Every enzyme in the human body functions optimally at a narrow pH range. The body maintains arterial pH at 7.35–7.45 (corresponding to [H⁺] of ~35–45 nmol/L). When pH deviates beyond this range, protein structures denature, enzyme kinetics fail, and cellular functions collapse.

Normal arterial pH: 7.35–7.45; pH 7.40 corresponds to [H⁺] ≈ 40 nmol/L. ^[1]

The slide labels pH < 7.1 or > 7.7 as “lethal.” Treat these as markers of extreme, immediately dangerous physiology, not absolute survival cut-offs: prognosis depends on cause, duration and reversibility.

$pH = 6.1 + \log \frac{[HCO_3^-]}{0.03 \times pCO_2}$

This equation tells us pH is determined by the ratio of HCO₃⁻ (metabolic component, controlled by kidneys) to pCO₂ (respiratory component, controlled by lungs). If HCO₃⁻ drops or pCO₂ rises, pH falls (acidosis). If HCO₃⁻ rises or pCO₂ drops, pH rises (alkalosis) ^[2][3].

Mnemonic: Acidity = Bicarb / Carbon Dioxide (A = B/CD) ^[3].

Acidosis = a process leading to increase in plasma [H⁺]. Alkalosis = a process leading to removal of plasma [H⁺]. Acidaemia = [H⁺] > normal. Alkalaemia = [H⁺] < normal. ^[1]

Physiological compensation moves pH toward normal and does not itself overshoot to the opposite pH disturbance. A normal pH does not prove a single compensated disorder; it may reflect two opposing primary disorders.

Lungs compensate immediately; Kidneys take several days. ^[1]

^[1]

Expected Compensation Formulas (from senior notes, useful for data interpretation) ^[4]:

If compensation is outside expected ranges → mixed acid-base disorder.

Characterized by ↓HCO₃⁻ (Normal: 22–28 mmol/L; < 22 = metabolic acidosis). Compensated with hyperventilation → reduced pCO₂. ^[1]

Steps: (1) Confirm it is metabolic acidosis. (2) Determine the Anion Gap. (3) If normal AG → determine urine AG. (4) Look for any osmolar gap. (5) Check for mixed disorders (ΔAG vs ΔHCO₃⁻). ^[1]

(The lecturer explicitly notes steps 3 and 5 are "advanced/too advanced for MBBS" but step 2—the anion gap—is absolutely core.)

Why does it exist? Plasma must be electrically neutral—total cations = total anions. We routinely measure Na⁺, Cl⁻, and HCO₃⁻, but there are unmeasured anions (albumin, phosphate, sulphate, organic acids) that make up the "gap."

AG = Na⁺ − Cl⁻ − HCO₃⁻. Example: 140 − 105 − 25 = 10. Normal AG ≈ 8–14 ^[1]

The reference range is laboratory- and analyser-specific. Because albumin is the dominant unmeasured anion, hypoalbuminaemia can conceal a raised AG. A commonly used estimate is:

$Corrected\ AG \approx Observed\ AG + 2.5 \times (4.0 - albumin\ [g/dL])$

Why the AG matters in metabolic acidosis:

When an acid (HA) is added to blood, it dissociates into H⁺ + A⁻. The H⁺ consumes HCO₃⁻ (buffering), so HCO₃⁻ drops. Meanwhile, A⁻ (the conjugate base anion) accumulates. If A⁻ is a "measured" anion like Cl⁻, Cl⁻ replaces HCO₃⁻ and the AG stays normal. If A⁻ is "unmeasured" (like lactate, ketoacids), the AG rises because HCO₃⁻ drops without a compensatory Cl⁻ rise.

In normal AG acidosis, ↓HCO₃⁻ is compensated by ↑Cl⁻ (hyperchloraemic acidosis). In high AG acidosis, ↓HCO₃⁻ is due to accumulation of unmeasured anions. ^[1]

Causes of ↑AG: ^[1]

• DKA, alcoholic ketoacidosis
• Lactic acidosis
• Ingestion: salicylate, formic acid (methanol), glycolate (ethylene glycol)
• Renal failure: sulphate, phosphate, hippurate
• Rhabdomyolysis: release of organic acids
• Remarks: altered AG in paraproteinaemia (e.g., ↓ in IgG gammopathy; ↑ in IgA gammopathy)

Paraproteinaemia and AG: charge depends on the specific protein and pH, but the common teaching pattern is that cationic IgG paraproteins can lower the AG, whereas some anionic IgA paraproteins can raise it. Do not use AG alone to screen for myeloma.

Characterised by ↑Cl⁻. Causes: ^[1]

• GI loss of HCO₃⁻: diarrhoea
• Renal loss of HCO₃⁻: proximal RTA (type II), carbonic anhydrase inhibitors
• Failure to excrete H⁺: distal RTA (type I), type IV RTA
• Ingestion of excessive Cl⁻: NH₄Cl
• Increased reabsorption of Cl⁻: ureterosigmoidostomy

Why ureterosigmoidostomy? The sigmoid colon actively absorbs Cl⁻ and secretes HCO₃⁻. When urine drains into it, the colon exchanges Cl⁻ for HCO₃⁻ → patient loses HCO₃⁻ and gains Cl⁻ → hyperchloraemic metabolic acidosis.

When concentrations are in mmol/L: calculated osmolality ≈ 2×[Na⁺] + urea + glucose. Osmolal gap = measured − calculated osmolality. ^[1]

This is clinically useful when toxic alcohol ingestion is suspected, but the gap is time-dependent: a normal gap does not exclude late methanol or ethylene glycol poisoning after the parent alcohol has been metabolised to toxic acids. Send specific levels where available and contact toxicology/poisons services without waiting for every result.

Lactate is produced when pyruvate is reduced under anaerobic conditions (glycolysis without oxidative phosphorylation). Normal lactate < 2 mmol/L.

Type A (O₂ deficiency—overproduction): ^[1]

• Circulatory: hypotension
• Respiratory: hypoxia
• Haemoglobin: CO poisoning
• Increased metabolic demand: grand mal seizure, severe exercise

Type B (without overt tissue hypoxia; altered production and/or clearance): ^[1]

• Liver disease
• Alcoholism
• Thiamine deficiency
• Phenformin, metformin

Rate of production up to 72 mmol/min with total hypoxia. Diagnosis: High AG metabolic acidosis + measure plasma lactate (normal < 2 mmol/L). ^[1]

Treatment of Type A L-lactic acidosis: Most effective = improve O₂ delivery to tissue (correct hypotension, hypoxaemia). NaHCO₃ therapy ineffective unless lactate production is controlled—its use may buy time. Na⁺ load limits massive use. Haemodialysis with bicarbonate dialysis is an option. ^[1]

Determine cause and treat the underlying cause. Some causes have independent threat to life (e.g., methanol poisoning). There may be specific treatment (e.g., fomepizole/ethanol for methanol poisoning). Correction of HCO₃⁻ by NaHCO₃. ^[1]

This is a favourite exam topic because it tests understanding of physiology:

1. Induces hypokalaemia — NaHCO₃ raises pH → alkalosis shifts K⁺ into cells. Dangerous if patient already has low K⁺ (e.g., DKA where total body K⁺ is depleted but serum K⁺ appears normal due to acidotic shift out of cells) ^[1].

2. Decreases ionic calcium — raising pH increases the proportion of calcium bound to albumin → ↓free/ionized Ca²⁺. Problematic in CRF patients who already have hypocalcaemia ^[1].

3. Volume expansion from Na⁺ load — 1 mmol HCO₃⁻ carries 1 mmol Na⁺. If 200 mmol NaHCO₃ given, that's 200 mmol Na⁺ = more than 1 litre of normal saline (which has 154 mmol Na⁺) ^[1].

4. Too rapid correction → paradoxical cerebral acidosis ^[1].

When NaHCO₃ is given IV, it reacts with H⁺ to form CO₂ and H₂O in the plasma. CO₂ crosses the blood-brain barrier (BBB) freely, but HCO₃⁻ does NOT cross the BBB easily. In the CSF, CO₂ is converted back to H⁺ + HCO₃⁻ by carbonic anhydrase → CSF pH drops (becomes more acidotic) even as blood pH is being corrected. ^[1]

This is why rapid NaHCO₃ infusion can paradoxically worsen neurological status.

The slide's body-weight “bicarbonate deficit” recipe is historical teaching, not a universal resuscitation protocol. Treat the cause and restore ventilation/perfusion first. Current sepsis guidance suggests against bicarbonate solely to improve haemodynamics in hypoperfusion-induced lactic acidaemia, but suggests it may be considered in septic shock with pH ≤7.2 plus moderate-to-severe AKI ^[9]. Other selected indications require cause-specific critical care, renal or toxicology input.

The visual mechanism explains an important safety condition: administered HCO₃⁻ buffers H⁺ to form CO₂; CO₂ crosses the BBB faster than HCO₃⁻ and can regenerate H⁺ in CSF. If bicarbonate is used, adequate ventilation plus serial blood gases, Na⁺, K⁺ and ionised Ca²⁺ are essential; dose and endpoint should follow the local specialist protocol rather than an estimated full deficit.

Mechanism from first principles: The proximal convoluted tubule (PCT) normally reabsorbs ~85% of filtered HCO₃⁻. It does this via the Na⁺/H⁺ exchanger on the apical membrane: H⁺ is secreted into the lumen → combines with HCO₃⁻ → forms CO₂ + H₂O (via carbonic anhydrase IV on the brush border) → CO₂ diffuses into the cell → reformed into HCO₃⁻ + H⁺ (via intracellular carbonic anhydrase II) → HCO₃⁻ exits basolaterally.

In proximal RTA, the reabsorption threshold for HCO₃⁻ is lowered (normally ~25 mmol/L). So when plasma HCO₃⁻ is above this lowered threshold, massive HCO₃⁻ is lost in the urine. Once plasma HCO₃⁻ falls to the new (lower) threshold, reabsorption "catches up" and a new steady state is reached at a lower plasma HCO₃⁻.

Characterised by ↓HCO₃⁻ reabsorption threshold → bicarbonaturia while plasma HCO₃⁻ is above that threshold → normal AG metabolic acidosis with compensatory hyperchloraemia. ^[1]

Urine is alkaline during active bicarbonate wasting or bicarbonate loading. Once plasma HCO₃⁻ has fallen below the new threshold, an intact distal nephron can still acidify urine to pH < 5.5—so a single low urine pH does not exclude proximal RTA.

Loss of Na⁺ coupling with loss of HCO₃⁻ → hypovolaemia → secondary hyperaldosteronism → hypoK⁺. ^[1]

Associated with hyperphosphaturia, hypercitraturia (which prevents nephrocalcinosis/stones), hyperuricuria. Hyperphosphaturia → rickets, osteomalacia. ^[1]

Fanconi syndrome = generalised proximal tubular dysfunction with bicarbonaturia, phosphaturia, normoglycaemic glycosuria, aminoaciduria and uricosuria. ^[1]

The slide's “hyperphosphataemia” is a label error: renal phosphate wasting more typically produces hypophosphataemia, causing rickets or osteomalacia.

Mechanism from first principles: The α-intercalated cells of the collecting duct secrete H⁺ via the H⁺-ATPase pump on the apical membrane. This creates a steep H⁺ gradient (urine pH can go as low as 4.5). In distal RTA, either the pump is defective or H⁺ leaks back through a permeable membrane.

Due to inability to excrete H⁺: (a) an acidification transporter defect, or (b) H⁺ back-leak. During systemic metabolic acidosis, urine pH is inappropriately high—classically > 5.5. ^[1]

↓H⁺ excretion → ↑K⁺ excretion for exchange of Na⁺ reabsorption in distal tubule → hypoK⁺. ^[1]

Why hypoK⁺ in distal RTA? Normally, both H⁺ and K⁺ can be secreted in exchange for Na⁺ reabsorption at the collecting duct. When H⁺ secretion fails, K⁺ secretion increases to compensate for Na⁺ reabsorption → renal K⁺ wasting → hypoK⁺.

Acidosis → ↑Ca²⁺ resorption from bone AND ↓tubular Ca²⁺ and PO₄ reabsorption → hypercalciuria → nephrocalcinosis/kidney stones. ^[1]

Proximal RTA causes: Hereditary (cystinosis, galactosaemia, Wilson's disease, Lowe's syndrome); Acquired (dysparaproteinaemia, heavy metal poisoning, carbonic anhydrase inhibitors, amyloidosis, renal transplant rejection, Sjögren's). ^[1]

Distal RTA causes: inherited defects in distal acidification transporters; autoimmune tubulointerstitial disease (especially Sjögren disease); amphotericin B; obstruction or chronic tubulointerstitial disease; and selected hereditary/systemic disorders. ^[1]

The slide's older hereditary list (including primary hypercalciuria, Marfan and Ehlers–Danlos syndromes) is not the modern core classification; for exams, anchor inherited distal RTA to defects in the H⁺-ATPase/anion exchanger apparatus and acquired distal RTA to autoimmune or tubulointerstitial disease.

Clinical suspicion: normal AG metabolic acidosis, then use K⁺ and renal acid excretion to subtype it. Types I/II are usually hypokalaemic; type IV is hyperkalaemic. ^[1]

Urine pH > 5.5 during systemic acidosis supports distal RTA, but can be confounded by a urease-positive UTI, low distal Na⁺ delivery or a stale specimen. Where available, urine ammonium is more direct; the urine anion gap is only a surrogate and must be interpreted in context.

Confirmatory tests: ^[1]

• FEHCO₃⁻ (Fractional Excretion of Bicarbonate): Proximal RTA > 15% (sensitivity increases after NaHCO₃ infusion). Distal RTA < 5%.
• NH₄Cl acid loading test: Normal urine pH < 5.5. Distal RTA: urine pH remains > 6.0. Proximal RTA: variable.

The bicarbonate- and ammonium-chloride loading recipes shown in the deck are specialist dynamic tests, not bedside self-contained protocols. They can worsen sodium load or acidaemia and are unnecessary in many patients once the clinical pattern, urine studies and cause are clear.

Characterised by normal AG metabolic acidosis + hyperK⁺. Mechanism: aldosterone deficiency/resistance, with hyperkalaemia also suppressing renal ammoniagenesis and therefore net acid excretion. Acidosis is often mild; urine pH can still be < 5.5. ^[1]

Causes: Drugs (ACEI, ARB, mineralocorticoid-receptor antagonists, ENaC blockers, trimethoprim, heparin, ciclosporin/tacrolimus); hyporeninaemic hypoaldosteronism in diabetic kidney disease; CKD; adrenal mineralocorticoid deficiency; and transplant/tubulointerstitial disease. ^[1]

Type I & II RTA: ^[1] 1. Correct acidosis with oral NaHCO₃ (very high dose required in proximal RTA because of urinary HCO₃⁻ loss). 2. Potassium citrate is a better alternative for distal RTA (citrate → converted to HCO₃⁻ by liver, also ↑urinary citrate to prevent stones). 3. K⁺ supplement for hypoK⁺. 4. Identify and treat the underlying tubulointerstitial or systemic disease. Immunosuppression for Sjögren disease is individualised specialist care, not automatic treatment for every associated distal RTA.

Type IV RTA: ^[1] 1. Stop/reduce inciting drugs. 2. Loop diuretics + low K⁺ diet for hyperK⁺.

[Na⁺] does not reflect absolute content of Na⁺ in body, but the amount of solvent—water. Na⁺ is primarily an extracellular cation. In the absence of Na⁺ loss or retention: hypoNa⁺ = water retention; hyperNa⁺ = water depletion. Complicated when there is also Na⁺ loss or retention. ^[1]

This is the single most important concept in sodium disorders: serum [Na⁺] is a marker of water balance, not sodium balance. Volume status (assessed clinically) tells you about total body sodium ^[3].

Na⁺ Handling Along the Nephron ^[1]:

The nephron diagram makes the pharmacology intuitive: proximal tubule and loop perform bulk work, while the small distal fraction provides powerful fine control through thiazide-sensitive, aldosterone-sensitive and ADH-sensitive segments.

The balance figure depicts about 2800 mEq of exchangeable extracellular sodium, with intake from food/condiments/medications and output predominantly through the kidney; stool and sweat contribute smaller variable losses ^[1]. Its 150 mEq/day example is illustrative, not a fixed physiological requirement—the kidney adjusts urinary sodium excretion to match widely varying intake. The body also contains non-osmotically stored sodium in skin and connective tissues, so serum [Na⁺], extracellular volume and total body sodium are related but not interchangeable concepts.

Pseudohyponatraemia is a measurement artefact: markedly increased lipid or protein reduces the plasma-water fraction, causing an indirect ion-selective electrode to report a low sodium even though plasma-water sodium and measured osmolality are normal. A direct ion-selective electrode (for example, many blood-gas analysers) resolves the discrepancy. ^[1]

CNS: meningitis/encephalitis, brain abscess, head trauma, SAH/stroke, raised ICP. Pulmonary: lung cancer, infection, positive-pressure ventilation. Drugs: SSRIs, MDMA and many others. Transient stimuli include pain, nausea and postoperative stress. ^[1]

SIAD is a diagnosis of exclusion: confirm hypotonicity and inappropriate urine concentration, assess clinical euvolaemia, and exclude adrenal insufficiency, clinically significant thyroid dysfunction, kidney failure and diuretic effects. Hypothyroidism is therefore a mimic to exclude, not itself a “cause of SIAD.”

Current Symptom-Led Management

Management is driven by neurological symptoms and acuity, not a sodium number alone ^[10]:

1. Severe symptoms (seizure, markedly reduced consciousness, cardiorespiratory distress attributable to hyponatraemia) require urgent senior/critical-care input and 3% hypertonic saline boluses according to the local protocol. European guidance uses 150 mL over 20 minutes, rechecking and repeating only as needed to obtain about a 5 mmol/L initial rise or symptom improvement ^[10]. The aim is not immediate normalisation.
2. After the initial rescue, stop hypertonic therapy and apply diagnosis-specific treatment. Measure sodium frequently and monitor urine output; rapidly increasing dilute urine warns of overcorrection.
3. Avoid a rise > 10 mmol/L in the first 24 hours and > 8 mmol/L in each subsequent 24 hours; use the more conservative ≤8 mmol/L/24 h ceiling in patients at high risk of osmotic demyelination (very low starting Na⁺, alcohol misuse, malnutrition, liver disease or hypokalaemia) ^[10]. Expert-directed desmopressin and/or electrolyte-free water may be needed to halt or reverse an overshoot.
4. Stable SIAD management starts with cause/drug review and usually fluid restriction. Urea, salt plus loop diuretic, or a vasopressin antagonist are selected specialist options; vaptans are not rescue therapy for severe symptomatic hyponatraemia.

This replaces the deck's 5.85% saline mixture, fixed Na⁺ thresholds, routine frusemide and < 12 mmol/L/day rule, which are not safe as a current universal algorithm.

Non-specific: malaise, lethargy, headache. Confusion, convulsion, coma. More serious with acute hyponatraemia. ^[1]

Acute (< 48 h) hyponatraemia allows less time for brain adaptation and may cause cerebral oedema; chronic (≥48 h) or unknown-duration hyponatraemia carries greater risk from overcorrection. Symptoms depend on both acuity and magnitude, so no single sodium threshold predicts severity. ^[1]

Why the difference? In chronic hyponatraemia, brain cells adapt by extruding osmolytes (organic solutes like taurine, myoinositol) to match the low extracellular osmolality. If you rapidly correct the Na⁺, the extracellular osmolality rises faster than the brain can re-accumulate osmolytes → water rushes out of brain cells → oligodendrocyte damage → central pontine myelinolysis (osmotic demyelination syndrome).

Osmotic demyelination syndrome (ODS) is illustrated by the symmetric central pontine MRI abnormality on the slide ^[1], but demyelination may also be extrapontine. Neurological deterioration is often delayed after overly rapid correction. The slide's bedside percentage estimates of volume loss are rough teaching aids, not precise replacement calculations; use haemodynamics, perfusion, weight trend, input/output and serial laboratory values.

Estimated free-water deficit = TBW × (measured [Na⁺]/140 − 1). This is only a starting estimate: TBW fraction varies with age/body composition and ongoing renal/extrarenal losses must be added. ^[1]

If circulation is compromised, restore it first with isotonic crystalloid; then replace free water orally/enterally where possible or with an appropriate hypotonic IV fluid. For chronic or unknown-duration hypernatraemia with no/mild symptoms, Society for Endocrinology guidance limits correction to ≤0.5 mmol/L/h and ≤10 mmol/L/24 h ^[11]. Acute symptomatic hypernatraemia may be treated faster by specialists. The deck's fixed “one-third” schedule is not a substitute for serial sodium and fluid-balance reassessment.

Hypernatraemia Diagnostic Algorithm [1]

1. Confirm and characterise losses: RFT/glucose, measured osmolality, urine volume and urine osmolality, plus fluid balance and medication review.
2. Concentrated urine: intact renal water conservation suggests extrarenal water loss, reduced intake or sodium gain; treat the cause and deficit.
3. High-volume dilute urine: suggests diabetes insipidus or another water diuresis. In an already hypernatraemic/dehydrated patient, do not perform a routine water-deprivation test; prioritise controlled fluids, measure paired urine/plasma indices and obtain endocrine/nephrology advice. A supervised desmopressin response (and, where available, copeptin-based testing) helps distinguish central from nephrogenic DI.
4. Treat DI safely: fluid replacement takes priority; give desmopressin only when central DI is established or strongly suspected and monitor for a sudden fall in sodium. For nephrogenic DI, remove causes such as lithium/hypercalcaemia and individualise low-solute diet, thiazide and/or amiloride therapy. NSAIDs are not routine long-term treatment because of renal and gastrointestinal harm ^[11].

K⁺ is predominantly intracellular (about 98% of total-body K⁺, especially in muscle); serum K⁺ is normally about 3.5–5.0 mmol/L. Na⁺/K⁺-ATPase, insulin, catecholamines, acid-base status and cell breakdown alter transcellular distribution, while the kidney controls long-term balance. ^[1]

The body-compartment figure explains why a small serum change can represent a large shift or deficit. Acid-base effects are not uniform: mineral/inorganic acidosis more reliably shifts K⁺ out of cells than organic acidoses. In DKA, insulin deficiency and hypertonicity raise serum K⁺ even though osmotic diuresis produces a major total-body deficit.

The lecture calculates TTKG = (urine [K⁺] × serum Osm)/(serum [K⁺] × urine Osm), with a worked value of 7.1. ^[1]

TTKG attempted to estimate cortical collecting-duct K⁺ handling, but its assumptions about distal solute and urea handling are unreliable. KDIGO concludes that it has too many limitations to recommend ^[12]. Preserve it as historical lecture material, not a routine diagnostic threshold. In current practice, use the clinical context plus a 24-hour urine K⁺ or spot urine K⁺:creatinine ratio, then integrate acid-base status, Mg²⁺, blood pressure, urine chloride and drugs.

1. Initial investigations: RFT, serum osmolarity, TFT, Mg²⁺, HCO₃⁻, urine [K⁺], urine osmolarity.
2. Exclude intracellular K⁺ shift: insulin, catecholamines, β₂-agonists, metabolic alkalosis, hypokalaemic periodic paralysis.
3. If HCO₃⁻ ↑ (metabolic alkalosis):
   • Low urine chloride → vomiting/remote diuretic effect is likely.
   • Renal K⁺ loss + normal BP → current diuretics, Bartter or Gitelman physiology (check drug history, Mg²⁺, urine Ca²⁺).
   • Renal K⁺ loss + hypertension → assess renin/aldosterone and mineralocorticoid states after correcting K⁺ and accounting for interfering drugs.
4. If HCO₃⁻ ↓ (normal AG metabolic acidosis):
   • Urine AG negative → Diarrhoea, Proximal RTA
   • Urine AG positive → Distal RTA

DKA presents with high AG metabolic acidosis (ketoacids). Serum K⁺ may be normal or high initially because insulin deficiency and hypertonicity shift K⁺ out of cells, while total-body K⁺ is depleted by osmotic diuresis and vomiting. Insulin then drives K⁺ into cells, so monitor and replace potassium according to the DKA protocol ^[7].

Relevant to distal RTA (hyperCa²⁺ damages the collecting duct → failure to acidify urine). Also connects to the 2025 MCQ Q13: chronic smoker with haemoptysis, bone pain, and lung mass → likely hypercalcaemia from PTHrP-secreting squamous cell lung cancer ^[5].

Both cause metabolic alkalosis + hypoK⁺. Bartter's mimics furosemide effect (thick ascending limb defect → hypokalaemia, metabolic alkalosis, hypercalciuria). Gitelman's mimics thiazide effect (distal tubule defect → hypokalaemia, metabolic alkalosis, hypocalciuria, hypomagnesaemia) ^[8].

Advanced CKD → accumulation of phosphate, sulphate → high AG metabolic acidosis. Also common to develop hyperK⁺ (↓GFR → ↓K⁺ excretion). Type IV RTA is common in diabetic nephropathy ^[1].