SHPOSIUM: NEPHROLOGY Renal tubular disorders David Broodbank Martin T Christian Abstract Renal tubular disorders are challenging and comprise a heterogeneous ‘10up of disorders This review concentrates on those presenting in chi hood with electrolyte abnoemaltes. Pater recognition of these abr malts is important in making siagnoses and abasic understanding of renal tubular physoloy f helpful to understané why these paerns Cinical cases ae used as ilustations inthis review, supported by physological descriptions a the dsorders and notes about their manage ment. [Athough these disorders almost invalably come under the lng term management of padi nepivoogss they wills as imal pre- sent t geneal pacdiatiars. This review should equip general paca tans wit the skis to request the appropiate inal investigation to make the correct agnosis. Theres also some advice on when to suspect diagnosis ofa renal tubular dsorder and how to spot a child with a senuine polycnsa, Keywords Barter: cstnesss diabetes insipidus: Fanconi: Gelman’: oldie: polyutia: pseudohypoalosteronism renal tubular acidosis: renal tubular disorder tubulopathy Introduction Pacdiatricians find tubular disorders challenging: sor them as cerebral challenges to explore when children have abnormal electrolytes; others still come out in a sweat at the thought of having to remember the classifications of renal tubular acidosis for membership! There is a tendency for membership candidates to focus on renal tubular acidosis as the beall and end-all of renal tubular lisorders. This is unhelpful since proximal renal tubular acidosis, in fsolation is extremely rare and even distal renal tubular acidosis is not one of the most common tubulopathies encoun- tered in clinical practice. 11 is more helpful, we believe, for the paediatrician to have a feel for the clinical features of the more common pattems of electrolyte disturbance and learn how liffering diseases ft into these patterns. In their entirety, renal tubular disorders are a heterogeneous group affecting different aspects of tubular function and as such may present in a variety of ways. Many present with growth faltering and polyuria/polydipsia as a consequence of salt-wasting but renal tubular disorders may also be David Broodbank wacrs maces i an SpR in Poediarc Nephvology at [Nottingham University Hospitals, Q€C Campus, Nottingham, UK. Con- Picts of interest: none. ‘Martin T Christan escmo crc i Consultant Palate Nephrologst {at Nottingham University Hospitals, QMC Campus, Nottingham, UK. Conflicts of interest: rane. responsible for renal calculi or hypertension in otherwise healthy children, Most commonly, paediatricians encounter renal tubular dis- lers in the context of investigating a child with abnormal electrolytes. The disorders are caused, directly or indiscetly, Lough dysfunction of transporter proteins which are respon sible for the tubular reabsorption or secretion of various elec: lrolytes. Within recent years many genes encoding for these lransporter proteins have been located and these genctic ad vances have served to improve our understanding of tubular physiology. However, as yet there is no gene therapy available for these challenging disorders. A comprehensive review ofall tubular disorders takes several chapters in paediatric nephrology texts so this article will offer a flavour of tubular disorders by focussing on several of the more common tubulopathies. The individual conditions are ilustrated through case presentations but the names of patients have been changed, [At the end of this article, the reader should have a basic u derstanding of the role of the renal tubule in homeostasis, un- derstand how tubular disorders deviate from the norm to result In their characteristic biochemical patterns and have confidence in how to begin to investigate a child presenting with electrolytic derangement Renal physiology Faced with abnormal elecicoyte results there is @ need for a foundational understanding of renal tubular physiology. ‘The three major functions ofthe kidneys comprise ‘© Maintenance of a constant extracellular environment for optimum eel functioning (homeostasis). + Hozmone secretion (including: erythropoietin for red blood cell production; renin and angiotensin It affecting renal and systemic haemodynamies; and hydroxylated vitamin D affecting caleiaes, phosphate and bone metabolise ‘+ Miscollaneous functions including peptide hormone catabolism and gluconeogenesis, Homeostasis is achieved through the kidney excreting waste products (eg urea and uric acid) and specifically adjusting the unary excretion of water and electrolytes (Solute) to match the body's dietary intake and endogenous production through metabolism “The human body contains around one million nephrons in each kidney. This is the functional unit of the kidney and its precise homeostatic function is achieved through «iffering properties of cells that define each segment of the tubule 3s well 28 a numberof internal feedback mechanisms which requite the close juxtaposition of the distal tubule with its parent slomerulus. Each nephron comprises a glomerulus and tubule. The glomerulus, the initial part ofthe nephron, is 3 tal of capillaries ot by epithelial cells. The endothelial coll and epithelial cell sandwich the glomerular basement membrane and these struc tures together constitute a sieve which results in a glomerular ultrafilyate passing into Bowman's space at the start of the tw bule. A schematic view ofthe nephron is shown in Figure | The average adult glomerular filtration rate (GFR) is 125 ml mnin/1.73 um. Therefore the glomeruli of a healthy adult (of‘Plesee cite this article in press ax: Broodbank D, Christian MT, Renal tubular disorders, Pamdiatrics amd Chibi Health (2014), beige //slx.docxpy | 10.1016/).paed.2014.03.008 SHPOSIUM: NEPHROLOGY conex Bulk iconametic reabsorption < Concentration Medulla Figure 1 Simplified drawing of a nephron. Isonatremic reabsorption of ‘tubular Rid takes place inthe proximal tubule inthe cortex. The thick _ascending limb ofthe loop af Henle ica citing segment in which sodium Chlotide is avidly recovered but water does na follow. Al the distal nephron can be regarded asa functional whole. It is derived from the ginal ureteric bud. IIs responsive to hormones that regulate volume ‘osmolality and potassium concentiate. Note that the junction between the diluting and concentrating segments meets at the juntaglomersar apparatus ofthe sel-same nephron providing 3 point at wich tubular performance regulates the rate of glomerular ftration. (From Forfar and ‘melt figure 16.1) average body surface area 1.73 m) filter 180 litre of plasma each day. Since the average daily adult urine production is only 1.5 litre, itis clear that the reabsorptive properties ofthe tubule, for water at least, must be highly efficient, The fact that 180 litre of plasma are filtered each day also means that the extracellular fluid volume is turned over approximately 10 times daily. hence homeostatic mechanisms with regard to acid—base and electro: Iyte regulation need to be able to respond rapidly and precisely to avoid major perturbations in body chesmisty In gross terms, the proximal tubule and loop of Henle are bulk resorbers of water and solute whilst the distal tubule has an important role in fine-tuning may be across the tubular cells (transcellular) or passively across the Light junctions in between tubular eells (paracellular). It is the polarity of tubular cells that gives them their unique properties Polarity means that the apical (that side of the cell adjacent to the tubular lumen) and basolateral (that side ofthe cell adjacent to peritubular capillaries) membranes have differing propertios through expressing different channels oF transporters. The po- larity is maintained by the intercollular tight junctions. Most twansport, both reabsorption and secretion, is Linked directly or The reabsor indirectly to sodium reabsorption. ‘The sodium~potassium ‘AtPase pump on the basolateral membrane actively pumps three sodium ions from the tubular cell into the peritubular space (where they are subsequently absorbed into peritubular capillaries) in exchange for two potassium ions, at the cost of fone molecule of ATP. This active wansporter thus generates a state of intracellular sodium depletion which favours entry of sodium from the tubular lumen down an electrochemical gradient, Sodium is reabsorbed through sodium channels or co- transporters which link the absorption of sodium to that of other ‘molecules against their own electrochemical gradient. Sodium seabsomplion in exchange for hydrogen ion secretion in the proximal tubule is an important example of this and is shown in Figure 2. Renal regulation of potassium and acid base balance Around 65% of filtered potassium is reabsorbed in the proximal tubule where itis closely linked to the reabsorption of sodium and water. Here sodium—potassiuim co-ransporters reabsorb potassium in a similar way to the exeretion of acid shown in Figure 2, 4 further 30% is reabsorbed in the thick ascending limb ff the loop of Henle via a sodium co-transporter specific lo the loop ~ the sodium—potassium—chloride co-transporter, NKCC2 (Figure 3). This eo-transporter is the site of action of loop di uretics such as furosemide. In the loop there is further reab- sorption of potassium via the paracellular route which proceeds down an electrochemical gradient The remaining S~10% of filtered potassium is deivered to the distal tubule. In the cortical collecting tubule and duct, there is both potassium secretion (by principal cells) and potassium reabsorption (by intercalated cells) but the mote significant tors affecting potassium excretion process is secretion, include. ‘+ Hyperkalaemia (lavours increased potassium secretion, through a greater osmotic oad). 4 Aldosterone secretion. Aldosterone combines with a eyto- solic receptor to increase the number of open sodium PROXIMAL TUBULE ‘Tubular tumen Peri-capllay space Nak ATPase basolateral pump 23a" Net effect: excretion of resorption of “bicarbonate Cater cn Figure 2 The driving force isthe generation of alow intracellular sodium Concentration when oceure ue to the Na-K ATPase pump inthe baco- lateral membrane pumping out three sodium ions in exchange fortwo potassium ions atthe cost af one molecule of ATP10.1016/),paed.2014.03.005 Tease te saree in press as Boodbunk Dy Chisuan MT, Reval tubular dsorrs, Paciaics wad Chl Heath (2014), Mp0] SHPOSIUM: NEPHROLOGY LOOP OF HENLE -THICK ASCENDING LIMB ‘ubulat lumen Peri-capillary space wore o -rJ @ ™ Figure 3 In the thick ascending limb ofthe loop of Henle. sodium reab sorption occurs via the apical sodiumpotassium-chloride channel (NKCCR) whichis the target of loop dureties such as furosemide. intra Cellular ow sodium caused by extrusion of sodium by the basolateral [ATPase pump drives NKCC2. The apical potassium channel ROMK recycles, Potassium whichis essential for NKCC2 functioning. Chioride is removed basolateraly by two homologous chovide channels CICKa and CICKE. They fequite the presence ofthe subunit bartin for normal functioning. epithelial (ENaC) channels on the apical membranes of principal cells, thus favouring sodium reabsorption. The Jumen-negative potential difference that is created favours potassium excretion via the renal outer medullary potassium channel (ROMK) but aldosterone also directly increases the activity of ROMK (Figure 4). © Filtrate flow rate (greater filtrate flow favours increased potassium secretion). The principal cells which comprise 659% of the tubular cols in the cortical collecting tubule account for most sodium reab- sorption (via an epithelial sodium channel, ENaC, which is the site of action of the diuretic amiloride) ancl for most potassiu secretion (via the inwardly rectifying ROMK channels). ‘This is illustrated in Pigare 4 ‘The other type of tubular cell in the distal tubule is the intercalated cell, of which there are two subtypes, types A an B. Type A cells which are more numerous, are responsible for the secretion of hydrogen ions via apical H* ATPase and H K* ATPase pumps (Figure 5). Secreted hydrogen ions can then combine with urinary buffers, most importantly ammonia, forming ammonium which taps freely difusible the tubular lumen. Type B cells which are a reverse polarity form of type A cells, serve to excrete bicar- bbonate ions. The number and polarity of type B intercalated cells are determined by plasma pll: metabolic acidosis favours 4 reduction in the number of type B i reversal of polarity such that they act like type A cells. Loss of function of either of the apical ATPase pumps results in distal renal tubular acidosis, Aldosterone enhances the activity of the apical H* ATPase pump of type 4 intercalated cells, This is the reason that volume- contracted sates, such as a hypovolaemic child with nephrotic, syndrome, may provoke hypokalaemic alkalosis calated cells an CORTICAL COLLECTING TUBULE Pesicapilary space Figure 4 Sodium moves ito principal els trough fon-specific sodium epithelia channels (ENaC rather than eo-rancporters ivan by the electrical rather than the osmotic gradient. The distinction is‘to less than $ mmol/ and this is lower than the intracellular concentration of sodium. Sodium 10.1016/),paed.2014.03.005 Tease te is arco In press as Bodbank Dy Chisuan MT, Reval tabular disor Pacdwics wad Chil Heath 2014), Rp 01 On SHPOSIUM: NEPHROLOGY Case 1 Hugh presented at 17 months of age with 2 t-month history of vomiting and weight loss. On admission, despite clinical signs of hydration, he remained polyuric with & heavy nappies 2 day. He had signs suggestive of rickets with splayed wrists and ankles and ‘chic rosary. Weight and height wee both below the 0.4th centile Usnalysie showed lycosuria and proteinuria 4}. His i biochemistry shows! Na 127 mmoltive K 1.8 mole Ho, 15 mmole res 8.6 mmoytitre Creatinine 78 umole Calcium 2.34 mmole PO, 0.71 mmovtixe Hyponatracmia, hypokalaemia, low bicarbonate and hypo: phosphataemia are consistent with generalised proximal tubular dysfunction which is known as Fanconi syndrome. In the prox: imal tubule there are several types of co-transporter linking reabsorption of sodium to that of other ions as is demonstrated with the sodium—hydrogen exchanger illustrated in Figure 2. In the example sodium reabsorption is in exchange for hydrogen ons, but the absorption of other ions is Unked with sodium reabsorption in the same way. Proximal tubular cell funetion is dependent on the basolateral Na~K ATPase pump. Due to their ‘bulk resorbing capacity, Na~K ATPase dysfunction preferentially affects proximal tubular cell function. The diagnosis of Fanconi syndrome can be uy Findings such as glycosuria, generalised and inappropriately high urinary potassium and phosphate. Usine phosphate excretion can be quantified simply by cale lating tubular reabsorption of phosphate (TRP): TRP— 100. (2 Wr fa) where Up is usinary phosphate, Uc, is urinary creatinine, Pp is plasma phosphate and Poy is plasina creatinine. Uc, is usually measured in mmol/litre whereas Po, {8 usually measured in umol/litre and these need to be converted into the same ui Outside of infancy the normal TRP is more than 80%. ‘The most common cause of a Fanconi syndrome in Caucasian children is eystinosis but other rarer causes that are seen not infrequently by paediatric nephrologists include Lowe's syt drome, Dent's disease and mitochondrial eytopathies. In Hugh's case a diagnosis of eystinosis was made promptly by a referral 0 ophthalmology when corneal crystals were seen on slit ‘examination of the cornea. The diagnosis was conlirmed with a blood test by finding a high concentration of white cell cystine measured in a reference laboratory. cystinosis ‘The classical child with cystinosis is fairhaired, blue-eyed and Caucasian but it also occurs amongst other ethnic groups. The primary defect isin the gene CTNS which encodes for cystinosin Cystinosin transports cystine out of lysosomes and th ‘CORTICAL AND MEDULLARY COLLECTING TUBULE “Tubular lumen Pet-capilay space Figure 5 Hydrogen ion excretion takes place in the type A intercalated cells of the cortical and medullary collecting tubule. Intracellular water andeae ne one ee enone eeeneoeeneese ee een ose oes een oes ee ee Chloride exchanger in exchange for chloride. Hydrogen fons are secreted by either the H'-ATPase or the HK ATP pumps in the apical membrane. Secreted hydrogen ions can buffer with ammonia which has freely difused across cellular membrane but becomes trapped inthe tubular lumen 35. 10.1016/),paed.2014.03.005 ‘lease cite this aris m press as: Broodbank D, Chiltan MT, Renal tubular disorders, Paediatrics and Child Health (2018), Ripy//ax dolore SHPOSIUM: NEPHROLOGY cystinosis cystine is trapped within lysosomes causing malfunc- tion of the Na-K ATPase. Symptomatic treatment of cystinosis comprises electrolyte replacement (potassium and sodium citrate mixlures provide bicarbonate as well as sodium and potassium since citrate is ‘metabolised to bicarbonate in the liver). Phosphate and activated vitamin D are also needed to treat the rickets. Indometacin re duces the glomerular filtration rate and subsequent tubular los- ses but is also useful to reduce a frequently disabling degree of polyuria. The Fanconi syndrome causes chronic renal impair: ‘meat and eventually individuals with eystinosis will need renal replacement therapy. Children with cystinosis frequently have very poor appetites and severely reduced growth velocity whict is out of proportion to the degree of renal impairment. Specialist dietetic support is required and often growth hormone as well to optimise growth |A specific treatment for the lysosomal storage is available. Mereaptamine (previously called cysteamine) combines with cystine in the lysosome so that a mixed disulphide is able o exit the lysosome utilising a lysine transporter. The advent of mer: nine has slowed but not halted the decline of renal fune- is now more common for childzen with eystiaosis not to require dialysis or transplantation until at least the second decade, The drug may also improve growth and slow the development of other multi-system effects, Monitoring of leucocyte cystine levels is required after commencement of treatment, A three to four times daily regime and the unpleasant side ettects of mercapiamine can all affect concordance with the drug. Cystinosis is a multisystem disease and cystine deposition occurs in other organs through life so that even post-ransplant, mercaptamine needs to be taken regulary. Sequentially cystine deposition in other organs can cause hypo- Uyroidism, diabetes mellitus, male infertility, myopathy and nourological symptoms i Case 2 Carle's hypokalaemia was picked up following routine blood tests for investigation of lft thigh pain under the care of orthopaedic surgery at his local hospital. He was a 14-year-old boy with short stature, delayed puberty and persistent noctumal enuresis despite ‘multiple traps. Initial blood results were Na 136 mmole K 28 mmole Heo» 31 mmole a 90 mmo Urea 67 mmole Geatinine 42 umolitre a 2.41 mmolfire The pattern of electrolyte abnormalities here is different to the above Fanconi syndrome case where bicarbonate wasting and subsequent metabolic acidosis predominate, Metabolic alkalosis, in combination with hypokalaemia and hypochloraemia is char- acteristic of sal-wasting disorders of the loop of Henle (Bartter's syndrome) or early distal convoluted tubule (Citelman’s syn- drome). In this part of the nepliron, sodium reabsorption is linked {ochloride reabsorption through the furosemide-sensitive sodium potassium chloride channel (NKCC2) in the loop of Henle (see Figure 3) oF the structurally similar thiazide-sensitive sodium chloride channel (NCCT) in the early distal convoluted tubule respectively. Salt-wasting disorders from these parts of the nephron will always be associated with urinary chloride loss in ‘excess of urine sodium loss for the following reasons: «All chloride reabsorption is linked with sodium, with twice as much chloride as sodium reabsorbed via NKCC2. + Sodium reabsorption but not chloride reabsorption ean ‘occur partly via the paracellular route. # ‘There is no capacity for chloride reabsorptior distally To maintain electrochemical neutrality from increased chloride loss, other cations are lost which include ammonium and potas- sium, Ammonia isan important cartier of hydrogen ions in tubular fluid and so increased ammonium Joss will result in systemic alkalosis, The urinary potassium loss from this mechanism eom- bines with the byperkaluria caused by the subsequent secondary hyperaldosteronisi to cause a profound hypokalaemia, In Charlie's case the hypocalciuria and hypomagnes well as the age and el Iman’s syndrome. ical presentation are more consistent with Gitelman’s and Bartter’s syndromes ‘The constellations of symptoms in the first children to be described with a hypokalaemic, hypochloraemic, metabolic alkalotic salt-wasting disorder took the name of the clinician who published the paper in 1960, Frederic Bartter. As more cases were published, two clinical phenotypes emerged: younger children with bypercalciuria and nephrocaleinosis, and older children or adults with hypomagnesaemia and hypocalciuria ‘This latter group was renamed, again after the clinician who fist ‘made the description in 1966, Hille! Gitelman. More recently, possibly with advances in neonatal intensive care a third phenotype comprising matermal polyhydramnios, prematurity and severe polyuria in the neonatal period has been described and has become known as antenatal Bartte’s syndrome. Over the last 20 years, genes responsible for these disorders have been discovered which have greatly contributed to our understanding of the physiology of the loop of Henle and early distal convoluted tubule (DCT). Bartter syndrome may therefore be classified as type I-V which isa system based purely upon the lorder in which the affected genes were described. The fist to be described and most logical to understand is a defect in the gene SLCI2A1 encoding for NKCC2. This usually causes a severeAlbumin 36 gre Mg 0.64 motive sin calcium excretion was low and plasma renin and aldosterone were elevated. neonatal form of Bartter’s. If ROMK is dysfunctional and return of potassium to the tubular lumen impaired then this will sul sequently afect functioning of NKCC2 and thus these two groups will be phenotypically similar. Disorders of the CIC-Kb compo- reat of the basolateral chloride transporter cause “classical” 10.1016/),paed.2014.03.005 lease cite this acl i press as: Broodbank D, Chistian MT, Reval lubular donde, Paediatrics and Child Health (2018), Rip: /ax G01 or SHPOSIUM: NEPHROLOGY Classification of Bartter’s and Gitelman's syndromes Classification Gene affected ‘Transporter affected nica picture Barter syndrome type! SLCI2AY uxcea ‘Antenatal Barter syndrome Barter syndrome type oun RON Antenatal Barter syndrome Barter syndrome type IN CCKB ack Chssical Batter syndrome Barter syndrome type IV &SND Bartin subunit of CIC-Ka and CICKb Antenatal Batter syndrome and Barter syndrome type V__CLCNKA and cLCNKE Gelman syndrome Suc12a3 ect Table 1 Barttr’s syndrome, by which is meant children fitting the early descriptions of the disorder and not presenting in the neonatal period. The transporter is present in the thick ascending limb of the loop of Henle and the early part of the DCT so some of these children exhibit phenotypic crossover with Gitelman’s. Infants with a severe salt-wasting disorder and sensori-neural deafness hhave most recently been found to have a defect of the gene BSND Which encodes for barttin, a sub-unit of the basolateral chloride channel which is also present in the inner ear, or a defect of the ‘gene coding for the basolateral chloride channel CIC-Ka and CLC: kb themselves. The classification is summarised in Table | with the affected transporters illustrated in Figure 3 Older children with a pure defect of salt reabsorption in the early DCT have dysfunction of the apical thiazide-sensitive sodium tuansporter NCCT which s present only in this pat of the nephron, One ion each of sodium and chloride only is absorbed with this transporter and an abnormality here results in Citelman syndrome. ‘The I-V classification is rather arbitary and does not assist the clinician in deducing the underlying abnormality and hence the clinical presentation. Seyberth suggests that Bartet’s type cond tions are classified according to pharmacotype, that is, according to which diuretic the condition mimics. Under this system Type | would be "Furosemide Type”, Type Il "Furosemice-Armiloride Type” and so forth. A full description of this classification is beyond thescopeof this review butt may provide the doctor with a Uusoful alternative way to classify this group of tubulopathies. ‘Hypercalciuria occurs in Bartier’s because calcium reabsorp- tion isa linked paracellular process. Hypomagnesaemia does not jccur because of compensatory reabsorption inthe early DCT. By contrast, Gitelman’s has hypocaleiuria and hypomagnesaemia because of a compensatory mechanism in the early DCT which down-tegulates cells expressing NCCT (and an apical magnesium channel) in favour of cells which reabsorb sodium and calcium, Gitelman’s generally presents in older children or even adults with muscle weakness and cramps, and short stature, It is not ‘uncommonly diagnosed following investigation of growth, con- gtipation or enuresis. Classical Bartter’s evndrome Is generally a lca and lex sensorineural deafness ‘Antenatal Barter syndrome and sensorineural deafness Gelman syndrome ‘oxygenase inhibitor Indometacin is especially effective in Bartter’s syndrome since the salt-wasting is amplified through paracrine signalling of the prostaglandin PGE. Indeed, antenatal Barter syndrome is sometimes termed hyperprostaglandin Esyndrome. Case 3 ‘Abdul was the fist child to fst cousin parents. He was born at term with no neonatal complications. He presented at 2 weeks of age with ‘mucousy vomiting and probably poor feeding. He was acutely hypo. volaemic and it was very dificult to establish vascular acess. Mis Intat bloods were: Na 117 mmole K 9.5 mmolfitre Urea 113 mmole Creatinine 37 mole pM 698 HCO, 9.2 mmoyitre Be 19.4 Lactate 73 mmolfitre He was given emergency treatment for hyperkalaemia including nebulised salbutamol and an insulin-destose infusion as well as calcium gluconate to stabilise his myocardium. I was not possible to obtain a sample for 17a-hydroxyprogesterone intially but this was obtained several hours later after a dose of hydracotisone was given Renin and aldosterone were also checked at this tine. The results 17achydroxyprogesterone 20 nmal/itre (normal range for stressed neonates <40) Renin 275 mitre (adit reference ea pn a tinemore severe disorder, presenting in early childhood with growth faltering, dehydration, hypotonia and lethargy. There is often a history of maternal polyhydramnios with the classical form but this feature is always present in antenatal Bartler's ‘These is no targeted treatment for Barter’s of Gitelman’s, Both require potassium replacement though often magnesium replace meat alone is sufficient for Gitelman’s. The non-selective eyclo though high levels may be ‘seen in neonates) 3800 pmofitve (adult ambulant range: up to 860 pmovfire though may be higher in citdren) Aldosterone 10.1016/),paed.2014.03.005 ‘lease cite this aris m press as: Broodbank D, Chiltan MT, Renal tubular dsordes, Paediatrics and Child Health (2018), Rip//ax dolore SHPOSIUM: NEPHROLOGY The presentation is very similar to that of 21-hydroxylase det ciency or congenital adrenal hyperplasia (CAH) and a nor ‘7achydroxyprogesterone may have been caused by adrenal suppression from the hydrocortisone. However the severity of the hyperkalaemia is against CAH and hyperaldosteronism states tend to alkalosis. Renin and aldosterone are severely elevated despite the caveats in the adult reference ranges. This is not consistent with CAH. From the tubular pathophysiology angle, comparing this, pattern of salt-wasting to the above descriptions of Citelman’s and Fanconi syndromes, the obvious difference is hyperkalaemia rather than hypokalaemia. With intact distal tubular funetion, hhyperaldosteronism in the face of hypovolaemia should always {end to hypokalaemia, This is because the action of aldosterone, as described above, serves to promote sodium conservation and potassium loss in the cortical collecting duet. Therefore, hyper: kalaemia in association with salt-wasting is characteristic of a distal tubular disorder. This clinica picture is called pseudohy- ppoaldosteronism because itis the clinical picture of a low aldo- sterone slate (hyperkalaemia, volume depletion) whereas the ‘measured level of aldasterone is high. Its also known as type 4 renal tubular acidosis included within the classification of renal tubular acidosis disorders: the acidosis occurs as reduced luminal potassium provides less substrate for the apical K*-H" exchanger. Pseudohypoaldosteronism Type | pseudohypoaliosteronism exists a8 an autosomal domi rhant (senal specific) and autosomal recessive (multiple organ) form. The autosomal dominant form results from a gene muta tuon encoding for the mineralocorticald receptor. It presents generally in infancy with growth faltering, vomiting and delty ration with a biochemical picture of relatively. mild hyper- kalacmia and hyponatraemia. Plasma renin and aldestesone levels are elevated, ‘The autosomal recessive form, as might be expected, is more severe and presents with severe salt-wasting and life-threatening hhyperkalaemia soon after birth, The disorder is caused by mu lations in genes encoding for the p and + sub-units of ENaC. The ‘main principle of treatment is adequate sodium replacement (in the form of both sodium chloride and sodium bicarbonate usu ally) which may require in excess of 15 mmol/kg sodium per day, Increased sodium intake results in increased delivery of sodium to the distal tubule which t a limited extent can ameliorate the dysfunctional apical sodium channel and permit ‘more potassium secretion. However, the severity of the hyper: kalaemia is such that a low potassium diet and ion-exchange resins such as sodium resonium are also normally required to prevent life-threatening hyperkalaemia. In contrast to the auto- chronie kidney disease or a combination of these, The differen liating feature fron 1 above is abnormal renal imaging and usually the presence of impaired renal function, In this scenario the pseudohypoaldosteronistn is a secondary phenom- ‘enon caused by a transient tubular insensitivity to aldosterone. A this to be a surprisingly common compli- cation of severe urinary tract infection in young infants, recent review foun Case 4 Freddie was 3 months with a background of mild developmental concerms and constipation. He presented with sepsis. On admission to hospital, the plasma sodium was 152 mmole but this had Increased to 169 mmole ater he was given a bolus of 0.9% saline for presumed hypovolaemia Other biochemistry on admission was as follows: K 41 mmole Urea 5 mmobtitre Creatinine 56 wmofire Paired urine and plasma samples were taken with results as follows: Pq. 161 mmoles Pra 340 mOsmfitre u, ig, 12 mmole 1 164 mOseuire Hypernatracmia usually indicates volume contraction and itis an appropriate response to consider a fluid bolus in such a situation, The repeat plasma sodium result was a surprise and suggests impaired urine concentrating ability. This is confirmed by the paised samples showing inappropriately dilute urine for thy hyperosmolar plasma. Such a slate is called diabetes insipidus of which there are central and nephrogenic forms. Central forms ‘most commonly occur in association with cerebral neoplasms, craniopharyngiomas most commonly, and this is an unusual age for a brain tumour. The diagnosis of nephrogenic diabetes insipidus needs to be made with a desmopressin challenge demonstrating no improvement in urine concentrating ability in response to a dose of desmopressin, an arginine vasopressin analogue. As this child was already hyperosmolar there was no need to precede the desmopressin challenge with a water deprivation test. Both a desmopressin challenge and a full water deprivation tost may induce dangerous levels of dehydration and. hhypermatraemia. It should only be undertaken with a clear pro- tocol of weight and plasma/urine osmolality monitoring, with facilities for tanid reauit tummarcund a0 that the teat can he ome-ee i eee SS life-long. There is also abnor 4gans, for example increased pulmonary secretions that may mimic cystic fibrosis and the multiple organ type may be confirmed through a positive sweat test significantly maturely terminated if dehydrated ial sodium transport in other or Nephrogenic diabetes insipidus (NO). Under normal physiological conditions water is reabsorbed from the collecting duct via the water channels (AQP2) which are presented to the apical membrane (Iusninal side) of the principle cell of the collecting duct under the influence of arginine ‘Secondary psuedohypoaldosteronism Blochemically similar presentations to that described above may occur in the context of urosepsis, urinary tract malformation . 7 201 Evi Li ee lease cite this aici i press as: Broodbank D, Chistian MT, Renal tubular donde, Paediatrics and Chil Health (2018), Rip /ax G01 om 10.1016/),paed.2014.03.005 SHPOSIUM: NEPHROLOGY Membrane shuttle mechanism Physiologic Pathophysiologic ADH AQPS AQP pkaked QPS AQP2 Ho NO! HO - of ® of r. 2 asotomal reese 4ADH AQPS a No! no ne a mon Ho mm ¢ camo =E aara roe NN = es = oom Figure 6 Reproduced with permission of Curent Medicine Group. Under the influence of AVP the V2R receptor stimulates a series of cyclic adenosine ‘monophosphate-(AMP) mediated events that results in the fusion of cytoplasmic vesicles, caying water channel proteins (aquaporin? {AQP2D, with the apical membrane, thereby increasing the water permeability ofthis membrane. Water exits the cll through the basolateral water channels AQP3 and ‘AQP4, Thase with Xnked NOI have a defect inthe V2 receptor withthe remaining group having mutations InvoWing the AQP2 gene. “Guay Woodiord, eal. Renal tubular disordets, Als Dis Kidney 200: vasopressin (AVP). This allows water out of the tubule via the basolateral water channels AQP3 and AQP4 down the favourable cosmotic gradient created by the removal of solute in the loop of, Henle and distal tubule (See Figures 1 and 6). X-linked NDI, Which accounts for 90% of cases, presents in male infancy with failure to thrive, nonspecific symptoms including fever and constipation, and episodes of hypernatraemic dehydration. In X- linked NDI there is a mutation in the AVPR2 gene which encodes for the AVP receptor V2R with a consequent loss of AVP responsiveness and failure to mobilise the AQP2 water channels, Far less commonly, inherited NDI may be caused by muta tions in the AQP2 gene. This ean be inherited in both an auto- somal dominant and recessive manner and resulis in the failure of the AQP2 water channel to migrate to the apical surface of the collecting duet where concentrating ability is impaired. This strategy may result in hypokalaemia requiring supplements or the addition of amiloride. Indometacin may also reduce the polyuria probably through reducing the GFR and enhancing Case 5 ‘isha presented at 2 month of age with severe grawth falteing to second cousin parents who were otherwise healthy. At this point she weighed 2.3kg against a bith weight of3.5 k, She had no history of Aiarthoea but was dehydrated on examination. She had no rickets. Biochemistry results were as follows:principal cell, again impairis in inappropriately dilute urine. Management of NDI requires free access to water and as this, Is not possible for infants they should be fed every one to two hours. Infants and young children with NDI do not gain weight well and many need enteral feeding. Pharmacological therapies include thiazide diuretics and indometacin. tis counterintuitive to think that 2 diuretic may decrease polyuria but on a tubular level it makes sense: by inducing a mild degree of volume depletion sodium reabsorption (and thus water) in the proximal tubule is enhanced, resulting in less water delivery 10 the water reabsorption and resulting Na 140 mmotitre x 2.7 mmolfite a 118 mmole cos 12 mmole rea 5.8 mmole Creatinine 35 polite Comctad Ca 2.9 mmolfite PO, 17 mmofite Renal ultrasound showed nephrocacinosis. 10.1016/),paed.2014.03.005 ‘lease cite this aris m press as: Broodbank D, Chiltan MT, Renal tubular donde, Paediatrics and Child Health (2018), Ripy//ax dolor SHPOSIUM: NEPHROLOGY proximal sodium and water reabsorption although the exact ‘mechanism of its action remains unclear. Of particular importance to the general paediatrician is that daring intercurrent illnesses requiring intravenous fluids ebil- dren with NDI should be managed with 5% dextrose to avoid a sodium load which will drive the polyuria and rapidly lead to dangerous hypernatraemia, Strict fluid balance including weight assessment and frequent electrolyte monitoring is critical in these patients and they should ideally be managed with regular advice from a paediatric nephrologist Investigation of suspected salt-wasting tubular disorders In hyperchiloraemic metabolic acidosis, the anion gap (Na ~ [Cl + HCOs], which should be 5-11 mmol/itre) is normal. This implies either bicarbonate wasting (lrom gut or kidney) or failure o appropriately acidify the urine. This pattern of hyper- chloraemia, metabolic acidosis, hypokalaemia and nephrocal ‘nosis with normal renal function fits best with a distal renal tubular acidosis (ARTA). The diagnosis of ARTA would be further supported by a urine pH more than 5.3 and can be confirmed by an ammonium loading test or other test of distal tubular urinary acidification Test sine dipstick Venous blood 95 Magnesium Renin and aldosterone Usinary chloride Usinary calcium Usine pH sine amino acids Fractional excretion of sodium (Fy) ‘Transtubular potassium gradient (TTKG) Interpretation Gycosuria implies a proximal tubulopathy. Metabolic alkalosis seen with Barters/itelman's Metabolic acidosis seen with proximal and distal tubulopathies. Hypomagnesaemia occurs in Gtleman’. Elevated with volume-contracted states, ‘especialy Barter’, Gltelmars and severely so vith pseudohypoaldosteronism. High values (>10 mmofitre) in association with hypochloraemia exclude non-enal causes of chloride loss. Hypetcalcuria usually seen in Barter’ whereas hypocacira is usually seen in Gitiemar's. Should be performed in the laboratory with 3 glass electrode. Generalised aminoacidria seen in proximal ‘ubulopathies. In the Face of volume contaction,FEq, should be 1% (<2.5% in neonates). A result greater than this confirms a dlagnosis of salt-wastng. Should be <2.5 with hypokalaemia and >7 with hyperkalaemia. Notes Proteinuria may also be present. Frequently this Is tow molecular weight proteinuria in Fanconi syndrome. Requesting urine NAG or RBP may be helpful Metabolic acidosis can be investigated further to ascertain ste of renal tubular acidosis, Vial information to interpret hypo- or hryperkalaemia, Consult tables for age-specific reference ranges. Ideally spot sample shouldbe the second voided sample ofthe day. pH > 5.5 with a metabolic acidosis suggests ARTA, Remember to covert Us, to wmf. Use if tal tubular dysfunction is suspected as this fs an indirect index of potassium secretory activity in the cortical collecting tubule. TTKG = $t2fon Where an aNd Urnn are plasma and urinaryTubular reabsorption of phosphate (TRP) Values <80% in children >12 months implies TRP Osmotaiiy respectively. 00 — (") phosphate leak which, in combination with hypokalaemia, acidosis, glycosuria and generalised aminoaciduria implies a Fanconi ‘syndrome, Handjwise Xray To look for rickets which may be present with Fanconi syndromes or in association with hypercaliuia. Renal ultrasound malformations Table 2 To look for nephrocaeinos's and urinary tract Nephrocalenosis may be seen with Batters symdrome, Dent’ disease and distal renal tubular acidosis. lease cite this acl i press as: Broodbank D, Chistian MT, Renal tubular disorders, Paediatrics and Chil Health (2018), Rip: /ax G01 om 10.1016/).paed.2014.03.008 SHPOSIUM: NEPHROLOGY Renal tubular acidosis The renal contributions to acid-base balance are through bi- carbonate reclamation and acid secretion. Kidneys resorb 90% of filtered bicarbonate in the proximal tubule. The proximal tubule also regenerates bicarbonate so that all this reclaimed bicar bonate ean be used for buffering — forming carbonic acid and eventually carbon dioxide which is excreted by the lungs. ‘The collecting tubules are principally responsible for acid secretion, Buffers in the tubular Lumen bind free hydrogen ions, allowing excretion of the daily acid load within limits of the ‘miminal achievable urine pIT of 4.5~5. Ammonia and to a lesser extent phosphate are the main urinary buffers. Ammonia (NH). which is formed from amino acid metabolism, can freely diffuse across tubular membranes where it combines with protons to form ammonium (NIJ) which becomes trapped in the tubular lumen. Renal tubular acidosis (RTA) occurs in several ways: bicar bonate wasting in the proximal tubule (historically known as type 2 RTA) almost always occurs as part of a Fanconi syndrome (described incase 1 and associated with hypokalaemia): Impairment in formation of ammonia results in type 4 RTA (deseribed in case 3) and in renal failure, where the acidosis is associated with hyperkalaemia; and failure to adequately secrete hydrogen ions is the primary defect in dRTA (associated with hypokalaemia) In childhood dRTA, most cases are genetic. Autosomal recessive RTA can be associated with (ATP6VIB1) or without (ATPSVOAA) sensorineural deafness. Both mutations code for subunits of the H-ATPase apical hydrogen ion transporter. An autosomal dominant ARTA is caused by mutations of the SLC4A1 ‘gene which encodes the chloride-bicarbonate exchanger on the basolateral membrane (Figure 5) Urine pl in dRTa is always more than 5.5 in contrast to proximal RTA where it varies according to the pla Donate. Fractional excretion of bicarbonate ance serum bicat: bonate is normalised should be less than 5% for dRTA. The diagnosis of a distal RTA can further confirmed with other tubular functional tests including, acid loading and furosemide challenge Initial correction of acidosis needs to lake into accou po. -h will both decrease in response to alkali teatment. Maintenance treatment consists of sodium bi carbonate or citrate (sodium and/or potassium). Generally the lassium and caleium wh I a basic renal profile (Na, K, Cl, HCOs, urea, creatinine, C2, POs and albumin) suggests sat-wasting and electrolyte distur- bance, Table 2 shows the next set of investigations to consider. ‘An assessment of volume slalus is essential and weight al this point can be very helpful as a baseline before rehydration is commenced. A blood pressure should also be performed and the appropriate centile noted, Rarely does alow concentration ofa single electrolyte occurin isolation and pattern recognition is important as is illustrated with the cases. Asa general principle, when there isa low plasina lectrolyte it i usually helpful to look at its concentration in the urine if there is no other obvious source of loss. There are a rhumber of specific tests of tubular function based on this prin- ciple that are listed in the table. To calculate them it is necessary {0 request urinary creatinine or osmolality for a sample collected atthe same time as a blood test is earried out requesting the same P rs. It needs 10 be noted that if urine creatinine is requested, it will be measured in millimoles perlite (mmol/Litre) and needs to be converted to micromoles per litre (umol/lire) for the equations listed How to spot a polydipsic/potyuric child Many children drink excessively and the majority of these chil- dren will have behavioural polydipsia which in its most severe form ean cause a transient ypairment of urine concentrating ability. To identify true polydipsic children it is necessary (0 probe more specifically. Features that are suggestive of 1 polydipsia and polyuria include: ‘© Equally happy to drink water as squash © Night-time waking for drinks 4 Saturated nappies ‘Unusual drinking habits e.g. drinking water from from toilets, rom dog drinking bow! ‘© Dehydration-related problems such as low-grade fevers, inrtability oF constipation Children whose preference is always for sweetened drinks or juices, who sleep through the night and who are thriving are less likely to have pathological polyuria and polydipsia, bath, Conclusions Renal tubular disorders are rare usually life-long disorders that require specialist management and are therefore usually cared.doses of base required are less than for proximal acidosis. Chil- ‘deen require lifelong follow-up and are at risk of nephrolithiasis, and long-term deterioration in renal function fom the nephrocaleinosis. How to investigate suspected tubulopathies ‘Tubular disorders must always be considered in the following situations: ‘© Growth faltering or short stature ‘© Children or infants whose dehydration is out of proportion to the clinical history ‘© Suspected polyuria/polydipsia ‘© Muscle weakness or unusual lethargy ‘© Intractable nocturnal enuresis ‘or ln peecietric rene comines where they ane sue to access the ‘multi-diseiplinary team including dictitans, specialist nurses and psychosocial support. However, many who are stable will be cared for in paediatric renal shared-care clinics, Their presenta- tion will invariably be to general paediatricians. Prompt diag- nosis and good initial management may prevent further the case of certain disorders such as pseudo- FURTHER READING For a more detailed review of renal tubular disorders and ‘renal physiology the following texts are recommended: ‘Avner ED, Harmon WE, NiaudetP Yoshikawa N Pediatric nephrology. 6th dn. Bein Heidelberg: Springer Vetiag, 2009: 37-42. 20 Evi Lis ee SYHPOSIUM: NEPHROLOGY ‘Comprehensive pediatric nephrology. st edn. Mosby Elsevie, Philadel: hia PR: 27-32. Rose BD, Post TW. Clinical physiology of acid—base and eleclyte dis- ‘orders. 5th edn, New Yorks MeGraw-Hil, 2001 For a review of the terminology and classification of Bartter- like syndrome the following is recommended: Seyberth H. An improved terminology and classification of Barter ike ‘syndromes. Nat Cll Pract Nephr 2008: 4. For a brief review in the assessment and investigation of ‘children with apparent polyuria/polydipsia the following is recommended! Carr Gil. Polya, plydipsia,polypopsi: “Mummy want adrnk. Arch is Child Educ Pract Ed 2007; 92: 139-43. Geary OF, Schaefer, 2008. ‘The following reference is a recent case series and review of secondary pseudohypoaldosteronism BosdanovicR,StalicN, Putik J. Paripovic A. Transient type 1 pseudo- hypoaldesteronisme: report on an eight patent series and Uterature review. Pediatr Nephrol 2009; 24: 2167-75,PREDATES AMD OALD HEA u 201 Evi Li ee