|Year : 2019 | Volume
| Issue : 2 | Page : 75-81
Incidence and determinants of acute kidney injury in patients with nephrotic syndrome
Sunil Kushwah, Menka Yadav, Pankaj Hari, Jitendra Meena, Aditi Sinha, Arvind Bagga
Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||4-Dec-2019|
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Background: Retrospective studies from developed countries indicate an increasing prevalence of acute kidney injury (AKI) in nephrotic syndrome. Prospective information on incidence and determinants of AKI in nephrotic syndrome from developing countries is limited. Methods: This prospective study enrolled consecutive patients with nephrotic syndrome, 1 month–18 years old, admitted to a single tertiary care center. Patients were evaluated daily for the development of AKI using Kidney Disease Improving Global Outcomes serum creatinine criteria until day 14 or discharge, along with clinical and biochemical information to determine associated risk factors. Estimated glomerular filtration rate (eGFR) was reassessed at 3 months' follow-up. Results: Of 115 patients (72.2% boys) enrolled at median (interquartile range) age 64 (36–111) months, 25 (21.7%) developed AKI. The incidence density of AKI was 3.3 (2.2, 4.8) episodes per 100 person-days. Stage 3 AKI comprised 64% of cases. Steroid-resistant illness, hypoalbuminemia, and low baseline eGFR were independently associated with the occurrence of AKI. AKI recovered completely or partially in 48% and 20% cases, respectively; 20% of patients remained dialysis-dependent and 12% of patients died. Patients with AKI had significantly longer hospital stay, and lower median eGFR at 3-month follow-up, than those without AKI. Conclusions: AKI affects 21.7% of patients admitted with nephrotic syndrome, is predominantly severe, and is associated with adverse outcomes in one-third cases, prolonged hospital stay, and reduced eGFR at discharge and short-term follow-up. Steroid-resistant nephrotic syndrome, hypoalbuminemia, and low eGFR at admission were independently associated with the occurrence of AKI.
Keywords: Dialysis, Kidney Disease Improving Global Outcomes, renal failure
|How to cite this article:|
Kushwah S, Yadav M, Hari P, Meena J, Sinha A, Bagga A. Incidence and determinants of acute kidney injury in patients with nephrotic syndrome. Asian J Pediatr Nephrol 2019;2:75-81
|How to cite this URL:|
Kushwah S, Yadav M, Hari P, Meena J, Sinha A, Bagga A. Incidence and determinants of acute kidney injury in patients with nephrotic syndrome. Asian J Pediatr Nephrol [serial online] 2019 [cited 2020 May 30];2:75-81. Available from: http://www.ajpn-online.org/text.asp?2019/2/2/75/272311
| Introduction|| |
Nephrotic syndrome, a common chronic kidney disease (CKD) in childhood, is usually managed on an outpatient basis with corticosteroids and immunosuppressive agents. Occasionally, complications such as severe infections, hypovolemia, venous thromboembolism, and acute kidney injury (AKI) are observed chiefly in patients with frequent relapses or steroid resistance, and require inpatient care. While AKI was considered to be uncommon in nephrotic syndrome, its incidence appears to be increasing. AKI in nephrotic syndrome is postulated to result from intravascular volume depletion, acute tubular necrosis (ATN), interstitial nephritis, nephrotoxic medications, diuretics, infections or renal vein thrombosis, and might represent reversible renal vasoconstriction during relapse.,
Most studies on AKI with nephrotic syndrome in childhood are either retrospective,,,, or limited to developed countries.,,, Two recent studies from South Asia, including one prospective study, have evaluated for incident AKI in nephrotic syndrome. The present study aimed to determine the incidence and risk factors of AKI in children with idiopathic nephrotic syndrome admitted to a tertiary care hospital in north India. The evaluation of incidence is expected to guide the intensity of vigilance for AKI, while the identification of risk factors would enable the timely prevention of AKI and its progression to severe stages.
| Methods|| |
Following ethics approval and written informed parental consent, consecutive patients, 1-month–18-year-old, admitted with complications of idiopathic nephrotic syndrome at the All India Institute of Medical Sciences, New Delhi, were assessed for eligibility over a 16-month period. Patients lacking baseline value of serum creatinine, previously known estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2, anticipated hospital stay of <24 hours, and patients readmitted during the study were excluded.
Standard definitions were used for nephrotic syndrome and its course. Information was collected on demographic variables, vital signs, anthropometry, diagnosis, comorbidities, therapies, presence of hypovolemia, sepsis or shock, use of diuretics or nephrotoxic medications, need for oxygen, mechanical ventilation, vasopressors or renal replacement therapy, length of hospital stay, and outcomes at discharge or death and at 3 months' follow-up. Data were anonymized on data entry.
Evaluation for acute kidney injury
Serum creatinine was estimated, using the modified Jaffe method with calibration traceable to the isotope dilution mass spectrometry method, on a Roche modular P800 autoanalyzer, in samples collected within 24 hours of admission, and subsequently on days 1, 3, 5, 7, 10, and 14 and/or at discharge. An additional sample was collected on day 7 for patients discharged earlier and at 3-month follow-up. AKI was defined and staged as recommended by the Kidney Diseases Improving Global Outcomes (KDIGO) guidelines. The baseline level of creatinine was the lowest available level during 90-day preceding admission and/or during the hospital stay. Complete recovery from AKI was defined as eGFR>90mL/min/1.73 m2 along with absence of hypertension and /or proteinuria. Any new-onset hypertension or persistent proteinuria or an eGFR of 15-90 ml/min/1.73 m2 was considered as partial recovery. CKD stage was classified according to eGFR.
Data were analyzed using STATA version 14.0 (StataCorp, Texas, USA). Categorical data were expressed as percentage and/or 95% confidence interval (CI) of the estimate, and compared using Chi-square or Fisher's exact test and/or relative risk (95% CI). Continuous data were expressed as median (interquartile range [IQR]) or mean ± standard deviation and compared using parametric or nonparametric tests, as appropriate; P ≤ 0.05 was considered statistically significant. Receiver operator characteristic (ROC) curves were used to categorize continuous variables at baseline for their prediction of AKI. Odds ratio (OR) for risk factors for AKI was determined using logistic regression; variables with P < 0.1 were included in multivariable analysis. The sample size was estimated to be 110 patients, assuming that 20% of patients admitted with a complication of nephrotic syndrome will develop AKI, allowing for 7.5% absolute precision and 95% confidence.
| Results|| |
From May 2016 to September 2017, 115 patients were enrolled from among 185 (62.2%) screened [Figure 1] and [Table 1]. These patients, including 72.2% boys, were enrolled at median 19 (IQR 5–55) months from disease onset, usually (78.3%) during relapse, or at diagnosis of steroid-sensitive (54.8%) or resistant (45.2%) nephrotic syndrome. The most common indications for admission were peritonitis (27.2%), acute gastroenteritis (27.2%), and pneumonia (21.7%).
|Figure 1: Flow of participants. Fourteen patients had acute kidney injury stage 1 or 2 at admission|
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|Table 1: Characteristics at baseline and during hospital stay in patients with and without acute kidney injury|
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Incidence and course of acute kidney injury
During 5 (4–7) days of inpatient stay, AKI developed in 25 patients, indicating an incidence of 21.7 (17.8%, 43.3%) and incidence density of 3.3 (2.2, 4.8) episodes per 100 person-days. AKI stage 1, 2, and 3 was seen in 3 (12%), 6 (24%), and 16 (64%), respectively [Figure 1]. [Table 1] shows the characteristics of these admissions. Fourteen (68%) patients had AKI at admission. Patients with AKI had a longer duration of hospital stay than those without AKI [Table 1]. At discharge from hospital, most patients showed complete (n = 12; 48%) or partial (n = 5; 20%) recovery; 5 (20%) patients remained dialysis-dependent at discharge, and 3 (12%) patients with stage 3 AKI died during hospital stay. At discharge, the median eGFR was significantly lower in patients who did (119; 60.3–174.3 ml/min/1.73 m2) compared to those who did not develop AKI (194.2; 142.8–228 ml/min/1.73 m2; P < 0.001).
Risk factors for acute kidney injury
As shown in [Table 1], patients who had AKI were more often steroid-resistant and receiving diuretic therapy and showed lower levels of hemoglobin, albumin, and eGFR at admission. During the hospital stay, patients with AKI were more likely to have developed sepsis or shock and required mechanical ventilation [Table 2]. On multivariable analysis, factors independently associated with the occurrence of AKI were eGFR (adjusted OR 0.97; 95% CI 0.96, 0.99; P < 0.0001), baseline serum albumin (OR 0.02; 0.002, 0.24; P = 0.002), and steroid-resistant disease (OR 15.00; 2.03, 110.64; P = 0.008). The ROC analysis showed that eGFR < 109.9 ml/min per 1.73 m2 and serum albumin <1.2 g/dl discriminated best between patients with or without AKI [Figure 2].
|Figure 2: Receiver operator characteristic curves for prediction of acute kidney injury based on inverse of (a) estimated glomerular filtration rate and (b) serum albumin at baseline. The area under the curve for inverse of estimated glomerular filtration rate was 0.86 (95% confidence interval 0.76, 0.95); an estimated glomerular filtration rate threshold of 109.9 ml/min per 1.73 m2 had 76.0% sensitivity and 88.9% specificity for, and correctly classified 86.1% cases of acute kidney injury. The area under the curve for inverse of serum albumin was 0.67 (0.58, 0.78); serum albumin threshold of 1.20 g/dl had 58.3% sensitivity and 66.7% specificity, and correctly classified 64.9% cases of acute kidney injury|
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Follow-up data at 3 months were available for 105 (91.3%) patients. Four patients died, including three with AKI who died during the hospital stay; one patient without AKI died 2-months after discharge due to status epilepticus. Six patients without AKI were lost to follow-up. At 3 months, the median eGFR was significantly lower in patients with (119; IQR [60.3–174.3] ml/min per 1.73 m2) and without AKI (194.2; 142.8–228 ml/min per 1.73 m2; P = 0.0002). CKD was classified as stage 1 in most patients with or without AKI (68.2% vs. 94%), stage 2 in two patients each (9.1% vs. 2.4%) and stage 3 in three patients each (13.6% vs. 3.6%); one patient (4.6%) each in the AKI group progressed to stages 4 and 5. Differences in the severity of CKD were different in patients with and without AKI (P = 0.007).
| Discussion|| |
This prospective observational study was planned to assess the incidence, risk factors, and outcomes of AKI in children admitted with complications of nephrotic syndrome. AKI affected one-fifth of all such patients and occurred usually in a setting of relapse associated with sepsis, shock, mechanical ventilation, or use of diuretics. Multivariable analysis indicated that steroid-resistant nephrotic syndrome and low baseline eGFR and serum albumin were independently associated with AKI. While mild disease (stage 1–2 AKI) resolved completely or partially by discharge, severe AKI (stage 3), constituting two-thirds of cases, was associated with adverse outcomes in half of the cases. Overall, AKI was associated with prolonged hospital stay and led to significantly lower eGFR at discharge and after 3 months.
AKI is conventionally regarded as an uncommon complication of idiopathic nephrotic syndrome, a disease with preserved renal function. While its precise pathophysiology remains unclear, the majority are expected to have ATN. A study from Poland reported AKI in merely 0.8% of 1006 patients with pediatric nephrotic syndrome. Using a nationwide pediatric inpatient database, Rheault et al. demonstrated that the prevalence of AKI in nephrotic syndrome increased from 3.3% to 8.5% over a decade at the turn of the century. Recent studies from across the world, summarized in [Table 3], suggest that AKI is more common, affecting 11%–51% of admissions for nephrotic syndrome, likely reflecting the increasing complexity of illnesses in patients managed at tertiary care centers.,,,,,, The reported prevalence varies widely, reflecting differences in the definition of AKI, setting, and study design. Previous authors have relied on the pediatric risk, injury, failure loss, or end-stage classification,,, and the use of KDIGO criteria,, to grade the severity of AKI, similar to the present work, is more recent. Overall, the prevalence of AKI in nephrotic syndrome is fairly similar between older, retrospective,,,,, and the two recent prospective series summarized in [Table 3]. However, the former report a majority of cases in “risk” category, while the latter indicates a preponderance of severe AKI.
|Table 3: Review of incidence, risk factors, and outcome of acute kidney injury in nephrotic syndrome in children|
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Previous as well as the present study have evaluated for etiology and risk factors for the development of AKI in patients with nephrotic syndrome hospitalized with disease complications. Infections,,,, and the use of nephrotoxic medications,,, or diuretics were commonly associated with AKI in nephrotic syndrome. In the present study, univariate analysis found associations between AKI and these factors, as well as factors reflecting cardiorespiratory instability, such as shock and mechanical ventilation. However, the only factors independently associated with AKI were asteroid-resistant disease course and lower levels of serum albumin and eGFR at admission. Steroid-resistant nephrotic syndrome, often secondary to focal segmental glomerulosclerosis (FSGS) associated with tubulointerstitial damage, is known to carry a high risk of the development of end-stage renal disease, and such patients are expected to have low renal reserve that might predispose them to AKI. AKI was also associated with steroid resistance in a study in Japanese children. Steroid resistance, due to ongoing proteinuria, is also linked to hypoalbuminemia, but both were an independent risk factor for AKI in the present work. Albumin is proposed as a tubular toxin linked to increased intracellular stress, apoptosis, and heightened complement activation., Further, hypoalbuminemia indicates intravascular hypovolemia, which is expected to predispose to AKI. Levels of serum albumin and degree of proteinuria have also been reported to be higher in patients with, compared to those without AKI by other authors.,,, It is also possible that steroid resistance and/or hypoalbuminemia leading to edema predisposed patients to infections and septicemia, and therefore, AKI. A surge of endothelin-1 secretion at the onset of relapse in adult patients with minimal change disease has also been linked to AKI.
In the present study, AKI was associated with low baseline eGFR. As patients with known advanced CKD (stage 3–5) were already excluded, confounding by preexisting renal dysfunction is unlikely. However, patients in the AKI group included 14 patients with AKI at admission, as reflected by over 50% rise from baseline serum creatinine, if available, or decline by over 50% by discharge. Hence, low baseline GFR as a risk factor for AKI might, in fact, reflect preexisting AKI in a majority of the patients. While the inclusion of baseline eGFR as a risk factor of AKI might seem inappropriate in this context, it has been a part of the calculation of scores used to predict incident AKI, such as renal angina index and studies also report day 1 AKI stage as predictors of later AKI.,, Prior studies have demonstrated an almost 30% decline in GFR in association with relapse of nephrotic syndrome,, that has been attributed to reversible fusion of podocyte foot processes, plausibly also explaining the association of AKI with proteinuria and steroid resistance. Further, patients with steroid-resistant FSGS might possibly have low renal reserve that reflects in a lower baseline eGFR, despite normal serum creatinine.
We found that AKI was associated with a median of 5 days longer hospital stay as compared to patients without AKI that was further prolonged for patients with stage 3 AKI (data not shown). While the majority of stage 1 and 2 AKI recovered renal function partially or completely, stage 3 AKI had poor outcome, similar to that reported by other authors [Table 3]. Importantly, our study is the only one in the context of nephrotic syndrome that demonstrated that persistent difference in eGFR between patients with and without AKI at 3 months' follow-up, indicating that a significant proportion of patients develop irreversible renal injury. Prospective studies are required to evaluate the long-term effect of AKI in patients with nephrotic syndrome.
Our study has certain flaws in design and conduct that limit the interpretation of findings. Data from a unicentric tertiary care study and a significant number with steroid resistance may not be generalizable to all settings and might overestimate the proportions with severe AKI. Evaluation of AKI at admission was difficult in patients presenting without baseline serum creatinine, particularly if admitted at onset of nephrotic syndrome; in these patients the diagnosis of AKI relied on the serum creatinine at discharge. While isotope dilution mass spectrometry is the recommended method for serum creatinine estimation, we used the modified Jaffe method, considered susceptible to errors by noncreatinine chromogens. AKI was only assessed using serial serum creatinine as an accurate measurement of urine output was neither feasible nor reliable in assessing AKI during relapse of nephrotic syndrome. Furthermore, we were unable to attribute a specific etiology or provide histopathological correlate in these patients as diagnosis of acute tubular injury was presumed in most of the children. The strengths of our study are a prospective evaluation, inclusion of a large number of patients, reporting of AKI incidence using recent KDIGO criteria, and estimation of renal function at 3 months' follow-up.
| Conclusion|| |
AKI at admission is observed in one-fifth of hospitalized children with nephrotic syndrome. The occurrence of AKI is associated with prolonged duration of hospital stay and reduced eGFR at discharge, and short-term follow-up. Independent risk factors for the development of AKI are steroid-resistant disease course, hypoalbuminemia, and low eGFR at baseline. Our findings highlight the need to identify patients with nephrotic syndrome at risk of AKI, and apply strategies to prevent AKI in focused at-risk groups.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]