Change Over Time in Pre-End-Stage Renal Disease 24-Hour Urine Creatinine as Muscle Mass Surrogate and Post-End-Stage Renal Disease Mortality.

OBJECTIVE: Loss of muscle mass and sarcopenia are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD), and sarcopenia can worsen insidiously in patients with advancing CKD. The temporal dynamics of sarcopenia in patients with progressive loss of kidney function, and its association with future outcomes, is unclear. METHODS: In a contemporary national cohort of incident ESRD US veterans, we selected 661 patients who had at least 2 24-hour urine creatinine (24hrUC) measurements, a surrogate of muscle mass, performed during the 3-year prelude period prior to ESRD transition. We estimated 24hrUC slopes in mixed effects models. To assess the temporal dynamics of pre-ESRD changes in 24hrUC and its association with changing eGFR, we separately fitted in mixed effects models a penalized spline regression of 24hrUC on time and on eGFR. We examined the association of 24hrUC slopes with postdialysis all-cause mortality using Cox models adjusted for confounders. RESULTS: The mean slope of 24hrUC versus time was -78 mg/year (95% confidence interval: -102 to -54), with a steeper decline noted in the last year prior to ESRD. More severe decreases in 24hrUC were associated with higher all-cause mortality: a 100 mg/year decrease in 24hrUC was associated with a multivariable adjusted death hazard ratio of 1.41 (95% confidence interval: 1.00-1.98, P = .05). CONCLUSION: Patients with advanced CKD lose a substantial proportion of their muscle mass each year during pre-ESRD prelude. Loss of muscle mass accelerates near ESRD transition, and more loss of muscle mass is associated with higher mortality after ESRD transition.

Resolution of IgA and C3 immune deposits in Staphylococcus infection-associated glomerulonephritis in a kidney transplant recipient
.

Staphylococcus infection-associated glomerulonephritis (SAGN) is characterized by the presence of IgA and C3 as the predominant components present in the glomerular immune deposits. Glomerulonephritis frequently resolves after effective treatment of the staphylococcal infection. However, there have been few studies of repeat kidney biopsy after resolution of glomerulonephritis. We present a combined kidney-pancreas transplant patient who developed SAGN due to Staphylococcus aureus bacteremia from an old infected arteriovenous (AV) graft, which occurred after a long period of stable allograft function. Clinical improvement occurred following surgical debridement and appropriate antibiotics with subsequent clearance of bacteremia. However, 3 weeks later he presented with severe acute kidney injury related to rapidly progressive glomerulonephritis. Renal allograft biopsy revealed immune complex glomerulonephritis with predominance of IgA and C3 in subendothelial and mesangial deposits, consistent with SAGN. There was no evidence for recurrent staphylococcal infection. High-dose steroid therapy was followed by resolution of hematuria and improvement in allograft function with gradual return of serum creatinine concentration to near baseline levels. However, 1 year after the diagnosis of SAGN, he developed gradually worsening allograft function with persistent proteinuria. Repeat allograft biopsy showed sclerosing glomerular changes and extensive interstitial fibrosis and tubular atrophy. There was complete resolution of proliferative changes, and IgA and C3 deposits were no longer detectable. Despite transient allograft function stabilization, the patient progressed to end-stage renal disease (ESRD), and maintenance hemodialysis was reinitiated 2.5 years after the diagnosis of SAGN. Pancreatic allograft function remained normal.

Resolution of syphilis-related rapidly progressive glomerulonephritis with penicillin therapy: Case report
.

Renal manifestations of syphilis are variable, with membranous nephropathy being the most commonly described lesion. Rapidly progressive glomerulonephritis (RPGN) is rare and there is only one case report in the literature describing syphilis-associated crescentic glomerulonephritis. We report a rare case of RPGN secondary to latent syphilis, which resolved with penicillin treatment in the absence of immunosuppressive therapy. A 28-year-old Black male with a history of HIV was evaluated for severe acute kidney injury, nephrotic-range proteinuria, and active urine sediment. Serologies for glomerulonephritis were negative. Rapid plasma reagin and treponema pallidum particle agglutination assay were reactive, confirming syphilis diagnosis. Kidney biopsy revealed focal and segmental necrotizing and crescentic lesion. Patient received weekly benzathine penicillin (PCN) for 3 weeks, and renal function improved to baseline. This dramatic improvement happened with PCN alone, a finding which has not been previously reported. We recommend that syphilis be considered in the differential diagnosis of all patients with proteinuria or suspected glomerulonephritis.

Markers of kidney tubule function and risk of cardiovascular disease events and mortality in the SPRINT trial.

AIMS: Biomarkers of kidney tubule injury, inflammation and fibrosis have been studied extensively and established as risk markers of adverse kidney and cardiovascular disease (CVD) outcomes. However, associations of markers of kidney tubular function with adverse clinical events have not been well studied, especially in persons with chronic kidney disease (CKD). METHODS AND RESULTS: Using a sample of 2377 persons with CKD at the baseline Systolic Blood Pressure Intervention Trial (SPRINT) visit, we evaluated the association of three urine tubular function markers, alpha-1 microglobulin (α1m), beta-2 microglobulin (ß2m), and uromodulin, with a composite CVD endpoint (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes) and mortality using Cox proportional hazards regression, adjusted for baseline estimated glomerular filtration rate (eGFR), albuminuria, and CVD risk factors. In unadjusted analysis, over a median follow-up of 3.8 years, α1m and ß2m had positive associations with composite CVD events and mortality, whereas uromodulin had an inverse association with risk for both outcomes. In multivariable analysis including eGFR and albuminuria, a two-fold higher baseline concentration of α1m was associated with higher risk of CVD [hazard ratio (HR) 1.25; 95% confidence interval (CI): 1.10-1.45] and mortality (HR 1.25; 95% CI: 1.10-1.46), whereas ß2m had no association with either outcome. A two-fold higher uromodulin concentration was associated with lower CVD risk (HR 0.79; 95% CI: 0.68-0.90) but not mortality (HR 0.86; 95% CI: 0.73-1.01) after adjusting for similar confounders. CONCLUSION: Among non-diabetic persons with CKD, biomarkers of tubular function are associated with CVD events and mortality independent of glomerular function and albuminuria.

The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury.

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and ß-2-microglobulin [ß2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.

Acute esophageal necrosis (black esophagus) complicating calcific uremic arteriolopathy
.

The current case report describes a chronic hemodialysis patient presenting with painful penile ulceration that was clinically and histologically proven to be related to calcific uremic arteriolopathy. The patient subsequently developed severe upper gastrointestinal bleeding that was both endoscopically and histologically shown to be due to acute esophageal necrosis (AEN), also known as necrotizing esophagitis and "black esophagus". AEN is a rare condition characterized by diffuse necrosis of the esophageal mucosa. The condition is diagnosed endoscopically with demonstration of circumferential mucosal necrosis involving the distal esophagus that can extend proximally. Mortality rates for both calcific uremic ateriolopathy and acute esophageal necrosis are high. Management of both conditions is reviewed. The patient recovered from the acute illness, but expired 6 months later due to progressive failure to thrive. To our knowledge, AEN has not previously been described secondary to calcific uremic arteriolopathy.
.

Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention Trial (SPRINT).

BACKGROUND: Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events. STUDY DESIGN: Data for AKI resulting in or during hospitalization or emergency department visits were collected as part of the serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: 9,361 participants 50 years or older with 1 or more risk factors for cardiovascular disease. INTERVENTIONS: Participants were randomly assigned to a systolic BP target of <120 (intensive arm) or <140mmHg (standard arm). OUTCOMES & MEASUREMENTS: Primary outcome was the number of adjudicated AKI events. Secondary outcomes included severity of AKI and degree of recovery of kidney function after an AKI event. Baseline creatinine concentration was defined as the most recent SPRINT outpatient creatinine value before the date of the AKI event. RESULTS: There were 179 participants with AKI events in the intensive arm and 109 in the standard arm (3.8% vs 2.3%; HR, 1.64; 95% CI, 1.30-2.10; P<0.001). Of 288 participants with an AKI event, 248 (86.1%) had a single AKI event during the trial. Based on modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria for severity of AKI, the number of AKI events in the intensive versus standard arm by KDIGO stage was 128 (58.5%) versus 81 (62.8%) for AKI stage 1, 42 (19.2%) versus 18 (14.0%) for AKI stage 2, and 42 (19.2%) versus 25 (19.4%) for AKI stage 3 (P=0.5). For participants with sufficient data, complete or partial resolution of AKI was seen for 169 (90.4%) and 9 (4.8%) of 187 AKI events in the intensive arm and 86 (86.9%) and 4 (4.0%) of 99 AKI events in the standard arm, respectively. LIMITATIONS: Trial results are not generalizable to patients with diabetes mellitus or without risk factors for cardiovascular disease. CONCLUSIONS: More intensive BP lowering resulted in more frequent episodes of AKI. Most cases were mild and most participants had complete recovery of kidney function. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01206062.

Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans.

UNLABELLED: An estimated 4 million Americans have been exposed to the hepatitis C virus (HCV). The risks of incident and progressive chronic kidney disease and of mortality in patients with normal kidney function infected with HCV are unclear. In a nationally representative cohort of 100,518 HCV(+) and 920,531 HCV(-) US veterans with normal baseline estimated glomerular filtration rate (eGFR), we examined the association of HCV infection with (1) all-cause mortality, (2) incidence of decreased kidney function (defined as eGFR <60 mL/min/1.73 m(2) and 25% decrease in eGFR), (3) end-stage renal disease, and (4) rate of kidney function decline. Associations were examined in naive and adjusted Cox models (for time-to-event analyses) and logistic regression models (for slopes), with sequential adjustments for important confounders. Propensity-matched cohort analysis was used in sensitivity analyses. The patients' age was 54.5 ± 13.1 (mean ± standard deviation) years, 22% were black, 92% were male, and the baseline eGFR was 88 ± 16 mL/min/1.73 m(2) . In multivariable adjusted models HCV infection was associated with a 2.2-fold higher mortality (fully adjusted hazard ratio = 2.17, 95% confidence interval [CI] 2.13-2.21), a 15% higher incidence of decreased kidney function (adjusted hazard ratio = 1.15, 95% CI 1.12-1.17), a 22% higher risk of steeper slopes of eGFR (adjusted odds ratio = 1.22, 95% CI 1.19-1.26), and a 98% higher hazard of end-stage renal disease (adjusted hazard ratio = 1.98, 95% CI 1.81-2.16). Quantitatively similar results were found in propensity-matched cohort analyses. CONCLUSIONS: Infection with HCV is associated with higher mortality risk, incidence of decreased kidney function, and progressive loss of kidney function; randomized controlled trials are warranted to determine whether treatment of HCV infection can prevent the development and progression of chronic kidney disease and improve patient outcomes.

Chronic Kidney Disease Classification in Systolic Blood Pressure Intervention Trial: Comparison Using Modification of Diet in Renal Disease and CKD-Epidemiology Collaboration Definitions.

BACKGROUND: Interventional trials have used either the Modification of Diet in Renal Disease (MDRD) or chronic kidney disease (CKD)-Epidemiology Collaboration (CKD-EPI) equation for determination of estimated glomerular filtration rate (eGFR) to define whether participants have stages 3-5 CKD. The equation used to calculate eGFR may influence the number and characteristics of participants designated as having CKD. METHODS: We examined the classification of CKD at baseline using both equations in the Systolic Blood Pressure Intervention Trial (SPRINT). eGFR was calculated at baseline using fasting serum creatinine values from a central laboratory. RESULTS: Among 9,308 participants with baseline CKD classification using the 4-variable MDRD equation specified in the SPRINT protocol, 681 (7.3%) participants were reclassified to a less advanced CKD stage (higher eGFR) and 346 (3.7%) were reclassified to a more advanced CKD stage (lower eGFR) when the CKD-EPI equation was used to calculate eGFR. For eGFRs <90 ml/min/1.73 m2, participants <75 years were more likely to be reclassified to a less advanced CKD stage; this reclassification was more likely to occur in non-blacks rather than blacks. Participants aged ≥75 years were more likely to be reclassified to a more advanced than a less advanced CKD stage, regardless of baseline CKD stage. Reclassification of baseline CKD status (eGFR <60 ml/min/1.73 m2) occurred in 3% of participants. CONCLUSIONS: Use of the MDRD equation led to a higher percentage of participants being classified as having CKD stages 3-4. Younger and non-black participants were more likely to be reclassified as not having CKD using the CKD-EPI equation.

Spontaneous massive bilateral peri-renal hemorrhage as a complication of ANCA-negative granulomatous vasculitis.

Spontaneous retroperitoneal hemorrhage (SRH) is a rare, life-threatening clinical entity most commonly associated with renal cell cancers. Systemic vasculitis has also been described as a rare cause of SRH. The current report describes a patient with acute kidney failure complicated by massive SRH, which occurred in the setting of anti-neutrophil cytoplasmic antibody (ANCA)-negative systemic necrotizing angiocentric granulomatous vasculitis involving multiple organs with minimal constitutional symptoms and no respiratory tract involvement.

Successful use of rituximab in fibrillary glomerulopathy.

Fibrillary glomerulopathy (FG) can occur either alone or co-existing with other proteinuric glomerular disorders. FG has been associated with poor renal outcomes leading to End Stage Renal Disease (ESRD). Since FG is a relatively rare disorder, limited information is available concerning treatment protocols. We present two patients with FG who were treated with rituximab after they had already progressed to stage 3 chronic kidney disease (CKD) with worsening proteinuria. Rituximab therapy resulted in long-term stabilization of renal function.

Assessment of 24,25(OH)2D levels does not support FGF23-mediated catabolism of vitamin D metabolites.

Progressive elevations of fibroblastic growth factor 23 (FGF23) in chronic kidney disease may reduce serum 25-hydroxyvitamin D (25(OH)) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) levels, via stimulation of 24-hydroxylase (Cyp24a1)-mediated catabolism of these vitamin D metabolites. To test this possibility, we measured serum concentrations of 24,25-dihydroxyvitamin D (24,25(OH)(2)D), a product of Cyp24a1 hydroxylation of 25(OH)D, in the Col4a3 knockout mouse, a model of Alport syndrome-derived chronic kidney disease, and in patients with chronic kidney disease of variable severity. There was an inverse correlation between serum FGF23 and both 25(OH)D and 1,25(OH)(2)D in the mouse model, but no significant relationship was observed in the cross-sectional patient cohort. The FGF23-dependent increase in Cyp24a1 mRNA expression in the mouse kidneys was consistent with the possibility that FGF23 induces vitamin D catabolism. There was, however, a reduction in serum 24,25(OH)(2)D levels, rather than the expected elevation, in both the mice and patients with chronic kidney disease. Low 25(OH)D and elevated FGF23 and parathyroid hormone levels were correlated with the reduced serum 24,25(OH)(2)D concentrations of these patients. Thus, we failed to find support for FGF23-mediated catabolism of vitamin D metabolites in chronic kidney disease assessed by 24,25(OH)(2)D levels.

A clinical approach to the treatment of chronic hypernatremia.

Hypernatremia is a commonly encountered electrolyte disorder occurring in both the inpatient and outpatient settings. Community-acquired hypernatremia typically occurs at the extremes of age, whereas hospital-acquired hypernatremia affects patients of all age groups. Serum sodium concentration is linked to water homeostasis, which is dependent on the thirst mechanism, arginine vasopressin, and kidney function. Because both hypernatremia and the rate of correction of hypernatremia are associated with significant morbidity and mortality, prompt effective treatment is crucial. Chronic hypernatremia can be classified into 3 broad categories, hypovolemic, euvolemic, and hypervolemic forms, with each form having unique treatment considerations. In this teaching case, we provide a clinically based quantitative approach to the treatment of both hypervolemic and hypovolemic hypernatremia, which occurred in the same patient during the course of a prolonged illness.

Endovascular stent migration to the right ventricle causing myocardial injury.

Central stenosis of the subclavian and internal jugular veins is common in end stage renal disease. Treatment of these stenoses is difficult as these veins respond poorly to angioplasty alone and often require metallic stents to ensure patency. These stents are not without complications. Reports of stent fracture, thrombosis and vessel rupture abound in the literature. Stent migration can occur when used in large central veins leading to severe consequences such as pulmonary infarction, tricuspid regurgitation and right sided heart failure. In this report, we report a case of a subclavian vein stent which migrated into the right heart and caused subendocardial injury. As the use of vascular stents is becoming a common treatment option for central venous stenosis, the occurrences of serious complications associated with the stents are likely to rise.

Multiple myeloma with hypercalcemia and chloride resistant metabolic alkalosis.

This report describes a novel presentation of chloride resistant metabolic alkalosis in a patient with hypercalcemia related to Multiple Myeloma (MM). A 51-year-old male with newly diagnosed MM presented with widespread skeletal involvement, calcium (Ca(+2)) of 18 mg/dL, phosphorous (PO4) of 6 mg/dL, serum bicarbonate (HCO3) of 37 mEq/L, and serum creatinine (Cr) of 2.6 mg/dL Other causes of metabolic alkalosis such as vomiting, diuretics, alkali ingestion, mineralocorticoid excess and hypokalemia were excluded. Hypercalcemia and metabolic alkalosis were only partially corrected after rehydration, calcitonin and steroids. Subsequent treatment with zoledronic acid resulted in resolution of hypercalcemia and correction of metabolic alkalosis.The chloride resistant component of metabolic alkalosis was most likely related to extensive release of Ca(+2), carbonate and phosphate from bone by activated osteoclasts with inhibited osteoblastic activity. The additional reduction in glomerular filtration rate due to MM, contributed to a triad mimicking Calcium-Alkali syndrome.

Systemic Inflammatory Response Syndrome Secondary to Nitrofurantoin.

Nitrofurantoin is considered optimal treatment for acute uncomplicated cystitis by the Infectious Diseases Society of America and is being increasingly recommended due to microbial resistance to sulfamethoxazole/trimethoprim and various fluoroquinolone antibiotics. Adverse effects of nitrofurantoin are generally considered mild, with gastrointestinal complaints being the most common. However, there have been isolated case reports describing a more severe systemic inflammatory response syndrome-like reaction, which leads to diagnostic challenges and treatment complications. We report the case of a patient with repeat episodes of systemic inflammatory response syndrome secondary to nitrofurantoin, which was initially attributed to recurrent urinary tract infections.

Lactic acidosis in restrained cocaine intoxicated patients.

Severe lactic acidosis has been reported in patients struggling against restraints, especially in association with the use of stimulant drugs, such as cocaine. Profound acidosis occurring under these conditions can lead to cardiac arrhythmias, autonomic instability and cardiac arrest, a syndrome known as restraint associated asphyxia. Early recognition of this condition and removing the stimulus for lactic acid production (excessive muscle activity) by aggressive sedation and ventilatory assistance, coupled with fluid administration to improve tissue perfusion and lactate metabolism, can be life-saving. The current report describes a case of restraint associated severe lactic acidosis in a cocaine intoxicated patient that was successfully treated by sedation, muscular paralysis and mechanical ventilation. Public safety personnel must be aware of this potentially life threatening complication. Avoiding hobble and prone restraint positions may eliminate some of the problems that contribute to the pathophysiology of this condition.

Longer Predialysis ACEi/ARB Utilization Is Associated With Reduced Postdialysis Mortality.

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) improve predialysis outcomes; however, ACEi/ARB are underused in patients transitioning to dialysis. We examined the association of different patterns of predialysis ACEi/ARB use with postdialysis survival and whether potentially modifiable adverse events are associated with lower predialysis ACEi/ARB use. METHODS: This was a historic cohort study of 34,676 US veterans with, and 10,690 without, ACEi/ARB exposure in the 3-year predialysis period who subsequently transitioned to dialysis between 2007 and 2014. Associations of different patterns of predialysis ACEi/ARB use with postdialysis all-cause mortality and with predialysis acute kidney injury and hyperkalemia events were examined using multivariable adjusted regression analyses. RESULTS: The mean age of the cohort was 70 years, 98% were males and 27% were African Americans. Compared to ACEi/ARB nonuse, continuous ACEi/ARB use was associated with lower postdialysis all-cause mortality (adjusted hazard ratio [aHR]; 95% confidence interval [95% CI] 0.87; 0.83-0.92). In analyses modeling the duration of predialysis ACEi/ARB use, ACEi/ARB use of 50%-74% and ≥75% were associated with lower mortality compared to nonuse (adjusted hazard ratio, 95% confidence interval 0.96, 0.92-0.99 and 0.91; 0.88-0.94, respectively), whereas no increase in postdialysis survival was observed with shorter predialysis ACEi/ARB use. Predialysis acute kidney injury was associated with shorter duration (<50%) of ACEi/ARB use and hyperkalemia was associated with interrupted and ACEi/ARB use of <75%. CONCLUSIONS: Longer predialysis ACEi/ARB exposure was associated with lower postdialysis mortality. Prospective studies are needed to evaluate the benefits of strategies enabling uninterrupted predialysis ACEi/ARB use.