Aadil Kakajiwala

Post-streptococcal glomerulonephritis associated with atypical hemolytic uremic syndrome: to treat or not to treat with eculizumab?

A 7-year-old male with poststreptococcal glomerulonephritis (PSGN) developed hemolytic uremic syndrome (HUS) and achieved remission. He was treated with eculizumab for 1 year. The eculizumab was discontinued and the patient remained in remission. This is the 10th reported case of PSGN associated with HUS. The histopathological feature observed at the 1-year follow-up was indistinguishable from the expected findings in an individual with healed PSGN without associated HUS. The relatively good prognosis in most prior cases and the absence of any reported recurrences strongly suggest that this form of atypical HUS does not warrant long-term eculizumab therapy.

Emerging biomarkers of chronic kidney disease in children

Chronic kidney disease (CKD) has become a significant public health concern, as it is associated with substantial morbidity. Prior research has evaluated multiple novel CKD biomarkers to supplement serum creatinine and proteinuria. The ultimate goal of this research is to find biomarkers that can be used to accurately predict CKD progression and to better time outpatient follow-up, and referral for transplant. Also, an optimal panel of biomarkers can augment the predictive value of proteinuria and serum creatinine by enriching patient enrollment in clinical trials. In this review, we discuss salient findings on 12 candidate plasma and urine biomarkers and their reported association with CKD. We explore the common pathways of CKD progression and the pathophysiologic processes of tubulointerstitial injury, inflammation, repair, and fibrosis that are potentially classified by specific biomarkers. We describe both pediatric and adult findings and highlight the paucity of pediatric research in CKD progression. It will be important for cohorts with longitudinal follow-up to evaluate these CKD biomarkers for potential use in pediatric clinical trials and routine CKD management.

Variability in measures of mineral metabolism in children on hemodialysis: impact on clinical decision-making

BackgroundVariability in measures of mineral metabolism has not been studied in pediatric end stage kidney disease. We sought to determine the intra-individual variability in measures of mineral metabolism in children on hemodialysis (HD) and its impact on clinical decision-making.MethodsWe conducted a prospective single-center study of children (3.6–17.3 years old) on chronic HD. Serial twice weekly measures of serum calcium, phosphate and intact parathyroid hormone (PTH), as well as weekly measures of fibroblast growth factor 23 (FGF23) and vitamin D metabolites, were obtained over a 12-week period in 10 children. Samples (n = 226) were assayed in a single batch at the end of the study.ResultsThe median intra-individual coefficient of variation (CV) calculated by 4-week blocks was 5.1–6.5% for calcium, 9.5–14.9% for phosphate and 32.7–33.4% for PTH. The median overall CV for FGF23 was 44.4%. Using the first value of each block as a reference, subsequent values would dictate a discrepant management decision 33–56%, 19–28%, and 30–33% of the time for calcium, phosphate, and PTH, respectively. Adjusting for sex and age, most of the variability in phosphate and PTH was attributable to within-participant variability. For calcium, 49% of the variability was attributable to day of blood collection (Monday vs. Friday). The median (range) of an individual participant’s values within clinical target ranges was 55% (26–86%) for calcium, 58% (0–96%) for phosphate, and 21% (0–64%) for PTH.ConclusionsThere is considerable intra-individual variability in measures of mineral metabolism that serve as surrogate markers for bone health in children on HD. Within a 4-week period, at least 20–30% of measures would dictate a discrepant decision from the referent measure of that month. These findings have important implications for clinical decision-making and underscore the need to base therapeutic decisions on trends rather than single measurements.

Acute hypocalcemia and metabolic alkalosis in children on cation-exchange resin therapy

Background Sodium polystyrene sulfonate (SPS) is a chelating agent used for the treatment of hyperkalemia. SPS has a wide range of exchange capacity requiring close monitoring of serum electrolytes. We observed two patients who developed acute hypocalcemia and increased metabolic alkalosis after initiating SPS therapy. We report these cases to draw attention to the potential risk of this medication in pediatric patients. Case Diagnosis/Treatment Two children with chronic kidney disease on dialysis were started on SPS for hyperkalemia. Within a week after initiation of the medication, both patients developed hypocalcemia on routine labs without overt clinical manifestations. The hypocalcemia was rapidly corrected with oral supplementation and discontinuation of SPS. Conclusions Severe hypocalcemia can develop after SPS therapy. The metabolic alkalosis in these patients associated with the hypocalcemia put them at increased risk for complications. Hence, careful attention must be paid to the state of calcium metabolism in all patients receiving SPS. Often calcium supplementation is required to maintain normal calcium levels.

Pain Management in Pediatric Chronic Kidney Disease

Pain is a common problem in children with chronic kidney disease (CKD); however, limited data exist regarding its management. Although most pain is managed pharmacologically, in some instances non-pharmacologic management can aid in safely ameliorating discomfort. Because of the accumulation of toxic metabolites, many common pain medications have adverse effects on kidney function or altered pharmacokinetics in the setting of CKD. Decreased clearance impacts safe dosing of analgesics. The pain management of patients on renal replacement therapy requires an understanding of drug clearance due to the different modalities of dialysis. This educational review highlights pain medications that are safe, albeit often with adjusted dosing, as well as drugs best avoided in the management of pediatric kidney disease. Acetaminophen should be used as a first-line therapy for pain management in children with CKD. Opioids may be added to control moderate to severe pain. Although data are currently lacking, buprenorphine holds promise as a potentially useful drug for the treatment of pain in pediatric patients with CKD. The addition of adjuvant pain medications and non-pharmacologic therapies maybe also be helpful. Despite these options, pain often remains difficult to treat in children with CKD.

The light at the end of the tunnel: an unusual case of acute kidney injury in a pediatric patient: Answers

Monoclonal gammopathies are a rare diagnosis in pediatric patients. A 19-year-old female patient with past medical history of hypogammaglobulinemia and natural killer cell deficiency and stage III follicular lymphoma, in remission, presented with a right-sided pneumonia, noted to have acute kidney injury and proteinuria. Complement C3 and C4 levels were normal. Anti-double-stranded DNA antibodies, antinuclear antibodies, anti-extractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibodies were negative. A renal biopsy showed numerous fractured tubular casts that were periodic acid-Schiff and silver-stain negative and fuchsinophilic on trichrome stain, with associated giant cells, tubulitis, acute tubular injury, and tubular rupture. The tubular casts had 3+ staining for lambda light chains and 0–1+ staining for kappa light chains. These findings were consistent with light chain cast nephropathy (LCCN). Serum free light chains, serum immunofixation, urine protein electrophoresis, and urine immunofixation studies supported the renal biopsy diagnosis of LCCN. A bone marrow biopsy showed normal trilineage hematopoiesis and also revealed an atypical B cell population detected by flow cytometry. Pathology specimens from lesions in the distal small bowel were characteristic of diffuse large B cell lymphoma (DLBCL). Chemoreduction therapy followed by chemotherapy was initiated for the DLBCL. Three months after initiation of chemotherapy, the patient’s creatinine has improved by > 50%. The likely cause of her LCCN was the new diagnosis of a DLBCL. Other risk factors include her history of hypogammaglobulinemia, natural killer (NK) cell deficiency, community-acquired pneumonia, and prior follicular lymphoma. Our patient may be the youngest reported case of LCCN. Treatment of LCCN is based on treating the underlying clonal plasma cell or B cell proliferation, typically with chemotherapy.

Using the newer Kidney Disease: Improving Global Outcomes criteria, beta-2-microglobulin levels associate with severity of acute kidney injury

ABSTRACT Beta-2-microglobulin (B2M) is a marker of proximal tubular injury and glomerular filtration. Analyses using older/non-standardized definitions have shown low efficacy of B2M to predict acute kidney injury (AKI). We assessed if elevated levels of B2M would associate with either the diagnosis of AKI [under current Kidney Disease: Improving Global Outcomes (KDIGO) criteria] or recovery from AKI. We performed a retrospective study, including children who had urine B2M (uB2M) and/or serum B2M (sB2M) measured by immunoturbidimetry in our clinical laboratory between January 2011 and December 2015. We defined AKI based on KDIGO criteria [increase of serum creatinine (sCr) 0.3 mg/dL over 48 h or >50% baseline over 7 days] or urine output <0.5 mL/kg/h for 24 h. Recovery from AKI was defined as a return to baseline sCr within 6 months. We calculated receiver operating characteristics (ROC) area under the curve (AUC). Of 529 patients, 245 developed AKI. Serum and uB2M associated with AKI development (AUCs 0.84 and 0.73, respectively). Patients had a graded higher median sB2M and uB2M with each higher AKI stage. sB2M differentiated Stage I from Stage III AKI (P < 0.001) and Stage II from Stage III AKI (P = 0.004). However, neither uB2M nor sB2M levels associated with recovery from AKI. Only older age {hazard ratio [HR] 0.97, [95% confidence interval (CI) 0.94–0.99]} and need for dialysis [HR 0.39 (95% CI 0.23–0.61)] predicted incomplete recovery after AKI. Using KDIGO criteria, sB2M and uB2M associate with the severity of AKI. Given its relative ease and lower cost, we suggest more widespread use of B2M for AKI detection.

The 'hole' story of a lung: Questions.

The patient underwent his first living-related donor renal transplant at the age of 3 years from his mother. Eight years later, the transplant failed secondary to recurrent urinary tract infections (UTI) and chronic allograft nephropathy. The first transplant had been managed with thymoglobulin induction, prednisone, tacrolimus, mycophenolate mofetil (MMF), and sirolimus. He received a second living-related donor renal transplant from his father at the age of 12 years. He was induced with thymoglobulin and maintained on prednisone, MMF, and tacrolimus. One month after his second transplant, he was noted to have BK viremia, with titers of 5,236,070 copies/ml. In response, MMF was discontinued, and he was started on leflunomide. Four months later, he experienced a gradual increase in creatinine, with renal biopsy findings of mild chronic allograft nephropathy, focal interstitial inflammation, tubular atrophy, and focal vascular hyalinosis, suggestive of calcineurin toxicity. He was started on sirolimus for immunosuppression (with a goal sirolimus level of 5–8 ng/ml) and continued on a very low dose of tacrolimus of 1 mg twice daily, prednisone 5 mg (initially daily and switched to every other day 8 months after the transplant), and leflunomide 15 mg daily. He developed significant Epstein Barr virus (EBV) viremia 14 months after transplantation (titers up to 903,013 copies/ml). The EBVviremia improved by 18months posttransplantation (52,498 copies/ml). BK viremia also resolved and leflunomide was discontinued. Twenty months after transplantation, his tacrolimus was discontinued due to another rise in EBV titers (up to 645,692 copies/ml).

The ‘hole’ story of a lung: Answers

1. Invasive pulmonary aspergillosis. The images in the computed tomography (CT) scan show a solid nodule within the lung parenchyma with central cystic degeneration. The histological study (hematoxylin/eosin stain, 20× magnification) revealed a central area of necrosis, surrounded by a chronic inflammatory infiltrate. Staining of this tissue with Gomori methenamine silver stain revealed septated hyphae with 45° angle branching, suggestive of Aspergillus spp. 2. Invasive pulmonary aspergillosis should be strongly suspected in the setting of cavitary lesions after transplantation [1]. Other infective causes to consider in a immunosuppressed host include (1) bacterial causes, including Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Nocardia spp., septic emboli and typical and atypical Mycobacteria, Actinomyces spp.; (2) fungal infections with Aspergillus spp., Histoplasma spp., Coccidioides spp., Zygomycosis, Crytpococcus neoformas, Pneumocystis jiroveci; (3) parasites. 3. The presence of a nodule surrounded by a zone of groundglass attenuation, or the Bhalo sign,^ followed by cavitation with Bair crescent sign,^ is suggestive of invasive pulmonary aspergillosis. The lesion may be further complicated by necrosis and infarction. 4. Voriconazole is a cytochrome P450 3A4 isoenzyme inhibitor and can cause decreased metabolism of calcineurin inhibitors and sirolimus. Recent studies [2, 3] show that sirolimus and voriconazole may be safely given together if there is empiric reduction in the sirolimus dose combined with close monitoring of sirolimus trough levels.

Acute Kidney Injury

Any process that interferes with the architecture and function of the renal vascular supply, the glomeruli, the renal tubule, or the urinary tract can compromise renal function. Acute kidney injury (AKI) can be defined as the sudden loss of renal function measured by a decline in GFR that develops over hours to days as a result of decreased renal perfusion, renal cell injury, or obstruction to urine outflow. The term AKI is now preferred over acute renal failure to standardize the definition and to reflect the mechanisms and entire spectrum of the disease. The etiology is usually multifactorial. Advances in pediatric critical care and surgery depend on interventions that often involve nephrotoxic exposures. The systemic inflammatory response evoked after an extensive surgical procedure or from critical illness can also lead to organ hypoperfusion, compounding the effects of nephrotoxic exposures. AKI is an independent risk factor for mortality, prolonged intubation, and increased ICU and hospital length of stay, with even higher rates of mortality in patients receiving renal replacement therapy. Early AKI detection provides the opportunity for early intervention.