Nephrotic Syndrome

Nephrotic syndrome is a clinical syndrome resulting from significantly increased glomerular permeability to protein, defined by the combination of heavy proteinuria (generally above 3 to 3.5 grams per 24 hours), hypoalbuminemia, edema, and, frequently, hyperlipidemia.

In children, minimal change disease accounts for the large majority of cases and typically responds well to corticosteroid therapy.

In adults, the underlying cause is more varied and includes focal segmental glomerulosclerosis, membranous nephropathy (which may be primary, driven by autoantibodies against the PLA2R antigen, or secondary to an underlying cause such as malignancy, infection, or autoimmune disease), and diabetic nephropathy, which is an increasingly common cause of nephrotic range proteinuria in adults given the rising global prevalence of diabetes.

Periorbital and dependent edema is typically the presenting feature, often noticed first as facial puffiness on waking, and progressing to more generalized edema, ascites, and pleural effusion as the condition advances.

Frothy urine, reflecting the heavy proteinuria, is a symptom many patients notice themselves and volunteer if specifically asked. Fatigue and, in more advanced disease, breathlessness from fluid accumulation, may also be present.

Nephrotic syndrome carries several important, sometimes underappreciated, systemic consequences beyond the local effects of edema.

A hypercoagulable state arises from urinary loss of antithrombin and other regulatory proteins alongside a compensatory rise in hepatic procoagulant synthesis, predisposing particularly to renal vein thrombosis and pulmonary embolism, and this risk should be actively considered in any nephrotic patient presenting with flank pain, hematuria, or respiratory symptoms.

Increased susceptibility to infection results from urinary loss of immunoglobulins, with particular vulnerability to encapsulated organisms, and spontaneous bacterial peritonitis is a recognized complication in nephrotic patients with ascites, analogous to the phenomenon seen in cirrhosis.

Hyperlipidemia results from increased hepatic lipoprotein synthesis, occurring as a compensatory response to the ongoing protein loss.

Urinalysis and quantification of proteinuria, either by 24 hour urine collection or a spot urine protein to creatinine ratio (a more practical and widely used alternative), confirm the degree of proteinuria. Serum albumin is reduced, and a lipid profile typically shows significant hyperlipidemia.

Renal function (urea, creatinine, eGFR) should be assessed, since impairment at presentation carries prognostic significance and may point toward a specific underlying cause. Renal biopsy is generally required in adults to establish the specific histological diagnosis, since this determines both prognosis and the most appropriate treatment, in contrast to children, where minimal change disease is presumed and a trial of steroids is often given first without biopsy given how characteristically it responds.

Further investigation is directed toward identifying a secondary cause, particularly for membranous nephropathy: PLA2R antibody testing (supporting a primary, autoimmune cause when positive), age appropriate malignancy screening, hepatitis B and C serology, and autoimmune screening including ANA and complement levels where a connective tissue disease such as systemic lupus erythematosus is suspected as an underlying driver.

Differentials for the underlying histological cause are noted above; the differential for the clinical syndrome of generalized edema also includes heart failure, cirrhosis, and protein losing enteropathy, though the combination of heavy proteinuria and hypoalbuminemia on initial bloods and urinalysis typically distinguishes nephrotic syndrome from these fairly promptly.

General supportive measures apply regardless of the specific underlying cause. Salt restriction and diuretics, typically loop diuretics, are used to manage edema, titrated carefully since nephrotic patients can be intravascularly volume depleted despite visibly significant peripheral edema, given the low oncotic pressure driving fluid into the interstitial space.

ACE inhibitors or ARBs are used to reduce proteinuria and provide renal protection, a benefit that applies broadly across the different underlying causes of nephrotic syndrome, independent of blood pressure control alone.

Statin therapy addresses the associated hyperlipidemia. Prophylactic anticoagulation is considered in patients at particularly high thrombotic risk, guided by the degree of hypoalbuminemia and the specific underlying diagnosis, since the thrombotic risk varies somewhat by cause, being notably high in membranous nephropathy.

Specific treatment is directed by the underlying histological diagnosis once established by biopsy (or, in children, by the characteristic clinical response to steroids). Minimal change disease is treated with high dose oral corticosteroids, to which the large majority of children respond, with immunosuppressive agents such as calcineurin inhibitors or cyclophosphamide reserved for steroid resistant or frequently relapsing disease. Focal segmental glomerulosclerosis is also treated with corticosteroids as first line therapy, though response rates are lower than in minimal change disease, with calcineurin inhibitors used for steroid resistant cases. Membranous nephropathy management depends on the risk of progression, with observation and supportive care alone appropriate for lower risk disease, and immunosuppression, commonly rituximab or a calcineurin inhibitor based regimen, reserved for higher risk or progressive disease. Diabetic nephropathy is managed with optimized glycemic control, blood pressure control with an ACE inhibitor or ARB as foundational therapy, and SGLT2 inhibitors, which have demonstrated significant renal protective benefit independent of glycemic effect.

Referral: nephrology for all adult onset nephrotic syndrome, given the need for renal biopsy and specific immunosuppressive management; pediatric nephrology for children with atypical features or steroid resistant disease.

Clinical toolsCalculators

BMI GCS EDD Parkland Formula

Corrected Sodium Corrected Calcium Anion Gap Creatinine Clearance Insulin Calculations qSOFA Wells PE Wells DVT CHA₂DS₂-VASc HAS-BLED CURB-65 Centor/McIsaac

Hypercalcaemia

Also known as: Hypercalcemia, High calcium

Hypercalcaemia is a raised corrected serum calcium, graded broadly as mild (up to about 3.0 mmol/L), moderate (3.0–3.4 mmol/L) and severe (≥3.4 mmol/L, or any level with significant symptoms).

Because roughly 40% of calcium is albumin-bound, the corrected value must be used, or hypercalcaemia will be missed in hypoalbuminaemic patients and over-diagnosed in others.

Primary hyperparathyroidism and malignancy together account for around 90% of cases, and the distinction is usually straightforward: primary hyperparathyroidism tends to be chronic, mild and asymptomatic in an outpatient, while malignancy-associated hypercalcaemia is usually higher, symptomatic and of shorter history.

Other causes include granulomatous disease (sarcoidosis, tuberculosis), vitamin D toxicity, thiazides, lithium, thyrotoxicosis, immobilisation, milk-alkali syndrome and familial hypocalciuric hypercalcaemia.

The classic summary of "bones, stones, abdominal groans and psychic moans" remains a useful memory aid.

Renal: polyuria and polydipsia (nephrogenic diabetes insipidus), nephrolithiasis, nephrocalcinosis, and acute kidney injury from volume depletion
Gastrointestinal: anorexia, nausea, vomiting, constipation, abdominal pain, peptic ulceration and pancreatitis
Neuropsychiatric: fatigue, poor concentration, depression, confusion, and in severe hypercalcaemia drowsiness, stupor and coma
Musculoskeletal: bone pain, proximal muscle weakness, and in longstanding hyperparathyroidism osteitis fibrosa cystica
Cardiac: shortened QT interval, bradycardia, and arrhythmia in severe cases, with increased digoxin sensitivity

Volume depletion is central to the pathophysiology and drives a vicious cycle: hypercalcaemia causes polyuria and vomiting, which cause dehydration, which reduces renal calcium excretion, which raises calcium further. Breaking that cycle with fluid is the first therapeutic priority.

Corrected calcium, repeated to confirm, alongside albumin. Ionised calcium is preferable where available and where the correction is unreliable, as in critical illness or acid-base disturbance
PTH is the single most useful discriminating test: an inappropriately normal or raised PTH indicates primary (or tertiary) hyperparathyroidism, while a suppressed PTH points to a non-parathyroid cause, principally malignancy
If PTH is suppressed: PTHrP (humoral hypercalcaemia of malignancy), vitamin D metabolites (raised 1,25-dihydroxyvitamin D suggests granulomatous disease or lymphoma), myeloma screen, and imaging directed by the clinical picture
Renal function, phosphate, magnesium, alkaline phosphatase
ECG for QT shortening
24-hour urinary calcium and the calcium-creatinine clearance ratio to identify familial hypocalciuric hypercalcaemia, an important benign mimic in which parathyroidectomy is inappropriate and which is otherwise easily mistaken for mild primary hyperparathyroidism
Review medications, particularly thiazides, lithium, calcium and vitamin D supplements

Differentials: as above, with the practical task usually being to separate parathyroid-driven from non-parathyroid causes and then to identify the specific underlying disease.

Severe or symptomatic hypercalcaemia:

Intravenous isotonic saline is the first and most important step, typically several litres over the first 24 hours, correcting volume depletion and promoting calciuresis. This alone often produces a substantial fall
Loop diuretics are no longer recommended routinely and should be used only once the patient is genuinely volume replete and where fluid overload is a concern; giving furosemide to a dehydrated hypercalcaemic patient worsens the problem
Intravenous bisphosphonate (zoledronic acid or pamidronate) for malignancy-associated hypercalcaemia, with the important caveat that the effect takes 2–4 days, so it does not substitute for fluid in the acute phase. Dose adjustment is needed in renal impairment
Calcitonin works within hours and is useful as a bridge while awaiting bisphosphonate effect, though tachyphylaxis limits it to a few days
Denosumab is an option in bisphosphonate-refractory hypercalcaemia or significant renal impairment
Corticosteroids are effective specifically in granulomatous disease, lymphoma and vitamin D toxicity, where the mechanism is excess 1,25-dihydroxyvitamin D
Haemodialysis for severe hypercalcaemia with renal failure or where the patient is unable to tolerate fluid loading
Stop contributing drugs and mobilise the patient where possible

Underlying cause:

Primary hyperparathyroidism: parathyroidectomy where criteria are met; cinacalcet where surgery is not appropriate
Malignancy: treat the underlying disease, recognising that hypercalcaemia of malignancy carries a poor prognosis and that discussion of goals of care is often appropriate alongside treatment

Referral: endocrinology for parathyroid disease; oncology or palliative care for malignancy-associated hypercalcaemia; nephrology for dialysis or severe renal impairment.

Nephrotic Syndrome

Overview

Clinical Features

Diagnosis

Management

Overview

Clinical Features

Diagnosis

Management