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Podocytopathies

Nature Reviews Disease Primers volume 6, Article number: 68 (2020) Cite this article

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Abstract

Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin–angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

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Fig. 1: Worldwide prevalence of podocytopathies.
Fig. 2: Structure of the nephron, the glomerulus and the filtration barrier.
Fig. 3: Mechanical podocyte stress.
Fig. 4: Consequences of podocyte loss.
Fig. 5: Monogenetic diseases and SRNS.
Fig. 6: Causes and risk factors underlying podocytopathies across the lifespan.
Fig. 7: Pathology of podocytopathies.
Fig. 8: Diagnosis and management of paediatric patients with proteinuria or nephrotic syndrome.
Fig. 9: Diagnosis and management of adults with proteinuria or nephrotic syndrome.

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Acknowledgements

J.B.K. was supported by the NIDDK Intramural Research Program, NIH, Bethesda, MD (project ZO1 DK043308). K.S. is supported by NIDDK grants R01DK076077, R01 DK087635 and DP3 DK108220. H.-J.A. was supported by the Deutsche Forschungsgemeinschaft (AN372/24-1). F.H. was supported by the NIH through grant RO1-DK076683. This work was supported by the European Research Council under the Consolidator Grant RENOIR to P.R. (ERC-2014-CoG, grant number 648274). The authors thank A. M. Buccoliero, Meyer Children’s Hospital and Fiammetta Ravaglia, Florence, Italy, for help with histopathological images.

Author information

Authors and Affiliations

  1. Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA

    Jeffrey B. Kopp

  2. Division of Nephrology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

    Hans-Joachim Anders

  3. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Katalin Susztak

  4. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Katalin Susztak

  5. Department of Health Sciences, Università degli Studi di Milano, Milan, Italy

    Manuel A. Podestà

  6. Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

    Giuseppe Remuzzi

  7. Division of Pediatric Nephrology, Boston Children’s Hospital, Boston, MA, USA

    Friedhelm Hildebrandt

  8. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Friedhelm Hildebrandt

  9. Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy

    Paola Romagnani

  10. Nephrology Unit, Anna Meyer Children’s Hospital, Florence, Italy

    Paola Romagnani

Authors
  1. Jeffrey B. Kopp
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  2. Hans-Joachim Anders
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  3. Katalin Susztak
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  4. Manuel A. Podestà
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  5. Giuseppe Remuzzi
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  6. Friedhelm Hildebrandt
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  7. Paola Romagnani
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Contributions

Introduction (J.B.K., H.-J.A., K.S. and P.R.); Epidemiology (P.R.); Mechanisms/pathophysiology (J.B.K., H.-J.A., K.S., F.H. and P.R.); Diagnosis, screening and prevention (J.B.K., H.-J.A., M.A.P., G.R., F.H. and P.R.); Management (J.B.K., H.-J.A., M.A.P., G.R., F.H. and P.R.); Quality of life (H.-J.A. and P.R.); Outlook (J.B.K., H.-J.A., K.S. and P.R.); Overview of the Primer (P.R.). J.B.K. and H.-J.A. contributed equally.

Corresponding author

Correspondence to Paola Romagnani.

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Competing interests

F.H. is a co-founder and member of the scientific advisory board of Goldfinch-Bio. The other authors declare no competing interests.

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Nature Reviews Disease Primers thanks A. Bagga, K. Iijima, Moin Saleem and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

The American Kidney Fund: https://www.kidneyfund.org/

ClinGen: https://clinicalgenome.org

The Dutch Kidney Foundation: https://nierstichting.nl

European Rare Kidney Disease Reference Network: https://www.erknet.org/

The Federation for Each Renal Genetic Disease: http://federg.org

La Nuova Speranza non-profit foundation: http://www.lanuovasperanza.org

The National Kidney Foundation: https://www.kidney.org

The National Organization for Rare Disorders: https://rarediseases.org/

NephCure: https://nephcure.org/

The Nephrotic Syndrome Association, Italy: http://www.asnit.org

Supplementary information

Glossary

Chronic kidney disease

(CKD). Abnormalities in kidney structure or function (urine composition or impaired excretory function) lasting >3 months; progression is based on the cumulative degeneration of nephrons, the independent functional units of the kidney.

Glomerular filtration barrier

The parts of the nephron in which the filtration process of the blood takes place and the primary filtrate is formed; podocytes and their interdigitating foot processes, connected by the slit diaphragm, are essential components of the size-selective and charge-selective filtration barrier in the glomerulus.

Nephrotic syndrome

A clinical syndrome defined by symmetrical oedema, hypoalbuminaemia, hyperlipidaemia and proteinuria of >3 g per day, caused by podocyte injury (from any cause) and leading to severe alterations of the glomerular filtration barrier.

End-stage kidney disease

(ESKD). When nephron loss during chronic kidney disease reaches the point that homeostasis can no longer be maintained, presenting as renal failure (uraemia).

Glomerular filtration rate

(GFR). The central parameter of excretory kidney function that can be accurately measured as the clearance of injected tracers over time or can be estimated from a number of clinical and laboratory parameters, including creatinine and cystatin C.

Podocyte shear stress

The hydrostatic pressure gradient across the glomerular filtration barrier that podocytes must withstand to avoid detachment and loss into the urine.

Hyperfiltration

An elevated total glomerular filtration rate (GFR) is called hyperfiltration and implies hyperfiltration of every nephron; however, reduced total GFR implies compensatory hyperfiltration of the remnant nephrons, as a central mechanism for the progression of chronic kidney disease by promoting podocyte shear stress, podocyte detachment and adaptive focal segmental glomerulosclerosis.

Oncotic pressure

The pressure resulting from the difference within the extracellular fluid between the protein contents of plasma and interstitial fluid.

Syndromic disorders

Genetic diseases with manifestations in different organ systems due to the expression of the mutated gene in diverse tissues.

Mitotic catastrophe

A type of cell death that occurs during mitosis, resulting from DNA damage or deranged spindle formation and linked to checkpoint failure.

Overfill scenario

Nephrotic syndrome associated with oedema secondary to a positive sodium balance, mainly due to sodium retention; patients present with intravascular hypervolaemia (hypertension) and interstitial hypervolaemia (oedema).

Acute kidney injury

(AKI). An abrupt decrease in kidney function, resulting in the retention of urea and other nitrogenous waste products in the blood and in the dysregulation of extracellular volume and electrolytes.

Underfill scenario

Nephrotic syndrome associated with oedema secondary to a rapid fall in blood oncotic pressure with volume shifts into the interstitial compartments; patients present with intravascular hypovolaemia and interstitial oedema.

Renin–angiotensin system

The hormone system that regulates blood pressure, volume and electrolyte balance, and systemic vascular resistance.

Anasarca

General swelling of the whole body that can occur when the tissues of the body retain too much fluid.

Cushingoid features

Weight gain, hypertension, cutaneous striae rubrae and easy bruising.

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Kopp, J.B., Anders, HJ., Susztak, K. et al. Podocytopathies. Nat Rev Dis Primers 6, 68 (2020). https://doi.org/10.1038/s41572-020-0196-7

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