Fanconi syndrome

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

The proximal tubule normally retrieves nearly all filtered glucose and amino acids, most bicarbonate, phosphate and urate, and low-molecular-weight proteins through receptor-mediated endocytosis. A broad energy, transport or endosomal defect therefore creates a recognisable constellation of urinary wasting. Filtered bicarbonate loss produces type 2 renal tubular acidosis, while phosphaturia and insufficient active vitamin-D effect impair skeletal mineralisation. The urine may contain substantial non-albumin protein despite only modest albumin excretion.

The differential changes with age and context. In a child with growth failure, polyuria, rickets, photophobia or developmental features, inherited metabolic or tubular disease is prominent and paediatric nephrology and metabolic genetics should lead investigation. In an adult, newly acquired wasting prompts a meticulous drug, cancer and toxin history and a search for monoclonal protein. Small plasma-cell clones can be clinically important when a nephrotoxic light chain injures the proximal tubule, even without conventional myeloma burden.

Biochemical replacement treats consequences but is not a substitute for aetiological treatment. Tenofovir disoproxil toxicity may require an antiviral change, yet uncontrolled HIV or hepatitis B and rebound hepatitis are serious risks, so changes belong with the infection or liver team. A monoclonal lesion may need clone-directed haematology treatment based on tissue and multidisciplinary assessment. In inherited disease, diagnosis informs disease-specific therapy, surveillance, family testing and transition care.

Key points

Fanconi syndrome is a generalised proximal-tubule reabsorptive defect, not Fanconi anaemia, and produces urinary loss of several filtered solutes rather than one isolated abnormality.
Core clues include phosphate wasting, normoglycaemic glycosuria, aminoaciduria, bicarbonate loss causing proximal RTA, urate loss, potassium loss and low-molecular-weight proteinuria.
A normal creatinine does not exclude substantial proximal dysfunction because tubular transport can fail before glomerular filtration falls.
Acquired causes include monoclonal light-chain proximal tubulopathy, tenofovir disoproxil, ifosfamide, cisplatin, outdated tetracycline exposure and heavy metals; the precise medicine and host risk matter.
Inherited causes present more often in childhood but can reach adult services; cystinosis, Dent and Lowe syndromes, hereditary fructose intolerance, tyrosinaemia and mitochondrial disorders have distinctive extrarenal features.
Renal phosphate wasting causes defective mineralisation, bone pain, proximal weakness, insufficiency fractures or rickets, sometimes before the kidney diagnosis is recognised.
Pair serum and urine samples to establish inappropriate urinary loss; urine glucose in the presence of normal blood glucose is a particularly useful bedside clue.
Management requires removal or treatment of the cause plus individual replacement of water, bicarbonate, potassium and phosphate; oversupplementation can cause diarrhoea, hyperkalaemia or nephrocalcinosis.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Medicine and toxin injury

Tenofovir disoproxil, ifosfamide, cisplatin, outdated tetracycline and heavy metals can damage proximal tubular transport, with risk shaped by exposure and host renal reserve.

Monoclonal light-chain disease

Filtered monoclonal light chains can accumulate within proximal tubular cells and disrupt multiple transport systems, sometimes revealing an otherwise small plasma-cell clone.

Inherited proximal tubulopathies

Cystinosis, Dent and Lowe syndromes, hereditary fructose intolerance, tyrosinaemia and mitochondrial disorders produce generalised solute wasting, often with distinctive extrarenal features.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Proximal transport failure
Injured proximal tubular cells cannot reclaim the normal filtered load of bicarbonate, phosphate, glucose, urate, amino acids and low-molecular-weight proteins.
2
Broad urinary solute wasting
Simultaneous loss of phosphate, glucose, urate, bicarbonate, potassium and amino acids produces the characteristic multi-solute biochemical pattern.
3
Proximal acidosis
Urinary bicarbonate loss lowers plasma bicarbonate until the reduced reabsorptive threshold is reached, producing a normal-anion-gap metabolic acidosis.
4
Defective mineralisation
Chronic phosphate wasting and insufficient active-vitamin-D effect impair skeletal mineralisation, causing osteomalacia, bone pain, weakness and fractures in adults.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Normoglycaemic glycosuria

Urinary glucose despite a normal simultaneous plasma glucose suggests proximal reabsorptive failure, provided pregnancy and an SGLT2 inhibitor are considered.

Phosphate depletionRed flag

Bone pain, waddling gait, proximal weakness and insufficiency fractures with low phosphate may represent renal-wasting osteomalacia rather than osteoporosis alone.

Tubular protein pattern

PCR can exceed ACR because retinol-binding protein, beta-2 microglobulin and other low-molecular-weight proteins escape proximal uptake.

Drug-associated syndromeRed flag

Rising creatinine, hypophosphataemia and glycosuria during tenofovir disoproxil or ifosfamide exposure should trigger targeted renal safety review.

Inherited phenotype

Growth failure, rickets, ocular findings, stones, deafness, neurodevelopmental features or consanguinity point towards a syndromic diagnosis requiring genetics expertise.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Paired serum and urine chemistryFirst step
Why
Demonstrate inappropriate renal loss of phosphate, glucose, urate, bicarbonate and potassium.
Interpretation and limitations
Interpret urine concentrations against simultaneous serum values and kidney function; fractional excretion or TmP/GFR calculations should use correctly timed samples.
02
Blood gas and electrolytes
Why
Identify proximal RTA and grade potassium, bicarbonate, phosphate and magnesium deficits.
Interpretation and limitations
A hyperchloraemic normal-gap acidosis supports bicarbonate loss, but diarrhoea and reduced GFR must be excluded and mixed disorders can coexist.
03
Urine ACR, PCR and tubular proteins
Why
Differentiate albumin-predominant glomerular loss from low-molecular-weight tubular proteinuria.
Interpretation and limitations
A PCR disproportionately high relative to ACR supports tubular proteins; specialist assays such as retinol-binding protein can confirm proximal dysfunction.
04
Bone and mineral assessment
Why
Assess osteomalacia risk and complications of chronic phosphate depletion.
Interpretation and limitations
Measure calcium, phosphate, alkaline phosphatase, parathyroid hormone and vitamin D; targeted radiographs or bone imaging follow symptoms and specialist advice.
05
Monoclonal screen
Why
Find a plasma-cell or B-cell source of nephrotoxic light chains in acquired adult disease.
Interpretation and limitations
Serum immunofixation, urine immunofixation and serum free-light-chain results require renal-range interpretation; kidney or marrow tissue may define clinical significance.
06
Genetic and metabolic testing
Why
Diagnose inherited proximal tubulopathy when onset, family history or extrarenal features suggest it.
Interpretation and limitations
Testing is phenotype-led through specialist genetics; a variant of uncertain significance does not establish causality without segregation and clinical correlation.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Diabetes or SGLT2-associated glycosuria

Hyperglycaemia or SGLT2 inhibition explains isolated urine glucose, whereas normoglycaemic glycosuria accompanied by phosphate, bicarbonate and low-molecular-weight protein loss supports Fanconi syndrome.

Isolated proximal renal tubular acidosis

Bicarbonate wasting without glycosuria, phosphaturia, aminoaciduria or urate loss suggests a selective acid-base defect rather than generalised proximal dysfunction.

Distal renal tubular acidosis

Persistently alkaline urine during systemic acidosis, nephrocalcinosis and hypocitraturia favour distal hydrogen-secretory failure rather than generalised proximal multi-solute wasting.

Primary phosphate-wasting disorder

Isolated renal phosphate loss with an endocrine, tumour-related or genetic pattern lacks the accompanying bicarbonate, glucose and amino-acid losses expected in Fanconi syndrome.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01DetectConfirm multi-solute wastingFirst stepHypophosphataemia, glycosuria or tubular proteinuria suggests proximal dysfunction.

1Repeat serum phosphate, bicarbonate, potassium, glucose, urate, magnesium and creatinine while collecting appropriately timed urine chemistry.
2Demonstrate at least a coherent pattern of inappropriate urinary losses rather than diagnosing Fanconi syndrome from isolated glycosuria.
3Assess symptoms and ECG where needed, admitting for severe phosphate or potassium depletion, dehydration, rhabdomyolysis or neurological compromise.

02ExplainFind the proximal insultGeneralised proximal tubulopathy has been established.

1Review tenofovir formulation, chemotherapy, antimicrobials, supplements, toxins and occupational exposure, including timing against the biochemical change.
2In adults, investigate monoclonal gammopathy and malignancy context; in younger or syndromic presentations, involve metabolic and genomic services early.
3Use biopsy only when nephrology judges that tissue can distinguish a treatable light-chain, interstitial or other lesion and procedural risk is acceptable.

03ReplaceRestore solutes safelyOngoing urinary loss causes acidosis, weakness or skeletal disease.

1Correct severe potassium, phosphate or volume deficits in hospital when necessary, following local infusion limits and cardiac monitoring.
2For chronic disease, prescribe divided oral phosphate, alkali and potassium individually through renal or metabolic teams, with dietetic support.
3Recheck blood and urine indices after every change because correcting acidosis can alter potassium and calcium-phosphate balance.

04CoordinateTreat the cause without destabilising careA medicine, monoclonal clone or inherited disorder is identified.

1For suspected tenofovir or chemotherapy toxicity, contact the responsible infection, hepatology or oncology team promptly and agree substitution or interruption.
2Refer monoclonal proximal tubulopathy to the renal-haematology pathway for biopsy review and clone-directed decisions even when the clone appears numerically small.
3Provide inherited-disease surveillance, disease-specific treatment where available, family counselling and planned paediatric-to-adult transition rather than supplementation alone.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Replaces ongoing renal phosphate loss and supports healing of hypophosphataemic osteomalacia alongside cause-specific treatment.

Oral phosphate salts

Start only with renal or metabolic specialist advice, using divided local-formulary doses titrated to symptoms, serum phosphate and urinary calcium rather than normalising one result rapidly.

Can cause diarrhoea, secondary hyperparathyroidism, hyperphosphataemia and nephrocalcinosis. Dose requirements change as tubular function and GFR change.

May support mineralisation in selected chronic phosphate-wasting disorders when active vitamin-D therapy is judged necessary.

Alfacalcidol or calcitriol

Use only for a defined specialist indication with an agreed low starting dose and frequent calcium, phosphate and urine-calcium surveillance.

Hypercalcaemia, hypercalciuria, stones and nephrocalcinosis can result; native vitamin-D deficiency should be assessed separately and pregnancy requires specialist review.

Replaces bicarbonate wasted by the proximal tubule and reduces chronic acid buffering by bone and muscle.

Sodium bicarbonate or citrate alkali

Individualise and divide oral dosing through the renal team to control proximal-RTA symptoms and bicarbonate, recognising that urinary loss may demand substantial amounts.

Sodium preparations can worsen hypertension or oedema; alkali can aggravate hypokalaemia, and citrate products containing potassium are unsafe when potassium excretion is impaired.

Corrects proximal potassium wasting and prevents weakness and arrhythmia, particularly during alkali replacement.

Potassium supplementation

Choose oral or intravenous formulation and rate from the local potassium protocol according to severity, ECG, renal function, magnesium and continuing urinary loss.

Intravenous replacement requires concentration and rate safeguards. Recovery of kidney function or addition of potassium-sparing drugs can convert depletion to hyperkalaemia.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Osteomalacia and fractures

Sustained phosphate wasting causes painful defective mineralisation, proximal muscle weakness, insufficiency fractures and impaired mobility in adults.

Electrolyte and acid-base instability

Bicarbonate and potassium losses can cause chronic acidosis, severe weakness and arrhythmia, especially during intercurrent illness or incomplete replacement.

Volume depletion and AKI

Polyuria and urinary solute loss reduce effective circulating volume, increasing susceptibility to hypotension and acute kidney injury.

Progressive renal impairment

Acquired or inherited proximal tubular disease can coexist with reduced filtration, so creatinine and eGFR still require longitudinal assessment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend phosphate, potassium, bicarbonate, magnesium, calcium, creatinine and alkaline phosphatase according to severity and replacement changes.
Repeat paired urine indices when establishing recovery or continuing loss; serum normality on supplements does not prove tubular resolution.
Ask about bone pain, weakness, gait, fractures, polyuria, thirst and adherence or gastrointestinal effects from divided supplements.
For tenofovir disoproxil, follow the current product and specialty renal-monitoring schedule, including creatinine clearance, serum phosphate and targeted urine glucose when abnormalities arise.
Monitor urine calcium and renal imaging when long-term phosphate and active vitamin-D treatment create nephrocalcinosis risk.
Review the underlying clone, inherited disorder or drug plan with the relevant multidisciplinary team rather than treating laboratory losses in isolation.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Creatinine can lag

A proximal transport defect may be clinically severe while eGFR remains near normal, so creatinine-only screening misses early toxicity.

SGLT2 therapy mimics one clue

Expected glycosuria from an SGLT2 inhibitor is not Fanconi syndrome unless other proximal solute losses and clinical evidence coexist.

Small clones can injure

A low-burden plasma-cell clone may still produce a nephrotoxic light chain and meet the renal concept of clinical significance.

Bone disease is osteomalacia

Phosphate-wasting mineralisation failure is pathophysiologically different from low bone mass and requires correction of the tubular disorder.

Replacement reshapes physiology

Alkali can lower potassium and phosphate therapy can alter parathyroid and urinary calcium responses, making serial review essential.

11Common pitfallsFrequent interpretation and management errors.

01
Confusing Fanconi syndrome with Fanconi anaemia, an unrelated inherited marrow-failure disorder.
02
Diagnosing the syndrome from glycosuria alone in diabetes, pregnancy or during SGLT2-inhibitor treatment.
03
Using a normal eGFR to dismiss hypophosphataemia, tubular proteinuria and bone pain.
04
Stopping tenofovir disoproxil abruptly without HIV or hepatitis expertise and risking viral or hepatic harm.
05
Replacing phosphate and active vitamin D without monitoring calcium, parathyroid hormone and urine calcium.
06
Missing a monoclonal light-chain process because the paraprotein or marrow clone appears small.