It is a great pleasure to introduce this special issue on renal diseases and disorders of the urinary tract. We are very grateful to all the contributors who kindly put so much effort into their contributions, and also to Alberto Edefonti and Mabel Sandoval Diaz and Giovanni Montini for writing the editorial.
Post-infectious glomerulonephritis (PIGN) is one of the most common causes of glomerulonephritis in children, and in >95% of cases it is owing to post-streptococcal glomerulonephritis (PSGN). Ramnath Balasubramanian and Stephen Marks have undertaken an in-depth review of PIGN with particular reference to PSGN. This includes the aetiology, pathogenesis, clinical features, investigations (including indications for renal biopsy), management and prognosis. They also mention three sub-types: endocarditis-associated glomerulonephritis, IgA dominant PIGN and shunt nephritis.
Group A streptococcus is the cause of most PSGN, but epidemics have been caused by group C. The list of causes of PIGN worldwide in adults and children is extensive and includes many bacteria and viruses as well as parasites and, occasionally, fungi.
PIGN is an immune-mediated glomerular injury which occurs as a result of host immune response to an extra-renal infection. Following a streptococcal infection, streptococcal antigens in the bloodstream localise in the glomerulus. Antibodies specific to these antigens are formed and interact with these antigens to form immune complexes in situ. Later, some of the antigen/antibody immune complexes formed in the circulation also lodge in the glomeruli. Certain M types of streptococcus which cause upper respiratory infection and different M types involved in skin sepsis are implicated in the cause of PSGN but the M protein itself is not nephrogenic. Two proteins – (a) nephritis-associated plasmin receptor (NAPlr, commonly detected in the Japanese population) and (b) streptococcal pyrogenic exotoxin B (SPeB) which is a super-antigen – commonly detected in Latin America, the United States and Europe are implicated in the pathogenesis of PSGN and are detected in the glomeruli. Both activate the alternative complement system, resulting in low C3 levels which usually return to normal within 6 weeks. SPeB titres correlate with the presence of glomerulonephritis better than either anti-streptolysin O (ASO) or anti-D Nase B antibodies. Of the three serological markers ASOT, anti-DNase B and anti-hyaluronidase, one or the other may be positive in 80–95% of cases, but the specificity of ASOT is only 80% as 20% may represent only streptococcal exposure.
The sub-clinical form of PSGN is around four to five times more common than overt glomerulonephritis. On the other hand, extreme forms may manifest as hypertensive crises without the typical urinary findings at presentation.
The prognosis is usually good in high-income countries in which clinical features on presentation are usually mild, although urinary findings can persist for some time. In low- and middle-income countries (LMIC), where often only the more serious forms of PSGN present at hospital, the outcome may be poorer in the acute phase.
Mallory Downie and co-authors have undertaken a comprehensive review of childhood nephrotic syndrome (NS), including the classification, epidemiology, pathophysiology, management and prognosis, with a brief overview of congenital forms. Current knowledge of the aetiology and pathophysiology are discussed in depth.
In European studies, children of South Asian origin are reported to have a higher incidence of idiopathic NS than those of European origin. Historical data from the United States have shown a higher incidence of NS in African-American children than in those of European descent. Renal histology of the former was more likely to demonstrate focal segmental glomerulosclerosis (FSGS).
Minimal change disease (MCD) and FSGS are beginning to be considered a spectrum with MCD representing an earlier stage, more responsive to treatment, and FSGS a more advanced and resistant stage of the disease.
In the pathophysiology of NS, disorders of podocytes associated with glomerular filtration barrier defects, immune dysregulation and systemic circulating factors are all considered to play a role. Podocytes are composed of a cell body that extends many foot processes which wrap around glomerular capillaries and support and maintain the kidneys’ glomerular basement membrane filtration mechanism. They are vulnerable to injury and destruction can lead to glomerulosclerosis. In addition, there may be genetic mutations in podocyte structure, as seen in congenital NS. The rationale for considering immune dysregulation, particularly affecting T-cell function, concerns the relationship between allergen exposure, malignancy and infection, e.g. measles, which can cause temporary spontaneous remission of NS. There are a number of examples to support an association between circulating factors and MCD and FSGS, including the ability of the vascular permeability factor and haemopexin to affect glomerular permeability.
The cause of oedema in NS has been debated for many years and two hypotheses have been suggested – the underfill and overfill theories – although there may be an overlap between the two. The underfill hypothesis proposes that high-grade proteinuria leads to hypoalbuminaemia which causes a decrease in oncotic pressure, leading to fluid leak into the interstitium, hypovolaemia and the resultant activation of the rennin–angiotensin–aldosterone system. The overfill hypothesis proposes that protein loss in the urine leads to sodium retention and intravascular volume expansion and increased fluid in the interstitium.
The main effect of corticosteroids in the management of NS is through regulation of cytokine gene expression via the glucorticoid receptor, acting to induce genes coding for anti-inflammatory cytokines and suppressing genes for pro-inflammatory cytokines. They may also suppress T-cell function and stabilise the podocyte cytoskeleton. Second-line agents for the treatment of idiopathic NS, which, similarly to corticosteroids, act in an immunomodulatory or immune suppressive role, include cyclophosphamide, levamisole, calcineurin inhibitors, e.g. cyclosporine and tacrolimus, mycophenolate mofetil and rituximab, are described in detail.
The present generation of paediatric nephrologists in Africa might have heard of quartan malaria nephropathy (QMN) but may not know how it came about. This is explained in the review by Wasiu Olowu and co-authors of the historical and recent presentations of childhood nephrotic syndrome in tropical Africa (TpAfr) during 1960–2016.
QMN was reported predominantly in Nigeria, from Ibadan, and also in Malawi, Uganda and Côte d’Ivoire during the 1960s–1970s. The renal histopathology was a pseudo-amalgam of membranous (MN) and membranoproliferative glomerulonephritis (MPGN). The glomerular capillary walls demonstrated splitting or a double contour pattern. There was less cellular proliferation than that characteristic of MPGN. Patients had a significantly greater frequency of P. malariae parasitaemia than controls. However, evidence of P. malariae was not demonstrated on renal histology and treatment for malaria did not affect outcome. Proteinuria was poorly selective, there was a lower response to corticosteroids than in other forms of NS and mortality was high owing to frequent progression to chronic renal failure. Immunofluorescence microscopy demonstrated coarse, granular, immunofluorescent IgG and C3 deposits in the glomeruli, supporting a diagnosis of immune complex-mediated glomerular injury. A report on NS in children from Ibadan in 1972 described 81% of patients with QMN. A study of NS in Zaria, northern Nigeria in 1990 reported only 20%, and a report from Ibadan in 1999 found no cases. Similar to Zaria, the dominant histological pattern was now MPGN. It is considered that the decline in QMN is likely to be owing to improved living conditions and health care, and better protection from malaria.
In a comparison of clinical and histological features of NS between 1960 and 1989 and 1989 and 2016 in TpAfr, the mean (SD) percentages of complete remission were, respectively, 26.5 (19.2) and 66.6 (28.0) (p = 0.01), and of steroid resistance were 73.5 (19.2) and 27.4 (25.3) (p < 0.001). In both periods, however, MCD remained around 20% with the majority of patients having non-MCD histology, including focal segmental glomerulosclerosis, MPGN, proliferative glomerulonephritis and MN, in that order.
In the second period, there were more reports of idiopathic NS and also of secondary NS owing to HBV, HIV, sickle cell disease and systemic lupus erythematosus.
Acute kidney injury (AKI) is a relatively common condition, especially in rural areas of LMIC where it is associated with poverty, poor hygiene, poor sanitation, a lack of readily available safe water, lack of education and, in particular, limited access to health care. The epidemiology, investigation, management and prevention of AKI in LMIC are outlined by Mohamed Abdelraheem.
A meta-analysis of AKI by the Acute Kidney Injury Advisory Group of the American Society of Nephrology estimated the overall pooled incidence of AKI in hospitalised children in Asia to be 33.7% and the mortality rate 13.8%, with wide variations between regions. There are no reports on the incidence in Africa, but a pooled mortality rate was estimated to be 34%. In LMIC, AKI is commonly secondary to a community-acquired infection, e.g. malaria, leptospirosis and dengue fever, volume depletion owing to gastroenteritis, drug and herb nephrotoxicity and animal envenoming. Awareness that these conditions can cause shock and/or dehydration and that early, simple treatment can prevent AKI is important. This requires education of health practitioners and the public in general and training of local health authorities in implementing preventive programmes. It is also necessary to emphasise the importance of AKI and its management in specific endemic disease programmes.
Delayed recognition of AKI is an independent risk factor for mortality. Recognition commences with recording urine output and fluid balance and undertaking urinalysis. A major problem is the lack of available facilities to estimate serum urea and creatinine. Estimation of salivary urea nitrogen might be a simple alternative.
Health facilities below district hospital level might not have a regular supply of intravenous fluids, antibiotics and appropriate anti-malarials. Peritoneal dialysis is appropriate for the management of most causes of AKI and should be available in all regional and at least some district hospitals. The International Society of Nephrology has launched an ambitious strategic programme, ‘0 by 25’, with the aim of eliminating preventable deaths from AKI by 2025 which will require enormous effort to initiate widespread programmes throughout low- and middle-income countries.
Although, to clinicians, the diagnosis and management of urinary tract infections (UTI) may appear straightforward, it remains among the most contentious issues in paediatrics. Lindsey Korbel and John Spencer review in depth the clinical diagnosis and management of UTI in children and adolescents.
Urinary tract infection affects up to 2% of boys and 8% of girls in the first 7 years of life. In young children, UTI has a peak incidence in infancy and a second peak in the toddler toilet-training years. Of children and adolescents who develop a UTI, 12–13% will have subsequent infections. Urinary tract infections in the first year of life occur more commonly in uncircumcised boys owing to the foreskin harbouring a high concentration of uropathogens. The American Academy of Pediatrics (AAP) supports circumcision at this age for families who desire it.
A positive urine culture is defined as at least 50,000 colony-forming units/ml of a uropathogen from an appropriately collected urine specimen. Urine obtained from a plastic bag attached to the perineum has a high risk of contamination and this is therefore unreliable and unacceptable for diagnosing UTI; however, a negative result should rule out infection. Suprapubic aspiration (SPA) and transurethral bladder catheterisation are strongly recommended by AAP. Clean-catch urine specimens are supported by NICE, the Italian and the Royal Children’s Hospital, Melbourne, Australia guidelines. In comparison with SPA, it is estimated that the sensitivity of clean-catch urine specimens for diagnosing UTI ranges from 75 to 100% and the specificity from 57 to 100%. Urine dipsticks detect the presence of nitrites or leucocyte esterase. The conversion of dietary nitrates to nitrites by enteric Gram-negative bacteria in the urine requires up to 4 h, and not all uropathogens reduce nitrates to nitrites, which explains the lower sensitivity for detecting bacteria compared with microbiological methods, but specificity is high. The sensitivity of the leucocyte esterase test is 94%, but false positives are common.
Microscopy (>10 white blood cells per high power field) is considered useful in children under 2 years of age, but may not have any advantage over the leucocyte esterase dipstick. Microscopy (Gram stain on an uncentrifuged urine specimen) combined with detection of pyuria has a positive predictive value of 85% but low sensitivity.
For the first febrile UTI, some professional societies advise routine ultrasound, others only for atypical cases or those aged <3–6 months. Voiding cystourethrogram (VUR) is not generally advised unless there is a suspected abnormality on ultrasound. The benefits of antibiotic prophylaxis for recurrent UTI are discussed and may be most effective in patients with VUR.
Neurogenic bladder is a dysfunctional urinary bladder caused by disease of the central or peripheral nervous system involved in the control of micturition. In LMIC, the major cause is myelomeningocele. Failure to manage paediatric neurogenic bladder leads to renal failure in 50% of untreated patients by 5 years of age, and is the main cause of early death in affected children. Urinary incontinence is the major symptom which has a profound effect on patients’ social integration. Patrick Maison and John Lazarus outline the aetiology, presentation and complications of paediatric neurogenic bladder and describe the optimal investigations and management in high-income countries and adaption of these to low-resource settings. Children with neurogenic bladder should be monitored from birth and managed with the main aim of preservation of renal function and achievement of social continence. Although the disability caused by myelomeningocele is well recognised by health workers in LMIC, sadly, a lack of awareness of the neurological effects on the urinary tract result in late presentation of urological complications.
Investigations include urinalysis, serial ultrasound of the urinary tract and urodynamic studies. Urodynamic studies evaluate the storage and emptying functions of the bladder. In resource-limited countries, this can be performed using ‘eye-ball’ urodynamics with a burette and three-way stopcock. A micturating cystography is important to detect vesicoureteric reflux and bladder outflow obstruction.
The primary aims of management are to normalise vesical pressure, preserve renal function, control constipation and achieve social continence. The mainstay of treatment is clean intermittent catheterisation (CIC), preferably commencing in infancy and teaching self-catheterisation before the child goes to school. Antimuscarinic drugs, commonly oxybutynin, are prescribed to reduce detrusor over-activity. Combined with CIC, the risk of developing renal failure is reduced by 90%, and up to 85% of children achieve social continence. When pharmacological measures fail, surgical procedures to enlarge the bladder, augmentation cystoplasty, may be required. One of the most common procedures is enterocystoplasty whereby a section of the ileum, ileocaecum or sigmoid colon is grafted to the bladder to enlarge it.
Si-Yan Jin and co-authors have reported on 788 Chinese children with lupus glomerulonephritis (LN). This is probably one of the largest studies on the subject. A questionnaire was completed by paediatric renal units from 26 Grade 3A hospitals for 619 girls and 169 boys with a mean (SD) age of onset of 10.9 (2.90) and range 1–18 years. The proportions of the main renal complications of LN were as follows: isolated haematuria or proteinuria or both 25%, acute glomerulonephritis 20%, nephrotic syndrome 50%, rapid progressive glomerulonephritis 2.5% and chronic nephritis 2%. The mean (SD) SLE disease activity index (SLEDAI) was 13.5 (5.53). LN was complicated by acute kidney injury in 242 (30.7) patients. A total of 549 children (69.7%) underwent a renal biopsy which was classified according to the International Association of Nephrology and the Renal Pathology Society (2003) and graded into eight histopathological types. The most common types were Class IV: diffuse LN (45.5%), followed by Class II: mesangial proliferation (14.6%); and V membranous LN + Class IV 10.6%. In the induction treatment phase, cyclophosphamide and mycophenolate mofetil were equally effective in patients with the same pathological type.
In children, tuberculosis of the kidney usually presents 5–7 years or more after the primary infection. Typically, there is sterile pyuria with or without red cells. Even when the disease is advanced, there might be very few leucocytes in the urine. Thus, it may remain asymptomatic and an occult disease for many years. Because it is rare in children, most of the knowledge on renal tuberculosis is based on experience of the disease in adults.
The three case reports by Nimisha Arora and co-authors highlight important points in the diagnosis of tuberculous pyelonephritis. Despite the fact that it is a chronic disease, all three patients presented with acute symptoms. If tuberculous pyelonephritis is considered and urinalysis is unhelpful, one must look elsewhere for evidence, e.g. tuberculin testing and chest radiograph. A smear for acid-fast bacilli can detect Mycobacterium tuberculosis in urine, and culture is positive in 10–80%, depending on disease severity. Three early morning specimens should be taken. GeneXpert MTBI RIF and, when available, PCR should also be considered while awaiting mycobacteria culture. Although ultrasonography may detect an abnormality in the kidney or abdominal lymphadenopathy, a CT scan or intravenous pyelogram is more likely to identify a typical, often destructive lesion in the kidney, ureter or bladder. Calcification in the kidney is common. Long-term follow-up to monitor renal function is essential.
Editor-in-chief