Structural and functional changes in the kidney caused by adverse fetal and neonatal environments.

Health and disease risk in the adulthood are known to be affected by the early developmental environment. Kidney diseases are one of these diseases, and kidneys are altered both structurally and functionally by adverse pre- and perinatal events. The most known structural change is low nephron number seen in subjects born low birth weight and/or preterm. In various animal models of intrauterine growth restriction (IUGR), one of the causes of low birth weight, the mechanism of low nephron number was investigated. While apoptosis of metanephric mesenchyme has been suggested to be the cause, I showed that suppression of ureteric branching, global DNA methylation, and caspase-3 activity also contributes to the mechanism. Other structural changes caused by adverse fetal and neonatal environments include peritubular and glomerular capillary rarefaction and low podocyte endowment. These are aggravated by postnatal development of focal glomerulosclerosis and tubulointerstitial fibrosis that result from low nephron number. Functional changes can be seen in tubules, endothelium, renin-angiotensin system, sympathetic nervous system, oxidative stress, and others. As an example, I reported that aggravated nitrosative stress in a rat IUGR model resulted in more severe tubular necrosis and tubulointerstitial fibrosis after unilateral ureteral obstruction. The mechanism of various functional changes needs to be clarified but may be explained by epigenetic modifications.

Caspase-3 regulates ureteric branching in mice via cell migration.

Inhibition of caspase-3 (Casp3) reduces ureteric branching in organ culture but the mechanism remains unclear. Since Casp3 has non-apoptotic functions, we examined whether Casp3 regulates ureteric branching by promoting cell migration, using a ureteric bud (UB) cell line and Casp3-deficient (Casp3-/-) mice. Also, we examined whether Casp3 plays a role in the reduced ureteric branching of metanephroi from nutrient restricted mothers, in which Casp3 activity is suppressed. A Casp3 inhibitor Ac-DNLD-CHO reduced FGF2-induced cord formation of UB cells in 3D culture. UB cell migration assessed by Boyden chamber and wound healing assays was inhibited by Ac-DNLD-CHO. Glomerular number was reduced by ≈ 30%, and ureteric tip number was lower in Casp3-/- mice compared with controls. Maternal nutrient restriction decreased ureteric tip number in controls but not in Casp3-/-. In conclusion, Casp3 regulates ureteric branching by promoting UB cell migration. Inhibited ureteric branching by maternal nutrient restriction may be mediated by Casp3.

Tubular dysfunction in extremely low birth weight survivors.

BACKGROUND: Extremely low birth weight (ELBW) survivors may develop glomerulosclerosis due to low nephron number, whereas their tubular function remains unknown except for hypercalciuria and phosphaturia. METHODS: Fifty-three subjects (30 boys and 23 girls, aged 7 months-19 years, median 36 months) were studied retrospectively. The median gestational age and birth weight were 26 weeks (range 22-32) and 745 g (range 316-999), respectively. Urine calcium-to-creatinine ratio (Ca/Cr), N-acetyl-ß-D-glucosaminidase-to-creatinine ratio (NAG/Cr), ß2 microglobulin-to-creatinine ratio (ß2m/Cr), uric acid-to-creatinine ratio (UA/Cr), glucose-to-creatinine ratio (glu/Cr), and microalbumin-to-creatinine ratio (malb/Cr) were examined. We also assessed the association between urine parameters and current age, gestational age, birth weight, and predictors of renal injury. Follow-up data were analyzed in 43 subjects 4-6 years later. RESULTS: Ninety percent of subjects had at least one tubular dysfunction. Frequency of elevated values was NAG/Cr 77.5%, UA/Cr 54.1%, ß2m/Cr 38.2%, malb/Cr 30.4%, Ca/Cr 21.5%, and glu/Cr 20.5%. There were significant negative correlations between the current age and Ca/Cr, NAG/Cr, glu/Cr, and UA/Cr, suggesting tubular function maturation. Urine ß2M/Cr and glu/Cr were negatively correlated with the gestational age. There were significant associations between elevated glu/Cr and asphyxia or neonatal acute kidney injury, and elevated NAG/Cr and indomethacin use, although these were not confirmed by multivariate analysis. At follow-up, the frequency of elevated NAG/Cr, glu/Cr, UA/Cr, and malb/Cr was reduced but that of elevated Ca/Cr, IgG/Cr, and ß2m/Cr remained similar or increased. CONCLUSION: Tubular dysfunction is common in ELBW survivors. Some abnormalities resolved with age while some remained persistent or even increased.

Visit-to-visit blood pressure variability in children and adolescents with renal disease.

BACKGROUND: Increase in blood pressure (BP) variability (BPV) is associated with cardiovascular events, target organ damage, and arterial stiffness in adults. We previously reported that 24-h BPV may be associated with arterial stiffness and underlie white-coat hypertension (WCH). In this study, we examined whether visit-to-visit variability (VVV) could predict WCH and whether VVV correlated with eGFR, eGFR slope, and albuminuria/proteinuria in children and adolescents with renal diseases. METHODS: VVV was determined as average real variability of office BP measurements between visits, and 24-h BPV as the standard deviation of 24-h ambulatory BP. In 35 renal patients (25 boys and 10 girls, 7-18 years of age), divided into normotension (NT), WCH, and hypertension (HTN), the relationships between VVV and 24-h BPV and VVV in each BP category were studied. In separate 48 renal patients (24 boys and 24 girls, 2-18 years of age), the correlation between VVV and eGFR, eGFR slope, urine albumin or protein excretion was examined. RESULTS: Systolic VVV was significantly correlated with systolic office BP index. There was no correlation between VVV and 24-h BPV or 24-h pulse pressure. In addition, VVV was not different among NT, WCH, and HTN. Systolic VVV was significantly negatively correlated with eGFR but not with eGFR slope, albuminuria, or proteinuria. A cut-off value of systolic VVV for detecting eGFR < 60 ml/min per 1.73 m2 was 8.5. CONCLUSION: VVV could not predict WCH. Systolic VVV correlated with eGFR but not with eGFR slope, albuminuria/proteinuria. Increased VVV could be a marker of decreased eGFR.

Masked Isolated Nocturnal Hypertension in Children and Young Adults.

Isolated nocturnal hypertension (INH) is characterized by normal daytime blood pressure (BP) and elevated nighttime BP diagnosed by ambulatory BP monitoring. Masked isolated nocturnal hypertension (MINH) is a subtype of INH in which office BP is normal. We studied the frequency and characteristics of INH and MINH in children and young adults. One hundred and ninety-eight subjects seen by the pediatric nephrology service were studied retrospectively. Isolated nocturnal hypertension (INH) and MINH were diagnosed according to daytime and nighttime ABP and office BP in the case of the latter. One hundred and eighteen subjects (60%) had normotension, 6 (3%) had isolated daytime hypertension, 32 (16%) had INH, and 42 (21%) had day-night hypertension. Sixteen subjects had MINH (8.1%). The underlying diseases of MINH were as follows: no underlying disease 9 (56%), renal disease 6 (38%), and endocrine disease 1 (6%). There was no significant difference in the underlying disease, gender, age, and BMI between MINH and INH with elevated office BP. In conclusion, MINH is present in children and young adults. Since there were no specific features for MINH, screening with ambulatory or home BP monitoring during sleep may be appropriate.

Polycythemia, capillary rarefaction, and focal glomerulosclerosis in two adolescents born extremely low birth weight and premature.

BACKGROUND: Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs. CASE-DIAGNOSIS/TREATMENT: We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction. CONCLUSIONS: Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

Targeting the ERK signaling pathway as a potential treatment for insulin resistance and type 2 diabetes.

Extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now examined the potential of pharmacological targeting of the ERK pathway with MEK (ERK kinase) inhibitors (PD184352 and PD0325901) for the treatment of obesity-associated insulin resistance. The effects of PD184352 and PD0325901 on the expression of adipocytokines and lipolysis activity were thus examined in 3T3-L1 adipocytes maintained in long-term culture as a model of adipocyte hypertrophy. Leptin receptor-deficient (db/db) mice and high-fat diet-fed KKAy mice, both of which are models of type 2 diabetes, were also treated orally with PD184352 to examine its effects on the diabetic condition. ERK activity was increased in hypertrophic 3T3-L1 adipocytes as well as in adipose tissue of db/db mice and high-fat diet-fed KKAy mice, and this enhanced ERK signaling was associated with dysregulation of adipocytokine expression and increased lipolysis activity. Specific blockade of the ERK pathway in hypertrophic 3T3-L1 adipocytes by MEK inhibitors ameliorated the dysregulation of adipocytokine expression and suppressed the enhanced lipolysis activity. Furthermore, repeated oral administration of PD184352 normalized hyperglycemia and hyperlipidemia and improved insulin sensitivity and glucose tolerance in the diabetic mice. These results suggest that sustained activation of the ERK pathway in adipocytes is associated with the pathogenesis of type 2 diabetes and that selective blockade of this pathway with MEK inhibitors warrants further study as a promising approach to the treatment of insulin resistance and type 2 diabetes.

Utility of fractional excretion of urea in the differential diagnosis of acute kidney injury in children.

INTRODUCTION: The fractional excretion of sodium (FENa) has been used as an index for the differential diagnosis of acute tubular necrosis (ATN) and prerenal acute kidney injury (AKI). The reliability of this index, however, decreases with the use of the diuretic agent furosemide. The fractional excretion of urea nitrogen (FEUN) has been shown to be useful in such settings in adults. The objective of this study was to examine whether FEUN is also useful in these settings in children. METHODS: We assessed 102 episodes of AKI in 74 children, classifying these into three groups based on history, physical examination, urine examination and subsequent clinical course: (1) prerenal AKI without furosemide (N = 37), (2) prerenal AKI with furosemide (N = 32) and (3) ATN (N = 33). RESULTS: Of the 37 prerenal AKI episodes without furosemide, 35 showed low FENa of <1 %, with an overall average of 0.35 ± 0.11 %, whereas prerenal AKI with furosemide (1.63 ± 0.37 %) and ATN (8.76 ± 2.11 %) were associated with a higher FENa. FEUN in the clinical setting of prerenal AKI was lower than that in ATN (27.9 ± 2.1 vs. 51.6 ± 3.8 %, respectively) and, in contrast to FENa, not significantly different between the categories of prerenal AKI with and without furosemide (29.2 ± 3.1 vs. 25.1 ± 2.9, respectively). The sensitivity of FEUN <35 % was 75 % in prerenal AKI with furosemide, whereas that of FENa was 53 %. CONCLUSIONS: FEUN is useful in detecting prerenal AKI in children administered furosemide.

White-Coat and Reverse White-Coat Effects Correlate with 24-h Pulse Pressure and Systolic Blood Pressure Variability in Children and Young Adults.

Masked hypertension (MH) and white-coat hypertension (WCH) are associated with organ damage. In the present study, we examined the correlation between the magnitude of white-coat effect (WCE) or reverse WCE (RWCE) and 24-h pulse pressure (PP), an indicator of target organ damage and arterial stiffness, in children and young adults. We also examined the relationship of WCE or RWCE and blood pressure (BP) variability, another predictor of clinical outcomes. One hundred and ninety-eight subjects were studied. According to the office BP and ambulatory BP, they were divided into normotension, WCH, MH, and hypertension. The magnitude of WCE or RWCE, along with male gender and 24-h systolic BP, was the determinant of 24-h PP. In subjects with 24-h PP ≥ 61 mmHg, the magnitude of WCE or RWCE, age, male ratio, height, weight, BMI, the percentage of secondary hypertension, that of MH, office systolic BP, and 24-h systolic BP were significantly greater. There was a progressive increase in 24-h PP from normotension, WCH, MH, to hypertension. BP variability in subjects with MH was numerically highest in both systolic and diastolic. Diastolic BP variability of WCH, MH, and hypertension was significantly higher than that of normotension. Finally, the magnitude of WCE or RWCE in systolic showed a significant correlation with systolic BP variability. In conclusion, the magnitude of WCE or RWCE correlates with 24-h PP and systolic BP variability, which may suggest increased arterial stiffness in WCH and MH.

Renal complications in 6p duplication syndrome: microarray-based investigation of the candidate gene(s) for the development of congenital anomalies of the kidney and urinary tract (CAKUT) and focal segmental glomerular sclerosis (FSGS).

6p duplication syndrome is a rare chromosomal disorder that frequently manifests renal complications, including proteinuria, hypoplastic kidney, and hydronephrosis. We report a girl with the syndrome, manifesting left hydronephrosis, proteinuria/hematuria, and focal segmental glomerular sclerosis (FSGS) resulting in chronic end-stage renal failure, successfully treated with renal transplantation. Microarray comparative genomic hybridization showed the derivative chromosome 6 to have a 6.4-Mb duplication at 6p25.3-p25.1 with 32 protein-coding genes and a 220-Kb deletion at 6p25.3 with two genes of no possible relation to the renal pathology. Review of the literature shows that variation of renal complications in the syndrome is compatible with congenital anomalies of the kidney and urinary tract (CAKUT). FSGS, observed in another patient with 6p duplication syndrome, could be a non-coincidental complication. FOXC1, located within the 6.4-Mb duplicated region at 6p25.3-p25.2, could be a candidate gene for CAKUT, but its single gene duplication effect would not be sufficient. FSGS would be a primary defect associated with duplicated gene(s) albeit no candidate could be proposed, or might occur in association with CAKUT.

Maternal nutrient restriction inhibits ureteric bud branching but does not affect the duration of nephrogenesis in rats.

BACKGROUND: Maternal nutrient restriction produces offspring with fewer nephrons. We studied whether the reduced nephron number is due to the inhibition of ureteric branching or early cessation of nephrogenesis in rats. Signaling pathways involved in kidney development were also examined. METHODS: The offspring of dams given food ad libitum (control (CON)) and those subjected to 50% food restriction (nutrient restriceted (NR)) were examined. RESULTS: At embryonic day 13 (E13), there was no difference between NR and CON in body weight or kidney size. Ureteric buds branched once in both NR and CON. At E14 and E15, body and kidney size were significantly reduced in NR. Ureteric bud tip numbers were also reduced to 50% of CON. On the other hand, the disappearance of nephrogenic zone and a nephron progenitor marker Cited1 was not different between CON and NR. The final glomerular number of NR was 80% of CON. Activated extracellular signal-regulated kinase (ERK), p38, PI3K, Akt, and mammallian target of rapamycin (mTOR), and protein expression of ß-catenin were downregulated at E15. CONCLUSION: Ureteric branching is inhibited and developmentally regulated signaling pathways are downregulated at an early stage by maternal nutrient restriction. These changes, not early cessation of nephrogenesis, may be a mechanism for the inhibited kidney growth and nephrogenesis.

Utility of fractional excretion of magnesium in diagnosing renal magnesium wasting in pediatric nephrology practice.

BACKGROUND: Fractional excretion of magnesium (FEMg) is commonly used to diagnose of renal magnesium (Mg) wasting, but it can be affected by serum Mg (SMg) and serum creatinine concentration (SCr). We investigated the sensitivity and specificity of FEMg to diagnose Mg wasting in subgroups with different SMg and eGFR (estimated glomerular filtration rate) in pediatric nephrology practice. METHODS: One hundred and nineteen patients (59 males and 60 females, median 15 years) seen in our pediatric clinic were investigated for FEMg, SMg, eGFR, and urine Mg-to-creatinine ratio (Mg/Cr). Normal eGFR was defined as ≥ 90 ml/min/1.73 m2 or for infants SCr < chronic kidney disease stage 2. Urine Mg/Cr was compared with age-specific reference values. RESULTS: Sixteen of all patients (13 %) had hypomagnesemia. All had FEMg greater than the cut-off value of 2 %. Only 4 patients had elevated urine Mg/Cr. Of 65 patients with normal SMg and eGFR, 19 had FEMg above the cut-off value of 4 %. Of these, 13 patients had elevated urine Mg/Cr i.e. Mg wasting (sensitivity and specificity of FEMg, 93 % and 88 %, respectively). Among 38 patients with normal SMg and low eGFR, 30 had FEMg > 4 %, but only 6 had elevated urine Mg/Cr (sensitivity 100 % and specificity 25 %). Overall, hypomagnesemic patients and normomagnesemic patients with elevated urine Mg/Cr were diagnosed with Mg wasting (36/119, 30 %). CONCLUSIONS: FEMg has variable sensitivity and specificity depending on SMg and eGFR in the diagnosis of Mg wasting. Mg wasting is not uncommon in pediatric nephrology practice.

Persistent hypertension despite successful dilation of a stenotic renal artery in a boy with neurofibromatosis type 1.

Hypertension is one of the major complications in neurofibromatosis type 1 (NF1). It is known to be caused by renal artery stenosis or pheochromocytoma. However, more than half of hypertensive patients with NF1 do not have either disorder. We report here on a 13-year-old male with NF1 who had hypertension and a stenosis of the right renal artery associated with elevated renal vein renin on the diseased side. He underwent percutaneous transluminal renal angioplasty. In spite of successful dilation of the artery and normalized renin level, high blood pressure persisted beyond 6 months requiring antihypertensive medication. His wide pulse pressure suggested arterial stiffness due to NF1 vasculopathy. We posit that the cause of hypertension in this patient was considered to be arterial stiffness ascribed to NF1 vasculopathy rather than renal artery stenosis. Increased pulse pressure supports the hypothesis. This marker of arterial stiffness can be assessed non-invasively and should be evaluated routinely in NF1.

Leukemia kidney infiltration can cause secondary polycythemia by activating hypoxia-inducible factor (HIF) pathway.

UNLABELLED: Secondary polycythemia with increased production of erythropoietin (EPO) is known to occur in kidney diseases such as hydronephrosis and cystic disease, but the mechanism remains unclear. We report an 18-year-old female with isolated renal relapse of acute lymphoblastic leukemia accompanied by polycythemia. At the relapse, she presented with bilateral nephromegaly, mild renal dysfunction, and erythrocytosis with increased serum EPO levels up to 52.1 mIU/mL (9.1-32.8). Renal biopsy demonstrated diffuse lymphoblastic infiltration. The expression of hypoxia-inducible factor (HIF)-1α, which is undetectable in normal kidney, was observed in the renal tubule epithelium compressed by lymphoblastic cells. These findings suggest that erythrocytosis was caused by renal ischemia due to leukemic infiltration. Polycythemia probably became apparent because of the lack of leukemic involvement of the bone marrow. With chemotherapy, the serum EPO level rapidly decreased to normal range accompanied by the normalization of kidney size and function. Renal leukemic infiltration may enhance EPO production, although not recognized in the majority of cases because of bone marrow involvement. CONCLUSION: Our case has clarified the mechanism of previously reported polycythemia associated with renal diseases as renal ischemia. Furthermore, we have added renal ischemia resulting from tumor infiltration to the list of causes of secondary polycythemia.

A girl with membranous nephropathy associated with ventriculoperitoneal shunt infection.

Glomerulopathy associated with shunt infection is commonly membranoproliferative glomerulonephritis, whereas the causative organisms of secondary membranous nephropathy are usually viruses. We report a case of membranous nephropathy associated with shunt infection. The patient was born at 29-week gestation with a birth weight of 1178 g. Ventriculoperitoneal shunt surgery had been performed for congenital hydrocephalus. Thereafter, she had experienced seven shunt infections. At the age 13 years, proteinuria was detected in a school urinary screening. Urinalysis at our hospital demonstrated 3 + protein and 3 + blood. Laboratory testing demonstrated a serum creatinine 0.5 m/dl, albumin 2.5 g/dl, C-reactive protein (CRP) 13.7 mg/dl, and C3 182 mg/dl. Prior to repeat urinalysis, the patient developed vomiting and was admitted with suspected shunt infection. On admission, her body temperature was 36.0 ºC. Physical examination was unremarkable other than small stature and a palpable mass in the left upper quadrant. Urinalysis demonstrated 2 + protein and 1 + blood with no cells or casts. The urinary protein excretion was 3 g/day. Abnormal laboratory tests included erythrocyte sedimentation rate 102 mm/hr, CRP 11.67 mg/dl, IgG 2442 mg/dl, C3 177 mg/dl, and C4 44 mg/dl. Antibiotic therapy was initiated for a presumptive diagnosis of shunt infection and the shunt catheter was removed. Cultures obtained after antibiotic administration were negative. Proteinuria persisted after control of the shunt infection. Histology of a renal biopsy demonstrated membranous nephropathy with diffuse granular IgG staining and subepithelial deposits. Three possible pathomechanisms for her membranous nephropathy were considered.

Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting.

The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity. An X-linked recessive mode of transmission has been suggested for this condition based on the observation that male patients have preferentially been affected. Thus far, no candidate genes have been suggested on the X chromosome. We report a male patient with a full-blown Hartsfield syndrome phenotype who had microduplication at Xq24 involving four genes. He presented with bilateral ectrodactyly of the hands (both hands had four fingers with a deep gap between the 2nd and 3rd digits), cleft lip and palate, and a depressed nasal bridge. Magnetic resonance imaging of the brain revealed lobar holoprosencephaly. His G-banded karyotype was normal. Array comparative genomic hybridization (CGH) using the Agilent 244K Whole Human Genome CGH array revealed a microduplication at Xq24 of 210 kb. Parental testing revealed that the deletion was derived from the asymptomatic mother. Of the genes on the duplicated interval, the duplications of SLC25A43 and SLC25A5 appeared to be the most likely to explain the patient's phenotype. From a clinical standpoint, it is important to point out that the propositus, who performs relatively well with holoprosencephaly and has a developmental quotient around 70, has survived multiple life-threatening episodes of hypernatremia. Awareness of the risk of hypernatremia is of great importance for the anticipatory management of patients with ectrodactyly and an oral cleft, even in the absence of overt hypotelorism.

Ambulatory blood pressure in prehypertensive children and adolescents.

BACKGROUND: Prehypertension is defined as blood pressure (BP) ≥ 90 th percentile, or ≥ 120/80 mmHg, but <95th percentile for age, sex, and height. Since the definition is made by conventional BP measurements and office BP can be quite variable, we studied whether prehypertension could be differentiated by ambulatory BP monitoring from normotension or hypertension (HTN) in children and adolescents. METHODS: One hundred and fifty-eight children (84 boys and 74 girls, aged 6-17 years, median 12) were studied. According to the office BP values, they were divided into normotension (80), prehypertension (20), and HTN (58). RESULTS: Systolic BP index and systolic daytime ambulatory BP (ABP) were significantly higher in prehypertensive patients than in normotensives and lower than hypertensives. When daytime ABP was used to diagnose HTN, four normotensive (5.0%), four prehypertensive (20.0%), and 27 hypertensive (46.6%) patients had HTN. Thus, in patients with prehypertension, the prevalence of masked HTN is significantly higher than in those with normotension. On the other hand, the prevalence of daytime ambulatory HTN is significantly lower, i.e., white-coat effect is more frequent, compared with hypertensive patients. CONCLUSION: Prehypertension lies between normotension and HTN in ABP values as well and is a good candidate for identifying masked HTN. Our data emphasize the importance of identifying prehypertension in children and adolescents.

Isolated Nocturnal Hypertension in Children.

Isolated nocturnal hypertension (INH) is attracting attention because it has been shown to correlate with target organ damage as well as cardiovascular events in adults. INH has also been reported in children especially in those with underlying diseases including chronic kidney disease and some studies reported association with markers of early target organ damage. INH occupies the majority of nocturnal hypertension. On the other hand, masked hypertension is largely attributed to INH. INH is usually diagnosed by ambulatory blood pressure monitoring. Recently, it became possible to monitor sleep blood pressure by an automated home blood pressure device feasible also in children. The epidemiology, methodology and reproducibility, pathophysiology, relation to target organ damage, and treatment of INH in children will be reviewed here along with adult data.