The renoprotective effects of taurine against diabetic nephropathy via the p38 MAPK and TGF-ß/Smad2/3 signaling pathways.

Diabetic nephropathy (DN), a severe diabetes complication, causes kidney morphological and structural changes due to extracellular matrix accumulation. This accumulation is caused mainly by oxidative stress. Semi-essential amino acid derivative taurine has powerful antioxidant and antifibrotic effects. The aim of this study was to investigate the renoprotective effects of taurine through its possible roles in oxidative stress, extracellular matrix proteins, and the signaling pathways associated with the accumulation of extracellular matrix proteins in DN rats. 29 Wistar albino rats were randomly separated into control, taurine, diabetes, and diabetes + taurine groups. Diabetes animals were injected 45 mg/kg streptozosine. Taurine is given by adding to drinking water as 1% (w/v). Urine, serum, and kidney tissue were collected from rats for biochemical and histological analysis after 12 weeks. According to the studies, taurine significantly reduces the levels of malondialdehyde (MDA), total oxidant status (TOS), and protein expression of NADPH oxidase 4 (NOX4) that increase in diabetic kidney tissue. Also, decreased superoxide dismutase (SOD) activity levels significantly increased with taurine in diabetic rats. Moreover, increased mRNA and protein levels of fibronectin decreased with taurine. The matrix metalloproteinase (MMP)-2 and MMP-9 activities and their mRNA levels increased significantly, and this increase was significantly summed with taurine. There was a decrease in mRNA expression of Extracellular matrix metalloproteinase inducer (EMMPRIN). Taurine significantly increased this decrease. Diabetes increased mRNA expressions of transforming growth factor (TGF)-ß and Smad2/3. Taurine significantly reduced this induction. TGF-ß protein expression, p38, and Smad2/3 activations were also inhibited, but taurine was suppressed significantly. All these findings indicate that taurine may be an effective practical strategy to prevent renal diabetic injury.

Role of p38 MAPK, Akt and NFκB in renoprotective effects of nebivolol on renal ischemia-reperfusion injury in rats.

Renal ischemia-reperfusion (I-R) injury is a complex pathophysiologic condition characterized by oxidative stress, inflammation and apoptosis. We investigated the potential renoprotective effect of nebivolol, a ß1 adrenergic receptor blocker, against renal I-R injury. We focused on the role of nebivolol in activating p38 mitogen-activated protein kinase (MAPK) signaling, Akt (protein kinase B) and nuclear factor-κB (NFκB) transcription factors, which contribute to oxidative stress, inflammation and apoptosis during renal I-R. We divided 20 adult male Wistar albino rats into three experimental groups. Group 1 was a sham control in which only laparotomy was performed. Group 2 was the I-R group in which both kidneys were made ischemic for 45 min, then reperfused for 24 h. Group 3 was the I-R + nebivolol group in which 10 mg/kg nebivolol was administrated by gavage for 7 days before I-R. We measured Inflammation, oxidative stress and active caspase-3 as well as activation of p38 MAPK, Akt (protein kinase B) and NFκB transcription factor. Nebivolol significantly reduced oxidative stress and increased superoxide dismutase levels during renal I-R. We found that nebivolol significantly decreased interstitial inflammation, and TNF-α and interleukin-1ß mRNA expression. Nebivolol significantly reduced active caspase-3 and kidney injury molecule-1 (KIM-1) expressions. Nebivolol also significantly decreased activation of p38 MAPK signaling and NFκB, and induced Akt activation during renal I-R. Our findings suggest that nebivolol may be useful for management of renal I-R injury.

The association between geriatric nutritional risk index variability and mortality in peritoneal dialysis patients.

BACKGROUND: The objective of this study is to examine the association between the Geriatric Nutritional Risk Index (GNRI) and overall mortality in this population. METHODS: GNRI values were calculated by using the serum albumin levels and body weight and the GNRI variability reflects the changes in GNRI change slopes in the follow-up. RESULTS: GNRI values showed a decrease from the median baseline GNRI of 106.3 (IQR, 95.0,113.4) to 98.4 (interquartile range [IQR], 91.9108.9) (p < 0.001). The median GNRI variability was 4.7 (IQR, 2.5, 10.3). Both baseline GNRI levels (adjusted odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.93, 0.99, p = 0.04) and more profoundly GNRI variability (adjusted OR: 1.23, 95% CI: 1.01, 1.44, p = 0.03) were independently associated with mortality. CONCLUSION: The monitorization of the changes in GNRI values as a variability index is an easy tool that might improve the predictive accuracy of mortality in peritoneal dialysis patients.

Long-Term Outcomes of Patients With Amyloidosis Following Kidney Transplant.

OBJECTIVES: Reported graft and patient survival rates in amyloidosis after renal transplant differ considerably between studies. MATERIALS AND METHODS: Group 1 included 24 patients who had end-stage renal disease secondary to amyloidosis. Group 2 (the control group) included 24 consecutive patients who had kidney disease secondary to various causes other than amyloidosis. Comparisons between groups were made for kidney and patient survival rates and other complications following kidney transplant. We also compared survival rates of patients in group 1 versus another control group that included patients with amyloidosis who were treated with hemodialysis (group 3; n = 25). RESULTS: Mean follow-up was 109.5 ± 79.8 months. Biopsy-proven acute rejection and graft failure rates were not significantly different between groups. In group 1 versus group 2, the cumulative 10-year and 20-year patient survival rates were 68.2% versus 86.1% and 36.9% versus 60.3%, respectively (P = .041). Survival was not significantly different in group 1 compared with group 2 and group 3, although patients in group 3 had significantly shorter duration of time to death after the start of renal replacement therapy. CONCLUSIONS: Patient survival may be lower in kidney transplant recipients with amyloidosis compared with patients with end-stage renal disease due to other causes. However, graft failure and acute rejection rates seem to be similar.

Prevalence of Gastrointestinal Symptoms and Clinical Outcomes in Hospitalized Coronavirus Disease 2019 Patients: A Single-Center Study from Turkey.

BACKGROUND: In patients with coronavirus disease 2019, the gastrointestinal symptoms have been reported increasingly in addition to the respiratory system symptoms. The studies show that the prevalence of gastrointestinal system symptoms and how the gastrointestinal system contributes to the severity and prognosis of the disease is still not clear. This study aims to find the prevalence of gastrointestinal symptoms and the correlation between the gastrointestinal symptoms and the clinical results in hospitalized patients diagnosed with coronavirus disease 2019. METHODS: This study retrospectively analyzes patients diagnosed with coronavirus disease 2019 and hospitalized in the pandemic unit between March 2020 and August 2020 and compares their demographic and clinical characteristics, laboratory and radiologic findings, coronavirus disease 2019 treatments received, the clinical course of the disease, and the gastrointestinal symptoms. RESULTS: In our study, we included 322 patients diagnosed with coronavirus disease 2019 and hospitalized; 39 patients (12.1%) were admitted to the hospital with at least one gastrointestinal symptom (nausea and vomiting, diarrhea, abdominal pain, and the loss of taste). Nausea and vomiting are the most common gastrointestinal symptoms with a prevalence of 7.1%, followed by diarrhea with 2.8%, the loss of taste with 2.2%, and abdominal pain with 1.5%. The mean age and D-dimer levels of the patients showing gastrointestinal symptoms were lower than those who did not have any gastrointestinal symptoms. We did not find a significant correlation between the presence of the gastrointestinal symptoms and the severity of the disease, treatment received, risk of acute respiratory distress syndrome and septic shock, admission to the intensive care unit, the need for mechanical ventilation, the mortality rate or the length of hospitalization in the medical floor or the intensive care unit. CONCLUSION: In this study, we observed that 12.1% of coronavirus disease 2019 patients apply to the hospital due to gastrointestinal symptoms. Furthermore, the gastrointestinal symptoms do not seem to affect the severity and the course of the disease, it is important to identify coronavirus disease 2019 patients showing unusual symptoms such as the gastrointestinal symptoms at an early stage to protect healthcare professionals from infection risk.

Clinical and pathologic features of primary membranous nephropathy in Turkey: a multicenter study by the Turkish Society of Nephrology Glomerular Diseases Working Group.

BACKGROUND: We aimed to evaluate the features of primary membranous nephropathy (MNP) in Turkish people. METHODS: This is a retrospective analysis of patients with biopsy-proven primary MNP. We obtained the data collected between 2009 and 2019 in the primary glomerulonephritis registry of the Turkish Society of Nephrology Glomerular Diseases Study Group (TSN-GOLD). Patients with a secondary cause for MNP were excluded. Clinical, demographic, laboratory, and histopathological findings were analyzed. RESULTS: A total of 995 patients with primary MNP were included in the analyses. Males constituted the majority (58.8%). The mean age was 48.4 ± 13.9 years. The most common presentation was the presence of nephrotic syndrome (81.7%) and sub nephrotic proteinuria (10.3%). Microscopic hematuria was detected in one-third of patients. The median estimated glomerular filtration rate (eGFR) was 100.6 mL/min/1.73 m2 (IQR, 75.4-116.3), and median proteinuria was 6000 mg/d (IQR, 3656-9457). Serum C3 and C4 complement levels were decreased in 3.7 and 1.7% of patients, respectively. Twenty-four (2.4%) patients had glomerular crescents in their kidney biopsy samples. Basal membrane thickening was detected in 93.8% of cases under light microscopy. Mesangial proliferation and interstitial inflammation were evident in 32.8 and 55.9% of the patients, respectively. The most commonly detected depositions were IgG (93%), C3 complement (68.8%), and kappa and lambda immunoglobulin light chains (70%). Although renal functions were normal at presentation, vascular, interstitial, and glomerular findings were more prominent on biopsy in hypertensive patients. No significant effect of BMI on biopsy findings was observed. CONCLUSIONS: Despite some atypical findings, the main features of primary MNP in Turkey were similar to the published literature. This is the largest MNP study to date conducted in Turkish people.

Trends of primary glomerular disease in Turkey: TSN-GOLD registry report.

BACKGROUND: Although several renal biopsy registry reports have been published worldwide, there are no data on primary glomerular disease trends in Turkey. METHODS: Three thousand eight-hundred fifty-eight native kidney biopsy records were assessed in the Turkish Society of Nephrology Primary Glomerulopathy Working Group (TSN-GOLD) Registry. Secondary disease and transplant biopsies were not recorded in the registry. These records were divided into four periods, before 2009, 2009 to 2013, 2013-2017, and 2017-current. RESULTS: A total of 3858 patients (43.6% female, 6.8% elderly) were examined. Nephrotic syndrome was the most common biopsy indication in all periods (58.6%, 53%, 44.1%, 51.6%, respectively). In the whole cohort, IgA nephropathy (IgAN) (25.7%) was the most common PGN with male predominance (62.7%), and IgAN frequency steadily increased through the periods (× 2 = 198, p < 0.001). MGN was the most common nephropathy in the elderly (> 65 years), and there was no trend in this age group. An increasing trend was seen in the frequency of overweight patients (× 2 = 37, p < 0.0001). Although the biopsy rate performed with interventional radiology gradually increased, the mean glomeruli count in the samples did not change over the periods. CONCLUSIONS: In Turkey, IgAN is the most common primary glomerulonephritis, and the frequency of this is increasing.

Causes of Granulomatous Inflammation in Native and Allograft Kidneys: Case Series from A Single Center and A Review of the Literature.

OBJECTIVE: Granulomatous interstitial nephritis is a rare finding, and etiology differs by geography. We aimed to investigate the distribution of causes of granuloma/granulomata in the kidney and renal survival of these patients in a tertiary care hospital in Western Turkey. MATERIAL AND METHOD: Medical records of adults who underwent a kidney biopsy procedure in our institution between January 2000 and June 2019 were reviewed. Pathology reports were searched for biopsies where a granuloma was identified. RESULTS: Nineteen of 1121 (1.7%) kidney biopsies included granuloma, 17 in native kidneys, and 2 in transplants. The majority of indications for native kidney biopsy was a rise in serum creatinine. Etiologies of granuloma included the following: pauci-immune vasculitis (n=11, 64.7%), tuberculosis (n=2, 11.8%), drug-induced (n=2, 11.8%), tubulointerstitial nephritis/uveitis (TINU) syndrome (n=1, 5.9%), and systemic-lupus erythematosus (n=1, 5.9%). Despite treatment, 6 of 11 (54.5%) patients with vasculitis developed end-stage kidney disease (ESKD) during the median follow-up of 16 months. Both of the patients with tuberculosis, and the patient with TINU syndrome developed ESKD months after the kidney biopsy, despite appropriate therapies. The only case with drug-induced granuloma and both cases with allograft kidney granuloma responded well to glucocorticoids, achieving a complete renal recovery. CONCLUSION: The majority of our series had granuloma in the kidney secondary to vasculitis and renal outcomes appear considerably unfavorable despite treatment, probably related to the primary diagnosis. Multicenter studies are needed to better determine the etiology and outcome of each granuloma etiology at different geographic locations.

Alpha-lipoic acid alleviates colistin nephrotoxicity in rats.

Colistin methanesulfonate (CMS), a clinical form of colistin, is widely used as a last-line treatment for multidrug-resistant (MDR) gram-negative bacterial infections in critically ill patients presenting a considerably high mortality rate. However, nephrotoxicity is considered to be a critical adverse effect that limits CMS's clinical use. Alpha-lipoic acid (ALA) is a strong antioxidant that is effective in preventing nephrotoxicity in many models. The aim of this study was to investigate ALA's ability to protect against nephrotoxicity induced by colistin in rats. Male Wistar albino rats were randomly divided into four groups. Group 1 was the control group (Control; n = 6), in which isotonic saline was administered to the rats. Group 2 was the ALA group (ALA; n = 6) in which rats received 100 mg/kg ALA. Groups 3 was the CMS (CMS; n = 7) in which 450.000 IU/kg/day of CMS was administered to the rats. Groups 4 was the CMS + ALA group (n = 6), in which rats were injected with 100 mg/kg of ALA 30 min before administration of CMS. All injections were performed intraperitoneally at 1, 4, 7, and 10 days. Urine was collected by using a metabolic cage for 24 h after each administration. The rats were euthanized under ether anesthesia after 24 h of the last administration. Blood and kidney samples then were collected for histological and biochemical analysis. ALA pretreatment could reverse the effects of colistin-induced nephrotoxicity, partly through its suppressing effect on Nox4 and caspase-3, which in turn results in its antioxidant and antiapoptotic effect. Therefore, ALA may be an effective strategy for the management of colistin nephrotoxicity.

Acute kidney injury following colistin treatment in critically-ill patients: may glucocorticoids protect?

Nephrotoxicity following colistin administration is common and factors alleviating nephrotoxicity are yet to be determined. We retrospectively evaluated outcomes of subjects who were treated with colistin (n = 133) and with antibiotics other than colistin (control, n = 133) in intensive care units. Acute kidney injury (AKI) occurred in 69.2% and 29.3% of patients in colistin and control groups, respectively (p < 0.001). In the colistin group, glucocorticoid exposure was more common in subjects who did not develop AKI (p < 0.001). This was not the case in the control group. In the colistin cohort, older age (per 10 years, odds ratio [OR] 1.41, 95% CI 1.05-1.91; p = 0.025), PPI use (OR 3.30, 95% CI 1.18-9.23; p = 0.023) and furosemide treatment (OR 2.66, 95% CI 1.01-6.98; p = 0.047) were independently associated with the development of AKI while glucocorticoid treatment (OR 0.23, 95% CI 0.10-0.53; p = 0.001) was independently associated with reduced risk of AKI. Mortality was observed in 74 patients in the colistin cohort (55.6%). A higher APACHE-II score (OR 1.17, 95% CI 1.08-1.26; p < 0.001) was independently associated with mortality while a higher serum albumin level (per 1 g/dL increase, OR 0.20, 95% CI 0.070-0.60; p = 0.004) was associated with a lower risk of mortality. In conclusion, glucocorticoid exposure is associated with a lower risk of AKI caused by colistin therapy in critically-ill patients. Prospective studies are needed to confirm these findings and determine the optimal type, dose and duration of glucocorticoid therapy.

Characteristics of primary glomerular diseases patients with hematuria in Turkey: the data from TSN-GOLD Working Group.

PURPOSE: Hematuria is one of the most common laboratory findings in nephrology practice. To date, there is no enough data regarding the clinical and histopathologic characteristics of primary glomerular disease (PGD) patients with hematuria in our country. METHODS: Data were obtained from national multicenter (47 centers) data entered into the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) database between May 2009 and June 2019. The data of all PGD patients over the age of 16 years who were diagnosed with renal biopsy and had hematuria data were included in the study. Demographic characteristics, laboratory and biopsy findings were also recorded. RESULTS: Data of 3394 PGD patients were included in the study. While 1699 (50.1%) patients had hematuria, 1695 (49.9%) patients did not have hematuria. Patients with hematuria had statistically higher systolic blood pressure, serum blood urea nitrogen, creatinine, albumin, levels and urine pyuria. However, these patients had statistically lower age, body mass index, presence of hypertension and diabetes, eGFR, 24-h proteinuria, serum total, HDL and LDL cholesterol, and C3 levels when compared with patients without hematuria. Hematuria was present 609 of 1733 patients (35.8%) among the patients presenting with nephrotic syndrome, while it was presented in 1090 of 1661 (64.2%) patients in non-nephrotics (p < 0.001). CONCLUSION: This is the first multicenter national report regarding the demographic and histopathologic data of PGD patients with or without hematuria. Hematuria, a feature of nephritic syndrome, was found at a higher than expected in the PGDs presenting with nephrotic syndrome in our national database.

Alpha lipoic acid attenuates iron induced oxidative acute kidney injury in rats.

Iron has been implicated in oxidative tissue injury owing to its ability to generate reactive oxygen species (ROS). We investigated the reno-protective effects of alpha lipoic acid (ALA) by investigating its effects on the kidney isoform of NADPH oxidase (Nox4) and the specific signaling pathways, p38 MAPK and PI3K/Akt, which participate in apoptosis and survival, respectively. We established four groups of seven rats: control, 100 mg/kg ALA, 80 mg/kg iron sucrose (IS) and IS + ALA. IS and ALA were injected intravenously and rats were sacrificied after 6 h. The mRNA expression of the subunits of NADPH oxidase, Nox4 and p22phox; tumor necrosis factor-alpha (TNF-α); and kidney injury molecule-1 (KIM-1) were measured using quantitative real time polymerase chain reaction (qRT-PCR). Active caspase-3 protein expression was evaluated by immunostaining. Also, p38 MAPK and PI3K/Akt signaling pathways were analyzed using western blot. ALA suppressed the mRNA expression of Nox4, p22phox, TNF-α and KIM-1. Active caspase-3 protein expression induced by IS was decreased by ALA. ALA also suppressed p38 MAPK and activated the PI3K/Akt signaling pathway following IS administration. We found that ALA may be an effective strategy for preventing oxidative acute kidney injury caused by IS.

Epidemiological features of primary glomerular disease in Turkey: a multicenter study by the Turkish Society of Nephrology Glomerular Diseases Working Group.

BACKGROUND: The largest data on the epidemiology of primary glomerular diseases (PGDs) are obtained from the databases of countries or centers. Here, we present the extended results of the Primary Glomerular Diseases Study of the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group. METHODS: Data of patients who underwent renal biopsy and received the diagnosis of PGD were recorded in the database prepared for the study. A total of 4399 patients from 47 centers were evaluated between May 2009 and May 2019. The data obtained at the time of kidney biopsy were analyzed. After the exclusion of patients without light microscopy and immunofluorescence microscopy findings, a total of 3875 patients were included in the study. RESULTS: The mean age was 41.5 ± 14.9 years. 1690 patients were female (43.6%) and 2185 (56.3%) were male. Nephrotic syndrome was the most common biopsy indication (51.7%). This was followed by asymptomatic urinary abnormalities (18.3%) and nephritic syndrome (17.8%). The most common PGD was IgA nephropathy (25.7%) followed by membranous nephropathy (25.6%) and focal segmental glomerulosclerosis (21.9%). The mean total number of glomeruli per biopsy was 17 ± 10. The mean baseline systolic blood pressure was 130 ± 20 mmHg and diastolic blood pressure was 81 ± 12 mmHg. The median proteinuria, serum creatinine, estimated GFR, and mean albumin values were 3300 (IQR: 1467-6307) mg/day, 1.0 (IQR: 0.7-1.6) mg/dL, 82.9 (IQR: 47.0-113.0) mL/min and 3.2 ± 0.9 g/dL, respectively. CONCLUSIONS: The distribution of PGDs in Turkey has become similar to that in other European countries. IgA nephropathy diagnosed via renal biopsy has become more prevalent compared to membranous nephropathy.

Renoprotective Effects of Alpha Lipoic Acid on Iron Overload-Induced Kidney Injury in Rats by Suppressing NADPH Oxidase 4 and p38 MAPK Signaling.

We aimed to investigate the protective effect of alpha lipoic acid (ALA), a powerful antioxidant, against oxidative kidney damage induced by iron overload in rats. Male Wistar albino rats were separated into groups: control (n = 7), ALA (100 mg/kg (n = 7), iron sucrose (IS) (40 mg/kg) (n = 7), and IS + ALA (40 mg/kg IS administration followed by 100 mg/kg ALA) (n = 7). IS and ALA were injected weekly for 4 weeks via the tail vein. Blood and kidneys were collected at sacrification on day 29. Serum creatinine and iron levels were analyzed. Tubular injury and iron deposits were evaluated histopathologically. Additionally, iron, malondialdehyde (MDA), superoxide dismutase (SOD), catalase, and glutathione (GSH) levels and mRNA expressions of the subunits of NADPH oxidase, known as NOX4 and p22phox, tumor necrosis factor (TNF)-α, kidney injury molecule-1 (KIM-1), and also p38 MAPK signaling in the kidneys, were evaluated biochemically. In the IS group, serum creatinine and iron level, tubular dilation, and loss of brush border in the kidneys were significantly higher than those of the control. Although those changes were reduced by ALA, the differences were not statistically significant. However, ALA reduced significantly MDA level and increased SOD activity in the kidney during IS administration. ALA also significantly reduced mRNA expressions of NOX4 and p22phox induced by IS, which was parallel to significant decreases of TNF-α and KIM-1 mRNA expressions. Moreover, ALA could suppress the activation of p38 MAPK during IS administration. In conclusion, ALA may be an effective strategy to attenuate in IS-induced oxidative kidney injury.

Predictors and histopathological characteristics of non-diabetic renal disorders in diabetes: a look from the tubulointerstitial point of view.

BACKGROUND: Prevalence and characteristics of non-diabetic renal diseases (NDRD) in patients with type 2 diabetes mellitus is different between populations, and seems to be largely dependent on biopsy policies. AIM: To investigate clinical clues for NDRD in patients with type 2 diabetes mellitus and to analyse renal prognosis of patients based on pathological diagnosis. METHODS: We retrospectively searched medical records of 115 patients with type 2 diabetes who underwent a renal biopsy between 2004 and 2018. Patients were divided into three groups as diabetic nephropathy (DN), NDRD + DN or NDRD based on histopathological examination. RESULTS: Thirty-six (31.3%) patients had DN, 33 (28.7%) had DN + NDRD and 46 (40%) had NDRD. The absence of diabetic retinopathy, recent onset of diabetes, abnormal disease chronology, and blood haemoglobin was associated with the presence of NDRD in univariate analysis. Abnormal disease chronology which was defined as the presence of acute proteinuria and/or acute kidney injury that are unexpected to be related to evolution of diabetic nepropathy (odds ratio 4.65, 95% confidence interval 1.44-15.00; P = 0.010) and absence of diabetic retinopathy (odds ratio 3.44, 95% confidence interval 1.32-8.98; P = 0.012) were independently associated with the presence of NDRD in multivariate analysis. Focal segmental glomerulosclerosis was the most frequent type of NDRD. Diseases that affect tubulointerstitial area were more prevalent in the DN + NDRD group compared to the NDRD group (P = 0.001). Renal survival, which was defined as evolution to end-stage renal disease, was 59.5 ± 14.4 months, 93.7 ± 11.7 months and 87.2 ± 2.6 months for DN, DN + NDRD and NDRD groups, respectively (P = 0.005). CONCLUSIONS: Renal biopsy is essential in certain clinical conditions as diagnosis of NDRD is vital for favourable renal survival. DN may facilitate superimposed tubular injury in the presence of toxic insults.

Renal tubular P-glycoprotein expression is reduced in plasma cell disorders.

BACKGROUND: P-glycoprotein (P-gp) transports many chemicals that vary greatly in their structure and function. It is normally expressed in renal proximal tubular cells. We hypothesized that P-gp expression influences light chain excretion. Therefore, we investigated whether renal tubular P-gp expression is altered in patients with plasma cell disorders. METHODS: We evaluated renal biopsy specimens from patients with plasma cell disorders (n = 16) and primary focal segmental glomerulosclerosis (the control group, n = 17). Biopsies were stained with an anti-P-gp antibody. Loss of P-gp expression was determined semi-quantitatively. Groups were compared for loss of P-gp expression, and clinical variables. RESULTS: P-gp expression loss was more severe in patients with plasma cell disorders than it was in those with glomerulonephritis (P = 0.021). In contrast, clinical and histological parameters including serum creatinine, level of urinary protein excretion, and interstitial fibrosis/tubular atrophy grade were not significantly different between the groups. P-gp expression loss increased with age in patients with plasma cell disorders (P = 0.071). This expression loss was not associated with serum creatinine, the level of urinary protein excretion or the interstitial fibrosis/tubular atrophy grade. There was no significant association between the severity of P-gp expression loss with the types and serum levels of light chains, isotypes and serum immunoglobulin levels. CONCLUSION: Renal tubular P-gp expression is significantly down-regulated in patients with plasma cell disorders characterized by nephrotic range proteinuria. Additional studies are needed to determine whether reintroduction of renal tubular P-gp expression would mitigate the proximal tubular injury that is caused by free-light chains.

Clinical significance of mesangial IgM deposition in patients with IgA nephropathy.

BACKGROUND: Glomerular immunoglobulin G deposition in patients with immunoglobulin A nephropathy (IgAN) has been shown to be associated with adverse renal outcomes. Clinical significance of mesangial immunoglobulin M (IgM) deposition in these patients remains to be proven. METHODS: One hundred patients who had a diagnosis of IgAN between 2001 and 2017 were enrolled. Patients were divided into two groups based on mesangial IgM deposition status. Groups were compared for demographic, clinical, and pathologic variables at baseline and in follow-up. Cox regression analysis was performed to evaluate the effect of mesangial IgM positivity on renal survival. RESULTS: IgM-positive group included 51% of participants. Baseline demographic and clinical parameters were not significantly different between groups. Mesangial IgM deposition was significantly associated with a higher segmental sclerosis score (p = 0.008). At last visit, median serum creatinine was higher (p = 0.021) and eGFR was lower (p = 0.006) in IgM-positive group. Nineteen (19%) of all patients reached the combined primary outcome which includes doubling in serum creatinine or evolution to ESRD. Cumulative renal survival was lower (p = 0.001) and resistant disease was more frequent in IgM-positive group (p = 0.026). Renal survival at 15 years was 94.2% and 59.7% in IgM-negative and IgM-positive groups, respectively (p = 0.006). Time-averaged proteinuria (HR 2.9; 95% CI 1.9-4.5; p < 0.001) and mesangial IgM deposition (HR, 13.2; 95% CI 1.9-93.1; p = 0.01) were found to be independent predictors of unfavorable renal outcomes. CONCLUSIONS: In conclusion, we demonstrated that mesangial IgM deposition independently associated with worse renal outcomes in patients with IgA nephropathy.

IgA nephropathy: association of C4d with clinical and histopathological findings and possible role of IgM.

BACKGROUND: In patients with IgA nephropathy (IgAN) lectin and alternative pathways of the complement can be activated. Our aim was to analyze the association of glomerular and extraglomerular C4d staining--the representative of lectin pathway-with demographic, clinical and histopathological findings in primary IgAN patients. DESIGN: Seventy-three patients were enrolled and after re-evaluation 37 of them were included in this study. Biopsies were analyzed for staining with anti-C4d primary monoclonal antibody by immunohistochemistry. Patients were classified as positive and negative groups based on their glomerular C4d deposition. Groups were compared for their baseline clinical and histopathological findings. RESULTS: Sixteen (43.2%) of 37 patients were C4d-positive. Glomerular C4d-staining was associated with more severe proteinuria (2906 mg/day vs. 1091 mg/day; p = 0.002), lower GFR (54.87 mL/min vs. 95 mL/min; p = 0.023), higher blood pressure (p = 0.022), more severe endocapillary hypercellularity (p < 0.001) and more severe tubular atrophy (p < 0.01). Mesangial IgM deposition was found to be associated with glomerular C4d staining and nephrotic range proteinuria. CONCLUSIONS: Glomerular C4d deposition was found to be associated with more unfavorable histopathological and clinical findings at the time of diagnosis. Association of mesangial IgM deposition with the activation of lectin pathway is a novel finding. Mesangial IgM deposition in our patients may reflect the genetic heterology of IgAN between diverse populations. However, since these data are about association, a cause-and-effect about IgM and IgAN cannot be proven solely with these findings.

Pauci-immune necrotizing crescentic glomerulonephritis with crescentic and full moon extracapillary proliferation: clinico-pathologic correlation and follow-up study.

The prognostic value of the type and extent of extracapillary proliferation (ECP) in pauci-immune necrotizing crescentic glomerulonephitis (PIGN) was evaluated in this study. In 141 PIGN cases, all glomeruli with ECP were grouped according to type (cellular, fibrocellular and fibrous) and extent of the lesions in Bowman's space; (segmental, semicircumferential and circumferential, which might be termed full moon-FM). Cases with cellular and fibrous lesions involving ≥ 50% of glomeruli with ECP were classified as cellular and fibrous groups, respectively, while the remaining cases were classified as fibrocellular. Cases with segmental and circumferential (FM glomerulus) lesions involving ≥ 50% of glomeruli with ECP were classified as ECPI and ECPIII (FM) groups, respectively, while the rest were classified as ECPII. All the cases were classified according to Berden et al. Significant results were only nearly obtained for the FM group, including the need for dialysis. The Cox regression model revealed a 2.6-fold risk for FM cases regarding dialysis requirement. We propose that the percentage of FM glomeruli should be noted in the pathology report, and cases with more than 50% of FM glomeruli (FM group) should be identified in the group with increased risk of dialysis requirement. Our series also suggests that classification according to Berden et al. is of clinical relevance.

Naturally occurring polymerase and surface gene variants of hepatitis B virus in Turkish hemodialysis patients with chronic hepatitis B.

The aim of this study was to assess the frequencies and patterns of naturally occurring genotypic resistance to nucleos(t)ide analogues (NUCs) and typical hepatitis B surface antigen (HBsAg) amino acid substitutions in naive hemodialysis (HD) patients with chronic hepatitis B. In order to achieve this, the genotypic resistance to NUCs and HBsAg amino acid substitutions were classified into primary/compensatory resistance mutation and antiviral drug-associated potential vaccine-escape mutation (ADAPVEM)/typical HBsAg amino acid substitution, respectively. Direct sequencing of polymerase (pol) gene of hepatitis B virus (HBV) was performed on DNA samples obtained from 248 HBsAg-positive Turkish patients. Overall, 38% (n = 94) of HBsAg-positive HD patients had detectable HBV DNA in their serum. Naturally occurring primary and compensatory resistance mutations to NUCs were detected in 30% (n = 28) and 52% (n = 49) of HD patients, respectively. However, 6 types of ADAPVEMs and 48 types of typical HBsAg amino acid substitutions were found in 10.6% (n = 10) and 46% (n = 43) of the HD patients, respectively. Our study suggests that every HD patient diagnosed with chronic hepatitis B, who is a potential candidate for NUCs treatment, should also be monitored for the baseline pol gene sequence changes before the initial treatment, for a more effective management of future treatment options. Further, a relatively higher frequency of ADAPVEMs variants needs to be addressed as a public health problem.