Intrarenal Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors on Tubuloglomerular Feedback and Natriuresis

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.

Effect of shared decision-making education on physicians’ perceptions and practices of end-of-life care in Korea

Evidence of the ethical appropriateness and clinical benefits of shared decision-making (SDM) are accumulating. This study aimed to not only identify physicians’ perspectives on SDM, and practices related to end-of-life care in particular, but also to gauge the effect of SDM education on physicians in Korea. Methods: A 14-item questionnaire survey using a modified Delphi process was delivered to nephrologists and internal medicine trainees at 17 university hospitals. Results: A total of 309 physicians completed the survey. Although respondents reported that 69.9% of their practical decisions were made using SDM, 59.9% reported that it is not being applied appropriately. Only 12.3% of respondents had received education on SDM as part of their training. The main obstacles to appropriate SDM were identified as lack of time (46.0%), educational materials and tools (29.4%), and education on SDM (24.3%). Although only a few respondents had received training on SDM, the proportion of those who thought they were using SDM appropriately in actual practice was high; the proportion of those who chose lack of time and education as factors that hindered the proper application of SDM was low. Conclusion: The majority of respondents believed that SDM was not being implemented properly in Korea, despite its use in actual practice. To improve the effectiveness of SDM in the Korean medical system, appropriate training programs and supplemental policies that guarantee sufficient application time are required.

Urate Transporters in the Kidney: What Clinicians Need to Know

Urate is produced in the liver by the degradation of purines from the diet and nucleotide turnover and excreted by the kidney and gut. The kidney is the major route of urate removal and has a pivotal role in the regulation of urate homeostasis. Approximately 10% of the glomerular filtered urate is excreted in the urine, and the remainder is reabsorbed by the proximal tubule. However, the transport of urate in the proximal tubule is bidirectional: reabsorption and secretion. Thus, an increase in reabsorption or a decrease in secretion may induce hyperuricemia.In contrast, a decrease in reabsorption or an increase in secretion may result in hyperuricosuria. In the proximal tubule, urate reabsorption is mainly mediated by apical URAT1 (SLC22A12) and basolateral GLUT9 (SLC2A9) transporter. OAT4 (SLC22A11) also acts in urate reabsorption in the apical membrane, and its polymorphism is associated with the risk of hyperuricemia. Renal hypouricemia is caused by SLC22A12 or SLC2A9 loss-of-function mutations, and it may be complicated by exercise-induced acute kidney injury. URAT1 and GLUT9 are also drug targets for uricosuric agents. Sodium-glucose cotransporter inhibitors may induce hyperuricosuria by inhibiting GLUT9b located in the apical plasma membrane. Urate secretion is mediated by basolateral OAT1 (SLC22A6) and OAT3 (SLC22A8) and apical ATP-binding cassette super-family G member 2 (>ABCG2), NPT1 (SLC17A1), and NPT4 (SLC17A3) transporter in the proximal tubule. NPT1 and NPT4 may be key players in renal urate secretion in humans, and deletion of SLC22A6 and SLC22A8 in mice leads to decreased urate excretion. Dysfunctional variants of >ABCG2 inhibit urate secretion from the gut and kidney and may cause gout. In summary, the net result of urate transport in the proximal tubule is determined by the dominance of transporters between reabsorption (URAT1, OAT4, and GLUT9) and secretion (ABCG2, NPT1, NPT4, OAT1, and OAT3).

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Background@#Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. @*Methods@#Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys. @*Results@#Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice. @*Conclusion@#These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Background@#Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. @*Methods@#Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys. @*Results@#Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice. @*Conclusion@#These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.

Posterior nutcracker phenomenon with Down syndrome

No abstract available.

Tempol Attenuates Renal Fibrosis in Mice with Unilateral Ureteral Obstruction: The Role of PI3K-Akt-FoxO3a Signaling

This study investigated whether tempol, an anti-oxidant, protects against renal injury by modulating phosphatidylinositol 3-kinase (PI3K)-Akt-Forkhead homeobox O (FoxO) signaling. Mice received unilateral ureteral obstruction (UUO) surgery with or without administration of tempol. We evaluated renal damage, oxidative stress and the expression of PI3K, Akt, FoxO3a and their target molecules including manganese superoxide dismutase (MnSOD), catalase, Bax, and Bcl-2 on day 3 and day 7 after UUO. Tubulointerstitial fibrosis, collagen deposition, alpha-smooth muscle actin-positive area, and F4/80-positive macrophage infiltration were significantly lower in tempol-treated mice compared with control mice. The expression of PI3K, phosphorylated Akt, and phosphorylated FoxO3a markedly decreased in tempol-treated mice compared with control mice. Tempol prominently increased the expressions of MnSOD and catalase, and decreased the production of hydrogen peroxide and lipid peroxidation in the obstructed kidneys. Significantly less apoptosis, a lower ratio of Bax to Bcl-2 expression and fewer apoptotic cells in TUNEL staining, and decreased expression of transforming growth factor-beta1 were observed in the obstructed kidneys from tempol-treated mice compared with those from control mice. Tempol attenuates oxidative stress, inflammation, and fibrosis in the obstructed kidneys of UUO mice, and the modulation of PI3K-Akt-FoxO3a signaling may be involved in this pathogenesis.

Cat-induced Pasteurella multocida peritonitis in continuous ambulatory peritoneal dialysis

Pasteurella multocida is a zoonotic pathogen found in the oral cavities of both domestic and wild animals. Although P. multocida has been involved in a wide range of human diseases, only a limited number of studies on P. multocida peritonitis in patients undergoing peritoneal dialysis (PD) had been carried out. We herein present the case of P. multocida peritonitis in a patient undergoing continuous ambulatory PD, which is believed to have resulted from contact with cats. We suggest that patients undergoing PD and having domestic animals at home should be educated about the possible transmission of the infection from the animals; in addition, these patients should also maintain a high level of personal hygiene.

IgG4-Related Tubulointerstitial Nephritis Accompanied by Henoch-Schonlein Purpura / 대한내과학회지

Tubulointerstitial nephritis is one of the common manifestations of immunoglobulin G (IgG)4-related disease; however, among all cases of tubulointerstitial nephritis undergoing renal biopsies, IgG4-related tubulointerstitial nephritis seems to be relatively rare because of its trivial urinary findings. A previously healthy 54-year-old man was referred to our clinic with a 4-week history of lower leg purpura and renal dysfunction. A kidney biopsy was planned because of bilateral renomegaly, by imaging studies, and elevated serum creatinine levels. Pathological findings in the kidney showed prominent infiltration of IgG4-postive plasma cells in the tubulointerstitium, but not the glumeruli. A skin biopsy revealed leukocytoclastic vasculitis, accompanied by deposition of IgA and C3 in the vascular wall, indicating Henoch-Schonlein purpura (HSP). Although cases of combined IgG4-related disease and microvasculitis, including HSP, are extremely rare, the possibility of an association between two diseases deserves attention.

Risk Factors and Reversibility of Renal Failure in Patients with Newly Diagnosed Multiple Myeloma / 대한내과학회지

BACKGROUND/AIMS: Multiple myeloma (MM) is frequently accompanied by renal insufficiency, which has been regarded as a poor prognostic factor for MM. It is known that the incidence and characteristics of MM in Asia differ from those in Western countries. The aim of this study was to evaluate risk factors for renal impairment and to investigate reversible factors for renal failure in patients with MM. METHODS: Patients newly diagnosed with MM from 2005 to 2008 were included. We investigated factors associated with renal insufficiency and those related to recovery from renal dysfunction after 12 weeks of treatment of MM. RESULTS: Renal failure was recognized in 86 (39%) of 221 patients at diagnosis. In the binary logistic regression analysis, low hemoglobin (odds ratio [OR], 0.813; p = 0.02), high beta2microglobulin (OR, 1.006; p < 0.01), and use of angiotensin-converting enzyme inhibitors (ACEi) (OR, 2.783; p < 0.04) at initial presentation were independent risk factors for renal failure in patients with multiple myeloma. After 12 weeks of treatment, 25 of 86 (29%) patients with renal failure had recovered renal function. Good response to chemotherapy (OR, 6.044; p < 0.01) and higher eGFR (OR, 1.084; p < 0.01) were associated with renal function recovery. CONCLUSIONS: Levels of hemoglobin and beta2microglobulin, and use of ACEi were independent risk factors for the development of renal failure in MM patients. The response to chemotherapy and eGFR at diagnosis significantly influenced recovery of renal function.

Risk Factors and Reversibility of Renal Failure in Patients with Newly Diagnosed Multiple Myeloma / 대한내과학회지

BACKGROUND/AIMS: Multiple myeloma (MM) is frequently accompanied by renal insufficiency, which has been regarded as a poor prognostic factor for MM. It is known that the incidence and characteristics of MM in Asia differ from those in Western countries. The aim of this study was to evaluate risk factors for renal impairment and to investigate reversible factors for renal failure in patients with MM. METHODS: Patients newly diagnosed with MM from 2005 to 2008 were included. We investigated factors associated with renal insufficiency and those related to recovery from renal dysfunction after 12 weeks of treatment of MM. RESULTS: Renal failure was recognized in 86 (39%) of 221 patients at diagnosis. In the binary logistic regression analysis, low hemoglobin (odds ratio [OR], 0.813; p = 0.02), high beta2microglobulin (OR, 1.006; p < 0.01), and use of angiotensin-converting enzyme inhibitors (ACEi) (OR, 2.783; p < 0.04) at initial presentation were independent risk factors for renal failure in patients with multiple myeloma. After 12 weeks of treatment, 25 of 86 (29%) patients with renal failure had recovered renal function. Good response to chemotherapy (OR, 6.044; p < 0.01) and higher eGFR (OR, 1.084; p < 0.01) were associated with renal function recovery. CONCLUSIONS: Levels of hemoglobin and beta2microglobulin, and use of ACEi were independent risk factors for the development of renal failure in MM patients. The response to chemotherapy and eGFR at diagnosis significantly influenced recovery of renal function.

Percutaneous renal biopsy should be considered as a daycare procedure in select patients

No abstract available.

Abdominal Aortic Calcification is Associated with Diastolic Dysfunction, Mortality, and Nonfatal Cardiovascular Events in Maintenance Hemodialysis Patients

This study evaluated the significance of aortic calcification index (ACI), an estimate of abdominal aortic calcification by plain abdominal computed tomography (CT), in terms of left ventricular (LV) diastolic dysfunction, mortality, and nonfatal cardiovascular (CV) events in chronic hemodialysis patients. Hemodialysis patients who took both an abdominal CT and echocardiography were divided into a low-ACI group (n = 64) and a high-ACI group (n = 64). The high-ACI group was significantly older, had a longer dialysis vintage and higher comorbidity indices, and more patients had a previous history of CV disease than the low-ACI group. The ACI was negatively correlated with LV end-diastolic volume or LV stroke volume, and was positively correlated with the ratio of peak early transmitral flow velocity to peak early diastolic mitral annular velocity (E/E' ratio), a marker of LV diastolic function. The E/E' ratio was independently associated with the ACI. The event-free survival rates for mortality and nonfatal CV events were significantly lower in the high-ACI group compared with those in the low-ACI group, and the ACI was an independent predictor for all-cause deaths and nonfatal CV events. In conclusion, ACI is significantly associated with diastolic dysfunction and predicts all-cause mortality and nonfatal CV events in hemodialysis patients.

Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: A Closer Look at Hyperkalemia / 대한내과학회지

Therapeutic manipulation of the renin-angiotensin-aldosterone system (RAAS) is an important strategy for improving hypertension, diabetes, cardiovascular disease, and chronic kidney disease. Development of hyperkalemia after the administration of RAAS inhibitors is of particular concern because patients at highest risk for this complication are often the same patients who derive the greatest cardiovascular or renoprotective benefit. Based on an overview of the incidence of hyperkalemia during treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers alone and in combination, this review suggests approaches for monitoring, detecting, and managing hyperkalemia in patients treated with RAAS inhibitors. Although the incidence of hyperkalemia with RAAS inhibitors is generally low, hyperkalemia can be associated with increased mortality. When using RAAS inhibitors, it is important to monitor on-treatment electrolyte levels and renal function parameters in patients with a high risk for hyperkalemia.

Very-Late Onset Diffuse Large B-cell Lymphoma with CD3 Coexpression in a Kidney Transplant Patient / 대한신장학회지

B-lineage non-Hodgkin lymphoma may aberrantly coexpress T-cell markers. In general population, however, cases of diffuse large B-cell lymphomas with CD3 co-expression are rare because the CD3 marker is the most lineage specific T-cell antigen. We report a case of CD3 coexpressed diffuse large B-cell lymphoma in a 47-year-old male patient presented with dyspepsia who had transplanted a kidney 17 years ago. An esophagogastroduodenoscopy displayed an ulcerated mass in the gastric antrum. The pathology of the mass was monomorphic post-transplant lymphoproliferative disorder - specifically, CD20- and CD3-positive diffuse large B-cell lymphoma. Resection of the mass and postop chemotherapy were performed. A follow-up computerized tomography showed disapperance of tumor. No recurrence was observed until 7 month after treatment. Nevertheless, the patient's renal function gradually aggrevated and progressed to end stage renal disease. As far as we know, this is the first case of diffuse large B-cell lymphoma with CD3 coexpression after kidney transplant.

What is the Optimal Period of Observation after Percutaneous Renal Biopsy? / 대한신장학회지

No abstract available.

Role of Peroxisome Proliferator-Activated Receptor alpha in Diabetic Nephropathy

With a developing worldwide epidemic of diabetes mellitus, the renal complications associated with diabetes have become a serious health concern. Primary therapy for treating diabetic nephropathy is a multifactorial process. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists have been used primarily in clinical practice for the treatment of dyslipidemia and insulin resistance. Given that PPARalpha expression and regulation of metabolic pathways are involved in oxidative stress, inflammation, blood pressure regulation, and the renin-angiotensin aldosterone system, PPARalpha likely influences the development and pathogenesis of diabetic nephropathy via indirect effects on glucose and lipid homeostasis and also by direct action on the kidneys. These findings suggest that PPARalpha may become an important therapeutic target for treating diabetic renal complications.

Status of Initiating Pattern of Hemodialysis: A Multi-center Study

This study was to evaluate the status of initiating pattern of hemodialysis (HD). Five hundred-three patients in 8 University Hospitals were included. Presentation mode (planned vs. unplanned), and access type (central venous catheters [CVC] vs. permanent access) at initiation of HD were evaluated, and the influence of predialysis care on determining the mode of HD and access type was also assessed. Most patients started unplanned HD (81.9%) and the most common initial access type was CVC (86.3%). The main reason for unplanned HD and high rate of CVC use was patient-related factors such as refusal of permanent access creation and failure to attend scheduled clinic appointments. Predialysis care was performed in 57.9% of patients and only 24.1% of these patients started planned HD and 18.9% used permanent accesses initially. Only a minority of patients initiated planned HD with permanent accesses in spite of predialysis care. To overcome this, efforts to improve the quality of predialysis care are needed.

The Impact of the Aortic Pulse Wave Velocity on the Cardiovascular Outcomes of Hemodialysis Patients

The aims of our study were to identify the risk factors for an increased aortic pulse wave velocity (AoPWV) and to assess the impact of the AoPWV on the cerebro-cardiovascular (CV) outcomes of hemodialysis (HD) patients. Seventy two HD patients were included, and the AoPWV, the echocardiography and the biochemical parameters were measured. After dividing the patients into tertiles according to the AoPWV values, we defined the low, the middle and the high AoPWV groups. The patients in the high AoPWV group showed a significantly higher age and high-sensitivity C-reactive protein level, a greater prevalence of diabetes and statin use, left ventricular hypertrophy, average pulse pressure (PP), AoPWV and left ventricular mass index and a lower serum albumin level than those in the low AoPWV group (p<0.05). On multivariate regression analysis of the AoPWV, age and the average PP were independently related to the AoPWV (p<0.05). On the multivariate Cox analysis for CV outcomes, the AoPWV and the average PP remained significant independent predictors of CV events. Our data suggest that an increased AoPWV is an independent predictor for the CV outcomes of HD patients.

Clinical Presentation of Diabetes Mellitus after Kidney Tansplantation / 대한신장학회잡지

BACKGROUND: Incidence rate of diabetes mellitus (DM) after renal transplantation has been reported variably, ranging from 2.5% to 45%. The new diagnostic criterion of diabetes presented by American Diabetes Association and use of new immunosuppressants may increase the incidence of post-transplant DM. METHODS: We investigated the incidence of post- transplant DM in 135 patients, who underwent kidney transplantation at Hanyang University Hospital between March, 1998 and February, 2003. The association of risk factors (age, sex, types of immunosuppressive agents, presence of acute rejection, and relationship with donor) with post-transplant DM was retrospectively evaluated using multivariate analysis. RESULTS: The incidence of post-transplant DM was 19.3%, and the significant risk factors were age over 40 years and male sex. Presence of acute rejection and relationship between donor and recipient were not significantly associated with the occurrence of post-transplant DM. Notably, the frequencies of post-transplant DM between cyclosporine and low- dose tacrolimus were not significantly different. CONCLUSION: The incidence of post-transplant DM is higher than that of DM in general population. Blood glucose should be frequently monitored in older male patients, considering their significant risk for post-transplant DM. Low-dose tacrolimus regimen dose not seem to increase the risk for post-transplant DM compared with cyclosporine.