kidneys exhibited distinctly increased APA staining in areas of intact glomerular capillary loops. Moreover, BALB/c APA-knockout (KO) mice injected with a nephrotoxic serum showed persistent glomerular hyalinosis and albuminuria 96 hours after injection, whereas wild-type controls achieved virtually full recovery. We then tested the effect of 4-week infusion of AngII (400 ng/kg per minute) in APA-KO and wild-type mice. Although we observed no significant difference in achieved systolic BP, AngII-treated APA-KO mice developed a significant rise in albuminuria not observed in AngII-treated wild-type mice along with increased segmental and global sclerosis and/or collapse of juxtamedullary glomeruli, microcystic tubular dilation, and tubulointerstitial fibrosis. In parallel, AngII treatment significantly increased the kidney AngII content and attenuated the expression of podocyte nephrin in APA-KO mice but not in wild-type controls. These data show that deficiency of APA increases susceptibility to glomerular injury in BALB/c mice. The augmented AngII-mediated kidney injury observed in association with increased intrarenal AngII accumulation in the absence of APA suggests a protective metabolizing role of APA in AngII-mediated glomerular diseases.