IgA nephritis

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Classification according to ICD-10
N02.- Recurrent and persistent hematuria
ICD-10 online (WHO version 2019)

The IgA nephropathy or IgA nephropathy, formerly also called Crohn Berger, is the most common primary chronic disease of the renal corpuscles (glomeruli) , it is one of the idiopathic glomerulonephritis . It is characterized by the deposition of immunoglobulin A in the intermediate tissue (mesangium) of the kidney corpuscle. The most important symptom is the detection of red blood cells in the urine without symptoms ( asymptomatic hematuria ). Most of the time the course is benign, but about one in five sufferers has a progressive loss of kidney function . The treatment depends on the severity of the disease and ranges from follow-up controls to lowering blood pressure with ACE inhibitors and AT1 antagonists to immunosuppressive therapy.

Symptoms

Clinical symptoms of IgA nephritis are temporary (intermittent), painless macrohematuria (visible blood in the urine ) after unspecific infections of the upper respiratory tract, after gastrointestinal infections or pneumonia . However, constant microhematuria (invisible, but laboratory-detectable blood in the urine) can also exist. Optionally, there may be increased excretion of protein in the urine (proteinuria) ; nephrotic syndrome is rare. Some of the patients also develop high blood pressure (arterial hypertension) . Erythrocyte casts and dysmorphic (deformed) erythrocytes can be detected in the urine .

Epidemiology and course

IgA nephritis is the most common inflammatory disease of the kidney corpuscles ( glomerulonephritis ) worldwide . Men are affected about twice as often as women. The highest number of new cases ( incidence ) is described in Japan and Korea. In Japan, 50% of all new cases of glomerulonephritis and 40% of all cases of kidney failure requiring dialysis are due to IgA nephritis. In Europe, IgA nephritis accounts for 30% of the total number of glomerulonephritis; in the USA, the proportion is 10%. These differences suggest that certain populations have an increased hereditary (genetic) disposition (predisposition) to develop IgA nephritis.

The long-term prognosis is favorable. Only about 25 to 30 percent of patients develop dialysis-requiring kidney failure within 10 years. Risk factors for an unfavorable ( progressive ) course are high blood pressure , urine protein excretion (proteinuria) over 1 g / 24 h and constant detection of small amounts of invisible red blood cells (erythrocytes) in the urine ( microhematuria ).

Visible blood in the urine ( macrohematuria ) in connection with infections and the spontaneous improvement of proteinuria indicate a favorable course.

In the histological examination of a tissue sample from the kidney, certain findings indicate a poor prognosis:

The frequency of proliferative glomerulonephritis is between 8 and 36 percent of the biopsies in different studies. When interpreting these data, it should be borne in mind that a biopsy is usually only performed if the clinical findings indicate an unfavorable prognosis for the disease.

The correspondence between clinical and histological prognostic factors is often only slight.

Pathogenesis

In IgA nephritis, immune complexes containing IgA are deposited in the mesangium of the kidney corpuscle . However, there is no relationship between the amount of IgA in the glomeruli and the severity of the disease. The transition to normal results is fluid; IgA deposits (mostly together with IgG and C3 ) can be detected in the kidneys in 4 to 16 percent of the healthy population . For every 80 healthy people with IgA deposits in the kidneys, there is only one patient with IgA nephritis. When a kidney from a patient with IgA nephritis is transplanted into a patient without IgA nephritis , the immune complexes slowly dissolve.

The current model of disease development assumes that the IgA nephritis disease process proceeds in four stages:

Deviating glycosylation

Patients with IgA nephritis have an increased proportion of IgA1 molecules which, due to a genetic variation, have a reduced proportion of o-glycosidically bound, galactose- containing carbohydrate side chains .

IgG class IgA1 autoantibodies

The deviating glycosylation of the IgA molecules means that the immune system may recognize them as foreign. As a result, autoantibodies of the IgG class against the IgA1 molecules with reduced galactose-containing carbohydrate side chains are formed.

Formation of circulating immune complexes

The IgG autoantibodies bind to the IgA1 molecules, which have a reduced proportion of galactose-containing carbohydrate side chains, and circulating immune complexes are formed . These immune complexes are deposited in the mesangium of the kidney corpuscles.

Activation of the mesangial cells

The IgG / IgA1-containing immune complexes may activate the mesangial cells via a mechanism that is not yet known. These begin to divide and secrete extracellular matrix , cytokines and chemokines , which can lead to inflammatory damage to the kidney corpuscles.

genetics

IgA nephritis is usually sporadic, but families with an increased incidence of the disease have also been described. In both sporadic and familial cases, similar defects were found in galactosyltransferases and sialyltransferases , which are responsible for the glycosylation of IgA. In healthy first-degree relatives of patients with familial IgA nephropathy, elevated serum levels of IgA with decreased galactosylation are found.

Since the process of disease development takes place in several stages, each of which is controlled by very different genes, it is not surprising that genome-wide association studies have now identified five different loci that influence the risk of developing IgA nephritis: Im Main histocompatibility complex on chromosome 6p21 , in the locus of complement factor H (see also complement system ) on chromosome 1q32 and in a gene cluster on chromosome 22q22 .

diagnosis

Clinical picture, urine findings and possible proteinuria provide clues. The IgA level in the serum is occasionally increased, but not indicative of the presence of the disease.

The diagnosis can be confirmed with a kidney biopsy. Histologically there are changes in the mesangium in the renal corpuscles with matrix proliferation , immunohistochemical detection of IgA deposits and proliferation of mesangium cells . Indications of severe damage to the kidney corpuscle are cell growth outside the vascular cluster (extracapillary proliferation) or within the capillary loops (endocapillary proliferation), as well as dead cells (necrosis) .

The course of IgA nephritis is generally benign if the only symptom of the disease is blood in the urine (hematuria) . Special therapy is then not required. A kidney biopsy is therefore normally only performed if there are indications of a more severe course of the disease, such as urine protein excretion (proteinuria) over 0.5 g / 24 h (at least over 1.0 g / 24 h), increased serum creatinine as an indication of impaired kidney function or high blood pressure.

Differential diagnosis

Other glomerular diseases associated with blood in the urine (hematuria) are

Non-glomerular causes of hematuria are:

Cancer of the lower urinary tract in particular must be excluded at the age of 40 and over:

In old age, the

lead to hematuria.

classification

Oxford Classification
of Ig A Nephropathy
Mesangial hypercellularity
In ≤ 50% of the glomeruli M0
In> 50% of the glomeruli M1
Segmental glomerulosclerosis
Missing S0
Available S1
Endocapillary hypercellularity
Missing E0
Available E1
Tubular atrophy / interstitial fibrosis
0–25% of the area of ​​the renal cortex T0
26–50% of the area of ​​the renal cortex T1
> 50% of the area of ​​the renal cortex T2

IgA nephritis can be classified according to the severity of the tissue (histological) changes:

In 2009 a new classification system (Oxford Classification of IgA Nephropathy) was presented. The Oxford classification is based on only four pathological findings, the assessment of which depends only to a small extent on the person of the examiner (low interobserver variability ) and which enable a reliable prediction of the course of the disease:

  1. Increased cell content of the mesangium (mesangial hypercellularity),
  2. Scarring of sections of the kidney corpuscle (segmental glomerulosclerosis)
  3. increased cell content of the capillaries of the renal corpuscle (endocapillary hypercellularity) and
  4. Shrinkage of kidney tubules (tubular atrophy ) / increase in connective tissue ( interstitial fibrosis ).

therapy

The therapy depends on the severity of the disease, measured by protein excretion, blood pressure, kidney function (glomerular filtration rate) and changes in kidney tissue.

In patients with minor changes in the urine diagnosis , normal kidney function, and normal blood pressure, annual follow-up checks over a period of at least ten years are recommended. Drug therapy is not required.

If the proteinuria is over 0.5 g / 24 h, ACE inhibitors or angiotensin receptor blockers are prescribed. The dose is increased until the proteinuria falls below 1 g / 24 h. If the proteinuria is initially over 1 g / 24 h, a target blood pressure below 125/75 mmHg is aimed for, otherwise the target blood pressure is below 130/80 mmHg.

If these measures do not succeed in reducing proteinuria below 1 g / 24 h within 3 to 6 months, glucocorticoids have been given for 6 months if the glomerular filtration rate is above 50 ml / min. With absolute certainty, however, the value of an immunosuppressive treatment has not been established; The German STOP-IgAN study on this question was carried out with funding from the Federal Ministry (BMBF) and under the direction of the Aachen University Hospital. The study showed that with optimized basic therapy (i.e. blood pressure adjustment etc.) an additional cortisone therapy or even stronger immunosuppression did not bring any benefit, only side effects. Thus, immunosuppressive treatment for IgA nephritis should currently only be carried out after carefully weighing the risks and patient characteristics. If the kidney function is already severely restricted (glomerular filtration rate below 30 ml / min), immunosuppressive treatment is no longer beneficial, unless there is rapidly progressive glomerulonephritis .

In the American-speaking world, the administration of fish oil is common for therapy-resistant proteinuria .

With rapidly progressive loss of renal function with histological evidence of proliferative lesions in more than 50% of the renal corpuscles, glucocorticoids are combined with cyclophosphamide . However, this therapy recommendation is based on weak data and is not supported by randomized studies.

In the case of nephrotic proteinuria and histological evidence of minimal glomerular changes, the therapy is analogous to minimal change glomerulonephritis .

If the proteinuria can be reduced to below 1 g / day through treatment , this leads to a significant improvement in the prognosis of the disease.

Azathioprine , mycophenolate mofetil and platelet aggregation inhibitors do not appear to influence the course of the disease and their use is no longer recommended.

Surgical removal of the tonsils ( tonsillectomy ) is also no longer recommended.

If, despite adequate treatment, the impaired kidney function progresses to the terminal stage requiring dialysis , kidney transplantation is the treatment of choice. After a successful transplant, IgA nephritis recurs in about 20 to 50 percent of patients in the transplanted kidney. The disease is usually milder in the transplant. During the first ten years after transplantation, there is seldom loss of the graft due to the recurrence of the underlying disease, but in the long term the results are somewhat less favorable than with other kidney diseases.

Web links

Individual evidence

  1. ↑ Alphabetical directory for the ICD-10-WHO version 2019, volume 3. German Institute for Medical Documentation and Information (DIMDI), Cologne, 2019, p. 595
  2. ↑ F. Thaiss, RAK Stahl: IgA nephropathy: clinical features, pathogenesis and therapy of the most common glomerulonephritis . In: Deutsches Ärzteblatt . No. 97 , 2000, pp. 2708–2711 ( article [PDF]).
  3. ↑ JV Donadio, JP Grande: Medical Progress: IgA Nephropathy . In: N Engl J Med . No. 347 , 2002, pp. 738-748 ( abstract ).
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  5. ↑ a b Jwa-Kyung Kim, et al .: Clinical features and outcomes of IgA nephropathy with nephrotic syndrome . In: Clinical Journal of the American Society of Nephrology . 7, No. 3, March 2012, ISSN  1555-905X , pp. 427-436. doi : 10.2215 / CJN.04820511 . PMID 22223610 .
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  7. ↑ a b c James A. Tumlin et al .: Idiopathic IgA Nephropathy: Pathogenesis, Histopathology, and Therapeutic Options . In: Clin J Am Soc Nephrol . No. 2 , 2007, p. 1054-1061 ( abstract ).
  8. ↑ Jürgen Floege: The pathogenesis of IgA nephropathy: what is new and how does it change therapeutic approaches? . In: American Journal of Kidney Diseases . 58, No. 6, December 2011, pp. 992-1004. doi : 10.1053 / j.ajkd.2011.05.033 . PMID 21872377 .
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  12. ↑ Y Hiki, et al .: Analyzes of IgA1 hinge glycopeptides in IgA nephropathy by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry . In: Journal of the American Society of Nephrology: JASN . 9, No. 4, April 1998, ISSN  1046-6673 , pp. 577-582. PMID 9555659 .
  13. ^ AC Allen, et al .: Analysis of IgA1 O-glycans in IgA nephropathy by fluorophore-assisted carbohydrate electrophoresis . In: Journal of the American Society of Nephrology: JASN . 10, No. 8, August 1999, ISSN  1046-6673 , pp. 1763-1771. PMID 10446944 .
  14. ↑ J Mestecky, et al .: Role of aberrant glycosylation of IgA1 molecules in the pathogenesis of IgA nephropathy . In: Kidney & Blood Pressure Research . 31, No. 1, 2008, ISSN  1423-0143 , pp. 29-37. doi : 10.1159 / 000112922 . PMID 18182777 .
  15. ↑ Hitoshi Suzuki, et al .: Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity . In: The Journal of Clinical Investigation . 119, No. 6, June 2009, ISSN  1558-8238 , pp. 1668-1677. doi : 10.1172 / JCI38468 . PMID 19478457 .
  16. ^ Ali G Gharavi, et al .: Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy . In: Journal of the American Society of Nephrology: JASN . 19, No. 5, May 2008, ISSN  1533-3450 , pp. 1008-1014. doi : 10.1681 / ASN.2007091052 . PMID 18272841 .
  17. ↑ Ian SD Roberts, et al .: The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility . In: Kidney International . 76, No. 5, September 2009, ISSN  1523-1755 , pp. 546-556. doi : 10.1038 / ki.2009.168 . PMID 19571790 .
  18. ↑ Daniel C Cattran, et al .: The Oxford classification of IgA nephropathy: rational, clinicopathological correlations, and classification . In: Kidney International . 76, No. 5, September 2009, ISSN  1523-1755 , pp. 534-545. doi : 10.1038 / ki.2009.243 . PMID 19571791 .
  19. ^ Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group . KDIGO Clinical Practice Guideline for Glomerulonephritis. In: Kidney inter Suppl . No. 2 , 2012, p. 139–274 ( clinical guideline English). Clinical guideline ( Memento of the original from July 16, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and not yet checked. Please check the original and archive link according to the instructions and then remove this notice.  @1@ 2Template: Webachiv / IABot / www.kdigo.org
  20. ^ R. Coppo et al .: IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria . In: J Am Soc Nephrol . No. 18 , 2007, p. 1880-1888 ( abstract ).
  21. ^ Carlo Manno, et al .: Randomized controlled clinical trial of corticosteroids plus ACE inhibitors with long-term follow-up in proteinuric IgA nephropathy . In: Nephrology Dialysis Transplantation . 24, No. 12, December 2009, ISSN  1460-2385 , pp. 3694-3701. doi : 10.1093 / ndt / gfp356 . PMID 19628647 .
  22. ↑ Thomas Rauen, et al .: Intensive Supportive Care plus Immunosuppression in IgA Nephropathy . In: New England Journal of Medicine . 373, No. 23, December 2015, pp. 2225–2236. doi : 10.1056 / NEJMoa1415463 . PMID 26630142 .
  23. ↑ Jürgen Floege, Frank Eitner: Current therapy for IgA nephropathy . In: Journal of the American Society of Nephrology: JASN . 22, No. 10, October 2011, ISSN  1533-3450 , pp. 1785-1794. doi : 10.1681 / ASN.2011030221 . PMID 21903997 .
  24. ↑ HN Reich et al .: Remission of Proteinuria Improves Prognosis in IgA Nephropathy . In: J Am Soc Nephrol . No. 18 , 2007, p. 3177-3183 ( abstract ).
  25. ↑ Jürgen Floege, John Fehally: Treatment of IgA nephropathy and Henoch-Schönlein nephritis. . In: Nature Reviews Nephrology . 9, No. 6, June 2013, pp. 320-327. doi : 10.1038 / nrneph.2013.59 . PMID 23545591 .
  26. ↑ Bo Ying Choy, et al .: Renal transplantation in patients with primary immunoglobulin A nephropathy . In: Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association - European Renal Association . 18, No. 11, November 2003, ISSN  0931-0509 , pp. 2399-2404. PMID 14551373 .
  27. ^ AY Wang, et al .: Recurrent IgA nephropathy in renal transplant allografts . In: American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation . 38, No. 3, September 2001, ISSN  1523-6838 , pp. 588-596. PMID 11532693 .
  28. ↑ C Ponticelli, et al .: Kidney transplantation in patients with IgA mesangial glomerulonephritis . In: Kidney International . 60, No. 5, November 2001, ISSN  0085-2538 , pp. 1948-1954. doi : 10.1046 / j.1523-1755.2001.00006.x . PMID 11703614 .