Risk Assessment of Severe Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): A Birth Cohort

Recent advances in the early diagnosis of fetal CAKUT with an increase in fetal surgical interventions have led to a growing number of neonatal survivors born with severe renal dysfunction. This, in turn, has required the development of multi-disciplinary treatment paradigms in the individualized management of these infants with advanced stage kidney disease from birth. Early multi-modal management includes neonatal surgical interventions directed toward establishing adequate urine flow, respiratory support with the assessment of pulmonary hypoplasia, and establishing metabolic control to avoid the need for dialysis intervention. The development of specialized imaging to assess for residual renal mass with non-invasive 3-dimensional techniques are rapidly evolving. The use of non-radioactive imaging offers improved safety and allows for early prognostic-based planning including anticipatory guidance for progression to end stage renal disease (ESRD). The trajectory of kidney function during the neonatal period as determined by peak and nadir serum creatinine (SCr) and cystatin C (CysC) during the first months of life provides a guide toward individualized prospective management. This is a single center experience based on a birth cohort of 42 subjects followed prospectively from birth for an average of 6.1 ± 2.8 years at the University of Miami/Holtz Children's Hospital during the past decade. There was an 8:1 male: female ratio. The birth cohort was divided into 3 subgroups according to CKD Stages at the current age: CKD 1–2 (Group 1) (eGFR ≥ 60 ml/min/1.73 m2) (N = 15), CKD stage 3–5 (Group 2) (eGFR ≤ 59 ml/min/1.73 m2) (N = 12), and ESRD—Dialysis and/or Transplantation (Group 3) (N = 15). A neonatal CysC >3.0 mg/L predicted progression to ESRD while a nadir SCr >0.6 mg/dL predicted progression to CKD 3–5 with the highest specificity and sensitivity by ROC-AUC analysis (P < 0.0001). Medical management was directed toward nutritional support with novel formula designs, early introduction of growth hormone and strict control of mineral bone disorder. One of the central aspects of the management was to avoid dialysis for as long as feasible with a primary goal toward pre-emptive transplantation

Case report: Bordetella holmesii: A rare pathogen causing infective endocarditis associated glomerulonephritis

Infective endocarditis (IE) can cause multiorgan dysfunction and chronic kidney disease, in addition to cardiac sequelae. The presentation may be vague and can manifest as acute glomerulonephritis. While the most common pathogens of infective endocarditis are Staphylococcus and Streptococcus species, we report a rare pathogen Bordetella holmesii causing infective endocarditis associated glomerulonephritis. A 20-year-old male patient with tetralogy of Fallot with pulmonary atresia and aortopulmonary collaterals underwent several cardiac surgeries including prosthetic pulmonary valve replacement in the past. He was admitted for 3 days at an outside hospital for fever, cough, and hemoptysis, and diagnosed with streptococcal pharyngitis, for which he received antibiotics. Five weeks later, he presented to our institution with lower extremity edema and gross hematuria. On examination, he was afebrile, normotensive, had a 7-kg weight gain with anasarca, and a systolic murmur, without rash. Investigations revealed elevated serum creatinine, nephrotic range proteinuria, hematuria, and hypocomplementemia, consistent with acute glomerulonephritis. Given his cardiac history, blood cultures were collected from three sites. Broad-spectrum antibiotics were initiated when he subsequently developed fever. Renal pathology on biopsy showed diffuse proliferative immune complex-mediated glomerulonephritis. Transesophageal echocardiogram visualized a vegetation on the pulmonary valve. Bordetella holmesii was ultimately cultured from the prior and current hospitalization. A serum sample detecting microbial cell-free DNA sequencing confirmed Bordetella holmesii at very high levels. After completing 6 weeks of intravenous antibiotics with concurrent angiotensin receptor blockade, his kidney function recovered with improvement in hypocomplementemia and proteinuria. This case report highlights the early recognition and comprehensive evaluation of a rare organism causing IE-associated GN, which allowed for renal recovery and preserved cardiac function

Clinical predictors of chronic kidney disease in congenital lower urinary tract obstruction

Congenital lower urinary tract obstruction is associated with oligohydramnios and significant perinatal mortality and long-term chronic kidney disease. The counseling of families facing this diagnosis, especially when prenatal intervention is proposed, is fraught with ambiguity. This review aims to equip the provider with the current evidence behind the conventional and novel biomarkers predictive of chronic kidney disease. The relevant clinical predictors are categorized by when they are identified, antenatally or postnatally, and as either anatomic or chemical. They are considered for their prognostic value and the challenges in obtaining them, specifically the risk to the fetus in the case of prenatal biomarkers. Serum creatinine in infancy is the traditional chemical biomarker of kidney function and continues to be a consistent predictor of future serum creatinine. β-2 microglobulin may provide earlier information regarding fetal glomerular and tubular function and is also predictive of long-term serum creatinine. Renal parenchymal area is an anatomic surrogate of nephron mass that is used in both prenatal and postnatal settings. Understanding the anatomic and chemical biomarkers is essential for future refinement of the staging algorithm used to distinguish which patients may benefit from early in utero intervention

Cardio-renal consequences of low birth weight and preterm birth

In this comprehensive review of cardio-renal syndrome in preterm, low birth weight infants, we present contemporary evidence for alterations in nephrogenesis and vasculogenesis among this vulnerable population. There is substantial evidence that the nephron endowment, the number of nephrons that an individual is allotted for a lifetime, is determined by the length of gestation, the intra-uterine environment and the brief, but significant, postnatal course. Since nephrogenesis is complete by 36weeks' gestation in utero, preterm birth during active nephrogenesis predisposes to an abrupt cessation in development leading to a reduced nephron endowment. In addition, other organ systems are simultaneously developing by “branching morphogenesis” including the lungs, vascular tree and endocrine organs such as the pancreas. Importantly, elastin, the scleroprotein that imparts elasticity to the vascular tree, is laid down during angiogenesis in utero and its production after birth is negligible. Instead, elastin is replaced by collagen and fibrosis with aging imparting stiffness to the macro-vessels. Moreover, the micro-vessels (capillaries) are similarly affected with a decreased density, termed rarefaction, in vital organ tissues leading to retinopathy and insulin resistance. This developmental synergism predisposes to concordant abnormalities in endovascular function, nephropenia, hyperfiltration, vascular stiffness and simultaneous cardio-renal disease throughout a lifespan. The longevity of preterm-born adults has been substantially abbreviated by these structural and functional alterations in organ systems. It is essential to recognize early indicators of cardio-renal syndrome and to provide early life-style and pharmacological interventions directed towards preserving vascular and renal function throughout a lifetime with the goal to promote longevity and quality of life

Applied Metabolomics and Emerging Biomarkers in Neonatal Acute Kidney Injury

Acute kidney injury (AKI) in neonates presents a unique and ongoing challenge in the early diagnosis and subsequent management of these most vulnerable patients. The globally accepted traditional renal functional marker, serum creatinine (SCr), has long been recognized as unreliable in the neonate, particularly in those born preterm and of low birth weight [1]. In the immediate post-natal week, physiologic adjustments in systemic and renal perfusion lead to an increase in glomerular filtration rate (GFR) from as low as 20 ml/min/1.73 m2 to as high as 60 ml/min/1.73 m2 in term infants [1, 2]. Full maturation of GFR will not be achieved until about 2 years of age. Accordingly, the SCr is initially elevated due to the burden of excreting maternal creatinine. This accounts for a pattern of the SCr rising shortly after birth with a subsequent fall to a nadir <0.4 mg/dL (35 μM/L) in infants with normal post-natal renal development. In contrast, infants born preterm are more likely to have a decreased number of nephrons relative to their shortened gestation as well as intrauterine and perinatal stressors which impede a smooth and positive improvement in GFR [1, 2]. Hence, SCr may be inordinately elevated with a delay in decline to an appropriate nadir. A “true” measure of GFR or recognition of any degree of early kidney injury has been elusive in this setting [2]. While continuing to refine SCr-based definitions of neonatal AKI, a few pioneers have focused research efforts in the emerging field of “omics” in systems biology [3–5]. The suffix, “omics” emerged at the turn of the century to designate a field of biology devoted to the use of high throughput technologies to characterize the molecules that define the structure and function of an organism [5, 6]. Hence, the terms “genomics,” “proteomics,” “metabolomics” and others can be applied to better understand the pathophysiology and to develop biomarkers for the early diagnosis and treatment of neonatal AKI (Fig. 16.1)

Predictors of advanced chronic kidney disease in infancy after definitive vesicoamniotic shunting for congenital lower urinary tract obstruction

BackgroundSevere congenital lower urinary tract obstruction (cLUTO) is associated with poor postnatal outcomes, including chronic and end stage kidney disease, and high mortality. Studies of the impact of fetal intervention through vesicoamniotic shunting are marred by a device malfunction rate of up to 60%. In this study, we delineate the postnatal course and infant kidney function following definitive urinary diversion in utero. Materials and MethodsThis is a retrospective, single-center cohort study of 16 male infants who survived the fetal intervention to birth, from 2010 to 2014 at a single center. All had patent shunts in place at birth. Perinatal and biochemical characteristics were collected with patients followed for one year, or until demise, with serial measures of serum creatinine (SCr) and serum cystatin C (CysC). ResultsOf the 16 males, 81% were non-white (38% black, 43% Hispanic). Shunts were placed at a median of 20 weeks (IQR 19,23) gestation, with median fetal bladder volume of 39 cm(3) (IQR 9.9,65). All neonates were born preterm [median 34 weeks (IQR 31,35)] and the majority with low birth weight [median 2340 grams (1,895, 2,600)]. 63% required positive pressure ventilation. Advanced chronic kidney disease stage 4-5 at 1 year of age was predicted by neonatal characteristics: peak SCr >= 2 mg/dl, time to peak SCr > 6 days, discharge SCr >= 1.0 mg/dl, CysC >= 2.5 mg/l, urine protein:creatinine >= 4.8 mg/mg, urine microalbumin:creatinine >= 2.2 mg/mg. In infancy, a nadir SCr >= 0.5 mg/dl occurring before 160 days (5.3 months) of age was also predictive of advanced chronic kidney disease stage 4-5 at 1 year. Three patients died in the neonatal period, with 1 receiving kidney replacement therapy (KRT). Three additional patients required KRT before 12 months of age. ConclusionsEven with definitive vesicoamniotic shunting for cLUTO, postnatal morbidity and mortality remain high, emphasizing the role of renal dysplasia, in spite of urinary diversion, in postnatal kidney dysfunction. Neonatal and infant biochemical parameters exhibit distinct trends that offer families and physicians a better understanding of the prognosis of childhood kidney function

Therapeutic plasma exchange in familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis is a rare, life-threatening disorder characterized by impaired cytotoxicity, hypercytokinemia and immune-mediated organ injury. We report a 7-week-old male of consanguineous parents who presented with fever, pancytopenia and multi-organ failure. Elevated inflammatory markers and hypercytokinemia led to the diagnosis of familial hemophagocytic lymphohistiocytosis, which was confirmed with genetic testing. With the fulminant multiorgan failure, therapeutic plasma exchange was instituted, using the Prismaflex ® platform, followed by standard chemo-immunotherapy. There was dramatic reversal of the multi-organ failure and stabilization of the coagulopathy with this neo-adjuvant therapy. Thereafter, he was maintained in clinical remission with chemo-immunotherapy for 3 mo while awaiting stem cell transplantation