Hassib Chehade

Comparison of the glomerular filtration rate in children by the new revised Schwartz formula and a new generalized formula.

The most widely used formula for estimating glomerular filtration rate (eGFR) in children is the Schwartz formula. It was revised in 2009 using iohexol clearances with measured GFR (mGFR) ranging between 15 and 75 ml/min × 1.73 m(2). Here we assessed the accuracy of the Schwartz formula using the inulin clearance (iGFR) method to evaluate its accuracy for children with less renal impairment comparing 551 iGFRs of 392 children with their Schwartz eGFRs. Serum creatinine was measured using the compensated Jaffe method. In order to find the best relationship between iGFR and eGFR, a linear quadratic regression model was fitted and a more accurate formula was derived. This quadratic formula was: 0.68 × (Height (cm)/serum creatinine (mg/dl))-0.0008 × (height (cm)/serum creatinine (mg/dl))(2)+0.48 × age (years)-(21.53 in males or 25.68 in females). This formula was validated using a split-half cross-validation technique and also externally validated with a new cohort of 127 children. Results show that the Schwartz formula is accurate until a height (Ht)/serum creatinine value of 251, corresponding to an iGFR of 103 ml/min × 1.73 m(2), but significantly unreliable for higher values. For an accuracy of 20 percent, the quadratic formula was significantly better than the Schwartz formula for all patients and for patients with a Ht/serum creatinine of 251 or greater. Thus, the new quadratic formula could replace the revised Schwartz formula, which is accurate for children with moderate renal failure but not for those with less renal impairment or hyperfiltration.

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria≥300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside-induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2α, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease.

New combined serum creatinine and cystatin C quadratic formula for GFR assessment in children.

BACKGROUND AND OBJECTIVES The estimated GFR (eGFR) is important in clinical practice. To find the best formula for eGFR, this study assessed the best model of correlation between sinistrin clearance (iGFR) and the solely or combined cystatin C (CysC)- and serum creatinine (SCreat)-derived models. It also evaluated the accuracy of the combined Schwartz formula across all GFR levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Two hundred thirty-eight iGFRs performed between January 2012 and April 2013 for 238 children were analyzed. Regression techniques were used to fit the different equations used for eGFR (i.e., logarithmic, inverse, linear, and quadratic). The performance of each model was evaluated using the Cohen κ correlation coefficient and the percentage reaching 30% accuracy was calculated. RESULTS The best model of correlation between iGFRs and CysC is linear; however, it presents a low κ coefficient (0.24) and is far below the Kidney Disease Outcomes Quality Initiative targets to be validated, with only 84% of eGFRs reaching accuracy of 30%. SCreat and iGFRs showed the best correlation in a fitted quadratic model with a κ coefficient of 0.53 and 93% accuracy. Adding CysC significantly (P<0.001) increased the κ coefficient to 0.56 and the quadratic model accuracy to 97%. Therefore, a combined SCreat and CysC quadratic formula was derived and internally validated using the cross-validation technique. This quadratic formula significantly outperformed the combined Schwartz formula, which was biased for an iGFR≥91 ml/min per 1.73 m(2). CONCLUSIONS This study allowed deriving a new combined SCreat and CysC quadratic formula that could replace the combined Schwartz formula, which is accurate only for children with moderate chronic kidney disease.

Eculizumab to Treat Antibody-Mediated Rejection in a 7-Year-Old Kidney Transplant Recipient

We report on successful early eculizumab administration to treat acute antibody-mediated rejection (ABMR) in a highly sensitized kidney transplant recipient. The recipient is a 7-year-old boy who received, 6 months after a desensitization protocol with monthly intravenous immunoglobulin infusion, a second kidney transplant in the presence of low donor-specific antibodies (DSAs). Both pretransplant lymphocytotoxic and flow cytometric crossmatch were negative. Allograft function recovered promptly, with excellent initial function. On postoperative day (POD) 4, the child developed significant proteinuria with an acute rise in serum creatinine. Allograft biopsy showed severe acute ABMR. Intravenous eculizumab (600 mg), preceded by a single session of plasmapheresis, was administered on POD 5 and 12 along with a 4-day thymoglobulin course. After the first dose of eculizumab, a strikingly rapid normalization of allograft function with a decrease in proteinuria occurred. However, because circulating DSA levels remained elevated, the child received 3 doses of intravenous immunoglobulin (POD 15, 16, and 17), with a significant subsequent decrease in DSA levels. At 9 months after transplant, the child continues to maintain excellent allograft function with undetectable circulating DSA levels. This unique case highlights the potential efficacy of using early eculizumab to rapidly reverse severe ABMR in pediatric transplantation, and therefore it suggests a novel therapeutic approach to treat acute ABMR.

Acute Life-Threatening Presentation of Vitamin D Deficiency Rickets

CONTEXT Clinical manifestations of vitamin D deficiency rickets are widely described; however cardiorespiratory arrest is an extremely rare presentation. OBJECTIVE The aim of this paper is to present the symptoms of severe vitamin D deficiency rickets and to highlight the importance of vitamin D prophylaxis in infants. RESULTS We report a case of a 16-month-old infant who presented to emergency room with a stridor that evolved into a full cardiorespiratory arrest secondary to hypocalcemia. Medical history revealed that the infant was exclusively breastfed without vitamin D supplementation until the age of 10 months. Due to cultural habits, his diet was also grossly deficient in dairy products. Physical exam revealed clinical signs of rickets. Laboratory test showed severe hypocalcemia, elevated alkaline phosphatase, normal serum phosphorous, decreased 25(OH) cholecalciferol, increased intact parathyroid hormone level, and normal urine calcium excretion. The radiography of the wrist showed evidence of cupping, fraying, metaphyseal widening, and demineralization of the distal radial and ulnar metaphyses. The bone mineral density of the lumbar spine measured by dual x-ray absorptiometry showed a Z-score below -2 SD. His cardiorespiratory arrest secondary to hypocalcemia was therefore attributed to severe nutritional rickets. CONCLUSION Vitamin D deficiency rickets can be life threatening. Vitamin D supplementation is therefore crucial, especially in breastfed infants and some ethnic minorities (dark-skinned people, poor sun exposure), more at risk for developing severe rickets if not supplemented.

Acute norovirus-induced agranulocytosis in a pediatric kidney transplant recipient

Norovirus (NoV) infection is usually limited to the gastrointestinal (GI) tract. However, in immunocompromised patients, this infection might lead to severe life‐threatening complications. We herein describe a pediatric kidney transplant patient who presented with an acute NoV infection complicated by febrile agranulocytosis that resolved with improvement of her GI illness. This unusual presentation has not been described before, to our knowledge. The aim of this article is to highlight the sometimes dramatic clinical presentation of NoV infection in immunosuppressed patients, and the importance of including this infection in the differential diagnosis of neutropenia in that specific population.

Inappropriate antidiuretic hormone secretion: long-term successful urea treatment

Hyponatremia is the main complication of inappropriate antidiuretic hormone secretion (SIADH), sometimes fatal. Treatment strategy depends on the cause and the severity of the hyponatremia. Recent studies have shown the efficacy of urea in treating acute hyponatremia secondary to SIADH, by inducing an osmotic water drive. We describe an infant with chronic hyponatremia secondary to SIADH in which the long‐term oral treatment with urea was successful and well tolerated. The aim of this paper is to highlight the potential benefits of urea treatment in case of chronic hyponatremia secondary to SIADH.

Microalbuminuria and hyperfiltration in subjects with nephro-urological disorders

BACKGROUND Microalbuminuria (MA) has been shown to be an early biomarker of renal damage. It is postulated that MA is the early result of hyperfiltration, which could evolve into glomerular sclerosis and renal failure if hyperfiltration is left untreated. We hypothesized that MA is a good indicator of hyperfiltration in children with kidney disorders, obviating the need to calculate the filtration fraction (FF). METHODS A total of 155 children or young adults were prospectively included [42 single kidney (SK), 61 vesico-ureteral reflux, 23 obstructive uropathies, 29 other kidney diseases]. We measured inulin, para-aminohippuric acid clearances, FF and MA. Prediction of hyperfiltration was explored by studying the association between the FF and other variables such as urinary albumin (Alb), urinary albumin-creatinine ratio (ACR) and creatinine clearance. RESULTS A significant but weak association between urinary Alb or ACR and FF was found in subjects with an SK (Spearman correlation coefficients 0.32 and 0.19, respectively). Multivariate analysis also showed that urinary Alb and ACR significantly predict FF only in subjects with an SK (r(2) = 0.17, P = 0.01 and r(2) = 0.13, P = 0.02, respectively). This holds true only in subjects with an SK and inulin clearance >90 mL/min/1.73 m(2) (r(2) = 0.41, P < 0.001). There was no association between creatinine clearance and FF. CONCLUSIONS MA is not associated with FF in our subjects with nephro-urological disorders, except in those with an SK, where the association is weak, indicating that MA is due to other mechanisms than high FF and cannot predict hyperfiltration in such groups.

The Challenge of Acute Antibody-Mediated Rejection in Kidney Transplantation.

A antibody-mediated rejection (AMR), also termed acute humoral rejection, remains one of the most challenging clinical events in kidney transplantation. This clinicopathologic entity is characterized by allograft dysfunction, morphologic evidence of acute allograft injury with C4d deposition in peritubular capillaries, together with the presence of circulating donor-specific anti-HLA alloantibodies (DSA). Humoral sensitization to HLA antigens has become an important issue in both the adult and pediatric transplant population. Despite the great reduction of acute cellular rejection within the first year after transplantation with the use ofmodern immunosuppressive regimens, acute AMR still complicates the course of approximately 1% to 10% kidney transplant recipients, depending on the pretransplant sensitization status and the immunosuppressive treatment administered to the patient. Up to a third of highly sensitized recipients may develop acute AMR after transplantation, regardless of the desensitization protocols which may or not be used. It is well known that if not rapidly diagnosed and properly treated, acute AMR carries a high risk of allograft loss or of residual chronic allograft dysfunction. As a consequence, studies or clinical trials aiming at analyzing the potential benefits of the treatment of acute AMRare important, particularly in the current era of organ shortage, a problem that is not likely to improve in the near future. Despite its recognition for more than 2 decades, treatment strategies for acute AMR are still not standardized and solid evidence regarding which regimens might be optimal is lacking. In particular, well-designed, multicenter, prospective clinical trials of acute AMR have been notoriously difficult to be conducted. In general, most therapeutic strategies have been based on the removal of antidonor alloantibodies (eg, by plasmapheresis or immunoadsorption), associatedwith attempts to suppress antidonor humoral responses, for example, using IVIg and/or the anti-CD20 mAb rituximab directed against B cells. Rituximab, aiming at depleting B cells and possibly suppressing alloantibody production, was used as rescue therapy in some severe episodes of antilymphocyteresistant acute AMR. It should be mentioned that plasmapheresis and/or IVIg, as well as rituximab, have also been used

Avoidance of voiding cystourethrography in infants younger than 3 months with Escherichia coli urinary tract infection and normal renal ultrasound

Background and objective Urinary tract infection (UTI) represents the most common bacterial infection in infants, and its prevalence increases with the presence of high-grade vesicoureteral reflux (VUR). However, voiding cystourethrography (VCUG) is invasive, and its indication in infants <3 months is not yet defined. This study aims to investigate, in infants aged 0–3 months, if the presence of Escherichia coli versus non-E. coli bacteria and/or normal or abnormal renal ultrasound (US) could avoid the use of VCUG. Method One hundred and twenty-two infants with a first febrile UTI were enrolled. High-grade VUR was defined by the presence of VUR grade ≥III. The presence of high-grade VUR was recorded using VCUG, and correlated with the presence of E. coli/non-E. coli UTI and with the presence of normal/abnormal renal US. The Bayes theorem was used to calculate pretest and post-test probability. Results The probability of high-grade VUR was 3% in the presence of urinary E. coli infection. Adding a normal renal US finding decreased this probability to 1%. However, in the presence of non-E. coli bacteria, the probability of high-grade VUR was 26%, and adding an abnormal US finding increased further this probability to 55%. Conclusions In infants aged 0–3 months with a first febrile UTI, the presence of E. coli and normal renal US findings allow to safely avoid VCUG. Performing VCUG only in infants with UTI secondary to non-E. coli bacteria and/or abnormal US would save many unnecessary invasive procedures, limit radiation exposure, with a very low risk (<1%) of missing a high-grade VUR.