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Glomerular thrombotic microangiopathy is a hallmark feature of haemolytic uraemic syndrome, the leading cause of acute renal failure in childhood. This paper is a review of the different mechanistic pathways that lead to this histological picture in the kidney. It will focus on atypical HUS and complement dysregulation, but will also highlight some other recent advances in our understanding of this condition, including the potential role of the molecule vascular endothelial growth factor- A (VEGF-A).

Computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly valuable tools for assessing the urinary tract in adults and children. However, their imaging capabilities, while overlapping in some respects, should be considered as complementary, as each technique offers specific advantages and disadvantages both in actual inherent qualities of the technique and in specific patients and with a specific diagnostic question. The use of CT and MRI should therefore be tailored to the patient and the clinical question. For the scope of this article, the advantages and disadvantages of these techniques in children will be considered; different considerations will apply in adult practice.

There are a number of vasculitides that are not confined to a specific vessel size, do not have characteristic features, and/or are not secondary to another disease. Most of these vasculitides are rare in childhood. Behcet disease is representative of this group as it involves vessels of any size on both the arterial and venous side. In addition to renal vascular involvement, Behcet disease may involve the kidney through glomerulonephritis, secondary amyloidosis and, rarely, tubulointerstital involvement. Vasculitis secondary to infections, malignancy, and drugs are not common among children. However, vasculitis may be associated with a number of rheumatic diseases in childhood and the auto-inflammatory syndromes (periodic fever syndromes). Auto-inflammatory syndromes are diseases characterized by periodic attacks of clinical and laboratory inflammation. Studies carried out during the past decade have provided valuable information on the mechanism of inflammation and innate immunity in general. This group of vasculitides is associated with secondary amyloidosis of the kidney if not treated. Hypocomplementemic urticarial vasculitis is an interesting vasculitic disease with frequent kidney involvement. Here, we introduce the reader to the wide scope of these diseases; although rare, such diseases represent a challenge to the nephrologist.

Renal cysts in childhood can be found in a variety of diseases, which can be congenital or acquired, or renal cysts may be part of a multiorgan disease or restricted to the kidneys only. Ultrasonography is the first-line diagnostic tool and is informative in many cases. However, there is a broad spectrum in the sonographic appearance of renal cysts, and family or genetic studies, a search for extrarenal organ involvement, or additional imaging modalities may be required to make a definitive diagnosis. The aim of this article is to summarize the diagnostic potential and limitations of ultrasonography and depict typical examples of the most important cystic entities.

Children represent about 1% of all patients with urolithiasis, but 100% of these children are considered high risk for recurrent stone formation, and it is crucial for them to receive a therapy that will render them stone free. In addition, a metabolic workup is necessary to ensure a tailored metaphylaxis to prevent or delay recurrence. The appropriate therapy depends on localization, size, and composition of the calculus, as well as on the anatomy of the urinary tract. In specialized centers, the whole range of extracorporeal shock-wave lithotripsy (ESWL), ureterorenoscopy (URS), and percutaneous nephrolithotomy (PCNL) are available for children, with the same efficiency and safety as in adults.

Glomerulocystic disease is a rare renal cystic disease with a long descriptive history. Findings from recent studies have significantly advanced the pathophysiological understanding of the disease processes leading to this peculiar phenotype. Many genetic syndromes associated with glomerulocystic disease have had their respective proteins localized to primary cilia or centrosomes. Transcriptional control of renal developmental pathways is dysregulated in obstructive diseases that also lead to glomerulocystic disease, emphasizing the importance of transcriptional choreography between renal development and renal cystic disease.

Antibody-mediated rejection (AMR) is a unique, significant, and often severe form of allograft rejection that is not amenable to treatment with standard immunosuppressive medications. Significant advances have occurred in our ability to predict patients at risk for, and to diagnose, AMR. These advances include the development of newer anti-human leukocyte antigen (HLA)-antibody detection techniques and assays for non-HLA antibodies associated with AMR. The pathophysiology of AMR suggests a prime role for antibodies, B cells and plasma cells, but other effector molecules, especially the complement system, point to potential targets that could modify the AMR process. An emerging and potentially larger problem is the development of chronic AMR (CAMR) resulting from de novo donor-specific anti-HLA antibodies (DSA) that emerge more than 100 days posttransplantation. Therapeutic options include: (1) High-dose intravenously administered immunoglobulin (IVIG), which has many potential benefits. (2) The use of IVIG + rituximab (anti-CD20, anti-B cell). (3) The combination of plasmapheresis (PP) + low-dose IVIG with or without rituximab. Data support the efficacy of all of the above approaches. Newer approaches to treating AMR include using the proteosome inhibitor (bortezomib), which induces apoptosis in plasma cells, and eculizumab (anti-C5, anticomplement monoclonal antibody).

The approach to the pediatric patient with membranous nephropathy (MN) can be challenging to the practitioner. The clinical presentation of the child with this histologic entity usually involves some degree of proteinuria ranging from persistent, subnephrotic-ranged proteinuria to overt nephrotic syndrome. Patients often have accompanying microscopic hematuria and may have azotemia or mild hypertension. Children presenting with nephrotic syndrome are often steroid resistant; as such, their biopsy for steroid-resistant nephrotic syndrome results in the diagnosis of MN. The practitioner treating MN in the pediatric patient must weigh the risks of immunosuppressive therapy against the benefits. In general, the child with subnephrotic proteinuria and normal renal function can likely be treated conservatively with angiotensin blockade (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) without the need for immunosuppressive therapy. Those with nephrotic syndrome are usually treated with steroids initially and often followed by alkylating agents (cyclophosphamide or chlorambucil). Calcineurin inhibitors may also be useful, but the relapse rate after their discontinuation remains high. The absence of controlled studies in children with MN makes treatment recommendations difficult, but until they are available, using the patient’s clinical presentation and risk of disease progression appears to be the most prudent approach.

There is no unique optimal peritoneal dialysis prescription for all children, although the goals of ultrafiltration and blood purification are universal. In turn, a better understanding of the physiology of the peritoneal membrane, as a dynamic dialysis membrane with an exchange surface area recruitment capacity and unique permeability characteristics, results in the transition from an empirical prescription process based on clinical experience alone to the potential for a personalized prescription with individually adapted fill volumes and dwell times. In all cases, the prescribed exchange fill volume should be scaled for body surface area (ml/m2), and volume enhancement should be conducted based on clinical tolerance and intraperitoneal pressure measurements (IPP; cmH2O). The exchange dwell times should be determined individually and adapted to the needs of the patient, with particular attention to phosphate clearance and ultrafiltration capacity. The evolution of residual kidney function and the availability of new, more physiologic, peritoneal dialysis fluids (PDFs) also influence the prescription process. An understanding of all of these principles is integral to the provision of clinically optimal PD.

The biologics used in transplantation clinical practice include several monoclonal and polyclonal antibodies aimed at specific cellular receptors. The effect of their mechanisms of action includes depleting or blocking specific cell subpopulations, complement system, or removing circulating preformed antibodies and blocking their production. They are used in induction, desensitization ABO-incompatible renal transplantation, rescue therapy of steroid-resistant acute rejection, treatment of posttransplant recurrence of primary disease such as nephrotic syndrome or atypical hemolytic–uremic syndrome, and in late humoral rejection. There are various indications for the use of biologic agents before and early or late after renal transplantation in both high- and low-risk recipients. In the latter situation, the biologics-based induction is used to further minimize immunosuppression maintenance. The targets of several biologic agents are present across a variety of cells, and manipulation of the immune system with biologics may be associated with significant risk of acute and late-onset adverse events; therefore, clinical risk-versus-benefit ratio must be carefully balanced in every case. Several trials on novel biologics are reported in adults but not in the pediatric population.

Immunoglobulin A nephropathy is now recognized as the glomerular disease most often associated with progressive renal failure in patients around the world. In many cases it is not known when the disease starts to inflict glomerular injury, but recent studies that have shown genetically determined abnormalities in glycosylation of the IgA molecule suggest that this may begin in early life. This review focuses on recent advances in our understanding of IgA nephropathy, with special emphasis on clinical aspects of the disease when it presents in children and adolescents. In addition, the sections dealing with therapeutic options for patients with IgA nephropathy concentrate on studies that have been carried out on children. Whenever possible, data from randomized controlled clinical trials have formed the basis for recommendations. Unfortunately, this is not always possible, because of the lack of such trials in patients with IgA nephropathy.

The International Children’s Continence Society (ICCS) has undertaken an enormous effort to standardize both the terminology and management of various aspects of incontinence in children, including enuresis, bladder overactivity, dysfunctional voiding and psychological comorbidities. A number of guidelines have been published to aid those involved in the care of children with lower urinary tract symptoms. This review addresses a number of recommended diagnostic and therapeutic strategies, including urotherapy and pharmacological treatment, with emphasis on a focused medical history, information acquired from bladder diaries and uroflow evaluations. The major role of urotherapy is underlined with supportive pharmacotherapy, when indicated. The article provides both a summary of ICCS guidelines and a brief review of recently published papers related to the contemporary management of childhood incontinence, a health issue still underestimated by both the child’s caregivers and healthcare providers.

Health-related quality of life (HRQoL) is increasingly recognized as a key outcome in both clinical and research settings in the pediatric population with end-stage renal disease (ESRD). This review aims to: (1) summarize the current knowledge on HRQoL and socioprofessional outcomes and (2) provide strategies for incorporation of HRQoL assessment into clinical practice. Studies report that pediatric patients with ESRD have significantly lower HRQoL scores compared with children with other chronic diseases. Patients treated by dialysis are at particularly high risk for impaired HRQoL. Furthermore, patients more often have impaired neurocognitive functioning and lower academic achievement. Important determinants of impaired HRQoL include medical factors (i.e., receiving dialysis, disabling comorbidities, cosmetic side effects, stunted growth), sociodemographic factors (i.e., female gender, non-Western background) and psychosocial factors (i.e., noneffective coping strategies). Contrary to the situation in childhood, adult survivors of pediatric ESRD report a normal mental HRQoL. Despite this subjective feeling of well-being, these patients have on average experienced significantly more difficulties in completing their education, developing intimate relationships, and securing employment. Several medical and psychosocial strategies may potentially improve HRQoL in children with ESRD. Regular assessment of HRQoL and neurocognitive functioning in order to identify areas in which therapies and interventions may be required should be part of standard clinical care.

In the past 30 years there have been major improvements in the care of children with chronic kidney disease (CKD). However, most of the available epidemiological data stem from end-stage renal disease (ESRD) registries and information on the earlier stages of pediatric CKD is still limited. The median reported incidence of renal replacement therapy (RRT) in children aged 0–19 years across the world in 2008 was 9 per million of the age-related population (4–18 years). The prevalence of RRT in 2008 ranged from 18 to 100 per million of the age-related population. Congenital disorders, including congenital anomalies of the kidney and urinary tract (CAKUT) and hereditary nephropathies, are responsible for about two thirds of all cases of CKD in developed countries, while acquired causes predominate in developing countries. Children with congenital disorders experience a slower progression of CKD than those with glomerulonephritis, resulting in a lower proportion of CAKUT in the ESRD population compared with less advanced stages of CKD. Most children with ESRD start on dialysis and then receive a transplant. While the survival rate of children with ERSD has improved, it remains about 30 times lower than that of healthy peers. Children now mainly die of cardiovascular causes and infection rather than from renal failure. Electronic supplementary material The online version of this article (doi:10.1007/s00467-011-1939-1) contains supplementary material, which is available to authorized users

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood and the reason for chronic renal replacement therapy. It leads to significant morbidity and mortality during the acute phase. In addition to acute morbidity and mortality, long-term renal and extrarenal complications can occur in a substantial number of children years after the acute episode of HUS. The most common infectious agents causing HUS are enterohemorrhagic Escherichia coli (EHEC)-producing Shiga toxin (and belonging to the serotype O157:H7) and several non-O157:H7 serotypes. D(+) HUS is an acute disease characterized by prodromal diarrhea followed by acute renal failure. The classic clinical features of HUS include the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS mortality is reported to be between 3% and 5%, and death due to HUS is nearly always associated with severe extrarenal disease, including severe central nervous system (CNS) involvement. Approximately two thirds of children with HUS require dialysis therapy, and about one third have milder renal involvement without the need for dialysis therapy. General management of acute renal failure includes appropriate fluid and electrolyte management, antihypertensive therapy if necessary, and initiation of renal replacement therapy when appropriate. The prognosis of HUS depends on several contributing factors. In general "classic" HUS, induced by EHEC, has an overall better outcome. Totally different is the prognosis in patients with atypical and particularly recurrent HUS. However, patients with severe disease should be screened for genetic disorders of the complement system or other underlying diseases.

Although prospective randomized trials have provided important information and allowed the development of evidence-based guidelines in adult hemodialysis (HD) patients, with approximately 800 prevalent pediatric HD patients in the United States, such studies are difficult to perform in this population. Observational data obtained through the Center for Medicare & Medicaid Services’ (CMS’) End Stage Renal Disease (ESRD) Clinical Performance Measures (CPM) Project have allowed description of the clinical care provided to pediatric HD patients as well as identification of risk factors for failure to reach adult targets for clinical parameters such as hemoglobin, single-pool Kt/V (spKt/V) and serum albumin. In addition, studies linking data from the ESRD CPM Project and the United States Renal Data System have allowed evaluation of associations between achievement of those targets and the outcomes of hospitalization and death. The results of those studies, while unable to prove cause and effect, suggest that the adult ESRD CPM targets may assist in identifying pediatric HD patients at risk for poor outcomes.

Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosclerosis have been described. Though the immunosuppression used for each of the transplant types, cardiac, liver and HSCT is similar, the risk factors for developing CKD and the CKD severity described in patients after transplant vary. As the indications for transplant and the long-term survival improves for these children, so will the burden of CKD. Nephrologists should be involved early in the pretransplant workup of these patients. Transplant physicians and nephrologists will need to work together to identify those patients at risk of developing CKD early to prevent its development and progression to end-stage renal disease.

The recent discovery of genes involved in familial forms of nephrotic syndrome represents a break-through in nephrology. To date, 15 genes have been characterized and several new loci have been identified, with a potential for discovery of new genes. Overall, these genes account for a large fraction of familial forms of nephrotic syndrome, but they can also be recognized in 10–20% of sporadic cases. These advances increase diagnostic and therapeutic potentials, but also add higher complexity to the scenario, requiring clear definitions of clinical, histopathological and molecular signatures. In general, genetic forms of nephrotic syndrome are resistant to common therapeutic approaches (that include steroids and calcineurin inhibitors) but, in a few cases, drug response or spontaneous remission suggest a complex pathogenesis. Finally, syndromic variants can be recognized on the basis of the associated extra-renal manifestations. In this educational review, clinical, histological and molecular aspects of various forms of familial nephrotic syndrome have been reviewed in an attempt to define a rational diagnostic approach. The proposed model focuses on practical and economic issues, taking into consideration the impossibility of using genetic testing as starting diagnostic tool. The final objective of this review is to outline a diagnostic flow-chart for clinicians and geneticists and to generate a rational scheme for molecular testing.

Outcomes in critically ill neonates have improved over the past three decades, yet high residual mortality and morbidity rates exist. Acute kidney injury (AKI) is not just an innocent by-stander in the critically ill patient. Research on incidence and outcomes of AKI in the critically ill neonatal population is scarce. The objective of this publication is to (a) review original articles on the short- and long-term outcomes after neonatal AKI, (b) highlight key articles on adults and children with AKI in order to demonstrate how such insights might be applied to neonates, and (c) suggest clinical research studies to fill the gaps in our understanding of neonatal AKI. To date, observational studies suggest high rates of AKI and poor outcomes in critically ill neonates. Neonates with AKI are at risk of developing chronic kidney disease and hypertension. Large prospective studies are needed to test definitions and to better understand risk factors, incidence, independent outcomes, and mechanisms that lead to poor short- and long-term outcomes. Early biomarkers of AKI need to be explored in critically ill neonates. Infants with AKI need to be followed for sequelae after AKI.

Nail–patella syndrome (NPS) is a pleiotropic autosomal-dominant disorder due to mutations in the gene LMX1B. It has traditionally been characterized by a tetrad of dermatologic and musculoskeletal abnormalities. However, one of the most serious manifestations of NPS is kidney disease, which may be present in up to 40% of affected individuals. Although LMX1B is a developmental LIM-homeodomain transcription factor, it is expressed in post-natal life in the glomerular podocyte, suggesting a regulatory role in that cell. Kidney disease in NPS seems to occur more often in some families with NPS, but it does not segregate with any particular mutation type or location. Two patterns of NPS nephropathy may be distinguished. Most affected individuals manifest only an accelerated age-related loss of filtration function in comparison with unaffected individuals. Development of symptomatic kidney failure is rare in this group, and proteinuria (present in approximately one-third) does not appear to be progressive. A small minority (5–10%) of individuals with NPS develop nephrotic-range proteinuria as early as childhood or young adulthood and progress to end-stage kidney failure over variable periods of time. It is proposed that this latter group reflects the effects of more global podocyte dysfunction, possibly due to the combination of a mutation in LMX1B along with an otherwise innocuous polymorphism or mutation involving any of several genes expressed in podocytes (e.g.NPHS2,CD2AP), the transription of which is regulated by LMX1B.

The prevalence of nephrocalcinosis (NC) in preterm neonates in recent reports is 7-41%. The wide range in prevalence is a consequence of different study populations and ultrasound equipment and criteria, in addition to a moderate interobserver variation. NC in preterm neonates has a multifactorial aetiology, consisting of low gestational age and birth weight, often in combination with severe respiratory disease, and occurs as a result of an imbalance between stone-promoting and stone-inhibiting factors. A limited number of histological studies suggest that calcium oxalate crystals play an important role in NC in premature neonates. In 85% of children resolution of NC occurs in the first years of life. Prematurity, per se, is associated with high blood pressure, relatively small kidneys, and (distal) tubular dysfunction. In addition, NC in preterm neonates can have long-term sequelae for glomerular and tubular function. Long-term follow-up of blood pressure and renal function of prematurely born children, especially with neonatal NC, is recommended. Prevention of NC with (low) oral doses of citrate has not resulted in a significant decrease in the prevalence of NC; a higher citrate dosage deserves further study. Future research pertaining to prevention of NC in preterm neonates is crucial.

All stones share similar presenting symptoms, and urine supersaturation with respect to the mineral phase of the stone is essential for stone formation. However, recent studies using papillary biopsies of stone formers have provided a view of the histology of renal crystal deposition which suggests that the early sequence of events leading to stone formation differs greatly, depending on the type of stone and on the urine chemistry leading to supersaturation. Three general pathways for kidney stone formation are seen: (1) stones fixed to the surface of a renal papilla at sites of interstitial apatite plaque (termed Randall’s plaque), as seen in idiopathic calcium oxalate stone formers; (2) stones attached to plugs protruding from the openings of ducts of Bellini, as seen in hyperoxaluria and distal tubular acidosis; and (3) stones forming in free solution in the renal collection system, as in cystinuria. The presence of hydroxyapatite crystals in either the interstitial or tubule compartment (and sometimes both) of the renal medulla in stone formers is the rule and has implications for the initial steps of stone formation and the potential for renal injury.

Archeological findings give profound evidence that humans have suffered from kidney and bladder stones for centuries. Bladder stones were more prevalent during older ages, but kidney stones became more prevalent during the past 100 years, at least in the more developed countries. Also, treatment options and conservative measures, as well as ‘surgical’ interventions have also been known for a long time. Our current preventive measures are definitively comparable to those of our predecessors. Stone removal, first lithotomy for bladder stones, followed by transurethral methods, was definitively painful and had severe side effects. Then, as now, the incidence of urolithiasis in a given population was dependent on the geographic area, racial distribution, socio-economic status and dietary habits. Changes in the latter factors during the past decades have affected the incidence and also the site and chemical composition of calculi, with calcium oxalate stones being now the most prevalent. Major differences in frequency of other constituents, particularly uric acid and struvite, reflect eating habits and infection risk factors specific to certain populations. Extensive epidemiological observations have emphasized the importance of nutritional factors in the pathogenesis of urolithiasis, and specific dietary advice is, nowadays, often the most appropriate for prevention and treatment of urolithiasis.

Recent data indicate that the incidence of end-stage renal disease (ESRD) in pediatric patients (age 0–19 years) has increased over the past two decades. Similarly, the prevalence of ESRD has increased threefold over the same period. Hemodialysis (HD) continues to be the most frequently utilized modality for renal replacement therapy in incident pediatric ESRD patients. The number of children on HD exceeded the sum total of those on peritoneal dialysis and those undergoing pre-emptive renal transplantation. Choosing the best vascular access option for pediatric HD patients remains challenging. Despite a national initiative for fistula first in the adult hemodialysis population, the pediatric nephrology community in the United States of America utilizes central venous catheters as the primary dialysis access for most patients. Vascular access management requires proper advance planning to assure that the best permanent access is placed, seamless communication involving a multidisciplinary team of nephrologists, nurses, surgeons, and interventional radiologists, and ongoing monitoring to ensure a long life of use. It is imperative that practitioners have a long-term vision to decrease morbidity in this unique patient population. This article reviews the various types of pediatric vascular accesses used worldwide and the benefits and disadvantages of these various forms of access.

Dialytic intervention for infants and children with acute kidney injury (AKI) can take many forms. Whether patients are treated by intermittent hemodialysis, peritoneal dialysis or continuous renal replacement therapy depends on specific patient characteristics. Modality choice is also determined by a variety of factors, including provider preference, available institutional resources, dialytic goals and the specific advantages or disadvantages of each modality. Our approach to AKI has benefited from the derivation and generally accepted defining criteria put forth by the Acute Dialysis Quality Initiative (ADQI) group. These are known as the risk, injury, failure, loss, and end-stage renal disease (RIFLE) criteria. A modified pediatrics RIFLE (pRIFLE) criteria has recently been validated. Common defining criteria will allow comparative investigation into therapeutic benefits of different dialytic interventions. While this is an extremely important development in our approach to AKI, several fundamental questions remain. Of these, arguably, the most important are “When and what type of dialytic modality should be used in the treatment of pediatric AKI?” This review will provide an overview of the limited data with the aim of providing objective guidelines regarding modality choice for pediatric AKI. Comparisons in terms of cost, availability, safety and target group will be reviewed.

Visceral obesity and metabolic abnormalities typical for metabolic syndrome (MS) are the new epidemic in adolescence. MS is not only the risk factor for cardiovascular disease but also for chronic kidney disease (CKD). Thus, there are some reasons to recognize MS as a new challenge for pediatric nephrologists. First, hypertensive and diabetic nephropathy, the main causes of CKD in adults, both share the same pathophysiological abnormalities associated with visceral obesity and insulin resistance and have their origins in childhood. Secondly, as the obesity epidemic also affects children with CKD, MS emerges as the risk factor for progression of CKD. Thirdly, metabolic abnormalities typical for MS may pose additional risk for cardiovascular morbidity and mortality in children with CKD. Finally, although the renal transplantation reverses uremic abnormalities it is associated with an exposure to new metabolic risk factors typical for MS and MS has been found to be the risk factor for graft loss and cardiovascular morbidity after renal transplantation. MS is the result of imbalance between dietary energy intake and expenditure inducing disproportionate fat accumulation. Thus, the best prevention and treatment of MS is physical activity and maintenance of proper relationship between lean and fat mass.

Nephronophthisis (NPH) is an autosomal recessive disease characterized by a chronic tubulointerstitial nephritis that progress to terminal renal failure during the second decade (juvenile form) or before the age of 5 years (infantile form). In the juvenile form, a urine concentration defect starts during the first decade, and a progressive deterioration of renal function is observed in the following years. Kidney size may be normal, but loss of corticomedullary differentiation is often observed, and cysts occur usually after patients have progressed to end-stage renal failure. Histologic lesions are characterized by tubular basement membrane anomalies, tubular atrophy, and interstitial fibrosis. The infantile form is characterized by cortical microcysts and progression to end-stage renal failure before 5 years of age. Some children present with extrarenal symptoms: retinitis pigmentosa (Senior-Løken syndrome), mental retardation, cerebellar ataxia, bone anomalies, or liver fibrosis. Positional cloning and candidate gene approaches led to the identification of eight causative genes (NPHP1, 3, 4, 5, 6, 7, 8, and 9) responsible for the juvenile NPH and one gene NPHP2 for the infantile form. NPH and associated disorders are considered as ciliopathies, as all NPHP gene products are expressed in the primary cilia, similarly to the polycystic kidney disease (PKD) proteins.

Urolithiasis and nephrocalcinosis are more frequent in children then currently anticipated, but still remain under- or misdiagnosed in a significant proportion of patients, since symptoms and signs may be subtle or misleading. All children with colicky abdominal pain or macroscopic hematuria should be examined thoroughly for urolithiasis. Also, other, more general, abdominal manifestations can be the first symptoms of renal stones. The patients and their family histories, as well as physical examination, are important initial steps for diagnostic evaluation. Thereafter, diagnostic imaging should be aimed at the location of calculi but also at identification of urinary tract anomalies or acute obstruction due to stone disease. This can often be accomplished by ultrasound examination alone, but sometimes radiological methods such as plain abdominal films or more sensitive non-enhanced computed tomography are necessary. Since metabolic causes are frequent in children, diagnostic evaluation should be meticulous so that metabolic disorders that cause recurrent urolithiasis or even renal failure, such as the primary hyperoxalurias and others, can be ruled out. The stone is not the disease itself; it is only one serious sign! Therefore, thorough and early diagnostic examination is mandatory for every infant and child with the first stone event, or with nephrocalcinosis.

Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population.