acidify their urine normally in response to an NH4Cl acid load (Fig. 5.3.2). Investigations \200 Plasma or serum bicarbonate concentration is typically in the range 15 \200\22320 mmol/L, t hough not as low as 10 mmol/L, which can occur in dRTA. Hypokalemia does occur, but it is m ore usually seen, or becomes worse, when bicarbonate replacement therapy is given. Plain AX R may show nephrocalcinosis. Urinary potassium losses can be high, especially with bicarbon ate therapy. Etiology Inherited: \200 \200 \200 \200 \200 autosomal recessive pRTA; Dent \200\231s disease; Lowe syndrome; idiopathic (autosomal domi nant) renal Fanconi syn- drome; cystinosis; type 1 galactose de \201 ciency; Wilson \200 \231s disease; tyrosinemia; paroxysmal nocturnal hemoglobinuria. Special Investigations To demonstrate the renal bicarbonate leak, a bicarbonate loading tes t may be necessary. This consists of giving suf \201 - cient IV bicarbonate to normalize t he plasma bicarbonate concentration and then to measure the fractional excre- tion of bicar bonate, which will be >15%. The difference between urine and blood pCO2 (during a bicarbona te loading test) is a way of detecting reduced H+ secretion along the collecting duct (see Table 5.3.1) and thus dRTA, but it is unreliable in the presence of nephrocalcinosis. \200 \200 \200 \200 Acquired: \200 \200 \200 \200 \200 \200 \200 myeloma; amyloidosis; interstitial nephritis; chemotherapy (ifosfamide, cisplatin); antiret rovirals (adefovir, tenofovir); carbonic anhydrase inhibitors; heavy metal poisoning. Renal biopsy There are generally no speci \201 c features to indicate proxi- mal RTA. Mito chondrial cytopathies are sometimes evident on electron microscopy (EM) in some cases of th e renal Fanconi syndrome. Treatment and management Again, alkali therapy is the mainstay of treatment, but the more b icarbonate that is given, the more is lost in the urine. This can cause, or worsen, hypokal emia. Large amounts of bicarbonate (10 \200\22315 mmol/kg/day) may be required. Additional potassium supplements are usually necessary. A thiazide diuretic can also be used to (indir ectly) increase (paracellular) bicarbonate reabsorption in the proximal tubule, but again t his will increase urinary potassium losses. Regular follow-up is required, but this usually does not need to be more than once a year in the absence of complications. Epidemiology The genetic forms are rare. The acquired forms are more common and determine t he incidence and prevalence of pRTA. Clinical features Isolated inherited pRTA is associated with ocular defects when due to mut ations of SLC4A4, and with osteopetrosis, cerebral calci \201 cation and mental retardatio n when due to mutations of the gene for carbonic anhydrase. Both may have a phenotype simil ar to dRTA with renal stones, neph- rocalcinosis and hypokalemia. Systemic acidosis in pRTA is less severe than in dRTA, but the bone effects can be more signi \201 cant when it is part of a renal Fanconi syndrome, because of the associated phosphate wasting and vitamin D de \201 ciency. In this setting there may also be aminoaciduria, glycosuria, uricosuria a nd tubular proteinuria. Clinical features can include renal stones and nephrocalci- nosis, but these are less common than in dRTA, in part because of increased urinary citrate excret ion. Rickets and osteomalacia are more common, because of vitamin D de \201 ciency and pho sphate wasting. Other forms of RTA Type 3 RTA Although this was originally thought to be due to \200\230im maturity \200\231 of the acidi \201 cation mechanisms along the nephron, it is now de \201 ned as a rare autosomal recessive disorder that is due to de \201 ciency of the enzym e carbonic anhydrase. This is present in proximal tubules and catalyzes the intracellular r eaction that generates bicarbonate from CO2 (Fig. 5.3.1). This enzyme is also present in th e distal nephron and so type 3 RTA is often a mixture of pRTA and dRTA. Complications are o steopetrosis, cerebral calci \201 cation and mental retardation. Most cases are in Arab fa milies from the Middle East and the Maghreb, where rates of consanguinity are high. Diagnosis Proximal RTA must be distinguished from dRTA as well as other causes of a normal anion gap acidosis. Signs of a renal Fanconi syndrome can be helpful, but in some patients there is a mixture of pRTA and dRTA, for example in Dent \200\231s disease, and in some aut oimmune dis- eases (as well as type 3 RTA \200\223 see below). If the plasma bicarbonate c oncentration is low and the \201 l- tered bicarbonate load is reduced, patients with pRTA can Type 4 RTA This form of RTA is not really a primary tubular disorder; it is therefore disti nct from the other forms of RTA. S. WALSH AND R. UNWIN 212 potassium citrate or bicarbonate, especially when hypoka- lemia is present. In hyperkalemic dRTA, treatment is of the underlying min- eralocorticoid defect. The aim of correcting the acidosis in RTA has more to do with preserving growth in children and protecting the bones in adults; it seems to have a limited effect on the progression of nephrocalcinosis or ren al stone disease. As yet the recent and important genetic advances and insights in RTA have not translated into any new therapies, but they have highlighted the wider prevalence of R TA \200\223 \200\230presby-RTA \200\231 \200\223 and its earlier recognition and treatme nt. It is due to a lack of aldosterone and its actions on the col- lecting duct, which results in reduced potassium and H+ secretion. This leads to hyperkalemia, which suppresses ammonia synthesis in the proximal tubule and thus excretion of ammonium. This diminishes net acid excretion, resulting in a metabolic acidosis. Causes are: \200 \200 \200 \200 \200 \200 primary adrenal insuf \201 ciency; congenital adrenal hyperplasia; aldosterone synthase de \201 ciency; potassium-sparing diuretics; heparin and low molecular weight heparin. hypor eninemic hypoaldosteronism (in diabetic neph- ropathy); ACEIs or angiotensin receptor block ers (less likely); nonsteroidal in \202 ammatory drugs; cyclosporin; HIV infection; drugs (amiloride, spironolactone, triamterene, trimetho- prim, pentamidine); tubulointerstitial d isease. pseudohypoaldosteronism (types 1 and 2). Further reading Laing CM, Unwin RJ. Renal tubular acidosis. J Nephrol 2006; 19(Suppl 9): S46 \200\22352. \200 \200 \200 \200 Laing CM, Toye AM, Capasso G, Unwin RJ. Renal tubular acidosis: developments in our underst anding of the molecular basis. Int J Biochem Cell Biol 2005; 37: 1151 \200\2231161. Walsh SB, Shirley DG, Wrong OM, Unwin RJ. Urinary acidi \201 cation assessed by simultanou s furosemide and \202 udrocortisone treat- ment: an alternative to ammonium chloride. Kid ney Int 2007; 71: 1310 \200\2231316. \200 See also Clinical acid \200\223base disorders, p. 64 Hypo-/hyperkalemia, p. 46 Fanconi syndrome, p. 204 Hypokalemic tubular disorders, p. 214 The presence of hyperkalemia and mild metabolic acidosis can suggest the diagnosis of type 4 RTA. Its treatment depends on the underlying cause, but is mainly aimed at correcting the hyperkalemia. This may include a loop diuretic, but in most cases it will also mean minera locorticoid supplementation. Summary The treatment of RTA remains empirical and mainly involves oral alkali supplementat ion, which is best given as This page intentionally left blank S. WHITE, G. CAPASSO AND R. UNWIN 214 Hypokalemic tubular disorders De \201 nition Hypokalemia is conventionally defined as a serum or plasma potassium concen tration <3.5 mmol/L. The distribution of body potassium contrasts strikingly with that of s odium; whereas Na+ is predominantly extra- cellular, K+ is intracellular ( 98%; 3500 mmol) and is the most abundant intracellular cation (Fig. 5.4.1). A high intracellular \202 ui d (ICF) K+ concentration is neces- sary for regulation of cell volume, pH, enzyme function, DNA and protein synthesis, and growth. A low extracellular \202 uid (ECF) K+ concentrati on, and the associated steep K+ gradient across the cell membrane, is largely responsible f or the membrane potential of excit- able and nonexcitable cells; any change in this gradien t can disturb cell excitation and contraction \200\223 a doubling or halving of plasma pot assium concentration will have this effect. Chronic potassium depletion causes an impaired urinary concentrating ability, a tendency to metabolic alkalosis and increased ammonium exc retion. Normal potassium homeostasis depends on extrare- nal balance: intake (80 \200\22312 0 mmol/day) versus excretion (kidney 95%; colon 5%); and intrarenal balance: distribu- ti on of K+ between ICF (most in skeletal muscle cells) and ECF (Fig. 5.4.2). Note that a shif t of as little as 1% of ICF K+ into or from the ECF would cause a 50% change in plasma pot assium con- centration (Fig. 5.4.1). Indeed, a good steak meal could potentially double pla sma potassium concentration if there were no mechanisms to modulate extrarenal K+ distribu- tion acutely. The important ones are hormonal (insulin, - adrenergic agonists, e.g. epin ephrine) and they promote the rapid transfer of K+ from ECF to ICF via the ubiquitous \200 \230sodium pump \200\231: Na+/K+-ATPase (Fig. 5.4.1). (Aldosterone \200\231s action is slow er and it increases renal K+ excretion.) As predicted by the Nernst equation (Em = \200 \22361.5 log [K+]i /[K+]0), the ratio of intracellular to extracellular potas- sium ([K+]i /[K+]0) is critical in maintaining the resting mem- brane potential (Em) of all cells. Hypo kalemia increases [K+]i /[K+]0 and causes membrane hyperpolarization. Neuromuscular excitab lility can be de \201 ned as the arith- metic difference between Em and the membrane poten - tial required to trigger an action potential (its threshold). Hyperpolarization reduces e xcitability (which can cause muscle paralysis) by increasing this difference, because the E m is shifted further away (is more negative) from the threshold potential (which is unaffec ted); thus, a larger depolarization is required to activate the action potential. The proximal tubule The proximal tubule (PT) reabsorbs 70% of the \201 ltered load. In t he early PT, sodium-dependent electrogenic reabsorp- tion of solutes drives passive reabsor ption of water via the paracellular pathway. The movement of water molecules \200\230entra ins \200\231 (by solvent drag) movement of K+. In the late PT, potassium reabsorption conti nues by solvent drag, but also by diffusion driven by the reversal of the transepithelial p otential difference (Vte) in this nephron segment. Although hypokalemia can result from pro ximal tubu- lar disorders (see renal Fanconi syndrome), it is more usually associated with diuretics, overactivity of the renin \200\223 angiotensin \200\223aldosterone system (RAAS) or autosomal recessive disorders causing dysfunction along the thick ascending limb (TAL) of the loop of Henle (Bartter \200\231s syndrome) and distal tubule (Gitelman \200\231s syn drome). The thick ascending limb of the loop of Henle Salt reabsorption in the TAL is critical to u rinary concen- trating ability; 10% of the \201 ltered load of potassium is reabsorbed i n this segment. There is a lumen-positive Vte in the TAL due to the differ- ences in potass ium and chloride permeabilities of the apical and basolateral membranes (Fig. 5.4.3). Potas sium enters cells of the TAL by secondary active transportation via NKCC2, the loop diureti c-sensitive Na+/ K+/2Cl \200\223 cotransporter. The driving force for sodium and chloride e ntry is maintained by the action of the basola- teral Na+/K+-ATPase and by chloride exit ac ross the baso- lateral membrane via ClC-Ka and ClC-Kb channels, the activity of which is mo dulated by an accessory protein subunit \200\230Barttin \200\231. The apical membrane pote ntial difference favors exit of potassium via secretory potassium channels known as \200 \230SK \200\231. SK channels are composed of various isoforms of the ROMK (Kir1.1) potassiu m channel family. \200\230Recycling \200\231 of potassium across the apical membrane (from its absorption via NKCC2 and its secretion via ROMK) maintains adequate levels of luminal potassium to sustain NKCC2 function. This process also maintains the electrical (lumen- pos itive Vte) driving force for paracellular reabsorption of cations, including the divalent c ations calcium and magnesium. The activity of ROMK is inhibited by activation of the extrac ellular calcium-sensing receptor (CaSR) that is located in the basolateral membrane. In thi s way, increases in peritubular (but not luminal) calcium concentration (hypercalcemia) red uce TAL sodium and potassium reab- sorption and increase their delivery to more distal neph - ron sites. Maintenance of Vte, and reabsorption of sodium and potas- sium by the TAL, is critical for paracellular reabsorption of calcium and magnesium through selective tight jun ctional pores composed of members of the claudin (CDN 16 and 19) family of membrane protein s. Pathophysiology The kidneys are the major route of potassium excretion, excreting 90% of t he daily dietary intake (Fig. 5.4.2). At the glomerulus, potassium is freely \201 ltered and its con- centration in Bowman \200\231s space matches that in plasma. The daily \201 ltered load is 720 mmol/day. As \202 uid moves along the nephron, potassium is reabsorbe d and secreted (Fig. 5.4.3). CHAPTER 5.4 Hypokalemic tubular disorders 215 K+ gradient across the cell membrane sets its membrane potential \200\230Sodium pump \200\231 \200\22370 mV [Na+] = 140 mmol/L [Na+] = 20 [K+] = 120 [K+] = 4 mmol/L ICF ( 28 L) ECF ( 14 L) K+ 65 mmol ECF 3300 mmol ICF 2% TBK: 98% Fig. 5.4.1 Distribution of total body potassium (TBK) between intracellular (ICF) and extra cellular (ECF) \202 uid spaces, and the key role of the \200\230sodium pump \200\231 (Na +/K+-ATPase). Note that dietary intake of potassium can range from 80 to 120 mmol/day and t hat this could easily double the plasma potassium concentration, unless there is a \200 \230buffering \200\231 mechanism, which involves rapid transfer into the ICF (see text for details). Fig. 5.4.2 Pathways and contributions to normal potassium balance. The numbers refer to the amount of potassium (in mmol) per day. ECF, extracellular \202 uid; ICF, intracellular \202 uid; GIT, gastrointestinal tract. NCCT Na+ CI \210\222 Na+ K+ CI \210\222 K+ K+ Filtered load 100% Maxi-K 20 \200\223 80% DCT Glom CNT PC 75% Na+ Na+ K+ PCT CCD K+ K+ +ve Na+ K+ TAL Na+ X IC Na+ H+ H+ H2O K+ K+ 10% K+ Na+ K+ H+ \210\222ve Na+ NKCC2 2C \210\222 IC K+ CI \210\222 K+ Na+ K+ ROMK K+ Na+ K+ H+ CIC-K/Barttin K+ H+ +ve K+ 10 \200\223 150% Fig. 5.4.3 Main sites of potassium reabsorption and secretion, and models of potassium move ment across cell membranes (see text for details). Basolateral exit of potassium also occur s to varying degrees along the nephron, but the molecular identity of the channels involved is not yet completely resolved. PCT, proximal convoluted tubule; DCT, distal convoluted tu bule; CNT, connecting tubule; TAL, thick ascending limb; CCD, cortical portion of collectin g duct; / IC, intercalated cells. S. WHITE, G. CAPASSO AND R. UNWIN 216 Approximately 20% of \201 ltered calcium is reabsorbed in the TAL. Therefore, like chroni c loop diuretic therapy, loss of function of these key TAL ion channels and trans- porters (or gain of function of the CaSR) in Bartter \200\231s syn- drome (Bartter \200\231s types I \200\223V; see Table 5.4.1) results not only in impairment of urinary concentrating abili ty and losses of sodium and potassium, but also in hypercalciuria. Although the TAL is resp onsible for reabsorption of the major fraction (>70%) of \201 ltered magnesium, in Bartte r \200\231s syndrome, perhaps surprisingly, hypomagnesemia is not usually present. In the CCD, any factor that increases sodium delivery and reabsorption (e.g. aldosterone) w ill increase potassium secretion. 2. Intercalated cells (ICs) are a minority cell populatio n that consists of two subtypes ( and ) that participate in the regulation of acid \200 \223base balance and the reabsorption of potassium when dietary intake is restricted, or in meta- bolic acidosis. Acid secretion by -ICs takes place via an electrogenic H+- ATPase in the apical membrane. Reabsorption of potassium by acid-secreting -ICs and bicarbonate- secreting -ICs takes place via an H+/K+-ATPase present in the apical membrane of these ce lls: potassium reabsorption is coupled to proton (H+) secretion. Both types of IC might als o secrete potassium when tubu- lar \202 ow rate is increased because, like PCs, they also express maxi-K channels. Aldosterone increases potassium secretion due to its stim- ulator y effect on sodium reabsorption (via ENaC and increased Na+/K+-ATPase activity). Aldosteron e also increases acid secretion by direct stimu- lation of H+-ATPase in -ICs, and indirec tly by stimulating sodium reabsorption in PCs and increasing the lumen- negative Vte (favor ing H+, as well as K+, secretion). Hypokalemic alkalosis in Bartter \200\231s and Gitelman \200\231s syndromes In Bartter \200\231s syndrome, inhibition of sodium and chloride reabso rption in the TAL leads to an increase in delivery of these ions, as well as an increase in tubular \202 ow, to the distal nephron. Increased delivery of sodium, combined with acti vation of the RAAS following salt and water losses, augments secre- tion of both potassium and protons in the collecting duct, leading to their increased urinary excretion and a hypo ka- lemic alkalosis. The hypokalemia of type II Bartter \200\231s (Table 5.4.1) is less sev ere than in the other types, because of reduced K+ secretion in the CCD via ROMK. Indeed, n eonatal type II patients can display transient and severe hyperkalemia, reflecting a reduct ion in potas- sium secretion in the CCD. These individuals go on to develop more modest lev els of hypokalemia in the post- neonatal period, because of the emergence of flow- dependen t potassium secretion via the maxi-K channel (see earlier). Loss of NCCT activity in the DC T in Gitelman \200\231s syndrome results in a milder and delayed onset of hypokalemia, con- sistent with a less marked increase in tubular \202 ow rate compared with a defect in th e TAL. The distal nephron The distal nephron is an anatomically complex structure that can exhibit net reabsorption or secretion of potas- sium, depending on potassium balance. In addition, the overlapping expression of some channels from TAL to distal convoluted tubule (DCT) (Ta ble 5.4.1) makes genotype \200\223phenotype correlations in Bartter \200\231s and Gitelman \200\231s syndromes difficult, because the degree of \200\230upstream \200\231 compensatio n can vary according to the under- lying gene defect. The DCT consists of early (DCT1) and late (DCT2) segments. The activity of the basolateral Na+/K+-ATPase maintains the driving f orce for sodium and chloride entry via the thi- azide-sensitive sodium chloride (NaCl) cotr ansporter (NCCT). Chloride exits across the basolateral membrane via Barttin \200\223ClC \200\223Kb channels. Although ROMK channels are expressed in both DCT1 and DCT2, there is l ittle evidence for signi \201 cant net potas- sium secretion in DCT1. Loss of function mut ations in NCCT results in the symp- toms and signs of chronic thiazide diuretic treatment ( Gitelman \200\231s syndrome). In marked contrast to Bartter \200\231s syndrome, Gitelman \200\231s syndrome is accompanied by hypoc- alciuria and severe hypomagnesemia. These contr asting effects on divalent cation handling result from incompletely understood differences in the han- dling of calcium and magnesium between cells of DCT1 and DCT2. The late DCT, th e connecting tubule (CNT) and the cortical portion of the collecting duct (CCD) are all pri mary sites of net potassium secretion (Fig. 5.4.3). In these segments there are two distinc t types of cell: 1. Principal cells (PCs) reabsorb sodium via an amilo ride- sensitive sodi um channel (ENaC) by an electro genic process that creates a lumen-negative Vte favoring se cretion of potassium through SK channels (thus coupling indirectly sodium reabsorption with potassium secretion). A second potassium-conducting channel known as \200\230maxi-K \200 \231 or \200\230Slo \200\231 is also present in the apical membrane of PCs. These channels have a higher electrical conductance than SK channels, but unlike SK channels, they are no t open at normal resting membrane potentials. However, they are activated by an increase in tubular \202 uid \202 ow rate, which increases potassium secretion and loss in the uri ne. In the distal nephron, as sodium delivery increases, so does sodium reabsorption. As a result, potassium secretion also increases. Etiology and clinical features Lack of dietary potassium alone does not cause hypoka- lemia . Hypokalemia can arise because of: \200 \200 \200 potassium shift into the cells (ICF); extrarenal losses of potassium; renal losses of potas sium. Hypokalemia due to potassium shifts Since most potassium is in the ICF, a small shift from the ECF to the ICF can cause signi \201 cant hypokalemia. CHAPTER 5.4 Hypokalemic tubular disorders 217 Table 5.4.1 The genes and their proteins causing hypokalemic metabolic alkalosis in Bartter \200\231s syndrome (BS) and Gitelman \200\231s syndrome (GS) Polyhydramnios in pregnancy is an important clue. It is due to fetal polyuria, which contin ues in the neonatal period and usually lasts up to 6 weeks; it may cause severe and life-th reatening \202 uid and electrolyte depletion. Mutations have been described in two genes; SLC12A1 and KCNJ1 (Table 5.4.1). Familial hypomagnesemia with nephrocalcinosis can be conf used with this form of antenatal Bartter \200\231s syndrome. Protein Disease Nephron segment affected Gene name Ensemble cytogenetic band 15q21.1 NKCC2 BS I TAL SLC12A1 11q243 Kir1.1 (ROMK) BS II TAL KCNJ1 Classical Bartter \200\231s syndrome (BS III) This presents in infancy or early childhood with a variety of clinical features ranging fro m severe volume depletion and failure to thrive (as in BS I and II) to only mild muscle wea kness. It usually presents before the age of 6 years and symptoms include polyuria (manifes t as nocturia and bedwetting), polydipsia, vomiting, constipation, salt-craving and chronic fatigue. Muscle weakness and cramps are also common. BS III is caused by mutations in the basolateral chloride channel ClC-Kb (Table 5.4.1 and Fig. 5.4.3). Nephrocalcinosis is not a feature. BS VIa 1p36.13 CLC-Ka tAL + TAL CLCNKA 1p36.13 CLC-Kb BS III TAL + DCT CLCNKB 1p32.3 Barttin BS IV TAL + DCT BSND 3q21.1 CaSR BS V TAL CASR 16q13 NCCT GS DCT SLC12A3 a BS VI is a digenic disorder resulting from loss of function of both ClC-Ka and ClC-Kb. tAL, thin ascending limb of Henle; TAL, thick ascending limb. Insulin, catecholamines, alkalosis, barium poisoning, and hypokalemic periodic paralysis ca n all cause hypokalemia due to a reversible shift in potassium from ECF to ICF. Antenatal Bartter \200\231s syndrome with deafness (BS IV and VI) This form of Bartter \200 \231s syndrome is rare and particularly disabling. It is caused by loss of function of the protein Barttin, which regulates the two chloride channels ClC-Ka and ClC-Kb; both also pre sent in the inner ear, hence the association with deafness. Bartter \200\231s syndrome type VI is similar to type IV, but is due to a digenic mutation affecting the genes for ClC-Ka and ClCKb. Extrarenal potassium loss Potassium is reabsorbed in the small intestine and secreted in th e colon (which is aldosterone-dependent). Diarrhea is the main cause of extrarenal potassiu m loss. Protracted vomiting and the associated metabolic alkalosis lead to secondary renal losses of potassium due to increased renal bicarbonate excretion, which increases renal pot assium excretion, and activation of the RAAS as a result of volume deletion. Hypocalcemia with Bartter \200\231s syndrome (BS V) This is a very rare form of Bartter \200\231s syndrome due to het- erozygous activating mutations of the calcium-sensing recept or, CaSR. Clinical features include hypocalcemia and hypoparathyroidism. Renal potassium loss Renal potassium wasting is suggested by losses in urine of >20 mmol pe r day in the presence of hypokalemia. Once an extrarenal cause for hypokalemia has been exc luded, it is generally suf \201 cient to think of clinical situa- tions that: (a) increase the delivery of Na+ to the K+-secreting distal Gitelman \200\231s syndrome (GS) Gitelman \200\231s syndrome was originally described as a variant of Bartter \200\231s syndrome. It has similar clinical features to Bartter \200\231 s syndrome, except for hypomagnesemia, which is common, and hypocalciuria, which is charact eristic. Gitelman \200\231s syndrome is often not diagnosed until adoles- cence or early ad ulthood; it is frequently detected on rou- tine blood testing. Hypokalemia in Gitelman \200 \231s is typically milder than in Bartter \200\231s syndrome: 2.5 \200\2233.0 vs 1.5 \200 \2232.5 mmol/L, respectively. Diagnosis can be difficult and delayed, though many patients are symptomatic and complain of fatigue, muscle cramps and in some cases tetany with carpo- pedal spasm. They are often intolerant of alcohol and exercise, which can worsen their symp toms. Diuretic or laxative abuse and eating disorders can all mimic Gitelman \200\231s synd rome or worsen its clinical signs and symptoms. Unlike Bartter \200\231s syndrome, so far o nly one gene defect has been shown to cause the Gitelman phenotype, SLC12A3 (Table 5.4.1). A large number of different mutations have been described, but most patients are compound h eterozygotes; so unlike nephron (and its PCs); (b) increase the mineralocorticoid status (primary hyper- aldosteronism with hypertension, with or without hyper- reninism or secondary hyperaldosteronism); or (c) directly affect distal nephron (TAL, DCT and CCD) function (genetic tubulopathies). As already alluded to, the rare genetic tubulopathies pre- senting with hypokalemia and nor motension are Bartter \200\231s and Gitelman \200\231s syndromes (autosomal recessives). Ge netic forms of hypokalemia presenting with hyperten- sion are Liddle \200\231s syndrome (au tosomal dominant), the syn- drome of apparent mineralocorticoid excess (AME, autosomal rece ssive) and glucocorticoid-responsive aldos- teronism (GRA, autosomal dominant). Diagnosis Bartter \200\231s syndrome (BS) (Table 5.4.1) Antenatal neonatal Bartter \200\231 s and hyperprostaglandin E syndromes (BS I and II) These are the most severe forms of Bartter \200\231s syndrome and are associated with hyper calciuria and nephrocalcinosis, which can lead to renal failure. S. WHITE, G. CAPASSO AND R. UNWIN 218 Above all, supportive care and long-term follow-up are required. Genetic screening is still not widely available, but it may help in diagnosis and eventually improve tailored manage- ment; moreover, many of these patients appreciate having a de \201 nite diagnosis. Bartter \200\231s syndrome, in which \201 rst-cousin marriages are more common, there is usually no consanguinity. Another complication that is characteristic of Gitelman \200\231s syndrome is chondrocalcinosis, which has been linked to reduced activity of the magnesium- dependent enzyme pyrophosphatase. Other normotensive hypokalemic tubulopathies As already mentioned, some proximal tubular di sorders, including the renal Fanconi syndrome, can have Bartter \200\231s- like features. O ther speci \201 c examples are patients with the mitochon- drial disorder Kearn \200\223Sa yre syndrome and patients with a form of familial hypokalemic alkalosis known as Gullner \200\231s syndrome. Further reading Giebisch G, Krapf R, Wagner C. Renal and extrarenal regulation of potassium. Kidney Int 2007; 72: 397 \200\223410. Reinalter SC, Jeck N, Peters M, et al. Pharmacotyping of hypokalae- mic salt-losing tubular disorders. Acta Physiol Scand 2004; 181: 513 \200\223521. Unwin RJ, Capasso G. Bartter s and Gitelman s syndromes: their relationship to the actions of loup and thiazide diuretics. Curr Opn Pharmacol 2006; 208: 208 \200\223213. Treatment Despite the new genetic knowledge about these syn- dromes, and our improved under standing of the underlying pathophysiology, treatment and management remain empirical. Trea tment is based on oral potassium (1 \200\2233 mmol/kg/day in children) and magnesium (bewar e of causing diarrhea) sup- plements, as required, and are guided by symptoms rather than a target blood level for potassium or magnesium. For hypokalemia, ACE inhibitors and angiote nsin recep- tor blockers can be used (in low doses) to block the activated RAAS, and spiron olactone (10 \200\22315 mg/kg/day in children) can be used to antagonize hyperaldosteronism . Potassium-sparing diuretics such as amiloride can be added, and where prostaglandin excre tion is high, NSAIDs such as indomethacin (2 \200\2235 mg/kg/day in children) can be given. These treatments have to be tried and tailored to suit indi- vidual patients. The main pro blem is compliance with what is often a large number of tablets to be taken life-long, and which are prescribed \200\230off label \200\231. Advice about a potassium- and magnesium-r ich diet is also important. Internet resources The Bartter Site (Bartter \200\231s and Gitelman \200\231s syndrome reso urce): http://www.barttersite.org/ Online Mendelian Inheritance in Man (online catalog of genes an d diseases): h t t p : / / w w w . n c b i . n l m . n i h . g o v / s i t e s / entrez?db=omim Gitelman \200\231s: http://www.ncbi.nlm.nih.gov/ent- rez/dispomim.cgi?id=263800 Bartter \200\231s: http://www.ncbi.nlm.nih.gov/entrez/ dispomim.cgi?id=241200 See also Hypo-/hyperkalemia, p. 46 Hypo-/hypermagnesemia, p. 60 This page intentionally left blank D. BOCKENHAVER, D. BICHEL, AND R. UNWIN 220 Nephrogenic diabetes insipidus \200 De \201 nition Nephrogenic diabetes insipidus (NDI) is de \201 ned as the kid- ney \200 \231s inability to concentrate urine, despite the presence of adequate levels of circulatin g vasopressin (antidiuretic hormone (ADH)); it is an endocrine example of end-organ failure . Almost all cases are diagnosed in childhood. The kidneys continue to excrete dilute urine independent of a raised plasma or serum osmolality, resulting in polydip- sia and predispo sing to hypernatremic dehydration if water intake is impaired (e.g. loss of physical access or vomiting) or if there are additional \202 uid losses (e.g. from diarrhea). hypokalemia (chronic); hypercalciuria (acute and chronic). Clinical features Congenital NDI Patients with congenital NDI typically present in the \201 rst few weeks of life with polyuria, dehydration, fever, irritability, constipation an d a failure to thrive. Often parents report that the child is always thirsty and suckling v igorously, but vomiting shortly after feeds; vomit- ing may be due to re \202 ux from the large volume of \202 uid ingested. Interestingly, breast-fed infants with NDI typically d o better than those given formula feeds; probably because breast milk contains a lower osmo lar load than most standard formula feeds (see below). It is worth noting that in pregnancy with a fetus with NDI, polyhydramnios does not occur (cf. classical Bartter \200\231s syn- drome), because the AVP-dependent mechanism of urine concentration is not fully developed until after birth, and any osmolar load is cleared by the placenta. Symptoms typically impr ove with increasing age, especially once food has changed to solids and there is free acces s to water, allowing self-regulation of plasma osmolality. However, patients remain polyuri c and problems such as constipation and bedwetting often continue. The frequency and volume of voiding and drinking, particu- larly at night, is useful information in assessing the s everity of NDI. Parents often also report problems with the attention span and mental conce ntration of an affected child, which may be partly due to the constant interruptions needed to drink and to void. With adequate treatment patients with NDI can function well. In cont rast, untreated patients typically have a persist- ent failure to thrive, as the constant i ntake of \202 uid limits their appetite. Mental retardation used to be an almost invariab le feature, probably as a result of repeated episodes of hypernatremic dehydration, but it is rarely seen in patients who have been diagnosed and treated early. Some patients develop dilatation of the lower urinary tract from the high urine \202 ow rate ( \200\230functio nal out \202 ow tract obstruction \200\231) especially if they have poor voiding habits an d they are not encouraged to \200\230double micturate \200\231 to ensure bladder emptying. Pathophysiology Blood (plasma or serum) osmolality is centrally monitored by the hypothalam us: in response to a rise in osmolality, arginine vasopressin (AVP or ADH) is secreted. In the kidney, AVP binds to a receptor (AVPR2) in the \201 nal (distal) part of the nephron, the collecting duct. The urine entering the collecting duct is dilute and has an osmolalit y that is much lower than that of plasma ( 100 vs 300 mOsm/kg), because of active solute r emoval (transportation) in the thick ascending limb (TAL) of Henle \200\231s loop. In the a bsence of circulating AVP, the collecting duct is water impermeable and the \201 nal urin e will remain dilute. However, binding of AVP to its receptor (and through a series of inte rmediate steps) leads to the insertion of water channels (aquaporin 2 or AQP2) in the lumin al (urine-facing) membrane of collecting duct (principal) cells, making them water permeabl e. Since the osmolality in the interstitium of the renal medulla is high (because of the co unter-current multiplier mecha- nism), water is reabsorbed, which concentrates the urine (t o a maximum of 1000 mOsm/kg). Thus, AVP regulates water permeability of the collect- ing d uct so that the \201 nal urine concentration can vary between the osmolality of the urine entering the collect- ing duct ( 100 mOsm/kg) and that of the interstitium ( 1000 mOsm/kg) . In NDI, the kidney \200\231s ability to respond to AVP is impaired and the urine remains maximally dilute (with an osmolality <100 mOsm/kg). Etiology Congenital This presents in the \201 rst weeks to months of life: \200 \200 \200 Acquired NDI The presenting symptom in acquired NDI is typically poly- uria and frequency, including nocturia, but the onset is usu- ally much later than in congenital NDI and there is usually no family history. X-linked recessive due to mutations in AVPR2 (90%); autosomal recessive due to mutations in AQP2 (10%); (autosomal dominant DI due to mutations in AQP2 is very rare; autosomal domina nt DI is more likely to be of the central rather than nephrogenic type). Diagnosis of DI An inappropriately dilute urine in the face of a raised plasma osmolality d e \201 nes DI. A large urine volume in a dehydrated patient should always raise the possib ility of a urinary concentrating defect. The diagnosis is easily made by obtaining plasma a nd urine biochemistries, particularly osmolalities. Acquired This presents at any age: \200 \200 obstructive uropathy ( \200\230post-obstructive diuresis \200\231); renal failure/tubular d ysfunction (e.g. nonoliguric acute kidney injury, tubulo-interstitial nephritis, renal dysp lasia, nephronophthisis, cystic kidney diseases); lithium (in 20% of patients treated with lithium); CHAPTER 5.5 Nephrogenic diabetes insipidus 221 A diagnostic algorithm for patients with hypernatremic dehydration and suspected diabetes i nsipidus (DI) with a urine output >1 mL/kg/h. Urine osmolality >800 mOsm/kg? (>500 mOsm/kg in infants)? no yes No DI DDAVP test Urine osmolality >800 mOsm/kg (>500 mOsm/kg in infants)? no yes Evidence for acquired DI? Central DI History: lithium? Biochemistry: hypokalemia? hypercalciuria? generalized tubulopathy? renal failure? Radiology: obstructive uropathy? yes no Inherited NDI Proceed to molecular genetic testing Acquired NDI Fig. 5.5.1 A diagnostic algorithm for patients with hypernatremic dehydration and suspected diabetes insipidus (DI) with a urine output > 1 ml/kg/h. Maximal urinary concentrating ability increases during the \201 rst year of life, but a u rine osmolality <500 mOsm/kg (infant) or <800 mOsm/kg (adult) in the presence of hypernatre mia indicates DI. In classic inherited NDI the urine osmolality is always <200 mOsm/kg (and typically 100 mOsm/kg). A diagnostic algorithm for a child or adult presenting with hyper natremic dehydration is given in Fig. 5.5.1. Interestingly, intravenous DDAVP at high doses (0.3 g/kg) can cause systemic side-effects : a mild decrease in blood pressure and an increase in heart rate via AVPR2. Patients with mutated AVPR2 (X-linked recessive NDI) do not experience these hemodynamic effects, while p atients with intact AVPR2, but mutated AQP2 (autosomal reces- sive and dominant NDI), do. T hus, the intravenous DDAVP test can help to discriminate between these two forms of NDI. A typical protocol for the DDAVP test is given in Table 5.5.1. A rare complication of the DDA VP test is hyponatremia. Patients with an intact thirst mechanism and who respond normally to DDAVP will stop drinking water as their plasma osmolality falls. Hyponatremia may develo p in those patients with psycho- genic polydipsia who keep on drinking, despite lowered pla sma osmolality, and in infants who continue to be fed by their parents or carer during the test. Therefore, close observation and limitation of \202 uid intake to a volume equal to the amount of urine excreted during the test period is necessary to avoid this potentially serious complication. DDAVP test interpretation (see also Fig. 5.5.1) If urine osmolality after DDAVP in the test period is: \200 \200 Diagnostic procedures DDAVP test A DDAVP test is used to discriminate central (cranial) fro m nephrogenic DI. The effects of AVP are mediated by two different receptors: \200 AVP re ceptor type 1 (AVPR1) mediates vasocon- striction; AVP receptor type 2 (AVPR2) mediates ant idiuresis. The AVP analog 1-desamino-8-D-arginine vasopressin (DDAVP) has a high speci \201 city for AVPR2 and can be used to assess the renal response, while avoiding the system ic effects mediated by AVPR1. DDAVP can be given intranasally (20 g), intramuscularly (0. 4 g if <10 kg, 2 g if >10 kg), intravenously (0.3 g/kg) or orally (200 g). While in tranasal DDAVP is less invasive, absorption is less reliable; if the result of the test is inconclusive, it may need to be repeated using injected DDAVP. DDAVP given intravenously or orally requires a shorter observation period (2 \200\2234 h) than when given by the other routes (4 \200\2236 h). <200 mOsm/kg: the diagnosis of NDI is established; >800 mOsm/kg: normal renal concentrating ability: NDI is excluded; 200 \200\223800 mOsm/kg: this is an intermediate response, arisi ng because: The test is invalid and needs to be repeated. 2 2 2 D . B O C K E N H A V E R , D . B C H E L I Table 5.5.1 Typical protocol for the DDAVP test , Time (min) Actual time (e.g. 09:00) \200\22330 \200\22315 0 10 15 20 30 40 50 60 75 90 110 130 150 A N D __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ __:__ R . U N W N dDAVP infusion I