History and exam

Key diagnostic factors

common

presence of risk factors

Key risk factors include: childhood, urinary tract obstruction, diabetes mellitus, primary biliary cirrhosis, nephrocalcinosis, nephrolithiasis, and certain medications/toxins.

growth retardation

Children with inherited RTA (proximal or distal) commonly show growth retardation. This improves with treatment of the acidosis. A review of 30 children in the Netherlands and three centers in Belgium found that a decreasing weight standard deviation score in children aged younger than 3 years was an adequate indication for blood gas evaluation, but blood gas evaluation was not justified in patients older than 3 years with weight change in the absence of other symptoms or signs.[134]

muscular weakness

May be observed in children with Fanconi syndrome resulting from heritable metabolic disorders and also in acquired disease. One proposed mechanism is carnitine deficiency caused by carnitine loss in the urine. Phosphate depletion and hypokalaemia may also contribute. Adults with distal RTA may present with hypokalaemic paralysis, especially patients with primary Sjogren's syndrome.[12]

uncommon

failure to thrive (children)

May prompt investigation for RTA. May also be associated with growth retardation and bone disease, especially if Fanconi syndrome is present.

hypoglycaemia after fructose ingestion

Characteristic of fructose intolerance.

rickets

Children with Fanconi syndrome and proximal RTA have persistent renal phosphate loss that is resistant to vitamin D. Genu valgum is the most obvious finding in this complication.

ethnicity/national origin

In Fanconi syndrome attributable to Balkan nephropathy, there is a history of long residence in the Balkan area.[135]

In addition, some of the heritable metabolic conditions associated with Fanconi syndrome are known to occur with high frequency in specific populations.

Patients with southeast Asian ancestry and a history of ovalocytosis may also have distal RTA.[111][112][113]

nephrolithiasis

Patients may have a history of renal calculi.

Other diagnostic factors

uncommon

sensorineural hearing loss

Distal RTA with sensorineural hearing loss can be inherited as an autosomal recessive or autosomal dominant condition. Sensorineural hearing loss occurs at similar frequency in both ATP6V1B1 and ATP6V0A4 mutations; occasionally, patients with sensorineural hearing loss may be found to have the SLC4A1 mutation. An enlarged vestibular aqueduct may be present in severe cases.[15][27][36][37]

liver dysfunction

Liver dysfunction is seen in untreated fructose intolerance, Wilson's disease, galactosaemia, and tyrosinaemia.

osteopenia, osteopetrosis, nephrocalcinosis, and cerebral calcifications

In the presence of hyperkalaemic metabolic acidosis, these conditions suggest carbonic anhydrase II deficiency.[4][60][61][62][33][34]

nephrocalcinosis

Patients with this disorder may have acidification defects and distal RTA. All forms of inherited distal RTA are at high risk of nephrocalcinosis. The acidosis may be incomplete and only revealed during acid-loading tests.[60][61][62]

Kussmaul's breathing

In patients with severe acidosis, there may be hyperventilation due to respiratory compensation.

ocular abnormalities (cataracts, glaucoma, band keratopathy), growth retardation, impaired intellect, calcification of basal ganglia

Autosomal recessive proximal RTA can present with ocular abnormalities.[4][33][34]

Risk factors

strong

childhood

Inherited (primary) forms of RTA have onset in infancy or childhood. In a study of 89 patients with diagnosis of distal RTA, the mean age of onset was reported to be 65.2 months in the group of 64 patients with causative mutations. Onset was earlier in patients with proton pump defects (ATP6V1B1 or ATP6V0A4 genes), who were 13.9 months and 28.6 months old at diagnosis, respectively, than in those with mutations of the AE1 chloride bicarbonate exchanger (SLC4A1 gene), who were 153.2 months old on average.[27] A second study of 340 patients reported a median age of presentation of 6 months across the spectrum of primary classic distal RTA.[53]

urinary tract obstruction

Hyperkalaemic distal RTA (type IV) is a well-described complication of urinary tract obstruction.[4][54][55]

Studies in animal models have shown that urinary tract obstruction depresses collecting-duct sodium transport and lumen negative potential.[56]

Obstruction also reduces the activity of the H+-ATPase.[57] The impaired H+-ATPase directly limits acid excretion. These defects are aldosterone-independent.[55]

The loss of the normal lumen negative potential in the distal nephron reduces potassium excretion and causes hyperkalaemia. Hyperkalaemia inhibits ammoniagenesis, further reducing urinary acid excretion.[51]

Hyperkalaemic distal RTA due to urinary tract obstruction is aldosterone resistant.

diabetes mellitus

Patients with diabetes are prone to develop hyporeninaemic hypoaldosteronism later in life.[4][58][59]

Aldosterone secretion is usually adequate to prevent severe salt wasting and hyponatraemia, but hyperkalaemia and hyperchloraemic metabolic acidosis are seen. Occasionally the serum renin concentration may be normal.

primary biliary cirrhosis

Hyperchloraemic acidosis has been reported, potentially due to the effect of deposition of copper in the kidneys of these patients.[31] Subclinical RTA is the rule. It has been suggested that up to 40% of patients with primary biliary cirrhosis have abnormal urinary acidification when tested.

nephrocalcinosis

Patients with classic distal RTA and patients with incomplete distal RTA develop nephrocalcinosis due to increased urinary loading by calcium released from the bone as acidosis is buffered by bone reabsorption.[60][61][62] In a cohort of 63 patients with primary distal RTA, with proven mutations of either the AE1 or the H+-ATPase, 59 demonstrated nephrocalcinosis clinically.

nephrolithiasis

Either classic distal RTA (type I) or incomplete distal RTA may underlie renal stone disease.[4][63][64][65] Nephrolithiasis may be more common in patients with primary classic distal RTA due to the SLC4A1 mutation.[53]

Calcium phosphate stones are typical. Stones develop because of increased calcium excretion and concurrent hypocitruria (low levels of citric acid in the urine). Metabolic acidosis increases the activity of a dicarboxylic acid transporter in the proximal tubule, and more citrate is reabsorbed at this site and does not reach the final urine.[28]

The renal calcium and phosphate loads are increased due to the release of calcium and phosphorus as part of bone buffering. Urinary citrate normally binds calcium and helps to prevent stones from forming. The absence of citrate increases calcium stone risk.

amphotericin-B therapy

Patients given amphotericin-B can develop proton backleak, potassium wasting, and distal RTA as an effect of the drug.[4][7][66][67]

toxic exposure to heavy metals, and cis-platinum

Proximal RTA and Fanconi syndrome are associated with exposure to heavy metals in the environment and platinum-containing drugs, such as cis-platinum.[4][7][68][69][70][71][72]

untreated primary adrenal insufficiency

Patients with primary adrenal insufficiency develop hyperkalaemic distal RTA in the absence of appropriate hormonal replacement.[19]

family history of inherited RTA

Although primary classic distal RTA is caused by both autosomal dominant mutations (SLC4A1) and autosomal recessive mutations (ATP6V1B1 and ATP6V0A4), a study of 64 genetically defined cases reported that most cases of distal RTA appear clinically to be sporadic although genetically transmitted.[27] In addition, patients with SLC4A1 mutations may also demonstrate autosomal recessive inheritance.[28] Family history of distal RTA is thus a risk for the disease, but the absence of family history does not exclude the diagnosis. Patients who meet the clinical criteria of the diagnosis of classic distal RTA should undergo genetic testing even in the absence of positive family history. Those with family history that demonstrates autosomal dominant inheritance should be first tested for the SLC4A1 gene.[27]

A family history of primary classic distal RTA and the presence of sensorineural hearing loss does not clearly define the gene affected. The reported prevalence of sensorineural hearing loss in patients with the ATP6V1B1 mutation is extremely high (88% to 92%), but a prevalence of 56.7% has been reported in well-defined cases with the ATP6V0A4 mutation.[27][53] Sensorineural hearing loss has also been seen in patients with distal RTA due to mutation of the SLC4A1 gene, albeit rarely.[27] Thus, the presence of sensorineural hearing loss suggests a mutation of either the ATP6V1B1 or the ATP6V0A4 gene, and testing for both should be done.

hereditary fructose intolerance

A known relationship between aldolase (abnormal in hereditary fructose intolerance) and the V-type H+-ATPase of plasma vesicles may be at the heart of Fanconi syndrome. If the mutated aldolase binds to the H+-ATPase and inhibits it, recycling of membrane transporters may be affected.[73] Patients with this disorder who ingest fructose can subsequently develop proximal RTA with Fanconi syndrome plus elements of distal RTA.[41][4][74]

Glycosuria, fructosuria, aminoaciduria, and metabolic acidosis (due to both lactic acidosis and to bicarbonaturia) are seen after fructose ingestion.

Wilson's disease

Because the defective protein in Wilson's disease is involved in the uptake of copper at the cell membrane, and accumulation of copper in lysozomes is seen in advanced, symptomatic cases, it is speculated that Fanconi syndrome seen in this setting is related to these membrane events. Mitochondrial injury has been described in hepatic disease, and inhibition of mitochondrial metabolism could also provide a pathophysiological explanation.[75][76][77]

galactosaemia

Although any of three different enzymes may be deficient and individual mutations abound, clinical presentations share some similarities, including the development of elements of Fanconi syndrome (bicarbonate wasting, aminoaciduria, glycosuria, albuminuria), which indicate a broad proximal tubule dysfunction.[78] The pathophysiology may involve the effect of impaired cellular energy metabolism on proximal reabsorption.

disorders of mitochondrial metabolism

Many disorders of mitochondrial energy metabolism have been described and all are rare. Inheritance can either be mendelian or mitochondrial. Lactic acidosis is often seen, owing to reliance on anaerobic metabolism. Fanconi syndrome has been clinically observed in a number of these disorders. The pathophysiological basis of the Fanconi syndrome in this setting is most easily ascribed to the impairment of cellular energy metabolism resulting in a failure to maintain an appropriate sodium gradient to drive sodium-linked transport mechanisms at the cell membrane.[23]

glycogen storage diseases

Type 1 glycogenosis (von Gierke's disease) is associated with Fanconi syndrome. The affected pathway in this disorder is the glucose-6-phosphate transporter. Glucose uptake, gluconeogenesis, and glycogenolysis are limited, as is dephosphorylation of glucose. Classically it has been held that glucose-6-phosphate accumulates, trapping phosphate, and glycolysis subsequently increases, with resultant lactic acidosis and depletion of ATP, owing to the impairment of aerobic metabolism.[23][79]

tyrosinaemia

Succinylacetone inhibits glucose and amino acid transport in the proximal tubule. Its accumulation in tyronsinaemia may be responsible for Fanconi syndrome in this disorder.[80][81]

Lowe syndrome

The link between the lipid phosphatase that is mutated in Lowe syndrome and the development of Fanconi syndrome has not been precisely elucidated. Proximal tubule dysfunction is broad, but may not involve glycosuria. Proteinuria is prominent. Urinary megalin is absent, and this clinical finding supports the argument that the Lowe syndrome protein (OCRL1) may be necessary for membrane recycling.[46][47]

lead exposure

Fanconi syndrome may be the first symptom of chronic lead poisoning and is seen in acute lead toxicity in children. Saturnine gout, another consequence of abnormal proximal tubule function, has long been associated with lead exposure. However, the precise pathophysiology of the transport defects is not certain. Lead has been shown in experimental animals to inhibit oxidative phosphorylation, leading to the proposition that the cause of disordered proximal tubule transport is depletion of cellular ATP.[71][74][82]

cadmium exposure

Accumulation of cadmium metallothionine complexes in the lysozymes of proximal tubule cells has been associated with the development of cadmium toxicity. A subsequent failure of membrane vesicle recycling has been postulated as the cause of Fanconi syndrome.[83][84]

ifosfamide therapy

Ifosfamide therapy has been noted to produce a Fanconi-like picture in approximately 4% of children, but most patients exposed can be shown to have some degree of reversible tubular dysfunction.[85] The toxicity is demonstrable in response to chloroacetaldehyde, a hepatic metabolite of this drug. Ifosfamide can lead to both proximal and distal RTA.[86]

cystinosis

The pathophysiology of Fanconi syndrome in cystinosis is poorly understood. The disorder is inherited in an autosomal-recessive fashion but has three distinct presentations. Proximal tubule cell injury follows the accumulation of cysteine in lysosomes. Fanconi syndrome develops early in life in the infantile form and is associated with volume depletion.[87] Loss of phosphate is clinically associated with renal rickets and significant growth retardation. Loss of carnitine may be responsible for muscular weakness.

antiviral therapy (cidofovir, adefovir, or tenofovir)

Fanconi syndrome has been described in patients treated with these antiviral medications.[118][119][120]

weak

older men

Partial urinary tract obstruction is a common finding in older men due to prostatic enlargement. The resultant increase in intraluminal pressure injures the collecting ducts and is associated with aldosterone-resistant hyperkalaemic distal RTA (type IV).[54]

cyclosporine therapy

Cyclosporine nephrotoxicity is associated with depression of renin, resulting in relative hyporeninaemic hypoaldosteronism and hyperkalaemic distal RTA. Cyclosporine itself may inhibit the basolateral Na, K-ATPase and interfere with distal nephron function.[88]

angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blocking drugs

Both these classes of drugs interfere with the interaction between angiotensin and aldosterone, and both are associated with hyperkalaemia as a result.[50]

Overt cases of RTA due to these drugs seem to be rare, and systemic evaluation for occult RTA is not usually performed.

However, the action of the drugs to cause hyperkalaemia suggests that cases should occur, and many texts list the drugs as a cause of RTA.[4]

heparin therapy

May induce a defect in aldosterone production, leading to hyperkalaemia and acidosis.[89]

medications interfering with sodium transport

Distal RTA has been noted in patients receiving drugs interfering with sodium transport in the distal nephron, including lithium, amiloride, spironolactone, triamterene, trimethoprim, cyclooxygenase inhibitors, and pentamidine.[4][90][50][91][92][93][94][95][96]

use of carbonic anhydrase inhibitors

These drugs induce reversible proximal RTA as a direct consequence of their mechanism of action.[97] Distal acidification may also be inhibited, resulting in both proximal tubule bicarbonate leak and impaired urinary acidification.[49]

abnormalities of filtered immunoglobulins

Conditions include cryoglobulinaemia, multiple myeloma, light chain nephropathy, amyloidosis, monoclonal gammopathy of unknown significance, monoclonal gammopathy of renal significance, and hypergammaglobulinaemia.

The literature includes cases of proximal RTA in patients with multiple myeloma with excess light chain production.[98][99] Fanconi syndrome may be seen.

interstitial nephritis

Multiple case reports and occasional small series associate a number of renal and systemic diseases characterised by interstitial nephritis with proximal and distal RTA.[4] These reports include cases of Wilson's disease and chronic active hepatitis, systemic lupus erythematosus, thyroiditis and Graves' disease, and renal allograft rejection.[100][101][102][103][104][105]

The pathophysiology in some instances is suggested by findings in a reported case of Sjogren's syndrome in which the absence of H+-ATPase in the distal nephron was demonstrated by immunofluorescent stain on renal biopsy material.[106][107]

RTA is a rare complication in most of the conditions listed above. Primary Sjogren's syndrome may represent a unique situation. A case series from India described 27 patients with Sjogren's syndrome, 22 of whom had marked hypokalaemia and 18 had hypokalaemic paralysis. Metabolic acidosis with an average bicarbonate of 15 mmol/L (15 mEq/L), and a mean potassium of 2.5 mmol/L (2.5 mEq/L) were reported. Five patients had interstitial nephritis on biopsy.[108]

hyperparathyroidism

Associated with proximal RTA and partial Fanconi syndrome. Parathyroid hormone depresses phosphate reabsorption and generally depresses proximal tubule reabsorption, including the reabsorption of bicarbonate.

environmental exposure to aristolochic acid

Aristolochic acid is a phytotoxin that is thought to cause distal RTA when ingested by individuals who are genetically susceptible. It has been implicated in Balkan endemic nephropathy.[109][110]

Thai or southeast Asian ancestry

Hereditary distal RTA with ovalocytosis and haemolytic anaemia has been reported in patients from this background.[111][112][113] SLC4A1 mutations can cause distal RTA and have been associated with hereditary spherocytosis, and southeast Asian ovalocytosis, as well as other red blood cell abnormalities, but red blood cell abnormalities and distal RTA do not co-exist in most patients. The combination of distal RTA and red blood cell changes appears to occur primarily in autosomal recessive distal RTA and is generally not seen in autosomal dominant disease. Autosomal recessive distal RTA due to SLC4A1 mutation is said to be more common in patients of southeast Asian ancestry, whereas autosomal dominant SCL4A1 mutations are more common in white people.[28]

cis-platinum therapy

Platinum, a heavy metal, causes generalised cellular toxicity. Cis-platinum is a clathrate designed to deliver the metal intracellularly. Multiple renal toxic effects are known.[23]

toluene, paraquat, lysol exposure

No precise pathophysiology has been suggested beyond nephrotoxicity.[80][114][115]

Dent's disease

Dent's disease may be caused by a mutation of the renal chloride channel CLC-5. The channel associates with the V-type H+-ATPase in acidifying intracellular vesicles of the type associated with protein and peptide reabsorption. Abnormalities of substrate reabsorption may be due to diminished recycling of apical transporters.[45]

ibuprofen overdose

Several case reports suggest that chronic ibuprofen use and acute ibuprofen overdose, in most instances in combination with hydrocodone, may present with mixed metabolic acidosis (high anion gap but inappropriately high urine pH) thus suggestive of RTA. The mechanism is unknown but it is suspected that ibuprofen may inhibit carbonic anhydrase in vivo.[25][116]

lamivudine

Reversible Fanconi syndrome has been reported in patients treated for hepatitis B and HIV with lamivudine-containing regimens. It is hypothesised that mitochondrial injury was responsible.[117]

programmed cell death protein 1 (PD-1)-inhibitors

Immune checkpoint inhibitors can cause acute interstitial nephritis. Several cases of distal RTA in the setting of PD-1 inhibitor use have been reported, with speculation that distal RTA is an indirect early sign for the development of acute interstitial nephritis.[121]

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