Jayanthi Chandar

Rituximab Targets Podocytes in Recurrent Focal Segmental Glomerulosclerosis

Rituximab treatment in high-risk patients with focal segmental glomerulosclerosis directly affects podocyte function and is linked to reduced incidence of recurrent proteinuria after kidney transplantation. Rituximab Prods Podocytes to Action Rituximab is a monoclonal antibody against CD20, a protein located on the surface of B cells. It is typically used to treat certain cancers and autoimmune disorders, but has also treated kidney conditions, including focal segmental glomerulosclerosis (FSGS)—a disorder that can affect both pediatric and adult patients. Recurrent FSGS is a problem for 30 to 40% of patients who have undergone kidney transplantation, and can be characterized by progression to end-stage renal disease and recurrence of proteinuria after transplant. Despite the ability of rituximab to treat FSGS, it has been unclear exactly how this drug achieves success in some patients, but not others. Fornoni and colleagues hypothesized that rituximab operates in a B cell–independent manner, targeting instead specific kidney cells called podocytes. To test this hypothesis, Fornoni et al. studied 41 patients at high risk for FSGS: 14 historical control patients who were not treated with rituximab and 27 patients who received rituximab at the time of kidney transplant. They found fewer podocytes with sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein in biopsies from patients who later developed recurrent FSGS. The authors had also collected serum from all patients before transplant and then later treated normal human podocytes in culture with the sera. Serum from patients who would later develop recurrent FSGS caused a decrease in both SMPDL-3b protein and acid sphingomyelinase activity. This phenomenon was prevented by rituximab. The FSGS serum from patients also disrupted the actin cytoskeleton of cultured podocytes, but pretreatment with rituximab, or even overexpression of SMPDL-3b protein, partially prevented this phenotype. Together, these data suggest that modulation of sphingolipid-related proteins plays a role in the pathogenesis of recurrent FSGS and, moreover, that these proteins and enzymes might be targets of rituximab treatment. With the mechanism solved, rituximab may represent a new therapeutic strategy to prevent recurrent proteinuria after kidney transplantation. Here’s to happy and healthy kidneys! Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b+ podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b–dependent manner.

Posterior reversible encephalopathy syndrome in the pediatric renal population

Posterior reversible leukoencephalopathy syndrome (PRES) clinically presents with seizures, severe headaches, and mental and visual changes. Our goal was to describe the clinical features, triggering factors, neuro-imaging findings, and electroencephalogram (EEG) findings in a pediatric cohort with renal disease. We retrospectively analyzed the records of 18 children with the diagnosis of PRES between January 2001 and June 2006 at the University of Miami/Holtz Children’s Hospital, USA. There were 22 PRES episodes. The most common clinical presentation was generalized tonic–clonic seizures in 59% (13/22). The most common identified trigger of PRES was hypertensive crisis in 59% (13/22). Almost half of the children had no evidence of on-going uncontrolled hypertension; 44% (8/18) had normal funduscopic examination findings, and 50% (9/18) had no or mild left ventricular hypertrophy. Two of the 18 patients had recurrent PRES episodes, three episodes each. Diffuse slowing was the most common finding on the EEGs. Atypical magnetic resonance imaging (MRI) findings were more prevalent in the imaged cases (62% vs 25%, P < 0.05). All the computerized tomography (CT) scans were normal, despite the positive MRI findings in four cases when both types of imaging was used. All the episodes had total clinical resolution. In conclusion, despite the diverse initial trigger, acute hypertension seems to be the common pathogenic pathway for pediatric PRES. MRI seems superior to CT, with better sensitivity due to its high resolution and diffusion-weighted imaging. The lesions do not necessarily have to be in the posterior white matter and may not be totally reversible.

Vitamin D insufficiency and deficiency in children with early chronic kidney disease.

OBJECTIVE To assess the prevalence of abnormal vitamin D status in children and adolescents with chronic kidney disease (CKD). STUDY DESIGN This was an outpatient cross-sectional, retrospective study of 258 patients, mean age 12.3 +/- 5.2 years, with an average estimated glomerular filtration rate (eGFR) of 106 +/- 51 mL/min/1.73 m2 (range, 0 to 220 mL/min/1.73 m2). Serum 25-hydroxy-vitamin D [25(OH)D], calcium, phosphorus, and parathyroid hormone levels, as well as selected anthropometric variables, were analyzed. RESULTS Reduced 25(OH)D concentrations (< 30 ng/mL) were found in 60% of the patients. In 28%, the concentration was < 20 ng/mL, indicating vitamin D deficiency. Patients with more advanced CKD were more likely to have vitamin D deficiency compared with those with incipient CKD or normal GFR (42% vs 26%; P = .03) and displayed more prominent hyperparathyroidism. Suboptimal vitamin D status was similar in males and females, but was significantly more prevalent in older (P < .01), non-Caucasian (P < .01), and overweight (P = .02) patients. Patients with early-stage CKD (eGFR > 60 mL/min/1.73 m2) and with vitamin D deficiency were significantly shorter than their counterparts with 25(OH)D levels > 20 ng/mL (P = .02). CONCLUSIONS Vitamin D insufficiency and deficiency are very prevalent in pediatric patients across all stages of CKD, particularly in non-Caucasian and obese patients, and may contribute to growth deficits during the earliest stages of CKD.

Hypertensive crisis in children

Hypertensive crisis is rare in children and is usually secondary to an underlying disease. There is strong evidence that the renin-angiotensin system plays an important role in the genesis of hypertensive crisis. An important principle in the management of children with hypertensive crisis is to determine if severe hypertension is chronic, acute, or acute-on-chronic. When it is associated with signs of end-organ damage such as encephalopathy, congestive cardiac failure or renal failure, there is an emergent need to lower blood pressures to 25-30% of the original value and then accomplish a gradual reduction in blood pressure. Precipitous drops in blood pressure can result in impairment of perfusion of vital organs. Medications commonly used to treat hypertensive crisis in children are nicardipine, labetalol and sodium nitroprusside. In this review, we discuss the pathophysiology, differential diagnosis and recent developments in management of hypertensive crisis in children.

Profiling proteinuria in pediatric patients.

This study was designed to characterize proteinuria in children with kidney disease. Random urine samples from 250 pediatric patients were examined by quantitative measures of total protein (pr), albumin (Alb), and creatinine (cr). Patient diagnoses were subjectively categorized as “Glomerular” (GD) or “Tubulo-interstitial” disease (TD) in origin. Proteinuria was quantitated by the random urine protein-to-creatinine (Upr/cr) ratio, and glomerular proteinuria was assessed as the albumin-to-creatinine ratio (Ualb/cr) and percentage albuminuria (%Alb=Alb/pr*100). The non-albumin fraction (1−Alb/pr) includes low-molecular-weight proteins and micro- and macroglobulins. Of the 250 patients, 112 (45%) had GD and 138 (55%) had TD. Both proteinuria and albuminuria correlated with a decline in glomerular filtration rate (GFR) (r=−0.4; p<0.0001). Those with GD averaged significantly greater %Alb than those with TD at all levels of proteinuria (p<0.0001). With loss in GFR, %Alb increased significantly in patients with TD (18±13 to 47±30%; p<0.001) and GD (56±26 to 74±15%; p<0.01), respectively. The %Alb at all levels of GFR averaged <50% in those with TD and >50% in those with GD. In conclusion, random Ualb/cr, Upr/cr, and %Alb provide a simple and inexpensive assessment of proteinuria and may profile renal disease activity and response to therapy in pediatric patients.

Comparison of tissue plasminogen activator–antibiotic locks with heparin–antibiotic locks in children with catheter-related bacteraemia

BACKGROUND An accepted pathogenesis of catheter-related bacteraemia (CRB) is the seeding of microorganisms from the intraluminal biofilm of central venous catheters. Antibiotic locks (ABL) are solutions containing high concentrations of antimicrobials with or without anticoagulants that aim to destroy the biofilm. METHODS In this study, two different ABL solutions, tissue plasminogen activator (TPA)-based and heparin-based ABL, used in conjunction with systemic antibiotics, were prospectively compared in the treatment of CRB. RESULTS A total of 42 children on chronic haemodialysis with 11,016 catheter-days were observed for signs and symptoms of CRB over a period of 10 months. Twenty-four CRBs were diagnosed in 18 children (2.2 CRB/1000 catheter-days) and were treated with the protocol. Symptoms of CRB resolved in 83% within 48 h of treatment. None of the infected catheters required early emergent exchange or removal for poorly controlled CRB. Six children had recurrence of CRB within 6 weeks, of which four required catheter exchange. There was no specific microorganism or type of CRB that predisposed to higher recurrence rates. The mean infection-free survival of the catheters following TPA-ABL treatment was shorter than that following heparin-ABL treatment, but was not statistically significant by the log-rank test (126.8 +/- 81.6 days versus 154.5 +/- 70.4 days). CONCLUSION Both TPA-ABL and heparin-ABL used in conjunction with systemic antibiotics can effectively clear CRB without significant late recurrence at 6 weeks. Early use of ABL for management of CRB can potentially decrease the need for catheter removal, thus salvaging vascular access sites.

ACE inhibition scintigraphy in the management of hypertension in children

Abstract Angiotensin converting enzyme (ACE) inhibition scintirenography was performed to help establish the diagnosis and plan treatment of renovascular hypertension (RVH) in 57 hypertensive pediatric patients, 33 infants and 24 children older than 1 year. In 16 of 33 hypertensive infants, ACE inhibition scintirenography established the diagnosis of RVH from renal ischemia (due to aortic or renal arterial thrombi). Two scintigraphic criteria were used for the diagnosis of RVH: criterion I, ischemic and damaged kidney (a non-functioning kidney on or off ACE inhibition) and criterion II, ischemic but not damaged kidney (ACE inhibition induced deterioration of function of the kidney). When criterion I was present and the contralateral kidney was normal, ACE inhibitors could be used for treatment of hypertension without deterioration of renal function; kidneys satisfying criterion I eventually involuted or manifested growth arrest and frequently caused persistent RVH, even after resolution of the thrombus, requiring nephrectomy. When criterion II was present bilaterally, or it was associated with criterion I contralaterally, the use of antihypertensive drugs other than ACE inhibitors was necessary in order to prevent renal insufficiency or failure from ACE inhibitors. However, kidneys with criterion II showed normal growth and, following retraction or dissolution of the aortic thrombus, hypertension resolved. In 2 of 24 hypertensive children older than 1 year, the test was diagnostic of branch renal artery stenosis; RVH was cured by selective angioplasty. ACE inhibition scintirenography is useful in the evaluation and planning of treatment in children with hypertension and may predict the outcome of therapy and ultimate renal function.

Role of Routine Urinalysis in Asymptomatic Pediatric Patients

This study was done to evaluate the spectrum of diagnoses and identify risk factors for significant kidney disease in asymptomatic children with proteinuria and/or microhematuria detected by routine urinalysis. Clinical and laboratory data were obtained by retrospective chart review of 239 patients referred to a tertiary care center. The predominant diagnosis in children with isolated microhematuria was hypercalciuria and with isolated proteinuria, orthostatic proteinuria. When microhematuria and proteinuria were present in combination, kidney disease was the predominant diagnosis. Urinalysis is a valuable tool to identify patients with kidney disease. The combination of microhematuria and proteinuria increases the risk of having significant kidney disease.

Controlling exit site infections: Does it decrease the incidence of catheter‐related bacteremia in children on chronic hemodialysis?

The aim of this retrospective study was to investigate whether the application of a chlorhexidine‐impregnated dressing (Biopatch®) at the exit site of tunneled‐cuffed hemodialysis catheters has any effect on the incidence and etiology of catheter‐related bacteremia (CRB). This study was carried out over a 5‐year period in a single center, where, in the first 2½ years, the exit sites were cleansed with betadine at every hemodialysis session and then covered with a transparent dressing (pre‐Biopatch® Era). During the next 2½ years, Biopatch® was applied to the exit site once a week after cleansing with betadine, and then covered with a transparent dressing (Biopatch® Era). The application of Biopatch® significantly decreased the incidence of exit site infections (ESI) (P<0.05). However, there was no difference in the incidence of CRBs or their microbiological distribution. The improved ESI rate had no effect on the overall catheter survival time. The antimicrobial sensitivities of the Gram‐positive microorganisms were statistically different for the 2 different types of infections (P<0.05). In conclusion, even though Biopatch® is effective in decreasing the incidence of ESI, it has no effect on the incidence of CRB, the etiology of CRB, or the overall catheter survival time. The distinct difference between the antimicrobial sensitivities of the ESI and CRB suggests that they are not a spectrum of the same pathogenesis. These preliminary data support the intraluminal pathogenesis of CRB, rather than the exit site as a possible entry point for the extraluminal route.

Antibiotic lock solutions allow less systemic antibiotic exposure and less catheter malfunction without adversely affecting antimicrobial resistance patterns.

There are current concerns that antibiotic lock solutions (ABL) can induce antimicrobial resistance in long‐term hemodialysis patients. Retrospective chart review of 157 children on hemodialysis between January 1997 and June 2006 was performed. In ERA I, only systemic antibiotics were used. In ERA II, ABL were added to systemic antibiotics when needed. In ERA III, ABL were used for treatment of all cases of catheter‐related bacteremia (CRB) and for CRB prophylaxis in high‐risk patients. The study includes 111,325 catheter days. The CRB incidence was 3.9 CRB/1000 catheter days. There was significant decrease for the total systemic antibiotic exposure (P = 0.0484) and the percentage of catheters lost to malfunction (P = 0.001) in ERA III. Protocol ABL exposure was associated with a trend to increased tobramycin‐gentamicin resistance for gram‐positive CRBs (P = 0.2586) but with improved tobramycin‐gentamicin resistance for gram‐negative (P = 0.0949) and polymicrobial CRBs (P = 0.1776) and improved vancomycin resistance for gram‐positive CRBs (P = 0.0985). This retrospective analysis does not support the premise that ABL use will promote antimicrobial resistance in the hemodialysis population. The decreased exposure to systemic antibiotics by vigorous ABL use may even improve the antimicrobial resistance patterns in this population in the long term.