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Renal disease-general


Saskia von Stillfried, M.D.
Peter Boor, M.D., Ph.D.

Last author update: 29 January 2024
Last staff update: 29 January 2024

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Renal disease nontumor

Saskia von Stillfried, M.D.
Peter Boor, M.D., Ph.D.
Page views in 2023: 7,196
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Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Microscopic (histologic) description | Microscopic (histologic) images | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: von Stillfried S, Boor P. Renal disease-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneyrenaldisease.html. Accessed April 26th, 2024.
Definition / general
  • Renal disease: basic terminology in nontumor kidney pathology and kidney diseases
Essential features
  • Each of the 3 anatomical kidney compartments should be assessed and reported (Am J Kidney Dis 2022;80:119)
    • Glomeruli (count overall number of glomeruli and number of globally sclerotic glomeruli)
    • Tubulointerstitium (semiquantitatively estimate the extent of interstitial fibrosis and tubular atrophy)
    • Vasculature (focusing on arteries and arterioles, estimate degree of narrowing of the vascular lumen)
  • Injuries should be categorized as active versus chronic lesions (Am J Kidney Dis 2022;80:119)
  • Lesions and nomenclature should be reported according to an international standards (Kidney Int 2020;98:1120)
    • Focal (< 50% of the glomeruli or the tubulointerstitium)
    • Diffuse (> 50% of the glomeruli or the tubulointerstitium)
    • Segmental (< 50% of a glomerulus)
    • Global (> 50% of a glomerulus, special case: global glomerulosclerosis denotes almost fully sclerotic glomeruli)
ICD coding
  • ICD-10
    • Q60 - Q64 - congenital malformations of the urinary system
    • N00 - N99 - diseases of the genitourinary system
Epidemiology
Sites
  • Kidney
Etiology
  • Causes of CAKUT (StatPearls: Embryology, Kidney, Bladder, and Ureter [Accessed 7 August 2023])
    • Disruptions to the signaling pathways of LIM1, PAX2 / PAX8 and ODD1, GDNF-RET, bone morphogenic protein 4 (BMP4) and gremlin
    • Genes associated with bilateral renal agenesis, including ANOS1, EYA1 and RET
    • Multicystic dysplastic kidney disease (MCDK) is thought to be caused by a defect in the genes involved in the GDNF-RET signaling pathway between the ureteric bud and the metanephric blastema
    • Autosomal dominant polycystic kidney disease (PKD) caused by heterogeneous mutations in PKD1 in 85% of cases, with the remaining 15% due to PKD2 mutations; autosomal recessive PKD caused by mutations in PKHD1
  • Causes of AKI (StatPearls: Acute Kidney Injury [Accessed 7 August 2023])
    • Prerenal
      • Reduced blood flow to the kidney (caused by hypotension, hypovolemia, renal vasoconstriction or glomerular efferent arteriolar vasodilation)
    • Renal
      • Acute tubular necrosis, acute interstitial nephritis, glomerulonephritis, intratubular obstruction
    • Postrenal
      • Obstruction of the urinary flow by renal / ureteral calculi, tumors, blood clots or any urethral obstruction
  • Causes of glomerulonephritis (GN) (StatPearls: Glomerulonephritis [Accessed 7 August 2023])
    • Immune complex GN
    • Pauci-immune GN
    • Antiglomerular basement membrane (GBM) GN
    • Monoclonal Ig GN
    • C3 glomerulopathy
  • Causes of CKD (StatPearls: Chronic Renal Failure [Accessed 7 August 2023], Lancet 2017;389:1238)
    • Diabetes mellitus type 2 (30 - 50%)
    • Diabetes mellitus type 1 (3.9%)
    • Hypertension (27.2%)
    • Primary glomerulonephritis (8.2%)
    • Chronic tubulointerstitial nephritis (3.6%)
    • Hereditary or cystic diseases (3.1%)
    • Secondary glomerulonephritis or vasculitis (2.1%)
    • Plasma cell dyscrasias or neoplasm (2.1)
    • Sickle cell nephropathy (SCN)
Clinical features
  • Clinical indications for renal biopsy (typical presentations) (adapted from BMJ Open 2019;9:e023479)
    • Microscopic or macroscopic hematuria (StatPearls: Hematuria [Accessed 7 August 2023])
      • Alport syndrome
      • Immune complex GN: IgA nephropathy, IgA vasculitis, infection related GN, lupus nephritis and fibrillary GN with polyclonal Ig deposits
      • Membranoproliferative glomerulonephritis
      • Antiglomerular basement membrane (GBM) GN (Goodpasture syndrome)
      • Pauci-immune GN: PR3 antineutrophil cytoplasmic antibodies (ANCA) GN, myeloperoxidase (MPO) ANCA GN and ANCA negative GN with systemic or renal vasculitis
      • C3 glomerulopathy: C3 glomerulonephritis, dense deposit disease
    • Nephrotic syndrome (proteinuria > 3.5 g/24 h or 40 mg/m2 per hour, edema, hypoalbuminemia < 30 g/L, hyperlipidemia, hyperlipiduria, hypercoagulability and thrombophilia) (StatPearls: Glomerulonephritis [Accessed 7 August 2023])
      • Minimal change disease
      • Focal segmental glomerulosclerosis
      • Membranoproliferative glomerulonephritis
      • Membranous nephropathy
      • Human immunodeficiency virus (HIV) associated nephropathy
      • Diabetic nephropathy
      • Amyloidosis
    • Nephritic syndrome (proteinuria < 3.5 g/24 h or 40 mg/m2 per hour, rapid decrease in glomerular filtration rate [GFR], oliguria, hematuria, systemic hypertension, decrease in serum complement levels) (StatPearls: Nephritic Syndome [Accessed 7 August 2023])
      • Antiglomerular basement membrane (GBM) GN (Goodpasture syndrome)
      • Immune complex GN: IgA nephropathy, IgA vasculitis, infection related GN, lupus nephritis and fibrillary GN with polyclonal Ig deposits
      • Pauci-immune GN: PR3 ANCA GN, MPO ANCA GN and ANCA negative GN with systemic or renal vasculitis
    • Impaired kidney function (acute or chronic decrease of estimated GFR [eGFR])
      • Acute decrease of eGFR / acute kidney injury (AKI) (StatPearls: Acute Kidney Injury [Accessed 7 August 2023])
        • Hypovolemia: hemorrhage, severe burns and gastrointestinal fluid losses, such as diarrhea, vomiting, high ostomy output
        • Hypotension from decreased cardiac output: cardiogenic shock, massive pulmonary embolism, acute coronary syndrome
        • Hypotension from systemic vasodilation: septic shock, anaphylaxis, anesthetics, hepatorenal syndrome
        • Renal vasoconstriction: NSAIDs, iodinated contrast, amphotericin B, calcineurin inhibitors, hepatorenal syndrome
        • Glomerular efferent arteriolar vasodilation: ACE inhibitors, angiotensin receptor blockers
      • Chronic decrease of eGFR (StatPearls: Chronic Renal Failure [Accessed 7 August 2023], Lancet 2017;389:1238)
        • Possible renal involvement in systemic disease in
          • Diabetes mellitus type 2 and type 1
          • Hypertension
          • Hereditary or cystic diseases
          • Plasma cell dyscrasias or neoplasm
          • Secondary glomerulonephritis or vasculitis
          • Sickle cell nephropathy (SCN)
Diagnosis
  • Clinical, laboratory, imaging and biopsy findings
Laboratory
  • Chronic kidney disease (CKD)
    • Glomerular filtration rate: GFR < 60 mL/min/1.73 m2 (GFR categories G3a - G5) (Kidney Int Suppl 2013;3:19)

        GFR categories in CKD
        GFR category GFR (mL/min/1.73 m2) Terms
        G1 ≥ 90 Normal or high
        G2 60 - 89 Mildly decreased*
        G3a 45 - 59 Mildly to moderately decreased
        G3b 30 - 44 Moderately to severely decreased
        G4 15 - 29 Severely decreased
        G5 < 15 Kidney failure
        Abbreviations: chronic kidney disease (CKD), glomerular filtration rate (GFR)
        *Relative to young adult level
        In the absence of evidence of kidney damage, neither GFR category G1 nor G2 fulfill the criteria for CKD

        Albuminuria categories in CKD
        (KDIGO: Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [Accessed 28 July 2023])
        ACR (approximate equivalent)
        Category AER (mg/24 hours) (mg/mmol) (mg/g) Terms
        A1 < 30 < 3 < 30 Normal to mildly increased
        A2 30 - 100 3 - 30 30 - 300 Moderately increased*
        A3 > 300 > 30 > 300 Severely increased**
        Abbreviations: albumin excretion rate (AER), albumin to creatinine ratio (ACR), chronic kidney disease (CKD)
        *Relative to young adult level
        **Including nephrotic syndrome (albumin excretion usually 42200 mg/24 hours [ACR 42220 mg/g; 4220 mg/mmol])

      • Decreased GFR can be detected by current estimating equations for GFR based on serum creatinine or cystatin C but not by serum creatinine or cystatin C alone
      • Albuminuria as a marker of kidney damage (increased glomerular permeability), urine albumin excretion rate (AER) ≥ 30 mg/24 hours, approximately equivalent to urine albumin to creatinine ratio (ACR) ≥ 30 mg/g (≥ 3 mg/mmol)
    • Urinary sediment abnormalities as markers of kidney damage (Kidney Int Suppl 2013;3:19)
      • Isolated, nonvisible (microscopic) hematuria with abnormal red blood cell (RBC) morphology (anisocytosis) in GBM disorders
      • RBC casts in proliferative glomerulonephritis
      • White blood cell (WBC) casts in pyelonephritis or interstitial nephritis
      • Oval fat bodies or fatty casts in diseases with proteinuria
      • Granular casts and renal tubular epithelial cells in many parenchymal diseases (nonspecific)
    • Renal tubular disorders (Kidney Int Suppl 2013;3:19)
      • Renal tubular acidosis
      • Nephrogenic diabetes insipidus
      • Renal potassium wasting
      • Renal magnesium wasting
      • Fanconi syndrome
      • Nonalbumin proteinuria
      • Cystinuria
  • Acute kidney injury (AKI) (PLoS One 2014;9:e114369)
    • Increased serum creatinine

      Diagnosis and staging criteria for AKI of RIFLE, AKIN, KDIGO definitions based on serum creatinine
      Classification Definition for AKI Stage Serum creatinine criteria for AKI staging*
      RIFLE Increase in SCr ≥ 50% within 7 days Risk To ≥ 1.5 times baseline
      Injury To ≥ 2 times baseline
      Failure To ≥ 3 times baseline or ≥ 44 μmol/L increase to at least 354 μmol/L
      AKIN Increase in SCr ≥ 26.5 μmol/L or ≥ 50% within 48 hours 1 Increase of ≥ 26.5 μmol/L or to 1.5 - 2 times baseline
      2 To 2 - 3 times baseline
      3 To ≥ 3 times baseline or ≥ 26.5 μmol/L increase to at least 354 μmol/L or initiation of RRT
      KDIGO Increase in SCr ≥ 26.5 μmol/L within 48 hours
      or ≥ 50% within 7 days       		1 Increase in SCr ≥ 26.5 μmol/L within 48 hours or to 1.5 - 2 times baseline
      2 To 2 - 3 times baseline
      3 To ≥ 3 times baseline or to at least 354 μmol/L or initiation of RRT
      For patients meeting diagnosis criteria for AKI according to RIFLE, AKIN or KDIGO, the stage based on percentage increase were determined by the ratio of peak SCr value obtained during hospitalization to baseline
      Abbreviations: acute kidney injury (AKI); risk, injury, failure, loss, end stage renal failure (RIFLE); Acute Kidney Injury Network (AKIN); Kidney Disease: Improving Global Outcomes (KDIGO); serum creatinine (SCr); renal replacement therapy (RRT)
      *Urine output was not used because records of hourly urine output were not available in the majority of patients

    • Markers such as NGAL, KIM1 and IL18 are surrogates for renal damage; their role as biomarkers to diagnose AKI, predict risk for AKI or predict progression of AKI to CKD is still under exploration
Microscopic (histologic) description
  • Developmental and cystic diseases
  • Glomerular disease (including monoclonal gammopathy of renal significance [MGRS] / paraprotein related kidney disease)

Glomerular lesion PAS / silver stain IF / IHC EM Differential diagnoses
Thick appearance of GBM Relatively acellular mesangial expansion / no double contour, feathery spikes on silver stain, Congo red positive Negative for IgG, IgA, IgM, C3 and C1q positive for 1 light chain, with smudgy mesangial and capillary wall pattern, often also in vessels (most often λ but κ can also form amyloid; rare cases of heavy chain amyloid exist) Randomly arranged, nonbranching fibrils of 9 - 11 nm diameter
Double contour Negative
Irregular or undetectable by LM Negative Basketweaving, thin GBM
Membranous (thick appearance of GBM), spikes by silver stain Granular capillary loop IgG polyclonal and C3 staining; in specific etiology positive for PLA2R, THSD7A, EXT1 / EXT2, NELL1 and others (Kidney Int 2023;103:469) Subepithelial deposits
Varying double contours by silver stain, negative Congo red Polyclonal IgG with lesser C3; positive DNAJB9 Randomly arranged fibrillary substructure 11 - 24 nm
Mesangial hypercellularity / mesangial expansion Varying mesangial expansion with nodules, thick GBM, arteriolar hyalinosis / no double contour Negative No deposits
Varying mesangial hypercellularity with nodules, thick GBM / no double contour Monoclonal light chain staining of GBM and tubular basement membrane Corresponding amorphous powdery deposits
Varying mesangial hypercellularity without nodules, thick GBM / no double contour Polyclonal IgG with full house staining (i.e., all immunoglobulins [IgG, IgA, IgM], C3 and C1q) Subendothelial deposits; may show fingerprint-like substructure; reticular aggregates in endothelial cells
IgA mesangial deposits Mesangial deposits
IgG (starry sky appearance by IF) or IgM predominant deposits Hump shaped deposits
C3 positive deposits Hump shaped deposits
Negative GBM thickening
Varying mesangial hypercellularity without nodules, thin GBM / no double contour Negative Extensive foot process effacement
Varying mesangial hypercellularity with segmental sclerosis / no double contour
Membranoproliferative glomerulonephritis (MPGN) Endocapillary / mesangial hypercellularity (membranoproliferative glomerulonephritis [MPGN]) can be nodular, double contour; crescents may be present (Am J Kidney Dis 2015;66:e19) C3 dominant or immunoglobulin (either monoclonal or polyclonal) Subendothelial deposits
Polyclonal IgG with full house staining (i.e., all immunoglobulins [IgG, IgA, IgM], C3 and C1q) Subendothelial deposits; may show fingerprint-like substructure; reticular aggregates in endothelial cells
Polyclonal IgG, C3, often C1q Mesangial deposits
Monoclonal light chain staining of GBM and tubular basement membrane Corresponding amorphous powdery deposits
IgG (starry sky pattern by IF) or IgM predominant deposits Hump shaped deposits
Polyclonal IgG with lesser C3; positive DNAJB9 Randomly arranged fibrillary substructure 11 - 24 nm
IgG predominance Microtubular or parallel array substructure
C3 only or C3 dominant staining, at least 2 intensity steps greater than IgG Dense mesangial nodules
C3 only or dominant staining, at least 2 intensity steps greater than IgG, limited or no immunoglobulin Deposits of varying density, which may be subendothelial, mesangial, often intramembranous permeating the GBM; can also have hump type subepithelial deposits
Strong, PAS positive deposits in capillary lumina Polyclonal IgG and strong IgM component, often with clonal shift (i.e., 1 light chain significantly dominant) Short fibrillary substructure
Glomerulosclerosis Usual type sclerosis, localized anywhere within the glomerular tuft, defined by obliteration of capillary lumens by increased matrix or hyalin Negative Extensive foot process effacement
Sclerosis involving the proximal tubular pole of the glomerulus, with adhesion to the proximal tubule, often with intracapillary foam cells
Sclerosis at vascular pole, often with vascular hyalinosis
  • Tip lesion variant of focal segmental glomerulosclerosis
    • Typically associated with maladaptive reaction to nephron loss, low nephron number or other overload (e.g., as in obesity related glomerulopathy) (Am J Kidney Dis 2015;66:e5)
Collapse and retraction of glomerular tuft, either segmental (involving part of the tuft) or global (involving all of the tuft), with proliferation of attached visceral epithelial cells Collapsing glomerulopathy due to HIV or SARS-CoV-2 may show reticular aggregates
Often with broad based adhesion, fibrous crescent or periglomerular fibrosis Nonspecific
Crescents Cellular, fibrocellular or fibrous, depending on degree of fibrous tissue Linear IgG stain along capillary wall, polyclonal, with discontinuous or even granular C3, of GBM No deposits
C3 dominant or immunoglobulin (either monoclonal or polyclonal) Subendothelial deposits
IgG (starry sky appearance by IF) or IgM predominant deposits Hump shaped deposits
IgA mesangial deposits Mesangial deposits
Minimal or no deposits
May also involve small vessels with vasculitis No deposits
  • Granulomatosis with polyangiitis (GPA)
  • Microscopic polyangiitis (MPA)
  • Eosinophilic polyangiitis (EPA)
  • Reference: Kidney Int Rep 2021;6:2718
Foamy podocytes No deposits Myelin body type inclusions in various cells, especially podocytes
Intraglomerular foamy macrophages No deposits
Varying mesangial hypercellularity and pale amorphous expansion of mesangial matrix Lobular pattern with membranoproliferative appearance with double contours of GBM No deposits Abundant type III banded collagen in glomeruli in mesangial, subendothelial areas
Abbreviations: DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9), exostosin 1 (EXT1) / exostosin 2 (EXT2), electron microscopy (EM), glomerular basement membrane (GBM), glomerulonephritis (GN), hematoxylin eosin staining (H&E), human immunodeficiency virus (HIV), immune fluorescence (IF), immunohistochemistry (IHC), lecithin cholesterol acyltransferase (LCAT), light microscopy (LM), neuroepidermal growth factor-like 1 ( NELL1), phospholipase A2 receptor (PLA2R), severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), thrombospondin type 1 domain containing 7A (THSD7A), thrombotic microangiopathy (TMA)
Adapted from Am J Kidney Dis 2022;80:119

  • Tubulointerstitial disease (including infectious disease)

Tubulointerstitial lesion PAS / silver stain Differential diagnoses
Tubular injury Cell detachment, individual cell injury / blebbing / degeneration / apoptosis
Cell detachment in isolation or with associated glomerular necrosis
Cell detachment in zones of injury
With immunglobulin deposition Tubulitis, TBMs stain strongly for IgG, variable C3 staining
Interstitial fibrosis and tubular atrophy Diffuse pattern Nonspecific
Striped pattern along medullary rays
Patchy / geographic, jigsaw puzzle pattern
  • Suggestive of chronic pyelonephritis, often with thyroidization appearance of the intratubular casts (resembling thyroid colloid) (Am J Kidney Dis 2016;68:e23)
Interstitial edema Increased interstitial space with loose appearance and normal thickness TBMs
Interstitial inflammation Medullary angiitis with increased neutrophils in vasa recta
Intratubular neutrophils forming plugs
Interstitial lymphocytic infiltrate
Lymphocytes and interstitial fibrosis
Plasmacellular infiltrate of IgG4 producing plasma cells and variable storiform fibrosis
Monomorphic sheets of lymphocytes, blasts or other cells
  • Kidney involvement by hematopoietic neoplasms
Eosinophils clustered in the interstitium
Nonnecrotizing granulomas
Necrotizing granulomas
Immune complex deposits Granular, discrete, immune complex deposits along TBM by IF and EM
Intratubular casts (Semin Diagn Pathol 2020;37:127) Pigmented (positive with Hall stain)
Pigmented (positive with antimyoglobin IHC and characteristic appearance by EM)
Iron pigment (positive with prussian blue stain and antihemoglobin IHC)
Tamm-Horsfall protein (pink, cloudy with PAS, pale eosinophilic with H&E)
  • Nonspecific
Fractured, glassy, PAS negative and H&E brightly eosinophilic casts with surrounding syncytial giant cell reaction
Crystals Polarizable
Nonpolarizable
Abbreviations: electron microscopy (EM), hematoxylin eosin staining (H&E), immunohistochemistry (IHC), tubular basement membrane (TBM)
Adapted from Am J Kidney Dis 2022;80:119

  • Vascular disease

Vascular lesion PAS / silver stain Differential diagnoses
Sclerosis Intimal fibrosis / medial hypertrophy
Thrombosis, necrosis and red blood cell fragments within vascular wall, mucoid intima expansion Arteriolar / glomerular predominance
Arteriolar / interlobular artery predominance, fibrinoid necrosis
Emboli Clear, needle shaped spaces with surrounding foreign body reaction in interlobular arteries, sometimes in smaller vessels, rarely in glomeruli
Vasculitis Inflammation with lymphocytes / PMNs; may be transmural or intimal
Endotheliosis Swollen endothelial cells
Abbreviations: antineutrophil cytoplasmic antibodies (ANCA), electron microscopy (EM), hematoxylin eosin staining (H&E), immunohistochemistry (IHC), International Society of Nephrology / Renal Pathology Society (ISN / RPS), tubular basement membrane (TBM), thrombotic microangiopathy (TMA)
Adapted from Am J Kidney Dis 2022;80:119

Microscopic (histologic) images

Contributed by Saskia von Stillfried, M.D.
Normal glomerulus

Normal glomerulus

Thick appearance of GBM

Thick appearance of GBM

Mesangial hypercellularity

Mesangial hypercellularity

Membranoproliferative glomerulonephritis

Membrano-proliferative glomerulonephritis

Focal segmental glomerulosclerosis

Focal segmental
glomerulosclerosis

Nodular glomerulosclerosis

Nodular glomerulosclerosis


Global glomerulosclerosis

Global glomerulosclerosis

Cellular crescent

Cellular crescent

Normal tubuli

Normal tubuli

Acute tubular injury

Acute tubular injury

Interstitial fibrosis and tubular atrophy

Interstitial fibrosis and tubular atrophy

Interstitial inflammation

Interstitial inflammation

Board review style question #1


Which glomerular lesion is present in the glomerulus shown in the image above?

  1. Endocapillary hypercellularity
  2. Extracapillary proliferation
  3. Membranoproliferative glomerulonephritis
  4. Mesangial hypercellularity
  5. Thick appearance of glomerular basement membrane
Board review style answer #1
D. Mesangial hypercellularity. There are > 4 mesangial cells per mesangial area. Answers A and B are incorrect because the glomerular tuft shows no endocapillary hypercellularity and no extracapillary proliferation is visible. Answers C and E are incorrect because the image shows mesangial hypercellularity but no basement membrane thickening as in membranoproliferative glomerulonephritis.

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Reference: Renal disease-general
Board review style question #2


Which glomerular lesion is present in the glomerulus shown in the image above?

  1. Extracapillary proliferation
  2. Fibrocellular crescent
  3. Global glomerulosclerosis
  4. Segmental glomerulosclerosis
  5. Tamm-Horsfall protein
Board review style answer #2
C. Global glomerulosclerosis. Global glomerulosclerosis is characterized by shrunken and retracted glomerular tuft with remaining PAS positive glomerular basement membrane and the faintly PAS positive fibrous matrix that replaces Bowman space. Answers A, B and D are incorrect because the glomerulus is completely sclerotic and not diagnostic for endocapillary hypercellularity, extracapillary proliferation or mesangial hypercellularity. Answer E is incorrect because the Bowman space is filled not with Tamm-Horsfall protein but with sclerotic matrix.

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Reference: Renal disease-general
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