Journal of Indira Gandhi Institute Of Medical Sciences

REVIEW ARTICLE
Year
: 2021  |  Volume : 7  |  Issue : 1  |  Page : 6--11

Chronic kidney disease in children


Om Kumar, Vikash Kumar Pandey, Prit Pal Singh, Amresh Krishna 
 Department of Nephrology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, India

Correspondence Address:
Vikash Kumar Pandey
Room No: 14, Department of Nephrology, Old Administrative Block, Indira Gandhi Institute of Medical Sciences, Sheikhpura, Patna - 800 014, Bihar
India

Abstract

Chronic kidney disease (CKD) is a major public health issue globally. Although not so common in children, its impact can be devastating with long-term consequences. Syndromal association, congenital abnormalities of the kidney and urinary tract, and other congenital anomalies usually present in childhood and have more impact in this population. Issues such as growth retardation, hormonal imbalance, psychosocial development, and transitions to adult care are specific to children and need to be addressed appropriately. With CKD, their nutritional requirement is quite different from adults and needs more careful planning and dietary modification to avoid growth retardation in these patients. Pharmacokinetics and pharmacodynamics of many drugs including immunosuppressants also differ from adults and need special considerations. Kidney transplantation is the best treatment modality available for end-stage renal disease (ESRD). Preemptive kidney transplantation is preferred to prevent growth retardation and psychosocial maladaptations in children with ESRD. Because lymphoid system development is on peak in adolescents and developing children, they are at high risk of graft rejection. Poor adherence to medication and recurrence of primary disease also affects long-term prognosis in adolescents adversely.



How to cite this article:
Kumar O, Pandey VK, Singh PP, Krishna A. Chronic kidney disease in children.J Indira Gandhi Inst Med Sci 2021;7:6-11


How to cite this URL:
Kumar O, Pandey VK, Singh PP, Krishna A. Chronic kidney disease in children. J Indira Gandhi Inst Med Sci [serial online] 2021 [cited 2021 Oct 23 ];7:6-11
Available from: http://www.jigims.co.in/text.asp?2021/7/1/6/318917


Full Text



 Introduction



Chronic kidney disease (CKD) is a major health problem globally with progressively increasing incidence and prevalence.[1],[2],[3],[4],[5] Besides the etiology, CKD is a clinical syndrome that is characterized by gradual loss of kidney function over a period of time.[6] CKD is defined by KDIGO as abnormalities of kidney structure or function present for more than 3 months having implications to health.[6] This definition has been formulated for the adult population and may not be fully applicable to the pediatric population. Childhood CKD presents with clinical features that are specific to the pediatric age group. Moreover, some typical characteristics of childhood CKD such as etiology or cardiovascular (CV) complications not only affect current health status but also determine future health prospects. Furthermore, the psychosocial impact of CKD in childhood need special attention as improving the health-care system leads to more and more children with CKD entering adulthood and also the economic burden on the existing health infrastructure.

 Epidemiology



The incidence of pediatric CKD has been stable for the last 30 years worldwide, but prevalence shows an increasing trend with the incidence of dialysis and renal transplant recipients.[7],[8] The incidence of renal replacement therapy (RRT) in children below 20 years of age was approximately 9 per million of the age-related population (pmarp) in 2008 globally and that of the United States was at 15.5 pmarp.[9] The pediatric incidence of CKD in Europe is reported to be around 11–12 pmarp for stages 3–5, while the prevalence is ~55–60 pmarp.[8],[10],[11],[12] The incidence of pediatric CKD rose slowly during the 1980s, then marginally until the first decade of the 21st century.[13] Among children, males outweigh females in the incidence and prevalence of CKD as there is higher frequency of congenital abnormalities of the kidney and urinary tract (CAKUT) in males.[10] Race and ethnicity is another very important factor that affects epidemiology of CKD. In North America, CKD is two to three times higher in African American children than Caucasians irrespective of gender.[14]

 Etiology of Chronic Kidney Disease in Children



The spectrum of causes of CKD in children varies greatly from that in the adult population; in fact, it varies greatly among different pediatric age groups also. CAKUT is the most common cause of CKD in children, followed by chronic glomerulonephritis (CGN) and inherited nephropathies.[11],[15] Other less common causes of CKD are medullary nephrocalcinosis, hyperparathyroidism, Alport syndrome, and urogenital infections.[16] Recent data show that obese children,[17] premature, low birth weight, and small for gestational age,[18] babies are prone to CKD in their adolescence. These conditions, together with the exploding burden of pediatric obesity are probably destined to significantly change the relative distribution of the causes of CKD.[17],[19]

The recent advent of next-generation sequencing has provided one of the most interesting and substantial clues in unraveling the etiology of early-onset CKD. Recent studies have demonstrated that quite a significant proportion of cases of CKD presenting before 25 years of age may be monogenic. In other words, a single gene can be detected as the cause of the disease in 20% of early-onset patients.[20] More than 200 genes are recognized as causative of the most common etiologic categories of CKD in children (CAKUT, steroid-resistant nephrotic syndrome, CGN, and ciliopathies).[20],[21],[22]

 Clinical Features and Future Implications of Chronic Kidney Disease in Children



Growth and development

Short stature can be defined as height two standard deviations below the mean for children of that sex, age, and race.[23] Growth impairment is a common and perhaps the most visible complication of CKD in children.[24],[25],[26] The degree of growth impairment increases as glomerular filtration rate (GFR) declines, even though a significant decrease in growth was seen at all levels of kidney function.[24],[25] The North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry data showed that around one-third of pediatric patients had short stature.[24] Even after recent advances in the management of CKD, approximately 30%–60% of patients have short stature.[27] Short stature is attributable to various factors such as uremic anorexia induced under-nutrition, increased protein catabolism, fluid and electrolyte abnormalities, hormone imbalance and resistance, persistent metabolic acidosis, mineral bone disease, anemia, and use of corticosteroids for management of glomerulonephritis and for transplantation.[28],[29],[30] Growth hormone resistance occurs due to chronic inflammation and acidosis.[30],[31] There is also an imbalance in the production of sex hormones in CKD. These factors are mainly responsible for the lack of pubertal growth spurt and underdevelopment of secondary sexual characters among adolescents with CKD. It has been observed that children transplanted before puberty, or those who are administered growth hormone regularly may achieve catch-up growth.[32],[33]

Chronic kidney disease–mineral and bone disorder

CKD-MBD is a systemic disorder of mineral and bone metabolism due to CKD that is defined by the presence of one or a combination of the following findings:

Abnormalities in calcium, phosphorus, parathyroid hormone, or vitamin D metabolismAbnormalities in bone histology, linear growth, or strengthVascular or other soft-tissue calcifications.[34]

Renal osteodystrophy is part of CKD-MBD which refers to bone pathology only. Early and effective management of CKD-MBD in childhood is of utmost importance as changes in calcium and phosphorus metabolism can significantly alter bone remodeling and somatic growth. Hence, normalization of bone health, growth with resulting final adult height should be focused in the management of CKD in children. Effective treatment of CKD-MBD retards CV disease progression as phosphate is a strong vascular toxin. Despite having international guidelines regarding the management of CKD-MBD, many patients still have a poorly controlled mineral metabolism, especially in the later stages of CKD. As phosphate control begins with dietary restriction, it is important for physicians to work closely with specialized dieticians. However, dietary restriction is very rarely adequate and phosphate binders become necessary even earlier than in adult patients.[35],[36],[37] Ultimate goal of therapy is to normalize mineral metabolism with the aim of improving growth and bone strength and at the same time, reducing bone deformities and minimizing the progression of extraskeletal calcification.[38],[39]

Anemia

It is a common complication in children suffering from CKD. The diagnosis of anemia in children with CKD is not as straightforward as in adults. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NFK-KDOQI) clinical practice guidelines use reference data from National Health and Nutrition Examination Survey (NHANES) III to define normal values in the pediatric population and recommend initiating an evaluation for anemia when hemoglobin levels fall below the age- and sex-specific 5th percentile value.[40],[41],[42] Data from the NAPRTCS show the prevalence of anemia in children to be 73% at CKD stage III, 87% at stage IV, and >93% at stage 5.[41],[42],[43] Anemia of CKD is multifactorial but decreased erythropoietin production by the diseased kidney and iron dysregulation remains one of the most important causes other than a nutritional deficiency.

Hypertension

CV complications have been found to be the most common cause of mortality in pediatric CKD similar to adult CKD.[44],[45] Recent work by the CKD in children (CKiD) cohort study and others showed that children with CKD have a high prevalence of CV risk factors, which persist even after the renal transplant.[46],[47] CKiD study also showed that hypertension (HTN) was present in 54% of participants at the time of enrolment and even more strikingly 48% of the children had high blood pressure (BP) despite being treated with antihypertensive regimen, which often excluded rennin angiotensin-aldosterone system inhibitors (RAAS-I). About 38% of the CKiD cohort had so-called masked HTN (normal office BP but elevated ambulatory BP) which is a known risk factor for left ventricular hypertrophy.[48],[49] Studies done in adults have clearly shown that effective control of BP not only reduces CV complications but also retards the progression of CKD.[50],[51] ESCAPE trial of 385 children with CKD showed that patients randomly assigned to intensified BP control (BP <50th percentile) had a 35% relative risk reduction in reaching the primary endpoint of a decline of 50% in the GFR or end-stage renal disease (ESRD) compared with those in the conventional BP control group (BP 50th–90th percentile). In summary, data from CKiD and other studies show that underdiagnosis and inadequate control of BP occur commonly in children with CKD. To improve this, 24 h ambulatory BP monitoring should be performed whenever possible and the use of RAAS-I should be part of an effective antihypertensive medication management, especially in children with proteinuria.

Cardiovascular disease

CVD remains the most important cause of death in children with CKD with risk of 1000 times higher compared to the age-matched non-CKD population and among CVD, cardiac arrhythmias, and cardiomyopathy top the chart.[52] Risk factors for CVD include uncontrolled BP, anemia, volume overload, vascular calcifications, hyperparathyroidism, and chronic inflammation so it is not to overemphasize that control of all above mentioned risk factors is of paramount importance to prevent mortality and morbidity.

Neurocognitive impairment and quality of life

CKD affects neurocognitive function even in the early stages of disease. Child suffering from CKD has impaired health-related quality of life and anxiety and depressive symptoms. Among the CKiD, cohorts' children with mild to moderate CKD had normal range of IQ, academic achievement, and executive functioning but were at risk of dysfunction with a significant portion at least one SD below the mean. They also found no association between neurocognitive deficits and glomerular etiology, years of life spent with CKD or HTN. But the influence of race and socioeconomic status could not be studied in the CKiD cohorts due to low representation.

Progression of chronic kidney disease

In a cohort study by Cerqueira et al., it was found that children with CKD stage 2–4 having the glomerular disease were found to progress more rapidly than those with CAKUT anomalies.[53] A predictive model identified severe proteinuria, glomerular disease, older age, non-Caucasian ethnicity, and CKD stage 4 at presentation as factors predicting rapid progression to ESRD.[53]

Wong et al. showed that a 10% decline in eGFR was associated with 14% increase in the urine protein-creatinine ratio, independent of the cause of CKD, and the non-Caucasian race was associated with higher levels of proteinuria.[54] Both Wong et al. and Warady et al.[55] revealed that glomerular etiology was associated with a significantly more rapid decline. Among nonglomerular diseases, factors leading to faster decline in eGFR were male, HTN, dyslipidemia, anemia hypoalbuminemia, and spot urinary protein-creatinine ratio >2 mg/mg.

The onset of puberty is associated with decline in renal function. ItalKid data showed that the probability of RRT was 9.4% in the first 10 years of life and 51.8% during the next 10 years of life.[56]

 Management of Childhood Chronic Kidney Disease



Management includes screening, early detection, implementing measures to retard progression of CKD, and finally renal replacement therapy (RRT) for those with ESRD. Screening of school children for CKD may be option for early diagnosis so that measures can be implemented to retard the progression of disease. Medical management is needed for control of HTN, management of anemia, and alleviation of acidosis.

Measures to retard progression of disease

Risk factors such as CGN, HTN, massive proteinuria, and anemia are associated with faster progression and need to be managed aggressively. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have been shown not only to reduce BP and proteinuria but also retard the progression of CKD and should be considered the first-line treatment of HTN and proteinuria.[51] The ESCAPE trial confirmed that intensive BP control was superior to conventional BP control in retarding the progression of ESRD.[57]

Correction of anemia

Correction of anemia is associated with decreased fatigability, CV risk, and improved quality of life. A target hemoglobin of 11–12 g/dL is recommended with iron and erythropoietin stimulating agent (ESA) supplementation. Serum iron studies need to be performed for every patient and iron stores need to be corrected before administering ESAs. If transferrin saturation is <20% and serum ferritin concentration <100 ng/ml then oral or parenteral iron therapy is recommended.[58] Recombinant human erythropoietin (rHuEPO) is both safe and effective in children with CKD treated conservatively and also in those on maintenance dialysis.[58],[59] The goal of treatment is to achieve a target hemoglobin level of around 11 g/dl or slightly more as in the adult population. Interestingly, the dose requirement of rHuEPO in young children is higher than adults, ranging from 275 to 350 U/kg per week for infants, to 200–250 U/kg per week for older children.[60],[61],[62] Supplemental iron therapy (either oral or parenteral) is also necessary for the treatment of anemia in children with CKD.

Growth and development

Adequate nutrition is of paramount importance in all CKD patients, especially children who are in their growing phase. Studies have shown that providing 80% of recommended nutrition prevents short stature in infancy and childhood.[31] Administration of recombinant human growth hormone over 2 years is usually associated with catch-up growth.[63]

Other interventions advised for proper growth and development are correction of metabolic acidosis, correction of CKD-MBD and anemia, and steroid-free/steroid avoidance regimen during renal transplantation.

 End Stage Renal Disease Therapies



Initiation of hemodialysis and peritoneal dialysis

Despite having benefits of preemptive renal transplantation, it is often necessary to initiate hemodialysis (HD)/peritoneal dialysis (PD) as a bridge therapy. According to NAPRTCS data, the use of PD has steadily declined over the last 30 years and in 2010, the use of HD surpassed the use of PD for the first time.[64]

The decision to start dialysis in children depends on various factors including residual renal function, laboratory values, psychosocial factors, and optimal timing of transplant. Estimation of eGFR is key to the initiation of dialysis, but available method like modified Schwartz equation is less accurate at the lower range of GFR and with malnutrition. As per KDOQI guidelines, maintenance hemodialysis should be considered in patients with eGFR <15 ml/min/1.73 m2, while European guidelines recommend a threshold of 6 ml/min/1.73 m2. Absolute indications to start dialysis are anuria, severe dyselectrolytemia, neurologic complications of renal failure (e.g., encephalopathy, seizures, foot drop), uremic pericarditis, bleeding diathesis, refractory nausea, and HTN. Malnutrition not responding to nutritional management is also an indication to begin dialysis.

There is a worldwide trend toward early initiation of dialysis, but it should be kept in mind regarding the loss of residual renal function and psychosocial impact on child put on dialysis and risks of infection.

Renal transplantation

After the introduction of renal transplantation in 1954, it has become the gold standard for renal replacement therapy in adults with ESRD owing to better understanding of the human immune system, advances made in the field of immunosuppressive therapy, and newer surgical techniques. In the initial days, pediatric kidney transplantation was associated with various technical and immunologic difficulties; however, over the last two decades with better techniques and facilities, there have been excellent patient and graft survival. At present, the 1- and 5-year patient survival rates associated with pediatric kidney transplantation are approximately 98% and 94%, respectively, and the 1- and 5-year graft survival rates are 93%–95% (from living donors) and 77%–85% (from deceased donors), respectively.[65]

As per the NAPRTCS database, approximately 80% of transplants are performed in pediatric recipients aged >6 years, and approximately 25% of patients undergoing primary transplants undergo preemptive transplantation.

From the year 1995–2000, 28% of pediatric recipients were preemptive and this group had the best 1-year allograft survival. Butani et al. showed that there was inverse relationship between duration of pretransplant HD (but not PD) and risk of allograft failure.[66] Renal transplantation confers 4 times increased survival benefit over dialysis. New immunosuppression regimens have led to great improvement in rejection rates from 55% in late 1980s to 10%–15% recently.[67]

 Conclusion



Childhood CKD is different from adult CKD in many aspects including etiology, presentations, and outcome. Effect of CKD on growth and development of children and psychosocial implications merit special attention and care. Adequate nutritional support and growth hormone supplementation are essential to the management of childhood CKD. Lots of progress have been made in unraveling the etiology and management of childhood CKD including renal transplantation such as preemptive renal transplantation and better immunosuppressive regimen prolonging allograft survival. However, much needs to be done regarding optimization of pretransplant management of CKD progression and complications of growth and CV disease, dialysis and access, and improving posttransplant outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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