Hartnup disease Hartnup disease is another autosomal recessive disorder, this time due to a mutation in SLC6A19, which encodes a neutral amino acid transporter (Table 5.1.3); althoug h this gene defect does not account for all cases. Many of those affected have no signs or symptoms, but typical cases have a pellagra-like rash and ataxia. These complications arise not from the renal losses of amino acids, but from impaired intestinal absorption of tryp- tophan, the precursor of nicotinic acid (niacin, vitamin B3), and can be treated with nico tinamide. Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 2003; 14: 2873 \200\2232882. Wright EM, Hirayama BA, Loo DF. Active sugar transportation in health and disease. J Intern Med 2007; 261: 32 \200\22343. Internet resources International Cystinuria Foundation: http://www.cystinuria.org/ See also Fanconi syndrome, p. 204 Hypo-/hyperphosphatemia, p. 56 Medical management of ston e disease, p. 270 Renal and urinary tract stone disease in children, p. 282 Iminoglycinuria This is a benign aminoaciduria due to a defect in PAT1 (SLC36A1) (Table 5.1 .3). A. HALL, R. KLETA AND R. UNWIN 204 Fanconi syndrome De \201 nition The renal Fanconi syndrome (FS) (also known as Fanconi renotubular syndrome and Lignac \200\223de Toni \200\223Debr \200\223Fanconi syndrome, and not to be confused with Fanconi \200\231s anemia) refers to a set of clinical features resulting from a gener al- ized loss or disturbance of the normal transportation processes in the proximal renal t ubule (PT) of the nephron. Originally described in the 1930s by the Swiss pediatrician Guid o Fanconi, its characteristic features are glycosuria, aminoaciduria and phosphaturia (hypo phosphatemia) in affected children (or adults). FS is recognized by urinary losses of subst ances normally reabsorbed by the PT, such as glucose, amino acids and phosphate (as already mentioned). It also includes loss of bicarbonate (leading to meta- bolic acidosis \200 \223 a form of renal tubular acidosis (RTA)) and low molecular weight proteins (LMWPs) (for example vitamin D binding protein which affects vitamin D metabolism, leading to phosphate wasting and rickets or osteomalacia). Urinary loss of LMWPs (a commonly measured example o f which is retinol-binding protein, RBP) is a consistent fea- ture of FS and a hallmark of the disorder, making it a useful screening test. Hypercalciuria is also commonly present, t hough the mechanism is not clear. cystinosis there is a wide range of estimates (from 0.03 to 0.4 per 10 000 live births), de pending on the population studied. The underlying pathogenic mechanisms that unite the diff erent causes of FS are still not fully understood. FS can be mild, with only tubular protei nuria, or severe, with all the classical features listed above. Unlike the monogenic tubula r disorders, such as Gitelman \200\231s or Bartter \200\231s syndromes, whatever the underl ying defect in FS may be, it leads to disturbed transportation (reabsorption) of more than one solute/ion. Originally thought to be a nonspeci \201 c cell toxic effect due to distur bed cell metabolism, it is now emerging that altered cell traf \201 cking of proteins is a signi \201 cant conse- quence of any underlying defect. Transportation in the PT is coupl ed to sodium (Fig. 5.2.1) and depends on the gradient for sodium generated by the basolater al ATP-dependent sodium pump: Na+/K+-ATPase. As mentioned before, tubular proteinuria is an important early \201 nding in FS. LMWPs (<70 kDa, the size of albumin) are \201 ltered at the glomerulus and are normally reabsorbed (together with small amounts of filtered alb umin) \200\223 \200\230reclaimed \200\231 \200\223 in the PT. The reabsorptive mechanism is not completely clear, but it does involve binding of LMWPs to two large receptor protei ns called megalin and cubilin, which seem to be associated and interdependent. Following bi nding, the receptor \200\223LMWP complex is internalized (endocytosed) by the PT cell and t ransported into the cytoplasm in endosomes (Fig. 5.2.1). Acidi \201 cation of these endoso mes then dissociates the receptor \200\223ligand complex and the receptor (megalin) is recy cled to the apical membrane for re-use. The LMWP is either broken down in lyso- somes or tr ansported to the basolateral membrane of the cell. Dent \200\231s disease and Lowe syndrome have shown us that this process is disturbed, which explains the presence of tubu- lar pro teinuria, but exactly how the other transportation proc- esses are dependent on this mechan ism and are affected in FS is less clear. FS is a heterogeneous disorder and its natural hi story var- ies, depending on the underlying cause. Cases due to drug toxicity are often rev ersible on stopping the offending drug. However, many patients with FS can develop chronic renal failure, although this is not universal and it is dif \201 cult to predict. Prevalence and pathophysiology There is no overall estimate for the prevalence of FS, becau se there are several different genetic and toxic causes (Tables 5.2.1 and 5.2.2). It was pr eviously thought of as a rare disease, particularly in adults. Development and wider use of assays for urinary LMWPs in urine ( \200\230tubular proteinuria \200\231) have made it pos si- ble to detect milder forms of PT dysfunction. However, the clinical signi \201 cance o f mild PT dysfunction and tubular (LMW) proteinuria remains unclear, although it is possibl e that some LMWPs are toxic to the renal tubule and this may partially explain the common a ssociation of FS with progressive renal impairment. Various drugs and toxins (Table 5.2.2) can cause renal FS, especially heavy metals (cadmium, uranium, lead and mercury), aminoglyc oside antibiotics, some antiretroviral drugs (e.g. azidothymidine (AZT)), and certain cytot oxic drugs (ifosfamide), many of which seem to affect mito- chondrial function (which might explain their predilection for the PT). Myeloma affecting the kidney and also some autoimm une diseases (e.g. lupus nephritis or Sj gren \200\231s) are important causes in adults. I nherited forms of FS include autosomal recessive dis- eases such as cystinosis, tyrosinemia , fructose intolerance, galactosemia, glycogen storage disease type I, and cyto- chrome c o xidase de \201 ciency; an autosomal dominant idio- pathic form of FS; and various inherite d mitochondrial diseases. Dent \200\231s disease and Lowe syndrome are X-linked Fanconi- li ke disorders in which glycosuria is often absent. The prevalence of FS is dif \201 cult to estimate, though most inherited cases are rare: even for the more common Clinical features Symptoms Children with FS may present with polyuria, polydipsia, rickets, or failure to thrive. In adults, the main clinical symptom and presenting feature of FS is bone pain and muscle weakness due to osteomala- cia and phosphate wasting. Hypokalemia and metabolic acidosis can also occur, but in less severe cases of FS there may be no symptoms or clinical signs. Patients often present with other symptoms or signs of the underlying d isease, for example, renal stones or unex- plained renal impairment in Dent \200\231s disea se, or cardiac and neurological complications in mitochondrial disorders. CHAPTER 5.2 Fanconi syndrome 205 Table 5.2.1 Genetic causes of the renal Fanconi syndrome Table 5.2.2 Drugs commonly known to cause a renal Fanconi syndrome Disorder Defective Encoded Protein Inheritance Nucleoside reverse transcriptase inhibitors (NRTIs) Aminoglycosides Sodium valproate Ifosfa mide Suramin Tetracyclines (outdated) Ethanol (chronic alcoholism) gene Unknown Unknown Autosomal dominant ADIF (autosomal dominant idiopathic Fanconi) CTNS Cystinosis lysozymal cystine transporter Autosomal recessive A thorough family history is required in all cases, especially in those without an obvious cause. A complete drug and occupational history is also important, particularly with regard to herbal remedies obtained from unknown or unapproved sources, and exposure to heavy meta ls or industrial solvents. COX Cytochrome c oxidase Autosomal recessive Cytochrome c oxidase de \201 ciency ALDOB Autosomal recessive Fructose intolerance Fructose- bisphosphate aldolase B Signs In children, short stature, volume depletion, and rickets are the main signs of FS. T here are no speci \201 c signs in adults, as volume depletion is generally less striking. Patients may have signs of the underlying disease causing FS (e.g. stones in Dent \200\231s disease and cataracts in Lowe syndrome). Galactosemia GALT Autosomal recessive Galactose- 1-phosphate uridyl transferase G6PC Glucose- 6-phosphatase Autosomal recessive Glycogen storage disease type Ia (von Gierke disease) fahA Tyrosinemia Fumarylacetoacetase Autosomal Diagnosis of FS The diagnosis is commonly made in childhood. The combination of hypophospha temia, glycosuria (in the absence of hyperglycemia), aminoaciduria, a hyperchlo- remic meta bolic acidosis with hypokalemia, and signs of vitamin D de \201 ciency is very suggestive of FS. If there is multisystem involvement, as in glycogen stor- age disease, detection may be prompted by the primary disorder. recessive ATP7B Wilson \200\231s disease Copper-transporting ATPase 2 Autosomal recessive CLCN5 Dent \200\231s disease Chloride channel 5 X-linked recessive OCRL X-linked recessive Lowe syndrome Inositol polyphosphate 5-phosphatase (PIP2 5-phosphatase) Apical Basolateral Na+ Na+ 3Na+ 3Na+ X \210\222 X \210\222 2K+ 2K+ 4 2K+ LMWPs 3 1 2 Fig. 5.2.1 The basic transportation mechanisms of the proximal tubule (PT). Substances (X) such as glucose, amino acids and phosphate are cotransported at the luminal (apical) cell m embrane with sodium (Na). The gradient for sodium entry is maintained by the basolateral so dium pump (Na+/K+-ATPase) with recycling of potassium across the basolateral cell membrane via a potassium channel. In the case of bicarbonate (not shown), its reabsorption depends i ndirectly on the apical Na/H exchanger (also not shown) that secretes protons (H+). LMWPs ( <70 kDa) are bound by two large nonselective receptors (megalin and an associated protein c ubilin) at the luminal membrane (1). They bind LWMPs and the complex is internalized (recep tor-mediated endocytosis) and packaged into early endosomes (2). Acidi \201 cation of the endosomes then dissociates the receptor \200\223ligand complex and the protein cargo is eit her transferred to lysosomes, where it is degraded, or transported to the basolateral membr ane and into the blood (3). The megalin receptor is recycled to the luminal membrane (4). A. HALL, R. KLETA AND R. UNWIN 206 In adults, a high index of suspicion is often necessary in the context of unexplained renal impairment, renal stone dis- ease or unexplained hypokalemia with other \202 uid and ele c- trolyte disorders. In some cases an \200\230incomplete \200\231 form of FS can occur: f or example in carriers of X-linked disorders such as Dent \200\231s disease or Lowe syndrom e, tubular proteinuria may be present in isolation. Milder forms of FS can lead to isolated abnormalities such as hypophosphatemia, and this needs to be differentiated from other cau ses like malabsorption from the gastrointes- tinal tract or primary hyperparathyroidism. Tu bular proteinuria can be either primary, due to a defect of the PT (FS), or secondary, due to glomerular disease. If in doubt, these two possibilities can be distinguished by compari ng the relative amounts of albumin and LMWP (e.g. RBP) in urine (see below). However, it mu st be noted that when glomerular proteinuria is heavy, tubular pro- teinuria will also be p resent. If a mitochondrial cytopathy is suspected, measure plasma creatine kinase (CK) and blood la ctate:pyruvate ratio. Investigate further by undertaking a skeletal muscle biopsy, an assay of respiratory chain enzyme activities, and an analysis of the more common mitochondrial D NA mutations. Renal biopsy There are no characteristic or diagnostic \201 ndings of FS, except in mitoc hondrial disease, in which mitochondria (on EM) in the proximal tubule are enlarged and dys morphic. Management Advice to patients Patients will need to be counseled about the more speci \201 c complications of FS, the need for vitamin and mineral sup- plements, the features of any underlying and associated disease, and the genetic implications of any inherited form of d isease. Treatment Speci \201 c treatment may be available for a particular form of FS (e.g. cystea mine in cystinosis, penicillamine in Wilson \200\231s disease, and diet in fructose intoler ance). In general, treatment of FS involves replacing electrolyte losses, including bicarbo nate for acidosis, and preventing osteomalacia/rickets: \200 Investigations Initial screening Urine dipstick testing (for glycosuria without hyperglyc- emia) and spot urine total protein/creatinine are useful initial screening tests in the cli nic for tubular and glomeru- lar disease, but isolated tubular proteinuria is not usually d etectable by these routine methods. Plasma or serum creatinine may be raised (and eGFR redu ced), either because of impaired PT secretion of creatinine, or because of glomerular disea se with reduced \201 ltration. Hypophosphatemia and hyperchloremic metabolic acido- sis a re common in full-blown FS. The latter is a proximal form of renal tubular acidosis (type 2 RTA) and can be dis- tinguished from distal (type 1) RTA, because patients with proximal R TA are able to acidify their urine to pH <5.5 following an acid load (e.g. with NH4Cl), whe reas patients with distal RTA cannot (see Chapter 5.3). Hypokalemia is a feature of more se vere cases; it is second- ary to the loss of bicarbonate, which behaves as an osmotic diure tic, and to sodium losses, which stimulate aldosterone release and increase potassium secre tion in the collect- ing duct. Vitamin D (calcitriol) and calcium supplements \200\223 but ensure that endogenous vitamin D (25-(OH) vitamin D) levels are also adequate \200\223 and also phosphate supple- ments, if hypophosphatemia is severe and is not respond- ing to vitamin D and diet. Oral bicarbon ate supplements (as sodium or potassium salt) for metabolic acidosis. Give 1 \200\2232 mmol /kg aiming to m a i n t a i n p l a s m a o r s e r u m b i c a r b o n a t e concentration >20 mmol/l. Oral potassium (as bicarbonate or chloride salt) supple- ments suf \201 cient to maintain plasma or serum potassium concentration >3.0 mmol/L. In addition, if there is evidence of chronic kidney disease (CKD): blood pressure control, antiproteinuric therapy if there is signi \201 cant glomerular proteinuria, and treatment of any cardiovascular risk factors that are present (e.g. use of statins for hyperlipidemia ). Follow-up This depends on the underlying disease, but in most forms of FS, patients need lo ng-term follow-up to monitor treat- ment and renal function, particularly if there is assoc iated renal stone disease. Exceptions may be reversible causes of FS, for example following drug-induced toxicity, when PT function has recovered after the withdrawal of the relevant drug (e.g. antiretroviral drugs). Many patients who have developed FS following chemo- the rapy are young and should be monitored long-term as part of the \200\230late effects of ca ncer chemotherapy \200\231 follow-up, because we do not yet know enough about the natural h istory of this form of nephrotoxicity. To con \201 rm that the PT is the site of the defect: 1. Screen for tubular proteinuria by assaying for RBP (or other LMWPs such as 1- or 2-microglobulin). 2. Screen for aminoaciduria. 3. Renal handling of phosphate can be assessed by calculat- in g the tubular maximum for phosphate reabsorption normalized for GFR; TmPi/GFR = PPi \200 \223 (UPi \227 Pcreat/ Ucreat) from a spot urine (ideally a fasting and early morning samp le). The normal range changes with age and in adults is 0.8 \200\2231.6 mmol/L. An alternat ive is to calcu- late the fractional excretion of phosphate ([UPi \227 Pcreat]/ [Ucreat \227 PPi] \227 100), which is normally <20%. 4. Renal biopsy (see below). To identify the underlying cause of FS: In children, appropriate screening tests for \200 \230inborn errors of metabolism \200\231 are necessary. Exclude cystinosis as it is the com monest cause of FS in childhood. Exclude myeloma in adults by serum protein electrophore- s is and urine testing for Bence \200\223Jones protein. Further reading Christensen EI, Gburek J. Protein reabsorption in renal proximal tubule-fun ction and dysfunction in kidney pathophysiology. Pediatr Nephrol 2004; 19: 714 \200\22321. Guggino SE. Mechanisms of disease: what can mouse models tell us about the molecular proces ses underlying Dent disease?. Natl Clin Pract Nephrol 2007; 3: 449 \200\223455. CHAPTER 5.2 Fanconi syndrome 207 UK Lowe Syndrome Trust: Malik A, Abraham P, Malik N. Acute renal failure and Fanconi syn- drome in an AIDS patient on tenofovir treatment \200\223 case report and review of literature. J Infect 2005; 51: E 61 \200\22365. http://www.lowetrust.com/ Hau Am, Unwin R. The not so mightychondrion . Emergence of renal diseases due to mitochond rial dysfuction. Nephron Physiol, 2007; 105: 1 \200\22310. See also Hypo-/hyperphosphatemia, p. 56 Plasma cell dyscrasias, p. 158 Renal tubular acidos is, p. 208 Hypokalemic tubular disorders, p. 214 Cystinosis, p. 628 Drug-induced nephropath ies, p. 698 Systemic cancer therapies and the kidney, p. 714 Skinner R, Cotterill SJ, Stevens MC. Risk factors for nephrotoxicity after ifosfamide treat ment in children: a UKCCSG Late Effects Group study. United Kingdom Children \200\231s Canc er Study Group. Br J Cancer 2000; 82: 1636 \200\2231645. Internet resources Galactosaemia Support Group: http://www.galactosaemia.org/ The Association for Glycogen Storage Diseases UK: http://www.agsd.org.uk/ S. WALSH AND R. UNWIN 208 Renal tubular acidosis Background Systemic acid \200\223base balance is maintained by the lungs (short-term via ca rbon dioxide loss or retention) and the kidneys (long-term via bicarbonate reabsorption or excre- tion, and net acid excretion). The kidneys reabsorb (reclaim) \201 ltered bicarbon ate, and synthesize the important urinary buffer ammonia/ ammonium, in the proximal tubule, and secrete acid in the distal tubule and collecting duct: Net urinary acid excretion = Ti tratable acid (TA, mainly +) \200\223 Bicarbonate (usually phosphate) + Ammonium (NH4 negl igible). Renal tubular acidosis (RTA) is a generic term that can be used to describe severa l disorders in which there is a fail- ure of normal (and appropriate) renal acid excretion. Acid retention due to impaired renal function occurs in chronic kidney disease (CKD), but in this setting the prob- lem is due to a reduction in nephron number and the avail- +: abi lity of urinary buffer (TA: less \201 ltered phosphate; NH4 reduced proximal tubular capa city to synthesize ammonia, NH3), rather than a primary defect in renal tubular func- tion and proton (H+) secretion. In \200\230true \200\231 RTA there is usually a hyperchloremic normal anion gap acidosis and normal (relatively) glomerular \201 ltra- tion rate (GFR). Ammonium excretion may be reduced, but this re \202 ects (probably) decreased conversion o f NH3 +, because of impaired H+ secretion, rather than to NH4 reduced synthesis of NH3 (cf. CRF; see also type 4 RTA). In CKD, the acidosis is usually of the increased anion gap type (due to retention of weak organic acids), and the GFR is signi \201 cantly reduced. Clinically, type 1 distal RTA commonly occurs in patients with autoimmune disease, especial ly in those with hypergammaglobulinemia. The numbered classi \201 cation of RTA is not easy to remem- ber or to use: \200 \200 \200 type1: distal renal tubular acidosis (dRTA); type 2: proximal renal tubular acidosis (pRTA) ; type 3: a rare autosomal recessive form due to a de \201 - ciency of the enzyme carbonic anhydrase 2 (CAII), which can lead to a mixture of types 1 and 2; type 4: hyperkalemia and hypoaldosteronism. Distal RTA (dRTA) De \201 nition This form of RTA is best thought of as a failure of acid secretion by the acid-secreting -intercalated cell ( IC) (see Fig. 5.3.1) of the distal nephron (distal tubule and col- lecting duct). Measuring urine pH alone cannot diagnose RTA , although a urine pH >5.5 (conventionally) in the setting of a sys- temic acidosis (as ind icated by a low plasma bicarbo- nate concentration) with a near normal GFR, and in the abse nce of urine infection, makes a diagnosis of RTA likely and appropriate investigations shou ld be undertaken. The best con \201 rmatory test is a urinary acidi \201 cation test with either oral ammonium chloride (NH4Cl) or oral furo- semide plus \202 udrocortisone, whic h should normally reduce urine pH to <5.3. In dRTA urine pH cannot reach this threshold, bu t in prox- imal RTA, if the plasma bicarbonate concentration is low and the \201 ltered b icarbonate load is reduced, urine pH can fall to <5.3 (see below and Fig. 5.3.2). Classi \201 cation of RTA The classi \201 cation of RTA can be based on the main sites an d mechanisms of renal tubular acid and base transportation along the nephron: 1. The proxim al tubule is responsible for reclaiming \201 ltered bicarbonate and generating \200\230n ew \200\231 bicarbonate as a by- product of NH3/ NH4 \200 Etiology Inherited Mutations in either of the two key acid \200\223base transportation prot eins in the IC (Fig. 5.3.1): 1. AE1 (or \200\230band 3 \200\231), the chloride/bicarbona te exchanger located in the basolateral membrane of the AIC. AE1 mutations can be autosomal dominant (in European cases) or autosomal recessive (in South-East Asian cases). + synthesis from glutamine. Impaired bicarbonate reabsorption is the hallmark of proximal RTA (or type 2 RTA), but this usually occurs as part of a renal Fanconi syndrome. There is, how- ever, a very rare genet ic form due a mutation of NBC1, the sodium bicarbonate cotransporter (SLC4A4) in the basola teral membrane of the proximal tubule. 2. As already mentioned, the distal tubule and colle cting duct are responsible for the net acid excretion that is necessary for normal acid \200\223base balance ( 1 mmol of H+/kg on a typical Western diet). \200 2. vH+-ATPase is the proton pump located in the apical membrane of the IC. vH+-ATPase mut ations are auto- somal recessive and can be associated with sensorineural deafness, as some mutations also affect the proton pump (a subunit) present in the inner ear. Acquired The pathogenesis in these cases is unclear: 1. Autoimmune disease (Sj gren \200 \231s syndrome, SLE, rheuma- A characteristic feature of distal RTA (or type 1 or classical RTA), the more commonly enco untered clinical form of RTA, is low urinary citrate excretion. This is not seen in proxima l RTA. Nephrocalcinosis, renal stone disease, and bone loss are also more common in distal RTA than in proximal RTA. Hypokalemia can be present in both forms of RTA. In the variant o f distal RTA associated with hyperkale- mia (type 4 RTA), the primary cause is usually redu ced aldosterone secretion (or its action). The associated hyperkalemia suppresses ammonia s ynthesis and impairs acid excretion. toid arthritis, hypergammaglogulinemia). 2. Obstructive uropathy. 3. Nephrocalcinosis (secondary dRTA, e.g. medullary sponge kidney). 4. Renal transplantation (often transient in the postopera- tive period). 5. Toxins (amphotericin, toluene ( \200\230glue snif \201 ng \200\231), ifosfamide, lithium). 6. Sickle cell anemia. CHAPTER 5.3 Renal tubular acidosis 209 DT/CD PT NaHCO3 K+ PT Na+ H+ Na+ K+ H+ Na+ Na+ H2CO3 HCO3 H2CO3 K+ CA(II) H2O + CO2 CA(IV) H2O + CO2 PC DT/CD \210\22240 mVp.d. K+ K+ Na+ \210\222 CI Glutamine H+ \210\222 HCO3 Na+ -keto glutarate CA(II) IC \210\222 HCO3 Na+ + NH4 (H+) Fig. 5.3.1 Current cell models of tubular acidi \201 cation. Schematic of the nephron illu strating the main sites of acidi \201 cation in the proximal and distal segments, and the cellular transportation processes involved in bicarbonate (HCO3 proximal tubule; DT, distal tubule; CD, collecting duct; PC, principal cell; IC, -intercalated cell; CA, carbonic anhydrase. \200\223) reabsorption and proton (H+) secretion. PT, especially in Sj gren \200\231s syndrome in which up to 40% of patients may be affected. Epidemiology This is unknown because of the different causes of dRTA: \200 Inherited dRTA due to AE1 mutations is rare in Europe, but more common in South-East Asia, where it is endemic in parts of Thailand and Papua New Guinea. vH+-ATPase mutations are rar e and most cases have been reported from Middle Eastern countries or isolated communities w here consanguinity is frequent. Acquired dRTA is more common and is probably underdiagnosed in patients with autoimmune disease, Clinical features The natural history of dRTA can vary from asymptomatic to symptoms and si gns of renal stone disease and nephrocalci- nosis, rickets and growth retardation in childr en, osteomala- cia and weakness in adults, and even (rarely) renal failure. Its main clinic al features are: \200 \200 variable metabolic acidosis with a normal anion gap; renal calculi (typically almost pure c alcium phosphate) due to hypocitraturia, hypercalciuria and alkaline urine; nephrocalcinosi s due to deposition of calcium salts in 4.0 Normal 5.0 pRTA 6.0 H p e n i r U 7.0 dRTA 8.0 5.0 10.0 15.0 25.0 20.0 Plasma or serum bicarbonate concentration (mmol/L) Fig. 5.3.2 Approximate relationship between urine pH and plasma or serum bicarbonate concen tration in response to an acid load (acidosis) in normal subjects and in patients with prox imal (pRTA) and distal (dRTA) RTA. Note that in pRTA the essentially normal curve is displa ced to the left, whereas in dRTA the curve is \202 attened. S. WALSH AND R. UNWIN 210 the renal medulla, which also leads to a urinary concen- trating defect and nocturia; bone demineralization due to bone buffering in chronic acidosis and urinary calcium losses causi ng rickets in chil- dren and osteopenia in adults; hypokalemia due to (incompletely explain ed) urinary losses causing muscle weakness and sometimes paralysis. Table 5.3.1 Indirect measures of urinary ammonium in RTA and the use of urine pCO2 Urine anion gap or net charge Normally negative ([Na] + [K] < [Cl]), because of unmeasured NH4 is low. + ( 80 mmol/L) and so it is positive when urinary ammonium Urine osmolal gap + with an anion other than Cl \200\223 will increase the Excretion of NH4 difference between the measured and the calculated (2[Na+] + [K+] + glucose + urea) urine osmolalities. \210 [NH4 (above) will be positive. Diagnosis Distal RTA needs to be distinguished from proximal RTA and other causes of a norm al anion gap metabolic acidosis from losses of bicarbonate (e.g. gastrointestinal). The res ponse to an acid load will identify dRTA and can distinguish it from proximal RTA (see Figu re 5.3.2). An underlying diagnosis of dRTA should always be considered in patients with rec urrent renal stone disease, particularly if nephrocalcinosis is present, and in patients wi th autoimmune disease, especially if there is hypokalemia. +] = urine osmolal gap/2; however, the urine net charge Urine pCO2 H+ secretion along the collecting duct generates CO2 in urine, because unlike in the proximal tubule there is no carbonic anhydrase in the apical membrane to hydrate it; t herefore, when the urine is alkaline and rich in bicarbonate the CO2 is high (>70 mmHg) and the difference from blood is >30 mmHg. Investigations \200 The acidosis is usually compensated and arterial blood pH normal, but plasma or serum bicar bonate concentra- tion is reduced and the anion gap is normal. Plasma bicarbonate concentra tion is often much lower in dRTA than in pRTA, but is usually <20 mmol/L and the urine pH > 5.5. However, many patients with dRTA have what is known as \200\230incomplete dRTA \200 \231, in which the plasma bicarbonate concentration is normal. Hypokalemia is common, but n ot invariable. A plain abdominal X-ray (AXR) often shows (medullary) nephrocalcinosis, whic h may also be detected on ultrasound scan. Urinary pH is >5.5 (in the absence of a urinary tract infection). Urinary potassium losses are increased. Urinary citrate excretion (and ci trate:creatinine ratio) is low. Urinary ammonium excretion is low (urine anion gap or net c harge is positive (it is normally negative) = [Na+] + [K+] \200\223 [Cl \200\223]) (see Ta ble 5.3.1). Urine osmolality may be reduced (due to a concentrat- ing defect). Treatment and management Those with renal stone disease are advised to maintain a high \202 uid intake (3 L per day), as well as to comply with their alkali-based replacement the rapy: \200 Correction of acidosis with oral alkali (1 \200\2232 mmol/kg) is given to achieve a plasma bicarbonate concen tr- ation >20 mmol/l. It is given to protect the bones and to promote ur inary citrate excretion. A drawback is that by further alkalinizing the urine (without a co mmensurate increase in citrate excretion), calcium phosphate stone precipitation can be exa cerbated. Correction of hypokalemia is important for any symp- toms of weakness, but also b ecause it increases urinary citrate excretion. Thus, alkali therapy is often given as a com bination of potassium and sodium bicarbonate (cit- rate salts can be given, but they are co nverted in the liver to bicarbonate). \200 \200 Long-term follow up consists of ensuring the adequacy of replacement therapy and monitoring patients with evidence of nephrocalcinosis and renal stone disease for disease progression . Special investigations In patients with \200\230incomplete \200\231 dRTA the diagnosis can be more dif \201 cult because there is no metabolic acidosis. An acidosis can be provoked by giving oral ammonium chloride (100 mg/kg) and monitoring the urine pH over the subseque nt 8 h. In dRTA the urine pH should not fall to <5.3 (see Fig. 5.3.3). An alternative is to use oral furosemide (40 mg) plus \202 udrocortisone (1 mg) and to monitor the urine pH o ver 4 h; again, failure to generate a urine pH <5.3 suggests dRTA. Renal biopsy Renal biopsy is not required or usually justi \201 ed to make a diagnosis of dRTA. Findings differ depending on the etiol- ogy of dRTA: widespread tubular damage with c alcium deposition and scarring, tubulo-interstitial cellular in \201 ltra- tion, loss of ICs, and reduced immunostaining for AE1 and vH+-ATPase may be observed. Fig. 5.3.3 Ammonium chloride urinary acidi \201 cation test: typical changes in urine pH o ver time following an oral ammonium chloride load in a normal subject and in a patient with dRTA. Note the \202 attened response in dRTA (cf. Fig. 5.3.2). CHAPTER 5.3 Renal tubular acidosis 211 Proximal RTA (pRTA) De \201 nition Proximal RTA is due to a failure of the proximal tubule to reabsorb \201 ltered bicarbonate, which results in urinary bicarbonate wasting and (i nitially) an alkaline urine. Proximal RTA is usually, though not always, part of a renal Fa nconi syndrome with generalized proximal tubular dysfunction. 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)