The purpose of this review is to describe the role prematurity plays in the development of chronic kidney disease (CKD) and to discuss potential reasons for this association including decreased ...nephron mass, as well as postnatal insults such as neonatal acute kidney injury (nAKI).
New observational studies in humans and experimental studies in animal models have strengthened the association between prematurity, low birth weight and CKD. Growing evidence suggests increased susceptibility to CKD is caused by decreased nephron mass at birth. Beginning with a low nephron count may cause only subtle abnormalities during childhood, however may result in CKD, hypertension and albuminuria in adolescence or adulthood. Recent studies in premature infants reveal a high incidence of nAKI, which may also contribute to ongoing CKD risk.
Children born at low birth weights (both due to prematurity and/or intrauterine growth restriction) show increased risk of kidney dysfunction during adulthood. A better understanding of the modulators of nephron mass in premature infants as well as the effects of the extrauterine environment is essential. Additionally, improved awareness of at-risk infants is important as is early evaluation and detection of kidney dysfunction, allowing interventions to slow the progression to CKD.
Children undergoing cardiac surgery are at risk for acute kidney injury (AKI) and cardiac dysfunction. Opportunity exists in protecting end organ function with remote ischemic preconditioning. We ...hypothesize this intervention lessens kidney and myocardial injury.
We conducted a randomized, double blind, placebo controlled trial of remote ischemic preconditioning in children undergoing cardiac surgery. Pre-specified end points are change in creatinine, estimated glomerular filtration rate, development of AKI, B-type natriuretic peptide and troponin I at 6, 12, 24, 48, 72 h post separation from bypass.
There were 45 in the treatment and 39 patients in the control group, median age of 3.5 and 3.8 years, respectively. There were no differences between groups in creatinine, cystatin C, eGFR at each time point. There was a trend for a larger rate of decrease, especially for cystatin C (p = 0.042) in the treatment group but the magnitude was small. AKI was observed in 21 (54%) of control and 16 (36%) of treatment group (p = 0.094). Adjusting for baseline creatinine, the odds ratio for AKI in treatment versus control was 0.31 (p = 0.037); adjusting for clinical characteristics, the odds ratio was 0.34 (p = 0.056). There were no differences in natriuretic peptide or troponin levels between groups. All secondary end points of clinical outcomes were not different.
There is suggestion of RIPC delivering some kidney protection in an at-risk pediatric population. Larger, higher risk population studies will be required to determine its efficacy. Trial registration and date: Clinicaltrials.gov NCT01260259; 2021.
Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because ...thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults.
The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections.
In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus.
TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.
The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are ...variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual’s TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.
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The term atypical hemolytic uremic syndrome has been in use since the mid-1970s. It was initially used to describe the familial or sporadic form of hemolytic uremic syndrome as opposed to the ...epidemic, typical form of the disease. Over time, the atypical hemolytic uremic syndrome term has evolved into being used to refer to anything that is not Shiga toxin–associated hemolytic uremic syndrome. The term describes a heterogeneous group of diseases of disparate causes, a circumstance that makes defining disease-specific natural history and/or targeted treatment approaches challenging. A working group of specialty-specific experts in the thrombotic microangiopathies was convened to review the validity of this broad term in an era of swiftly advancing science and targeted therapeutics. A Delphi approach was used to define and interrogate some of the key issues related to the atypical hemolytic uremic syndrome nomenclature.
Background
Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q
10
(CoQ
10
) deficiency. Pathogenic
COQ2
variants are a cause of primary CoQ
10
...deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease.
Case-Diagnosis/Treatment
We report three pediatric patients with
COQ2
variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ
10
levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ
10
supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria.
Conclusions
COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in
NPHS1
,
NPHS2
, and
WT1
. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ
10
levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.
Introduction
Kidney disease is common after pediatric heart transplantation. Serum creatinine‐based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria ...is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients.
Methods
This was a cross‐sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin‐to‐creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019.
Results
In 115 patients at a median duration of 10.2 years post‐transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria.
Conclusion
Albuminuria is a prevalent finding in medium‐term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria.
Introduction: Thrombotic microangiopathy (TMA) is a known complication of allogeneic hematopoietic cell transplantation (HCT). Though the presence of graft-versus-host disease (GVHD) predicts the ...development of TMA, only a small subset of patients with GVHD will develop this condition. In the current study, we examined soluble C5b-9 (sC5b9), the terminal complement complex, as a potential biomarker for the development of TMA among patients with active GVHD.
Methods: We performed a nested case-control study using a prospective cohort of adult allogeneic HCT recipients transplanted during 2006-2013 at the Fred Hutchinson Cancer Research Center. Cases (TMA) with antecedent GVHD were ascertained and validated as previously described (BBMT 2019;25:570). Two controls (non-TMA) were randomly selected for each case at the time of TMA via the incidence density sampling method after matching on the onset timing and severity of prior GVHD. We tested plasma sC5b9 levels (exposure) in longitudinal samples at matched time points (pre-transplant, onset of GVHD, onset of TMA or matched time point) using a commercially available immunoassay kit. Furthermore, we reviewed patient records to determine the onset of systemic infection (including Gram negative bacteremia, invasive aspergillosis, BK viremia, HHV-6 invasive disease, CMV invasive disease, and EBV reactivation). Mean sC5b9 values and 95% confidence intervals were estimated at each time point. Conditional logistic regressions were used to estimate the association (odds ratio, OR) between the outcome (TMA vs. non-TMA) and the exposure (sC5b9 level) after accounting for matching. sC5b9 was modeled both as a continuous variable and a binary variable dichotomized at the median value.
Results: Among 208 adult allogeneic patients enrolled in the prospective cohort, we identified 38 patients (13 TMA cases and 25 non-TMA controls) with antecedent GVHD of similar time of onset and clinical grading. The median time to the onset of GVHD and TMA was 21 days (IQR 14-31) and 37 days (IQR 23-80), respectively. Six out of 13 cases developed TMA by 28 days. Mean sC5b9 levels were significantly higher in the TMA group than the non-TMA group at the onset of TMA vs. matched time point (377 vs. 248 ng/mL) and GVHD (369 vs. 240 ng/mL) but less so prior to transplant (243 vs. 200 ng/mL) (Figure 1). Furthermore, mean sC5b9 levels were elevated in patients experiencing active infection (364.10 ng/mL) and the values for each type of infection were shown in Table 2. When considered as a continuous variable, every 100 ng/mL increase in sC5b9 at the onset of GVHD was associated with an OR of 4.18 for TMA (p=0.02) (Table 1). As a binary variable, sC5b9 ≧ 250 ng/mL vs. < 250 ng/mL had an OR of 5.51 for TMA (p=0.04).
Conclusions: In the nested case-control study, we found that elevated sC5b9 level at the onset of acute GVHD was associated with the development of TMA after accounting for the timing and severity of GVHD. Previous studies have shown that testing of sC5b9 at day 28 was associated with TMA development; however, the prognostic value of day 28 testing was limited by the early onset of disease. Our study suggests that sC5b9 screening at the onset of GVHD may help predict which individuals would later develop TMA. It remains unclear whether complement activation is the driver or the effect of endothelial injury among GVHD patients. Finally, we caution that activation of the terminal complement pathway can also signify serious systemic infection. The interpretation of sC5b9 must be individualized according to the clinical scenario.
Acknowledgement: We would like to acknowledge and thank Kypha Inc for providing us with the immunoassay kits. We performed the study design and data analysis independently without industry funding.
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Schmidt:Kypha Inc: Employment, Equity Ownership. Lee:Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.
Background
We investigated prevalence of acute kidney injury (AKI) at hospitalization and its association with in-hospital mortality among Ugandan children hospitalized with common acute infections, ...and predictors of mortality among AKI children.
Methods
We enrolled 2,055 children hospitalized with primary diagnoses of acute gastroenteritis, malaria, or pneumonia. Serum creatinine, albumin, electrolytes, hemoglobin, and urine protein were obtained on admission. Participants were assessed for AKI based on serum creatinine levels. Demographic and clinical data were obtained using a primary care provider survey and medical chart review. Logistic regression was used to determine predictors of in-hospital mortality.
Results
A total of 278 (13.5 %) of children had AKI on admission; for 76.2 %, AKI was stage 2 (98/278) or stage 3 (114/278) defined as serum creatinine >2- or 3-fold above normal upper limit for age, respectively. AKI prevalence was particularly high in gastroenteritis (28.6 %) and underweight children (20.7 %). Twenty-five percent of children with AKI died during hospitalization, compared to 9.9 % with no AKI (adjusted odds ratio (aOR) 3.5 (95 % CI, 2.2–5.5)). In-hospital mortality risk did not differ by AKI stage. Predictors of in-hospital mortality among AKI children included primary diagnosis of pneumonia, aOR 4.5 (95 % CI, 1.8–11.2); proteinuria, aOR = 2.1 (95 % CI, 1.0–4.9) and positive human immunodeficiency virus (HIV) status, aOR 5.0 (95 % CI, 2.0–12.9).
Conclusions
Among children hospitalized with gastroenteritis, malaria, or pneumonia, AKI at admission was common and associated with high in-hospital mortality.
Transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic cell transplantation (HCT) has not been well characterized in large population studies with clinically ...adjudicated cases. We performed a retrospective cohort study of adults who underwent allogeneic HCT between 2006 and 2015 to determine the incidence of and risk factors for TA-TMA and to describe its natural history and response to immunosuppressant withdrawal management. Among 2145 patients in this study, 192 developed TA-TMA with a cumulative incidence of 7.6% by 100days post-transplant. Independent pretransplant risk factors included the receipt of a second (or third) allogeneic HCT, HLA-mismatched donor, and myeloablative conditioning with or without total body irradiation; post-transplant risk factors included the antecedent development of acute graft-versus-host disease, diffuse alveolar hemorrhage, bacteremia, invasive aspergillosis, BK viremia, and higher sirolimus trough level. Among TA-TMA patients 27% achieved hematologic resolution and 57% remained alive as of 90days after diagnosis. Antecedent risk factors stratified patients into different survival groups, and immunosuppressant withdrawal alone did not improve patient outcomes. In conclusion, TA-TMA is a heterogenous disease that occurs after allogeneic transplantation. Management with immunosuppressant withdrawal does not impact patient outcomes. Until further evidence becomes available, the management of TA-TMA should focus on the treatment of underlying diseases.
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