Systematic review of nephrotoxicity of drugs of abuse, 2005-2016.

BACKGROUND: The United States is faced with an unprecedented epidemic of drug abuse. Every year thousands of Americans visit the emergency departments all over the country with illicit drug related complaints. These drugs have been known to be associated with a range of renal pathologies, from reversible acute kidney injuries to debilitating irreversible conditions like renal infarction. So far, no comprehensive study or systematic review has been published that includes the commonly used street drugs and designer drugs with potential nephrotoxic outcomes. METHODS: We conducted a systematic review of published case reports, case series, and cross sectional studies of nephrotoxicities related to drugs of abuse. Literature review was conducted using PubMed/Medline from January 1, 2005 -December 31, 2016 to search for publications related to drug abuse with a defined renal outcome. Publications which reported renal injury in relation to the use of illicit drugs were selected, specifically those cases with raised creatinine levels, clinically symptomatic patients, for instance those with oliguria and proven renal biopsies. RESULTS: A total of 4798 publications were reviewed during the search process and PRISMA flow chart and Moose protocol regarding systematic reviews were followed. 110 articles were shortlisted for the review. A total of 169 cases from case reports and case series, and 14 case studies were analyzed. Renal manifestations of specific illicit drug abuse were included in this review. CONCLUSION: Based on the evidence presented, a wide range of renal manifestations were found to be associated with drug abuse. If the trend of increasing use of illicit drug use continues, it will put a significant percentage of the population at an elevated risk for poor renal outcomes. This study is limited by the nature of the literature reviewed being primarily case reports and case series.

Hypertonic Saline Infusion for Hyponatremia: Limitations of the Adrogué-Madias and Other Formulas.

Hypertonic saline infusion is used to correct hyponatremia with severe symptoms. The selection of the volume of infused hypertonic saline ( VInf ) should address prevention of overcorrection or undercorrection. Several formulas computing this VInf have been proposed. The limitations common to these formulas consist of (1) failure to include potential determinants of change in serum sodium concentration ([ Na ]) including exchanges between osmotically active and inactive sodium compartments, changes in hydrogen binding of body water to hydrophilic compounds, and genetic influences and (2) inaccurate estimates of baseline body water entered in any formula and of gains or losses of water, sodium, and potassium during treatment entered in formulas that account for such gains or losses. In addition, computing VInf from the Adrogué-Madias formula by a calculation assuming a linear relation between VInf and increase in [ Na ] is a source of errors because the relation between these two variables was proven to be curvilinear. However, these errors were shown to be negligible by a comparison of estimates of VInf by the Adrogué-Madias formula and by a formula using the same determinants of the change in [ Na ] and the curvilinear relation between this change and VInf . Regardless of the method used to correct hyponatremia, monitoring [ Na ] and changes in external balances of water, sodium, and potassium during treatment remain imperative.

The Diagnostic Conundrum of Glomerular Crescents With IgA Deposits.

Introduction: Glomerulonephritis (GN) with crescents and IgA deposits in kidney biopsy poses a frequent diagnostic and therapeutic dilemma because of multiple possibilities. Methods: Native kidney biopsies showing glomerular IgA deposition and crescents (excluding lupus nephritis) were identified from our biopsy archives between 2010 and 2021. Detailed clinicopathologic features were assessed. One-year clinical follow-up on a subset of cases was obtained. Results: A total of 285 cases were identified, and these clustered into IgA nephropathy (IgAN, n = 108), Staphylococcus or other infection-associated GN/infection-related GN (SAGN/IRGN, n = 43), and antineutrophil cytoplasmic antibody-associated GN (ANCA-GN, n = 26) based on a constellation of clinicopathologic features, but 101 cases (group X) could not be definitively differentiated. The reasons have been elucidated, most important being atypical combination of clinicopathologic features and lack of definitive evidence of active infection. Follow-up (on 72/101 cases) revealed that clinicians' working diagnosis was IgAN in 43%, SAGN/IRGN in 22%, ANCA-GN in 28%, and others in 7% of the cases, but treatment approach varied from supportive or antibiotics to immunosuppression in each subgroup. Comparing these cases as "received immunosuppression" versus "non-immunosuppression," only 2 features differed, namely C3-dominant staining, and possibility of recent infection (both higher in the no-immunosuppression group) (P < 0.05). Renal loss was higher in the non-immunosuppression subgroup, but not statistically significant (P = 0.11). Conclusion: Diagnostic overlap may remain unresolved in a substantial number of kidney biopsies with glomerular crescents and IgA deposits. A case-by-case approach, appropriate antibiotics if infection is ongoing, and consideration for cautious immunosuppressive treatment for progressive renal dysfunction may be needed for best chance of renal recovery.

Renovascular Hypertension with Superimposed Aortic Arch Baroreceptor Failure: Case Report and Review of Literature.

BACKGROUND: Atherosclerotic renal artery diseases are among the most common causes of secondary hypertension. Baroreceptors, as carotid and aortic, are important regulatory mechanisms of blood pressure; their disruption can lead to labile blood pressure due to sympathetic overactivity: an entity called neurogenic hypertension. A disease such as aortic dissection can lead to a challenging combined etiology of secondary hypertension. It can affect both or one of the renal arteries leading to a renovascular pathology that can cause hypertension through RAAS activation. Also, surgical repair of the dissected aortic arch can disrupt baroreceptors leading to neurogenic hypertension. Case Report. We report a case of an 83-year-old female patient investigated for recurrent episodes of aphasia. She has a history of hypertension and coronary artery disease. Surgical history is significant for aortic valve replacement complicated by type A aortic dissection requiring surgical repair. Following surgery, the patient developed difficult-to-control and labile blood pressure. Workup included a CT angiogram of the abdominal aorta that showed an infrarenal dominant abdominal aortic aneurysm with juxtarenal aortic dissection; these findings were similar to previous findings. A diagnosis of aortic baroreceptor failure following aortic dissection repair was established, which lead to labile hypertension with superimposed renovascular pathology due to unilateral compromised renal artery blood flow following aortic dissection and thrombosis. CONCLUSIONS: This report highlights the importance of accurate diagnosis of secondary hypertension and its underlying mechanisms, as this has a huge impact on the choice of therapy to avoid undertreatment or overtreatment of hypertension.

Gut microbiome and diet in populations with obesity: Role of the Na+/K+-ATPase transporter signaling in severe COVID-19.

OBJECTIVE: The triad of obesity, a high-protein diet from animal sources, and disturbed gut microbiota have been linked to poor clinical outcomes in patients with COVID-19. In this report, the effect of oxidative stress resulting from the Na+ /K+ -ATPase transporter signaling cascade is explored as a driver of this poor clinical outcome. METHODS: Protein-protein interactions with the SARS-CoV-2 proteome were identified from the interactome data for Na+ /K+ -transporting ATPase subunit α-1 (ATP1A1), epidermal growth factor receptor, and ERB-B2 receptor tyrosine kinase 2, using the curated data from the BioGRID Database of Protein Interactions. Data for the gene expression pattern of inflammatory response were from the Gene Expression Omnibus database for cardiomyocytes post SARS-CoV-2 infection (number GSE151879). RESULTS: The ATP1A1 subunit of the Na+ /K+ -ATPase transporter is targeted by multiple SARS-CoV-2 proteins. Furthermore, receptor proteins associated with inflammatory response, including epidermal growth factor receptor and ERB-B2 receptor tyrosine kinase 2 (which interact with ATP1A1), are also targeted by some SARS-CoV-2 proteins. This heightened interaction likely triggers a cytokine release that increases the severity of the viral infection in individuals with obesity. CONCLUSIONS: The similarities between the effects of SARS-CoV-2 proteins and indoxyl sulphate on the Na+ /K+ -ATPase transporter signaling cascade suggest the possibility of an augmentation of gene changes seen with COVID-19 infection that can result in a hyperinduction of cytokine release in individuals with obesity.

Machine learning approach to predicting albuminuria in persons with type 2 diabetes: An analysis of the LOOK AHEAD Cohort.

Albuminuria and estimated glomerular filtration rate (e-GFR) are early markers of renal disease and cardiovascular outcomes in persons with diabetes. Although body composition has been shown to predict systolic blood pressure, its application in predicting albuminuria is unknown. In this study, we have used machine learning methods to assess the risk of albuminuria in persons with diabetes using body composition and other determinants of metabolic health. This study is a comparative analysis of the different methods to predict albuminuria in persons with diabetes mellitus who are older than 40 years of age, using the LOOK AHEAD study cohort-baseline characteristics. Age, different metrics of body composition, duration of diabetes, hemoglobin A1c, serum creatinine, serum triglycerides, serum cholesterol, serum HDL, serum LDL, maximum exercise capacity, systolic blood pressure, diastolic blood pressure, and the ankle-brachial index are used as predictors of albuminuria. We used Area under the curve (AUC) as a metric to compare the classification results of different algorithms, and we show that AUC for the different models are as follows: Random forest classifier-0.65, gradient boost classifier-0.61, logistic regression-0.66, support vector classifier -0.61, multilayer perceptron -0.67, and stacking classifier-0.62. We used the Random forest model to show that the duration of diabetes, A1C, serum triglycerides, SBP, Maximum exercise Capacity, serum creatinine, subtotal lean mass, DBP, and subtotal fat mass are important features for the classification of albuminuria. In summary, when applied to metabolic imaging (using DXA), machine learning techniques offer unique insights into the risk factors that determine the development of albuminuria in diabetes.

Acute and Chronic Hyponatremia.

Hyponatremia is the most common electrolyte disorder in clinical practice. Catastrophic complications can occur from severe acute hyponatremia and from inappropriate management of acute and chronic hyponatremia. It is essential to define the hypotonic state associated with hyponatremia in order to plan therapy. Understanding cerebral defense mechanisms to hyponatremia are key factors to its manifestations and classification and subsequently to its management. Hypotonic hyponatremia is differentiated on the basis of urine osmolality, urine electrolytes and volume status and its treatment is decided based on chronicity and the presence or absence of central nervous (CNS) symptoms. Proper knowledge of sodium and water homeostasis is essential in individualizing therapeutic plans and avoid iatrogenic complications while managing this disorder.

Viral Nephropathies, Adding SARS-CoV-2 to the List.

Viral infections in the immunocompetent host can cause both acute and chronic kidney disease either as a direct damage to the infected kidney cells or as a consequence of systemic immune responses that impact kidney function. Since identifying these entities in the 1970s and 80s, major breakthroughs in the understanding of the viral mechanisms have occurred. Viruses have evolved mechanisms to hijack signaling pathways of infected cells to evade antiviral immune responses by the host. Over time, the clinical presentations and management of these diseases have evolved along with our in-depth understanding of the various pathophysiological mechanisms causing these conditions. Similarly, both at the cellular and systemic levels, the host has evolved mechanisms to counter viral subversion strategies for mutual survival. Since the start of the current COVID-19 pandemic, numerous cases of acute kidney injury have been reported in the literature with various possible pathophysiological mechanisms. In this review, we summarize lessons learned from prior viral pandemics related to viral mechanisms utilized in the pathogenesis of numerous renal manifestations to attempt to utilize this knowledge in predicting post-COVID-19 kidney disease.

Can charcoal improve outcomes in COVID-19 infections?

COVID-19 infection causes considerable morbidity and mortality, especially to those who are aged, have impaired renal function and are obese. We propose to examine the potential utility of oral activated charcoal with the hypothesis that such treatment would lower absorption of microbiome derived toxins and ameliorate systemic oxidant stress and inflammation.

Relationship between dietary sodium and sugar intake: A cross-sectional study of the National Health and Nutrition Examination Survey 2001-2016.

Dietary sodium intake and cardiovascular outcomes have a reported J-shaped curve relationship. This study analyzes the relationship between dietary sodium and sugar intake as a potential mechanism to explain this association. The authors examined cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2001-2016 where dietary sodium, carbohydrate, fat, cholesterol, and sugar intakes were assessed by 24-hour dietary recall and were standardized to a total daily intake of 2000 calories. Sodium intake was categorized into sodium quintiles (SQ) as follows: SQ1(0.06-2.6 g/d); SQ2(2.6-3.0 g/d); SQ3(3.0-3.4 g/d); SQ4(3.4-4.0 g/d); and SQ5(4.0-29.3 g/d). Simple and multivariate linear regression using SQ3 as reference were used to assess associations between daily sodium intake and the other nutrients. Our results showed that among 38 722 participants that met our study criteria, the mean age was 43.6 years (SD 16.8 years) and sex was equally distributed (48.8% male vs 51.2% female). Sugar intake went down across increasing SQs and was significantly higher in SQ1 (141.2 g/d) and SQ2 (118.6 g/d) and significantly lower in SQ4 (97.9 g/d) and SQ5 (85.6 g/d) compared to SQ3 (108.6 g/d; all P < .01). These same trends remained unchanged and significant in the fully adjusted multivariate model. In conclusion, NHANES study participants reporting low sodium intake on 24-hour dietary recall have a higher consumption of sugar. The negative impact of low sodium diet on cardiovascular health may be explained at least partially by the associated high sugar intake.

A case of gabapentin overdose induced rhabdomyolysis requiring renal replacement therapy.

We report a rare case with gabapentin overdose that caused severe rhabdomyolysis and acute tubular necrosis which required renal replacement therapy. A better awareness of its adverse effect and a close follow-up of laboratory tests are recommended. Prescribers should also be aware of high-risk population and monitor for signs of abuse.

Ammonia vs. Lactic Acid in Predicting Positivity of Microbial Culture in Sepsis: The ALPS Pilot Study.

OBJECTIVE: The use of serum ammonia as a novel marker for sepsis compared to lactic acid levels in intensive care unit (ICU) patients. DESIGN AND INTERVENTIONS: Single arm, prospective clinical trial to collect arterial blood samples from patients with sepsis. Serial ammonia and lactic acid levels were sent every six hours for a total of three days. MEASUREMENTS AND RESULTS: Compare mean levels of ammonia and lactic acid in terms of diagnosing sepsis and patient outcome, including length of stay and mortality. A total of 30 patients were enrolled in the pilot study. On admission, mean ammonia level was 35.7 µmol/L and lactic acid was 3.06 mmole/L. Ammonia levels checked at the end of day 2 (ammonia 2-4) and the beginning of day 3 (ammonia 3-1) were higher in patients who had a microbial culture-proven sepsis (p-values 0.029 and 0.002, respectively) compared to those without culture-positive sepsis. Ammonia levels did predict a longer hospital stay; ammonia level of more than 40 µmol/L had a mean hospital stay of 17.6 days vs. patients with normal levels who had a mean hospital stay of 9.62 days (p-value 0.0082). CONCLUSION: Elevated ammonia level can be a novel biomarker for sepsis, comparable to conventional markers. Ammonia levels have a prognostic utility as elevated levels were associated with longer hospital stay.

Principles of quantitative water and electrolyte replacement of losses from osmotic diuresis.

Osmotic diuresis results from urine loss of large amounts of solutes distributed either in total body water or in the extracellular compartment. Replacement solutions should reflect the volume and monovalent cation (sodium and potassium) content of the fluid lost. Whereas the volume of the solutions used to replace losses that occurred prior to the diagnosis of osmotic diuresis is guided by the clinical picture, the composition of these solutions is predicated on serum sodium concentration and urinary sodium and potassium concentrations at presentation. Water loss is relatively greater than the loss of sodium plus potassium leading to hypernatremia which is seen routinely when the solute responsible for osmotic diuresis (e.g., urea) is distributed in body water. Solutes distributed in the extracellular compartment (e.g., glucose or mannitol) cause, in addition to osmotic diuresis, fluid transfer from the intracellular into the extracellular compartment with concomitant dilution of serum sodium. Serum sodium concentration corrected to euglycemia should be substituted for actual serum sodium concentration when calculating the composition of the replacement solutions in hyperglycemic patients. While the patient is monitored during treatment, the calculation of the volume and composition of the replacement solutions for losses of water, sodium and potassium from ongoing osmotic diuresis should be based directly on measurements of urine volume and urine sodium and potassium concentrations and not by means of any predictive formulas. Monitoring of clinical status, serum sodium, potassium, glucose, other relevant laboratory values, urine volume, and urine sodium and potassium concentrations during treatment of severe osmotic diuresis is of critical importance.

Fluid balance concepts in medicine: Principles and practice.

The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water (TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment (mainly sodium salts) and in the intracellular compartment (mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume (EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.

Bilateral renal cortical necrosis associated with smoking synthetic cannabinoids.

Synthetic cannabinoids have become a common drug of abuse in recent years and their toxicities have come to light as well. They are known to be notorious for the kidneys, with acute tubular necrosis, acute interstitial nephritis and rhabdomyolysis induced renal injury being the frequent nephrotoxic outcomes in users. We report a case of bilateral renal cortical necrosis, leading to irreversible renal damage and lifelong dialysis dependency.

Establishing the presence or absence of chronic kidney disease: Uses and limitations of formulas estimating the glomerular filtration rate.

The development of formulas estimating glomerular filtration rate (eGFR) from serum creatinine and cystatin C and accounting for certain variables affecting the production rate of these biomarkers, including ethnicity, gender and age, has led to the current scheme of diagnosing and staging chronic kidney disease (CKD), which is based on eGFR values and albuminuria. This scheme has been applied extensively in various populations and has led to the current estimates of prevalence of CKD. In addition, this scheme is applied in clinical studies evaluating the risks of CKD and the efficacy of various interventions directed towards improving its course. Disagreements between creatinine-based and cystatin-based eGFR values and between eGFR values and measured GFR have been reported in various cohorts. These disagreements are the consequence of variations in the rate of production and in factors, other than GFR, affecting the rate of removal of creatinine and cystatin C. The disagreements create limitations for all eGFR formulas developed so far. The main limitations are low sensitivity in detecting early CKD in several subjects, e.g., those with hyperfiltration, and poor prediction of the course of CKD. Research efforts in CKD are currently directed towards identification of biomarkers that are better indices of GFR than the current biomarkers and, particularly, biomarkers of early renal tissue injury.

Hypertonicity: Clinical entities, manifestations and treatment.

Hypertonicity causes severe clinical manifestations and is associated with mortality and severe short-term and long-term neurological sequelae. The main clinical syndromes of hypertonicity are hypernatremia and hyperglycemia. Hypernatremia results from relative excess of body sodium over body water. Loss of water in excess of intake, gain of sodium salts in excess of losses or a combination of the two are the main mechanisms of hypernatremia. Hypernatremia can be hypervolemic, euvolemic or hypovolemic. The management of hypernatremia addresses both a quantitative replacement of water and, if present, sodium deficit, and correction of the underlying pathophysiologic process that led to hypernatremia. Hypertonicity in hyperglycemia has two components, solute gain secondary to glucose accumulation in the extracellular compartment and water loss through hyperglycemic osmotic diuresis in excess of the losses of sodium and potassium. Differentiating between these two components of hypertonicity has major therapeutic implications because the first component will be reversed simply by normalization of serum glucose concentration while the second component will require hypotonic fluid replacement. An estimate of the magnitude of the relative water deficit secondary to osmotic diuresis is obtained by the corrected sodium concentration, which represents a calculated value of the serum sodium concentration that would result from reduction of the serum glucose concentration to a normal level.