Renal Pathology
1. What this chapter covers, and how NEET PG actually tests it
Renal pathology is dense, but almost all of it hangs on one anatomical question.
Which layer of the glomerular filtration barrier has been damaged?
The barrier has three layers: fenestrated endothelium, glomerular basement membrane, and podocyte foot processes with their slit diaphragms.
Damage the podocyte side and protein escapes, giving nephrotic syndrome. Inflame the endothelial and mesangial side and blood and inflammatory cells escape, giving nephritic syndrome.
That single distinction organises the glomerular diseases, and the tubulointerstitial, vascular and neoplastic sections then attach to it.
| Area | The question actually being asked | Usual clue |
|---|---|---|
| Glomerular disease | Nephrotic or nephritic | Protein versus blood and casts |
| Nephrotic pattern | Which podocyte lesion | Age, biopsy findings, steroid response |
| Nephritic pattern | Which immune mechanism | Immunofluorescence pattern, complement |
| Acute kidney injury | Pre-renal, renal or post-renal | Urea to creatinine ratio, urine sodium |
| Tubulointerstitial | Toxic, ischaemic or allergic | Drug history, eosinophils |
| Cystic disease | Which inheritance | Age at presentation, extrarenal features |
| Tumours | Which cell of origin | Age and histology |
2. Nephrotic syndrome: the podocyte diseases
2.1 The defining features
Proteinuria above 3.5 grams per day, hypoalbuminaemia, oedema and hyperlipidaemia.
Hyperlipidaemia occurs because the liver increases lipoprotein synthesis in response to falling oncotic pressure, and the resulting lipiduria produces oval fat bodies with a Maltese cross appearance under polarised light.
Loss of antithrombin III in the urine produces a hypercoagulable state, and renal vein thrombosis is the classic complication, particularly in membranous nephropathy.
Loss of immunoglobulins produces susceptibility to encapsulated organisms.
2.2 The five patterns
| Disease | Typical patient | Light microscopy | Immunofluorescence |
|---|---|---|---|
| Minimal change | Child | Normal | Negative |
| Focal segmental glomerulosclerosis | Adult, HIV, obesity | Segmental sclerosis | Usually negative |
| Membranous | Adult | Thickened capillary wall | Granular IgG and C3 |
| Membranoproliferative | Variable | Tram-track double contour | Granular |
| Diabetic nephropathy | Long-standing diabetes | Kimmelstiel-Wilson nodules | Linear, non-specific |
Minimal change disease shows a normal glomerulus on light microscopy, and only electron microscopy reveals the lesion: effacement of podocyte foot processes.
That is exactly why the disease is named as it is, and why the biopsy report can appear normal while the child has florid nephrotic syndrome.
It responds dramatically to steroids, which is why children with typical nephrotic syndrome are treated without biopsy.
Focal segmental glomerulosclerosis is the commonest cause of nephrotic syndrome in adults in many series, is associated with HIV, heroin and obesity, and responds poorly to steroids.
Membranous nephropathy has a defined autoantigen: the phospholipase A2 receptor on the podocyte, and antibody against it is detectable in serum in most primary cases.
Its secondary causes are solid tumours, hepatitis B, lupus and drugs such as penicillamine and gold, so a new diagnosis in an older adult prompts a search for malignancy.
Spike and dome appearance on silver staining reflects basement membrane material growing between subepithelial deposits.
2.3 Diabetic and amyloid kidney
Diabetic nephropathy begins with hyperfiltration and microalbuminuria, progresses to overt proteinuria, and ends in nodular glomerulosclerosis.
Kimmelstiel-Wilson nodules are the characteristic lesion, and hyaline arteriolosclerosis affects both afferent and efferent arterioles, which is relatively specific to diabetes.
Amyloid deposits in the mesangium and stains with Congo red, giving apple-green birefringence under polarised light.
3. Nephritic syndrome: the inflammatory diseases
3.1 The defining features
Haematuria with dysmorphic red cells and red cell casts, hypertension, oliguria, azotaemia and mild to moderate proteinuria.
Red cell casts are the single most specific finding, because they can only form in the tubule and therefore prove the bleeding is glomerular rather than urological.
3.2 Post-infectious and IgA nephropathy
Post-streptococcal glomerulonephritis follows a throat infection by one to three weeks or a skin infection by three to six weeks.
Complement C3 is low, antistreptolysin O titre is raised, and immunofluorescence is granular with subepithelial humps on electron microscopy.
IgA nephropathy presents with haematuria one to two days after an upper respiratory infection, with normal complement.
The interval separates them cleanly: IgA nephropathy is concurrent with the infection, post-streptococcal disease follows it by weeks.
That difference exists because IgA nephropathy involves pre-existing abnormal IgA being mobilised, while post-streptococcal disease requires time to generate a new antibody response and form complexes.
Henoch-Schonlein purpura is the systemic form of IgA nephropathy, adding purpura, arthralgia and abdominal pain.
3.3 Rapidly progressive glomerulonephritis
Crescents on biopsy define it, and crescents are proliferating parietal epithelial cells with fibrin, indicating severe capillary wall rupture.
Immunofluorescence sorts the causes into three groups.
| Pattern | Cause |
|---|---|
| Linear | Goodpasture, anti-GBM disease |
| Granular | Post-infectious, lupus |
| Pauci-immune | ANCA-associated vasculitis |
Pauci-immune means little or no immunofluorescence staining despite florid crescents, and it points to ANCA-associated disease rather than immune complex deposition.
This is a nephrological emergency, since untreated crescentic disease destroys the kidney within weeks.
3.4 The hereditary basement membrane diseases
Alport syndrome is an X-linked type IV collagen defect producing haematuria, sensorineural deafness and ocular abnormalities, with basket-weave splitting of the basement membrane.
Thin basement membrane disease produces isolated persistent haematuria with normal function and a benign course.
Lupus nephritis has six classes, and class IV diffuse proliferative disease is both the commonest and the most severe, with a full-house immunofluorescence pattern.
3.5 Complement as a second sorting tool
After the nephrotic and nephritic split, serum complement is the most efficient discriminator available, because only some mechanisms consume it.
A low C3 means complement is being consumed, which happens in immune complex and alternative pathway disease but not in the others.
Low complement occurs in post-streptococcal glomerulonephritis, lupus nephritis, membranoproliferative disease and cryoglobulinaemia.
Normal complement occurs in IgA nephropathy, anti-glomerular basement membrane disease, ANCA-associated vasculitis and Alport syndrome.
That single value therefore halves the differential in most nephritic stems.
Membranoproliferative glomerulonephritis deserves separate mention because it can present with either pattern or with both together.
Its tram-track double contour arises from mesangial cell processes interposing themselves between endothelium and basement membrane, and new basement membrane forming around them.
Dense deposit disease, now classified within C3 glomerulopathy, involves the C3 nephritic factor, an autoantibody that stabilises the alternative pathway convertase and drives relentless complement consumption.
3.6 Reading the urinary sediment
Casts are cylindrical moulds of the tubular lumen, so any cast proves that the material came from the kidney rather than from lower in the tract.
That is why casts are so useful: they localise a problem before any imaging is done.
| Cast | Meaning |
|---|---|
| Red cell | Glomerulonephritis |
| White cell | Pyelonephritis, interstitial nephritis |
| Muddy brown granular | Acute tubular necrosis |
| Fatty, with Maltese crosses | Nephrotic syndrome |
| Waxy and broad | Chronic kidney disease with dilated tubules |
| Hyaline | Non-specific, seen in concentrated urine |
Dysmorphic red cells, particularly acanthocytes, indicate that the cells were deformed while squeezing through a damaged capillary wall.
Isomorphic red cells with a normal shape point instead to bleeding from the collecting system, which redirects the workup towards stones and urothelial tumours.
4. Acute kidney injury and tubulointerstitial disease
4.1 Locating the injury
| Feature | Pre-renal | Intrinsic (ATN) |
|---|---|---|
| Urine sodium | Below 20 | Above 40 |
| Fractional excretion of sodium | Below 1 per cent | Above 2 per cent |
| Urine osmolality | Above 500 | Below 350 |
| Urea to creatinine ratio | Raised | Normal |
| Urine sediment | Bland | Muddy brown casts |
In pre-renal failure the tubules are intact and are working hard to conserve sodium and water, which is why the urine is concentrated and sodium-poor.
Once tubular cells are injured they cannot reabsorb, so sodium is wasted and the urine becomes dilute.
Muddy brown granular casts are sloughed tubular epithelial cells, and are the sediment finding of acute tubular necrosis.
4.2 Acute tubular necrosis
Ischaemic injury affects the proximal tubule straight segment and the thick ascending limb, both of which sit in relatively hypoxic zones.
Toxic injury from aminoglycosides, contrast, myoglobin or heavy metals affects the proximal tubule preferentially, because that is where reabsorption concentrates the toxin.
Recovery passes through a polyuric phase, during which the tubules regenerate but cannot yet concentrate, and electrolyte losses can be dangerous.
4.3 Interstitial nephritis and pyelonephritis
Acute interstitial nephritis is a drug hypersensitivity reaction, classically to penicillins, non-steroidal anti-inflammatory drugs, rifampicin and proton pump inhibitors.
Fever, rash, eosinophilia and eosinophiluria with a rising creatinine after starting a drug is the recognisable pattern, and stopping the drug is the treatment.
Acute pyelonephritis shows neutrophil casts and patchy suppurative inflammation, and reaches the kidney by ascending infection.
Chronic pyelonephritis produces coarse asymmetrical scarring with blunted calyces, and thyroidisation of tubules filled with eosinophilic casts.
Analgesic nephropathy causes papillary necrosis, as do diabetes, sickle cell disease and obstruction.
Those four causes share one feature: each compromises the blood supply to the papilla, which sits at the end of the medullary vascular supply and is therefore the most hypoxic part of the kidney.
A sloughed papilla can obstruct the ureter and present as renal colic in a patient with no stone.
4.4 Chronic kidney disease and its systemic consequences
Chronic kidney disease is staged by estimated glomerular filtration rate, and the systemic effects follow from which renal functions have been lost.
The kidney has three outputs beyond excretion, and each failure produces a recognisable syndrome.
Loss of erythropoietin produces a normocytic normochromic anaemia that responds to erythropoiesis-stimulating agents rather than to iron alone.
Loss of 1-alpha-hydroxylation produces calcitriol deficiency, so calcium absorption falls, and the resulting hypocalcaemia drives secondary hyperparathyroidism.
Phosphate retention compounds the problem by binding calcium and further stimulating parathyroid hormone.
The skeletal result is renal osteodystrophy, which combines osteitis fibrosa cystica from excess parathyroid hormone with osteomalacia from calcitriol deficiency.
If the parathyroid glands eventually become autonomous, the picture converts to tertiary hyperparathyroidism with hypercalcaemia rather than hypocalcaemia.
Cardiovascular disease, not uraemia, is the commonest cause of death in chronic kidney disease.
5. Vascular, cystic and neoplastic disease
5.1 Vascular
Benign nephrosclerosis produces hyaline arteriolosclerosis and a finely granular kidney surface.
Malignant hypertension produces hyperplastic onion-skin arteriolosclerosis and fibrinoid necrosis, with a flea-bitten surface from petechiae.
Renal artery stenosis from atherosclerosis or fibromuscular dysplasia causes renovascular hypertension, and fibromuscular dysplasia gives a string-of-beads appearance in young women.
Haemolytic uraemic syndrome follows Shiga toxin-producing Escherichia coli, with the triad of microangiopathic haemolysis, thrombocytopenia and acute kidney injury.
5.2 Cystic disease
Autosomal dominant polycystic kidney disease involves PKD1 or PKD2, presents in adulthood, and is associated with berry aneurysms, hepatic cysts and mitral valve prolapse.
Autosomal recessive disease presents in infancy with bilaterally enlarged kidneys and congenital hepatic fibrosis.
The inheritance pattern and the age of presentation always agree, so either detail identifies the condition.
Simple cysts are extremely common, increase with age, and are of no consequence.
5.3 Renal stones
Stone composition is examined through the urinary pH at which each forms and the condition each accompanies.
| Stone | Proportion | Formed in | Association |
|---|---|---|---|
| Calcium oxalate | Commonest by far | Any pH | Hypercalciuria, hyperoxaluria, Crohn disease |
| Struvite | Second | Alkaline urine | Urease-producing organisms, staghorn calculi |
| Uric acid | Less common | Acid urine | Gout, high cell turnover, radiolucent |
| Cystine | Rare | Acid urine | Cystinuria, children, hexagonal crystals |
Struvite stones form because urease-producing organisms such as Proteus split urea into ammonia, which alkalinises the urine and precipitates magnesium ammonium phosphate.
That mechanism explains why struvite stones grow into large staghorn calculi and why treatment must eradicate the infection as well as remove the stone.
Uric acid stones are radiolucent on plain radiography, so a patient with renal colic and a normal film has not been excluded.
Enteric hyperoxaluria in Crohn disease occurs because unabsorbed fat binds calcium, leaving oxalate free to be absorbed.
5.4 Tumours
Renal cell carcinoma arises from proximal tubular epithelium, and the clear cell type is commonest, associated with VHL loss on chromosome 3.
It presents with haematuria, flank pain and a mass, invades the renal vein, and may cause paraneoplastic polycythaemia through erythropoietin.
Wilms tumour is the childhood renal tumour, peaks at two to five years, shows a triphasic histology, and is associated with WT1 in the WAGR and Denys-Drash syndromes.
Angiomyolipoma is benign, contains fat, and is associated with tuberous sclerosis.
Urothelial carcinoma of the renal pelvis presents with painless haematuria and is linked to smoking and aromatic amines.
Its defining behaviour is field change: the entire urothelium has been exposed, so tumours are frequently multifocal and recur anywhere from renal pelvis to urethra.
That is why surveillance after treatment must cover the whole tract rather than only the original site.
Renal cell carcinoma is notable for late and unpredictable metastasis, with deposits appearing many years after apparently curative nephrectomy.
It is also one of the few tumours that characteristically grows along the renal vein into the inferior vena cava, which is why imaging must define the upper limit of any tumour thrombus before surgery.
6. Worked examples
Example 1
A 4-year-old has periorbital oedema and heavy proteinuria. Biopsy light microscopy is normal and immunofluorescence is negative.
Heavy proteinuria with a normal light microscopic appearance is itself the diagnostic combination.
Protein can only escape if the barrier is damaged, so a normal appearance means the damage is below the resolution of light microscopy.
Electron microscopy shows diffuse effacement of podocyte foot processes, which is minimal change disease.
The negative immunofluorescence excludes immune complex disease, and the expected response to corticosteroids is excellent.
Example 2
A 22-year-old develops visible haematuria one day after a sore throat. Complement is normal.
The timing does the work here. One day is far too soon for a new antibody response and complex formation.
Post-streptococcal disease requires one to three weeks after a throat infection and consumes complement, so a normal C3 argues against it directly.
Haematuria concurrent with an infection, with normal complement, is IgA nephropathy, in which pre-existing abnormally glycosylated IgA is mobilised rather than newly generated.
Immunofluorescence would show mesangial IgA deposition.
Example 3
A 68-year-old develops haemoptysis and a creatinine rising over ten days. Biopsy shows crescents with linear immunofluorescence.
Crescents indicate rapidly progressive glomerulonephritis, and the immunofluorescence pattern identifies which of the three groups it belongs to.
Linear staining means antibody directed against an antigen fixed in the basement membrane, rather than deposited complexes.
With pulmonary haemorrhage, this is anti-glomerular basement membrane disease, or Goodpasture syndrome, targeting the alpha-3 chain of type IV collagen.
The lung is involved because the same collagen chain is present in alveolar basement membrane, and plasma exchange is required urgently.
7. Traps the exam sets repeatedly
Confusing the timing of IgA and post-streptococcal nephropathy. Concurrent with infection means IgA; one to three weeks after means post-streptococcal, and the complement level confirms it.
Reading a normal light microscopy report as a normal kidney. In minimal change disease the lesion is visible only on electron microscopy.
Forgetting to look for malignancy in adult membranous nephropathy. Solid tumours are an important secondary cause.
Treating pauci-immune as meaning no disease. It means no immune deposits, and it identifies ANCA-associated vasculitis, which is among the most aggressive renal diseases.
Assuming a high urine sodium always means tubular injury. Diuretics invalidate the fractional excretion of sodium, and the fractional excretion of urea is used instead in that setting.
Summary
Every glomerular disease is a question about which layer of the filtration barrier is damaged.
Podocyte damage lets protein escape and produces nephrotic syndrome; endothelial and mesangial inflammation lets blood and cells escape and produces nephritic syndrome.
Minimal change disease is normal on light microscopy with foot process effacement on electron microscopy, and responds well to steroids.
Membranous nephropathy has the phospholipase A2 receptor as its autoantigen and requires a search for underlying malignancy in older adults.
Red cell casts prove that haematuria is glomerular, and are the most specific nephritic finding.
IgA nephropathy is concurrent with infection with normal complement; post-streptococcal disease follows by weeks with low complement.
Crescents define rapidly progressive glomerulonephritis, and immunofluorescence sorts it into linear, granular and pauci-immune groups.
Pre-renal failure conserves sodium because the tubules are intact; acute tubular necrosis wastes it and produces muddy brown casts.
Acute interstitial nephritis is a drug reaction with fever, rash and eosinophilia, treated by withdrawing the drug.
Polycystic disease inheritance and age of presentation always agree, and renal cell carcinoma arises from proximal tubule with clear cell histology and VHL loss.
