Title: Kidney Pain vs. Back Pain
Category: Diseases and Conditions
Created: 12/20/2019 12:00:00 AM
Last Editorial Review: 4/8/2020 12:00:00 AM

Title: Kidney Dysplasia: In Infants and Children
Category: Diseases and Conditions
Created: 5/22/2012 12:00:00 AM
Last Editorial Review: 4/14/2020 12:00:00 AM

Key Points

Novel TM lupus mouse strains develop spontaneous nephritis.

In C1q deficiency, kidney complement activation likely occurred via the LP.

In C3 deficiency, coagulation cascade contributed to kidney complement activation.

Background

Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR).

Methods

CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m² and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m²) and linear mixed effects models to analyze the effects on eGFR slope.

Results

At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m², respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin’s lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m², canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m². Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (–1.72 versus –4.33 ml/min per 1.73 m²; between-group difference 2.61 ml/min per 1.73 m²).

Conclusions

Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m². Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.

Clinical Trial registry name and registration number

Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

Background

Kidney injury associated with cold storage is a determinant of delayed graft function and the long-term outcome of transplanted kidneys, but the underlying mechanism remains elusive. We previously reported a role of protein kinase C- (PKC) in renal tubular injury during cisplatin nephrotoxicity and albumin-associated kidney injury, but whether PKC is involved in ischemic or transplantation-associated kidney injury is unknown.

Methods

To investigate PKC’s potential role in injury during cold storage–associated transplantation, we incubated rat kidney proximal tubule cells in University of Wisconsin (UW) solution at 4°C for cold storage, returning them to normal culture medium at 37°C for rewarming. We also stored kidneys from donor mice in cold UW solution for various durations, followed by transplantation into syngeneic recipient mice.

Results

We observed PKC activation in both in vitro and in vivo models of cold-storage rewarming or transplantation. In the mouse model, PKC was activated and accumulated in mitochondria, where it mediated phosphorylation of a mitochondrial fission protein, dynamin-related protein 1 (Drp1), at serine 616. Drp1 activation resulted in mitochondrial fission or fragmentation, accompanied by mitochondrial damage and tubular cell death. Deficiency of PKC in donor kidney ameliorated Drp1 phosphorylation, mitochondrial damage, tubular cell death, and kidney injury during cold storage–associated transplantation. PKC deficiency also improved the repair and function of the renal graft as a life-supporting kidney. An inhibitor of PKC, V1-1, protected kidneys against cold storage–associated transplantation injury.

Conclusions

These results indicate that PKC is a key mediator of mitochondrial damage and renal tubular injury in cold storage–associated transplantation and may be an effective therapeutic target for improving renal transplant outcomes.

Background

The inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression.

Method

To explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1, Stat3, and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines.

Results

Our findings indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1-deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells.

Conclusions

STAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

Background

Expression of SerpinB2, a regulator of inflammatory processes, has been described in the context of macrophage activation and cellular senescence. Given that mechanisms for these processes interact and can shape kidney disease, it seems plausible that SerpinB2 might play a role in renal aging, injury, and repair.

Methods

We subjected SerpinB2 knockout mice to ischemia-reperfusion injury or unilateral ureteral obstruction. We performed phagocyte depletion to study SerpinB2’s role beyond the effects of macrophages and transplanted bone marrow from knockout mice to wild-type mice and vice versa to dissect cell type–dependent effects. Primary tubular cells and macrophages from SerpinB2 knockout and wild-type mice were used for functional studies and transcriptional profiling.

Results

Cultured senescent tubular cells, kidneys of aged mice, and renal stress models exhibited upregulation of SerpinB2 expression. Functionally, lack of SerpinB2 in aged knockout mice had no effect on the magnitude of senescence markers but associated with enhanced kidney damage and fibrosis. In stress models, inflammatory cell infiltration was initially lower in knockout mice but later increased, leading to an accumulation of significantly more macrophages. SerpinB2 knockout tubular cells showed significantly reduced expression of the chemokine CCL2. Macrophages from knockout mice exhibited reduced phagocytosis and enhanced migration. Macrophage depletion and bone marrow transplantation experiments validated the functional relevance of these cell type–specific functions of SerpinB2.

Conclusions

SerpinB2 influences tubule-macrophage crosstalk by supporting tubular CCL2 expression and regulating macrophage phagocytosis and migration. In mice, SerpinB2 expression seems to be needed for coordination and timely resolution of inflammation, successful repair, and kidney homeostasis during aging. Implications of SerpinB2 in human kidney disease deserve further exploration.

Background

Mutations in CTNS—a gene encoding the cystine transporter cystinosin—cause the rare, autosomal, recessive, lysosomal-storage disease cystinosis. Research has also implicated cystinosin in modulating the mTORC1 pathway, which serves as a core regulator of cellular metabolism, proliferation, survival, and autophagy. In its severest form, cystinosis is characterized by cystine accumulation, renal proximal tubule dysfunction, and kidney failure. Because treatment with the cystine-depleting drug cysteamine only slows disease progression, there is an urgent need for better treatments.

Methods

To address a lack of good human-based cell culture models for studying cystinosis, we generated the first human induced pluripotent stem cell (iPSC) and kidney organoid models of the disorder. We used a variety of techniques to examine hallmarks of cystinosis—including cystine accumulation, lysosome size, the autophagy pathway, and apoptosis—and performed RNA sequencing on isogenic lines to identify differentially expressed genes in the cystinosis models compared with controls.

Results

Compared with controls, these cystinosis models exhibit elevated cystine levels, increased apoptosis, and defective basal autophagy. Cysteamine treatment ameliorates this phenotype, except for abnormalities in apoptosis and basal autophagy. We found that treatment with everolimus, an inhibitor of the mTOR pathway, reduces the number of large lysosomes, decreases apoptosis, and activates autophagy, but it does not rescue the defect in cystine loading. However, dual treatment of cystinotic iPSCs or kidney organoids with cysteamine and everolimus corrects all of the observed phenotypic abnormalities.

Conclusions

These observations suggest that combination therapy with a cystine-depleting drug such as cysteamine and an mTOR pathway inhibitor such as everolimus has potential to improve treatment of cystinosis.

Background

The utility of kidney organoids in regenerative medicine will rely on the functionality of the glomerular and tubular structures in these tissues. Recent studies have demonstrated the vascularization and subsequent maturation of human pluripotent stem cell–derived kidney organoids after renal subcapsular transplantation. This raises the question of whether the glomeruli also become functional upon transplantation.

Methods

We transplanted kidney organoids under the renal capsule of the left kidney in immunodeficient mice followed by the implantation of a titanium imaging window on top of the kidney organoid. To assess glomerular function in the transplanted human pluripotent stem cell–derived kidney tissue 1, 2, and 3 weeks after transplantation, we applied high-resolution intravital multiphoton imaging through the imaging window during intravenous infusion of fluorescently labeled low and high molecular mass dextran molecules or albumin.

Results

After vascularization, glomerular structures in the organoid displayed dextran and albumin size selectivity across their glomerular filtration barrier. We also observed evidence of proximal tubular dextran reuptake.

Conclusions

Our results demonstrate that human pluripotent stem cell–derived glomeruli can develop an appropriate barrier function and discriminate between molecules of varying size. These characteristics together with tubular presence of low molecular mass dextran provide clear evidence of functional filtration. This approach to visualizing glomerular filtration function will be instrumental for translation of organoid technology for clinical applications as well as for disease modeling.

Understanding fructose metabolism might provide insights to renal pathophysiology. To support systemic glucose concentration, the proximal tubular cells reabsorb fructose as a substrate for gluconeogenesis. However, in instances when fructose intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflammation, and fibrosis in the kidney. A recent scientific advance is the discovery that fructose can be endogenously produced from glucose under pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac hypertrophy, and with dehydration. Why humans have such a deleterious mechanism to produce fructose is unknown, but it may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.

The kidneys play an important role in many processes, including urine formation, water conservation, acid-base equilibrium, and elimination of waste. The anatomic and functional development of the kidney has different maturation time points in humans versus animals, with critical differences between species in maturation before and after birth. Absorption, distribution, metabolism, and excretion (ADME) of drugs vary depending on age and maturation, which will lead to differences in toxicity and efficacy. When neonate/juvenile laboratory animal studies are designed, a thorough knowledge of the differences in kidney development between newborns/children and laboratory animals is essential. The human and laboratory animal data must be combined to obtain a more complete picture of the development in the kidneys around the neonatal period and the complexity of ADME in newborns and children. This review examines the ontogeny and cross-species differences in ADME processes in the developing kidney in preterm and term laboratory animals and children. It provides an overview of insights into ADME functionality in the kidney by identifying what is currently known and which gaps still exist. Currently important renal function properties such as glomerular filtration rate, renal blood flow, and ability to concentrate are generally well known, while detailed knowledge about transporter and metabolism maturation is growing but is still lacking. Preclinical data in those properties is limited to rodents and generally covers only the expression levels of transporter or enzyme-encoding genes. More knowledge on a functional level is needed to predict the kinetics and toxicity in neonate/juvenile toxicity and efficacy studies.

SIGNIFICANCE STATEMENT

This review provides insight in cross-species developmental differences of absorption, distribution, metabolism, and excretion properties in the kidney, which should be considered in neonate/juvenile study interpretation, hypotheses generation, and experimental design.

Alemtuzumab is approved for the treatment of relapsing-remitting MS and is used off-label for patients with chronic lymphocytic leukemia and as induction and antirejection therapy in kidney transplant recipients.¹ Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) complicating alemtuzumab treatment was reported in 9 patients with hematologic malignancy or MS.^1–3 The risk of GBS or CIDP in solid organ transplant recipients treated with alemtuzumab is unknown.

OBJECTIVE

Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes.

RESEARCH DESIGN AND METHODS

A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m²) at baseline, participants were classified into the four DKD phenotypes—no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR—to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline.

RESULTS

During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher.

CONCLUSIONS

Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.

OBJECTIVE

To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² in people with diabetes.

RESEARCH DESIGN AND METHODS

We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006–2014) that linked the Sax Institute’s 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement <60 mL/min/1.73 m² recorded during the follow-up period. Participants with eGFR < 60 mL/min/1.73 m² at baseline were excluded. We used Poisson regression to estimate the incidence of eGFR <60 mL/min/1.73 m² and multivariable Cox regression to examine factors associated with the study outcome.

RESULTS

Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR <60 mL/min/1.73 m² over a median follow-up time of 5.7 years (interquartile range, 3.0–5.9 years). The eGFR <60 mL/min/1.73 m² incidence rate per 100 person-years was 6.0 (95% CI 5.7–6.3) overall, 1.5 (1.3–1.9) in participants aged 45–54 years, 3.7 (3.4–4.0) for 55–64 year olds, 7.6 (7.1–8.1) for 65–74 year olds, 15.0 (13.0–16.0) for 75–84 year olds, and 26.0 (22.0–32.0) for those aged 85 years and over. In a fully adjusted multivariable model incidence was independently associated with age (hazard ratio 1.23 per 5-year increase; 95% CI 1.19–1.26), geography (outer regional and remote versus major city: 1.36; 1.17–1.58), obesity (obese class III versus normal: 1.44; 1.16–1.80), and the presence of hypertension (1.52; 1.33–1.73), coronary heart disease (1.13; 1.02–1.24), cancer (1.30; 1.14–1.50), and depression/anxiety (1.14; 1.01–1.27).

CONCLUSIONS

In participants with diabetes, the incidence of an eGFR <60 mL/min/1.73 m² was high. Older age, remoteness of residence, and the presence of various comorbid conditions were associated with higher incidence.

OBJECTIVE

Metformin is the first pharmacological option for treating type 2 diabetes. However, the use of this drug is not recommended in individuals with impaired kidney function because of the perceived risk of lactic acidosis. We aimed to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD).

RESEARCH DESIGN AND METHODS

We conducted a retrospective observational cohort study of 10,426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. Taking into account the possibility that patients with less severe disease were prescribed metformin, propensity score matching (PSM) was conducted.

RESULTS

All-cause mortality and incident ESRD were lower in the metformin group according to the multivariate Cox analysis. Because the two groups had significantly different baseline characteristics, PSM was performed. After matching, metformin usage was still associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% CI 0.57–0.73; P < 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58–0.77; P < 0.001). Only one event of metformin-associated lactic acidosis was recorded. In both the original and PSM groups, metformin usage did not increase the risk of lactic acidosis events from all causes (aHR 0.92; 95% CI 0.668–1.276; P = 0.629).

CONCLUSIONS

In the present retrospective study, metformin usage in advanced chronic kidney disease (CKD) patients, especially those with CKD 3B, decreased the risk of all-cause mortality and incident ESRD. Additionally, metformin did not increase the risk of lactic acidosis. However, considering the remaining biases even after PSM, further randomized controlled trials are needed to change real-world practice.

Metabolic disorders are highly prevalent in kidney transplant candidates and recipients and can adversely affect post-transplant graft outcomes. Management of diabetes, hyperparathyroidism, and obesity presents distinct opportunities to optimize patients both before and after transplant as well as the ability to track objective data over time to assess a patient’s ability to partner effectively with the health care team and adhere to complex treatment regimens. Optimization of these particular disorders can most dramatically decrease the risk of surgical and cardiovascular complications post-transplant. Approximately 60% of nondiabetic patients experience hyperglycemia in the immediate post-transplant phase. Multiple risk factors have been identified related to development of new onset diabetes after transplant, and it is estimated that upward of 7%–30% of patients will develop new onset diabetes within the first year post-transplant. There are a number of medications studied in the kidney transplant population for diabetes management, and recent data and the risks and benefits of each regimen should be optimized. Secondary hyperparathyroidism occurs in most patients with CKD and can persist after kidney transplant in up to 66% of patients, despite an initial decrease in parathyroid hormone levels. Parathyroidectomy and medical management are the options for treatment of secondary hyperparathyroidism, but there is no randomized, controlled trial providing clear recommendations for optimal management, and patient-specific factors should be considered. Obesity is the most common metabolic disorder affecting the transplant population in both the pre- and post-transplant phases of care. Not only does obesity have associations and interactions with comorbid illnesses, such as diabetes, dyslipidemia, and cardiovascular disease, all of which increase morbidity and mortality post-transplant, but it also is intimately inter-related with access to transplantation for patients with kidney failure. We review these metabolic disorders and their management, including data in patients with kidney transplants.

Congenital anomalies of the kidneys and urinary tracts (CAKUT) are disorders caused by defects in the development of the kidneys and their outflow tracts. The formation of the kidneys begins at week 3 and nephrogenesis continues until week 36, therefore, the kidneys and outflow tracts are susceptible to environmental risk factors that perturb development throughout gestation. Many genes have been implicated in kidney and outflow tract development, and mutations have been identified in patients with CAKUT. In severe cases of CAKUT, when the kidneys do not form, the fetus will not survive. However, in less severe cases, the baby can survive with combined kidney and outflow tract defects or they may only be identified in adulthood. In this review, we will cover the clinical presentation of CAKUT, its epidemiology, and its long-term outcomes. We will then discuss risk factors for CAKUT, including genetic and environmental contributions. Although severe CAKUT is rare, low nephron number is a much more common disorder with its effect on kidney function increasingly apparent as a person ages. Low nephron number appears to arise by the same mechanisms as CAKUT, but it differs in terms of the magnitude of the insult and the timing of when it occurs during gestation. By understanding the causes of CAKUT and low nephron number, we can begin to identify preventive treatments and establish clinical guidelines for how these patients should be followed.

The kidney is a complex organ responsible for maintaining multiple aspects of homeostasis in the human body. The combination of distinct, yet interrelated, molecular functions across different cell types make the delineation of factors associated with loss or decline in kidney function challenging. Consequently, there has been a paucity of new diagnostic markers and treatment options becoming available to clinicians and patients in managing kidney diseases. A systems biology approach to understanding the kidney leverages recent advances in computational technology and methods to integrate diverse sets of data. It has the potential to unravel the interplay of multiple genes, proteins, and molecular mechanisms that drive key functions in kidney health and disease. The emergence of large, detailed, multilevel biologic and clinical data from national databases, cohort studies, and trials now provide the critical pieces needed for meaningful application of systems biology approaches in nephrology. The purpose of this review is to provide an overview of the current state in the evolution of the field. Recent successes of systems biology to identify targeted therapies linked to mechanistic biomarkers in the kidney are described to emphasize the relevance to clinical care and the outlook for improving outcomes for patients with kidney diseases.

Background and objectives

Walking while talking is a dual cognitive-motor task that predicts frailty, falls, and cognitive decline in the general elderly population. Adults with CKD have gait abnormalities during usual walking. It is unknown whether they have greater gait abnormalities and cognitive-motor interference during walking while talking.

Design, setting, participants, & measurements

Community-dwelling, nondisabled adults (n=330) ≥65 years of age underwent quantitative gait analysis, including walking while talking. Differences in walking-while-talking performance by CKD status were evaluated, and relative changes between walking-while-talking and walking alone performance were computed to quantify cognitive-motor interference (dual-task cost). Associations were tested using multivariable linear spline regression models, and independent gait domains were derived using factor analysis. CKD was defined as an eGFR<60 ml/min per 1.73 m².

Results

CKD was present in 134 (41%) participants. Participants with CKD had slower gait speed along with various gait cycle abnormalities during walking while talking: among those with CKD, every 10-ml/min per 1.73 m² lower eGFR was associated with 3.3-cm/s (95% confidence interval, 0.4 to 6.1) slower gait speed, 1.8-cm (95% confidence interval, 0.6 to 3.0) shorter step length, 1.1% (95% confidence interval, 0.6 to 1.7) less time in the swing phase, and 1.4% (95% confidence interval, 0.5 to 2.3) greater time in double support after multivariable adjustment. When comparing walking while talking with walking alone, every 10-ml/min per 1.73 m² lower eGFR was associated with 1.8% (95% confidence interval, 0.5 to 3.2) greater decrease in time in the swing phase and 0.9% (95% confidence interval, 0.2 to 1.5) greater increase in time in the stance phase. Factor analysis identified three walking-while-talking domains and three dual-task cost domains: eGFR was associated specifically with the rhythm domain for both walking-while-talking and dual-task cost. Every 10-ml/min per 1.73 m² lower eGFR was associated with a poorer performance of 0.2 SD (95% confidence interval, 0.1 to 0.3) for walking while talking and 0.2 SD (95% confidence interval, 0.03 to 0.3) for dual-task cost.

Conclusions

During walking while talking, CKD is associated with gait abnormalities, possibly due to increased cognitive-motor interference.

Background and objectives

Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion–transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl–CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use.

Design, setting, participants, & measurements

The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone.

Results

No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference –2.4%; 95% confidence interval, –11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; –7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3x upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; –2.0% to 4.7%).

Conclusions

Tolvaptan has been used safely in combination with statins in clinical trials.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3

Background and objectives

Uromodulin is exclusively produced by tubular epithelial cells and released into urine and serum. Higher serum uromodulin has been associated with lower risk for kidney failure in Chinese patients with CKD and with lower risk for mortality in the elderly and in patients undergoing coronary angiography. We hypothesized that lower serum uromodulin is associated with mortality, cardiovascular events, and kidney failure in white patients with CKD.

Design, setting, participants, & measurements

We measured serum uromodulin in 5143 participants enrolled in the German CKD (GCKD) study. The associations of baseline serum uromodulin with all-cause mortality, major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, nonfatal myocardial infarction or stroke, or incident peripheral vascular disease), and kidney failure (dialysis or transplantation) were evaluated using multivariable Cox proportional hazard regression analyses in a cohort study design, adjusting for demographics, eGFR, albuminuria, cardiovascular risk factors, and medication.

Results

The mean age of participants was 60±12 years, 60% were male. Mean serum uromodulin concentration was 98±60 ng/ml, eGFR was 49±18 ml/min per 1.73 m², and 78% had eGFR <60 ml/min per 1.73 m². Participants in lower serum uromodulin quartiles had lower eGFR and higher albuminuria, prevalence of diabetes, hypertension, coronary artery disease, and more frequent history of stroke at baseline. During a follow-up of 4 years, 335 participants died, 417 developed MACE, and 229 developed kidney failure. In multivariable analysis, the highest serum uromodulin quartile was associated with lower hazard for mortality (hazard ratio [HR], 0.57; 95% CI, 0.38 to 0.87), MACE (HR, 0.63; 95% CI, 0.45 to 0.90), and kidney failure (HR, 0.24; 95% CI, 0.10 to 0.55) compared with the lowest quartile.

Conclusions

Higher serum uromodulin is independently associated with lower risk for mortality, cardiovascular events, and kidney failure in white patients with CKD.

Clinical Trial registry name and registration number

Deutsches Register für Klinische Studien (DRKS; German national database of clinical studies), DRKS00003971.

The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population.We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro–B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, β-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A_1c [Hb A_1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016–2017; age 71–94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors.In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44–3.22]; no diabetes: OR, 2.31 [95%CI, 1.76–3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08–1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22–1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A_1c (OR, 1.76 [95% CI, 1.22–2.54]), fructosamine (OR, 1.71 [95% CI, 1.19–2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03–2.03]) with PN were significant only among participants with diabetes.Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Cardiovascular (CV) disease remains an important cause of morbidity and mortality for patients with chronic kidney disease (CKD). Although clustering of traditional risk factors with CKD is well recognized, kidney-specific mechanisms are believed to drive the disproportionate burden of CV disease. One perturbation that is frequently observed at high rates in patients with CKD is vascular calcification, which may be a central mediator for an array of CV sequelae. This review summarizes the pathophysiological bases of intimal and medial vascular calcification in CKD, current strategies for diagnosis and management, and posits vascular calcification as a risk marker and therapeutic target.

Recent FDA approvals of regimens targeting programmed death 1 (PD-1) in combination with anti-CTLA-4 or with VEGF tyrosine kinase inhibitors are reshaping front-line therapy for metastatic kidney cancer. In parallel, therapeutics specific for programmed death ligand 1 (PD-L1), one of the two major ligands for PD-1, are under continued investigation. Surprisingly, not all PD-1 and PD-L1 agents lead to similar clinical outcomes, potentially due to biological differences in the cellular expression and regulation of these targets. Here, we review current clinical data on combination immune checkpoint inhibitor therapy in metastatic kidney cancer and discuss the relevant biology of PD-1 and PD-L1. The design of future rational combination therapy trials in metastatic renal cell carcinoma will rely upon an understanding of this biology, along with an evolving understanding of immune cell populations and their functional states in the tumor microenvironment.

We investigated dose-fractionated polymyxin B (PB) on acute kidney injury (AKI). PB at 12 mg of drug/kg of body weight per day (once, twice, and thrice daily) was administered in rats over 72 h. The thrice-daily group demonstrated the highest KIM-1 increase (P = 0.018) versus that of the controls (P = 0.99) and histopathological damage (P = 0.013). A three-compartment model best described the data (bias, 0.129 mg/liter; imprecision, 0.729 mg²/liter²; R², 0.652,). Area under the concentration-time curve at 24 h (AUC₂₄) values were similar (P = 0.87). The thrice-daily dosing scheme resulted in the most PB-associated AKI in a rat model.

BACKGROUND AND PURPOSE:

The use of invasive cerebral angiography with CTA for active treatment of patients with suspected ischemic strokes has been increasing recently. This study aimed to identify the incidence of postcontrast acute kidney injury using baseline renal function when CTA and cerebral angiography were performed sequentially.

MATERIALS AND METHODS:

This retrospective observational study evaluated adults (18 years of age or older) with ischemic stroke who underwent CTA and cerebral angiography sequentially between 2010 and 2018. The incidence of postcontrast acute kidney injury was determined using the baseline estimated glomerular filtration rate. The value of the baseline estimated glomerular filtration rate at which the occurrence of postcontrast acute kidney injury increased was also determined.

RESULTS:

Postcontrast acute kidney injury occurred in 57/601 (9.5%) patients. Those with a baseline estimated glomerular filtration rate of <30 mL/min/1.73 m² showed a higher incidence of acute kidney injury. Age, chronic kidney disease, medication (nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, statins, and insulin) use following contrast media exposure, and serum albumin affected the incidence of postcontrast acute kidney injury. The incidence of postcontrast acute kidney injury increased when the baseline estimated glomerular filtration rate was <43 mL/min/1.73 m².

CONCLUSIONS:

Patients with low baseline renal function had the highest incidence of postcontrast acute kidney injury after CTA and cerebral angiography, but no fatal adverse effects were documented. Thus, patients suspected of having a stroke should be actively managed with respect to neurovascular function.

The guideline is designed to help healthcare professionals who are not kidney specialists to prevent, detect and manage AKI in hospitalised patients with suspected or confirmed COVID-19

Today's Daily Dose brings you news about the acquisition of Portola by Alexion; encouraging results from TG Therapeutics' chronic lymphocytic leukemia trial; Akebia's INNO2VATE trial results; and Vapotherm's Q1 financial results.

Although the health benefits of tea are roundly lauded, an Arkansas man recently found out that too much can be devastating.

A senior citizen from Kalina, Anwari Begum, 70, died after three top hospitals in the city refused to give her dialysis without her COVID-19 test results being in, the woman's family has claimed. The test results, which arrived on Monday, returned negative.

Begum had been undergoing dialysis at Guru Nanak Hospital in Bandra East for the past one year. Her last dialysis at the hospital was on April 18, when a COVID-19 positive patient was found in the hospital. The hospital asked her to visit on April 22 — which was also the day of her next dialysis — for a COVID-19 test.

Anwari Begum's two sons (from left) Zakaria Shaikh, Haroon Shaikh and Mohammed Hasan (right ) her son-in-law

"My mother-in-law's COVID-19 test was done on Wednesday, April 22. She was also supposed to get dialysis on the same day but the hospital refused, saying they will do it only after her test results come, which was going to take 48 hours. On Thursday, she had severe pain and needed the dialysis urgently. So we went to the hospital around 4 pm but they refused as her reports were pending. We waited for over two hours at the hospital, but they did not listen," said Mohammed Hasan, Begum's son-in-law.

"After Guru Nanak, we approached Nanavati Hospital. Many other patients like us were stopped at the gate. They took her files and after two hours, enquired about her COVID-19 test report and said that they are not taking outside patients. Some from the family took her to Kokilaben Dhirubhai Ambani Hospital around 8.30 pm and I went to look for a dialysis centre in Kalina and Sakinaka. At Kokilaben, my family was asked to finish formalities, which took two hours, but they too refused to treat her," Hasan said.

Guru Nanak Hospital in Bandra East. File pic

Found help, but too late
Dialysis patients all over the city have been suffering amid the Coronavirus pandemic. Despite guidelines from the State Health Department that do not necessitate a COVID-19 test for patients needing dialysis and only ask hospitals to take universal precautions, hospitals across the city are refusing to treat patients without the test.

Hospitals say that they are overburdened due to the closure of dialysis centres which has increased the volume of patients with kidney ailments and that they cannot accommodate every patient.

Hasan approached Axon Hospital in Sakinaka, which said that the dialysis centre is closed as their staff is unwell. "I requested them explaining the condition of my mother-in-law and pleaded with folded hands to have mercy. I also promised to pay whatever amount is required. After some time, the concerned doctor listened to me and called his dialysis staff. My mother-in-law reached the hospital around 11 pm. At 11.30 pm, the assistant doctor told me that her condition has worsened."
Begum died shortly after that. Her test results, which came on Monday, showed her negative for Coronavirus.

"The funeral was performed the next day at 10 am. Sometime later, I received a call from the person who had referred us to the nephrologist at Guru Nanak Hospital. He was apparently told by someone from the hospital that my mother tested positive. We live in a joint family and everyone panicked but no one from the hospital called us. A few days later, we got her report, which was negative," Hasan said.

According to BMC's Health Department, a COVID-19 test is not mandatory for dialysis patients. "Everyone has to take universal precautions, a COVID-19 test report is not mandatory," said Dr. Daksha Shah, BMC's deputy executive health officer.

"24 hours after sanitising the dialysis centre, the hospital can resume services as per the guidelines. If they suspect a patient to be positive, he/she can be quarantined," Dr Shah added.

'Followed task force rules'
Guru Nanak Hospital defended itself saying it was just following guidelines of the state government's task force committee, as per which, an affected dialysis centre must close for fumigation and surface cleaning. "Our dialysis centre is open 24x7. That day, a COVID-19 case was reported. As per the rules, we had to shut the dialysis centre for 24 hours, sanitise the area and quarantine the staff. Around seven workers from the dialysis centre were quarantined. They have tested negative," said Dr. Narendra Sharma, spokesperson of the hospital, who did not clearly remember on which day the case was reported.

"Dialysis patients travel through Containment Zones. Despite taking all precautions, such incidents are happening, which is the biggest challenge for us," Sharma said.

"As per my knowledge, the case was reported on Saturday. We needed the dialysis on Thursday. That makes five days. Why did Guru Nanak Hospital refuse to treat her when it is supposed to be shut only for 24 hours?" Hasan said.

Dr. Santosh Shetty, executive director and CEO, Kokilaben Dhirubhai Ambani Hospital, said, "We are not testing our existing dialysis patients. We take patients' history and screen them before every dialysis. Currently, we have nearly 200 patients on dialysis. We are following BMC and state task force's guidelines."

While the spokesperson of Nanavati Super Speciality Hospital said, "Nanavati Hospital is one of the very few quaternary care medical facilities in Mumbai to provide dialysis treatment for COVID-19 patients. Thus the high influx of patients ensures dialysis beds reserved for patients as per their COVID-19 status are occupied. However, the unavailability of a bed is immediately communicated to the patient or their family."

Apr 22
Day Anwari Begum was tested for Coronavirus

Apr 27
Day her test returned negative, four days after her death

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Gestational diabetes -- high blood sugar condition during pregnancy -- may cause early-stage kidney damage that can later lead to chronic kidney diseases among women, reported a study.

The study showed that women with gestational diabetes were more likely to have a high glomerular filtration rate (GFR) -- an estimate of how much blood per minute passes through the glomeruli, the tiny filters within kidneys that extract waste from the blood.

Women with gestational diabetes had more than triple the risk of an elevated GFR, which may precede the early kidney damage that accompanies pre-diabetes -- a condition with higher blood sugar levels but not high enough to be classified as diabetes.

"Our findings suggest that women who have had gestational diabetes may benefit from periodic checkups to detect early-stage kidney damage and receive subsequent treatment," said Cuilin Zhang from National Institutes of Health's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in Maryland, US.

The study, published in the journal Diabetes Care, included data from 601 Danish women having gestational diabetes and 613 non-diabetic women.

The results showed that women who had gestational diabetes and later developed diabetes were approximately nine times more likely to have an elevated GFR later in life, compared to women who did not have gestational diabetes.

They were also likely to have an elevated urinary albumin to creatinine ratio (UACR), which is an indicator of kidney disease.

The study could not prove that gestational diabetes causes kidney damage, and the authors noted that more research is needed to confirm their findings.

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Two types of diabetes drugs namely SGLT2 inhibitors and GLP-1 drugs were effective in reducing heart complications including stroke, heart attack, and

Sodium glucose cotransporter 2 (SGLT2) inhibitors which are primarily used to treat type 2 diabetes were found to lower the risk of serious kidney problems, revealed study published in The BMJ.

Sugary soda consumption downs kidney blood flow, and raise the risk of developing chronic kidney disease, according to a study in the iAmerican Journal of Physiology-Renal Physiology/i.

Exposure to higher levels of air pollution was associated with a higher level of albuminuria and higher risk for incident chronic kidney disease, reports a new study.

Chronic kidney disease (CKD) affects approximately 10% of the global population, and leads to five to ten million deaths annually. Growing in importance is a distinctive form with unknown/uncertain etiology (CKDu), the cause of which remains unknown and is not linked to factors normally associated with CKD.

Cancer cells which become "addicted" to glucose could open up fresh approaches to therapy strategies for cancers with high levels of an amino acid transporter