From screening to treatment: the new landscape of diabetic kidney disease.

Globally, diabetes mellitus is the leading cause of chronic kidney disease (CKD), and it is predicted to increase in the following years. Despite its high prevalence, CKD remains under diagnosed. In this BMC Medicine collection of articles on diabetic kidney disease (DKD), we place in context the importance of screening and early detection of DKD and the most accurate tools to monitor for optimal glycemic control in this his risk population. Further, we address this population's risk for severe complications such as stroke and all-cause mortality. We close this editorial by summarizing recent advances in management of this vulnerable population of patients with DKD, including guideline-directed medical therapy, novel treatments, and predictors of treatment failure.

An unusual cause of metabolic alkalosis: hiding in plain sight.

BACKGROUND: Sodium bicarbonate, in the form of baking soda, is widely used as a home remedy, and as an additive for personal and household cleaning products. Its toxicity has previously been reported following oral ingestion in the setting of dyspepsia. However, its use as a non-ingested agent, like a toothpaste additive, has not been reported as a potential cause of toxicity. CASE PRESENTATION: We are reporting a case of an 80-year-old woman who presented with chronic metabolic alkalosis and hypokalemia secondary to exogenous alkali exposure from baking soda as a toothpaste additive, which might have represented an underreported ingestion of the substance. CONCLUSIONS: Considering that one teaspoon of baking soda provides approximately 59 m-equivalents (mEq) of bicarbonate, specific questioning on its general use should be pursued in similar cases of chloride resistant metabolic alkalosis.

A review of the utility of tacrolimus in the management of adults with autoimmune hepatitis.

BACKGROUND: There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) is a promising salvage agent. We present a review of TAC therapy in AIH patients. METHODS: A search for studies with keywords 'autoimmune hepatitis' and 'tacrolimus' was performed. Reviews, studies of AIH post-transplant and AIH in children were excluded. Diagnosis of AIH was based on criteria established by the International Autoimmune Hepatitis Group. Complete biochemical response was defined as normalisation of aspartate aminotransferase (AST <45) and alanine aminotransferase (ALT <50). No biochemical response was defined as failure to return to normalisation at the end of follow-up. Demographic information and details of pre- and post-treatment liver biopsy were collected. RESULTS: Seven articles achieved the inclusion criteria and reported data for a total of 162 adult patients. The majority of studies reported average ages approximately 35 years old. Treatment duration ranged from 1 to 136 months. Indications for therapy were mostly AIH refractory to steroid treatment or inability to tolerate standard steroid treatment. Eighty-three patients (51.2%) were reported to have pre-therapy liver biopsy. Of 49 patients for whom stage was reported, 6 patients were stage 1, 16 were stage 2, 14 were stage 3 and 13 were stage 4. Of 40 patients for whom grade was reported, 1 patient was grade 0, 3 were grade 1, 9 were grade 2, 14 were grade 3 and 13 were grade 4. Dosing regimens were between 1 and 8 mg/day. Target trough TAC serum concentrations ranged from 0.5 to 10.7 ng/mL TAC was discontinued in 28 (17.3%) patients for various reasons. Renal function remained stable in most patients. One hundred and twenty-one patients (74.7%) demonstrated complete biochemical response to treatment. Post-therapy liver biopsy was obtained for 30 (18.5%) patients, and 25 (15.4%) of these patients were noted to have histological remission according to the grade of inflammation or stage of fibrosis. CONCLUSION: TAC is relatively effective in the treatment of AIH refractory to traditional therapy. It appears that liver function can be enhanced at a minimal cost to renal function. Key Points There is a cohort of patients with autoimmune hepatitis (AIH) who do not respond to standard therapy. Alternative treatment options for these patients have been explored, but outcomes have not been comprehensively examined. We report the use and efficacy of tacrolimus (TAC) in patients with AIH. We found that TAC can be safely and effectively used in patients with AIH with minimal side effects. TAC can be a potential treatment option for patients with AIH refractory to standard therapy.

Indoxyl sulfate is associated with mortality after AKI - more evidence needed!

Patients who develop acute kidney injury (AKI) have significantly higher short-term outcomes including in-hospital mortality. The development of AKI has been associated with long-term consequences including progression to chronic kidney disease (CKD) and higher rates of cardiovascular disease (CVD) and mortality. In recent years there has been a growing push for the discovery of novel methods to diagnose AKI at earlier stages, and for an improvement in risk stratification and prognosis following AKI.Wang and colleagues assessed the association of total serum indoxyl sulfate (IS) levels, a protein bound uremic toxin, with 90-day mortality after hospital-acquired AKI (HA-AKI). These authors found that serum IS levels were significantly elevated in patients with HA-AKI (2.74 ± 0.75 µg/mL) compared to healthy subjects (1.73 ± 0.11 µg/ml, P < 0.001) and critically ill patients (2.46 ± 0.35 µg/ml, P = 0.016).The mechanisms of this relationship remain unclear, with a limited understanding of cause-specific mortality associated with either the high or low-IS group. One limitation of this current study is an understanding of the acceptable or expected higher level in IS during episodes of AKI. IS levels remained persistently elevated at day 7 compared to ß2-microglobulin and serum creatinine which were both lower at 7 days. It is unclear, however, if levels of ß2-microglobulin and serum creatinine were lower for other reasons, such as if any patients with AKI required dialysis.This work provides an important addition to the field of AKI research, specifically in the evaluation of readily measurable biomarkers and outcomes after AKI. Moving forward, further validation in studies of acute kidney injury are needed to develop a better understanding of IS levels at the time of AKI diagnosis and trends during the course of AKI.

Transjugular Intrahepatic Porto-Systemic Shunt in Patients with Liver Cirrhosis and Model for End-Stage Liver Disease ≥15.

BACKGROUND: It is not known whether transjugular intrahepatic porto-systemic shunt (TIPS) is safe in patients with advanced liver cirrhosis. The aim of our study was to evaluate the impact of TIPS on transplant-free survival in patients with liver cirrhosis and MELD score ≥15. METHODS: All adult patients who underwent TIPS at our institution between 2004 and 2011 were identified (N = 470). A total of 144 patients had MELD ≥15 at the time of TIPS. These patients were matched 1:1 to patients with liver cirrhosis who did not undergo TIPS based on age and MELD score using the greedy algorithm. Patients were followed up until time of death or liver transplantation. Kaplan-Meier curves and log-rank tests were used to test for differences in survival outcome between the two groups. RESULTS: A total of 288 patients with liver cirrhosis were included, of whom 144 underwent TIPS and 144 did not. The two groups were matched based on age and MELD score and were comparable with regard to gender and ethnicity. Mean MELD and Child-Pugh scores in the study population were 20.9 ± 6.5 and 10.5 ± 1.8, respectively. The most common indication for TIPS was varices (49 %), followed by refractory ascites (42 %). In the first 2 months post-TIPS, there was increased mortality or liver transplantation in patients who had TIPS compared to those who did not, but this did not reach statistical significance (p = 0.07). However, after 2 months, TIPS is associated with 56 % lower risk of dying or needing liver transplantation (p < 0.01) than cirrhotic patients who did not undergo TIPS. CONCLUSION: In patients with liver cirrhosis and MELD ≥15, TIPS might improve transplant-free survival for patients who live for at least 2 months after the procedure.

Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two-center experience.

BACKGROUND: The interferon-free antiviral regimen, sofosbuvir (SOF) and simeprevir (SIM) without ribavirin has been reported to achieve high sustained virologic response (SVR) rates with few adverse effects when treating patients with hepatitis C genotype 1 (HCV GT1) infection. However, there is scarcity of safety and efficacy data in this regimen after liver transplantation (LT). AIM AND METHODS: We aim to report the safety, tolerability and efficacy of SOF + SIM to treat LT recipients with recurrent HCV GT1 in a multicenter cohort study. RESULTS: Eighty-one patients with HCV GT1 met criteria to be considered for treatment. Sixty-seven patients received SOF + SIM following LT to date: 69% male, 39% with HCV RNA >6 000 000 IU/mL, 22% advanced hepatic fibrosis (stage 3-4), 6% cholestatic recurrence. Fifty-eight percent previously failed or did not tolerate interferon-based treatments. Mean time from LT to treatment was 6.1 ± 5.2 yr. All patients had estimated GFR >30 mL/min. Tacrolimus was primary immunosuppression in 84% of patients and minimal immunosuppression dose adjustments were required during treatment. In intention-to-treat analysis, 90% achieved end-of-treatment virologic response and 88% achieved SVR. CONCLUSIONS: Sofosbuvir + SIM combination therapy without ribavirin is well tolerated and results in high virologic response rates in recurrent HCV GT1 infection after liver transplantation.

Treatment of Acute Kidney Injury: A Review of Current Approaches and Emerging Innovations.

Acute kidney injury (AKI) is a complex and life-threatening condition with multifactorial etiologies, ranging from ischemic injury to nephrotoxic exposures. Management is founded on treating the underlying cause of AKI, but supportive care-via fluid management, vasopressor therapy, kidney replacement therapy (KRT), and more-is also crucial. Blood pressure targets are often higher in AKI, and these can be achieved with fluids and vasopressors, some of which may be more kidney-protective than others. Initiation of KRT is controversial, and studies have not consistently demonstrated any benefit to early start dialysis. There are no targeted pharmacotherapies for AKI itself, but some do exist for complications of AKI; additionally, medications become a key aspect of AKI management because changes in renal function and dialysis support can lead to issues with both toxicities and underdosing. This review will cover existing literature on these and other aspects of AKI treatment. Additionally, this review aims to identify gaps and challenges and to offer recommendations for future research and clinical practice.

Real-Life Experience on the Effect of SGLT2 Inhibitors vs. Finerenone vs. Combination on Albuminuria in Chronic Kidney Disease.

BACKGROUND: There have been several recent advances in the care of patients with chronic kidney disease (CKD), including the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and selective mineralocorticoid receptor antagonists (MRAs). There are very few data reporting the outcomes of these treatments in real-world experience. The aim of this retrospective study is to report the effects of SGLT2 inhibitors, finerenone, and their combination in CKD patients in our community-based setting. METHODS: Ninety-eight patients with CKD with an estimated glomerular filtration rate (eGFR) between 25 and 90 mL/min per 1.73 m2 and a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g were included. Patients were divided into three groups: two monotherapy groups of SGLT2 inhibitors or finerenone and a third combination group of therapy with SGLT2 inhibitors for the first 4 months and SGLT2 inhibitors and finerenone subsequently. The primary outcomes were the timing and percentage of patients achieving a >50% reduction in UACR from baseline. RESULTS: Group 1 comprised 52 patients on SGLT2i, group 2 had 22 patients on finerenone, and group 3 had 24 patients on combination therapy. The baseline median UACR and mean eGFR were 513 mg/g and 47.9 mL/min per 1.73 m2 in group 1, 548.0 mg/g and 50.5 mL/min per 1.73 m2 in group 2, and 800 mg/g and 60 mL/min per 1.73 m2 in group 3. At baseline, 71 (72.4%) patients were on the angiotensin-converting enzyme inhibitor (ACEi) or the angiotensin receptor blocker (ARB), and 78 (79.5%) patients had type 2 diabetes. After 8 months of follow-up, a >50% decrease in albuminuria was achieved in 96% of patients in group 3, compared to 50% in group 1 and 59% in group 2 (p-values were <0.01 and <0.01, respectively). There was a statistically but not clinically significant change in mean potassium levels in group 2 (+0.4 mmol/L) compared to either group 1 (0.0 mmol/L with p-value: <0.01) or group 3 (-0.01 mmol/L with p-value: <0.01). However, there was no difference in potassium levels when comparing groups 1 and 3. At the end of the follow-up, the average difference in eGFR was -3.4 (8.8), -5.3(10.1), and -7.8 (11.2) mL/min per 1.73 m2 in groups 1, 2, and 3, respectively, without a statistically significant difference between groups. CONCLUSIONS: In this real-world experience in our community setting, the combination of SGLT2 inhibitors and finerenone in our adult patients with CKD was associated with a very significant and clinically relevant reduction in UACR, without an increased risk of hyperkalemia. Combination therapy of SGLT2 inhibitor and finerenone regarding background use of ACEi/ARB is feasible and should be encouraged for further albuminuria reductions in CKD patients.

The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis in patients with liver cirrhosis.

BACKGROUND: Primary prophylaxis of spontaneous bacterial peritonitis (SBP) may provide a survival advantage in cirrhotic patients with ascites and has become an integral part of clinical practice. Rifaximin is a poorly absorbable antibiotic with a broad spectrum of antibacterial action and has low risk of introducing bacterial resistance. AIM: To determine whether rifaximin is associated with decreasing the risk of SBP and improving transplant-free survival in cirrhotic patients with ascites. METHODS: The medical records of all adult patients with liver cirrhosis and large ascites justifying paracentesis evaluated in our clinic (2003 to 2007) were reviewed. Patients were stratified into 2 groups by the use of rifaximin. Patients were excluded if they had received another antibiotic for SBP prophylaxis or had a history of SBP before rifaximin therapy. RESULTS: A total of 404 patients were included, of whom 49 (12%) received rifaximin. The rifaximin and nonrifaximin groups were comparable with regards to age, sex, and race. The median follow-up time was 4.2 [1.0, 17.1] months. During this time period, 89% of patients on rifaximin remained SBP free compared with 68% of those not on rifaximin (P=0.002). After adjusting for Model of End-Stage Liver Disease score, Child-Pugh score, serum sodium, and ascitic fluid total protein, there was a 72% reduction in the rate of SBP in the rifaximin group (hazard ratio=0.28; 95% confidence interval, 0.11-0.71; P=0.007). The group treated with rifaximin also demonstrated a transplant-free survival benefit compared with those not on rifaximin (72% vs. 57%, P=0.045). CONCLUSIONS: Intestinal decontamination with rifaximin may prevent SBP in cirrhotic patients with ascites. Prospective randomized controlled trials are needed to confirm this finding.

Hypercalcemia, Acute Kidney Injury, and Metabolic Alkalosis.

Calcium regulation is tightly controlled in the body. Multiple causes of hypercalcemia have been studied including primary hyperparathyroidism, hypercalcemia of malignancy, and chronic granulomatous disorders. Among the less studied causes is calcium-alkali syndrome. Here, we discuss a case of hypercalcemia secondary to calcium-alkali syndrome, presenting with hypercalcemia, metabolic alkalosis, and acute kidney injury as a result of ingestion of a large amount of calcium supplements. Hypercalcemia can result in impaired collecting duct system sensitivity to antidiuretic hormone, afferent arteriole constriction, and activation of calcium sensor receptors in multiple tissues. The net effect is an increase in calcium reabsorption with a salt and water diuresis which leads to volume depletion, acute kidney injury, and metabolic alkalosis.