Renal manifestations of systemic autoimmune diseases

Manifestations rénales des maladies auto-immunes systémiques

Renal manifestations of systemic autoimmune diseasesIntroduction:

Systemic autoimmune diseases can have severe kidney involvement.Renal involvement may be clinically silent, but may also cause serious permanent damage that is extremely damaging to the patient.

This is why great vigilance is required vis-à-vis the renal involvement in any systemic disease involving this risk. In this article, we will review current knowledge about renal complications of major systemic autoimmune diseases, as well as screening and management modalities. The majority of patients with systemic autoimmune disease being followed simultaneously or successively by teams of nephrology, rheumatology or other specialties, it is essential that there is a good communication between all stakeholders.

The major systemic autoimmune diseases that affect the kidney with high frequency are systemic lupus erythematosus and systemic vasculitis. However, many other systemic conditions, including scleroderma and rheumatoid arthritis, may also be associated with kidney disease. Renal involvement is possible in rheumatoid arthritis, but infrequent, and most often results from treatments used or amyloidosis caused by the prolonged state of the acute phase of inflammation. In particular, the renal adverse effects of nonsteroidal anti-inflammatory drugs are better and better known. Severe vasculitis involving the kidney may occur in rheumatoid arthritis and should be treated in the same way as primary vasculitis with renal involvement. This review will focus on systemic lupus erythematosus, systemic vasculitis and scleroderma.

Systemic lupus erythematosus:

The etiology of systemic lupus erythematosus is poorly understood. It is characterized by the activation of polyclonal B cells and the presence of autoantibodies. In kidney disease, antibodies and complement components are usually present in the kidneys. In a retrospective study of approximately 1,000 patients with systemic lupus erythematosus hospitalized in a rheumatology department, 16% had renal involvement from the outset and this proportion increased to 50% during follow-up. In the many other published series, the number of patients with lupus who develop kidney disease ranges from 25 to 65%. In most cases, kidney disease develops within three years of the diagnosis of systemic disease.


The nature of renal disease caused by systemic lupus erythematosus varies widely from patient to patient and can result from various pathological processes. It may be minimally invasive nephropathy, proliferative glomerulonephritis, membranous glomerulonephritis, tubulointerstitial lesions and, in some cases, renal vascular thrombosis. The most commonly adopted classification system is anatomopathologically based and was developed by the World Health Organization. The abnormalities are classified among others according to the degree of cellular proliferation. In type 1, there is no obvious cell proliferation. Type 2 is characterized by mesangial cell proliferation. In type 3, cell proliferation is focal (present in a number of glomeruli only). In type 4, proliferation is diffuse (present in all glomeruli). Croissants can appear in types 3 and 4; they are caused by the proliferation of monocytes in Bowman’s capsule. Type 5 disease is membranous nephropathy.

Although the classification of the World Health Organization is useful, different types may be observed to varying degrees in the same patient, simultaneously or consecutively, and the classification focuses only on the predominant abnormalities. Other scoring systems, which quantify the degree of chronic fibrosis, particularly that affecting the tubules and interstitial tissue, are more usefully correlated with long-term renal prognosis. The activity / chronicity index of the US National Institutes of Health provides a measure of the current activity levels of the disease and irreversible chronic lesions. This may be useful in assessing the predictable degree of reversibility of the lesions and, therefore, the potential benefit of immunosuppression. About 60-70% of biopsied patients have tubulo-interstitial changes.

Proliferative disease:

The most common histopathological picture is proliferative glomerulonephritis. Proliferation ranges from mesangial proliferation to focal or diffuse proliferation with the presence of crescents. There is usually renal immunoglobulin and complement deposition that may be the direct cause of kidney damage.

Membranous disease:

Certain localizations of the immune deposits in the glomeruli may, through the inflammatory reaction they cause, associate with membranous nephropathy. The usual aspect is that of subepithelial deposits of immunoglobulins and complement with little cellular infiltration or proliferation.

Tubulointerstitial disease:

Renal inflammation, whether glomerular or otherwise, can lead to inflammatory and fibrotic changes in the renal tubules and interstitial tissue that may damage the tubules and interstitial support tissue around the tubules and glomeruli. In systemic lupus erythematosus, there are often immune complexes and an inflammatory infiltrate in the interstitial tissue.

Renal vascular thrombosis:

Renal vascular thrombosis of systemic lupus erythematosus is associated with the presence of antiphospholipid antibodies. It can be arterial or venous. Thrombosis of small vessels may cause noninflammatory microangiopathy.Thrombotic occlusion or narrowing of renal arterioles causes glomerular ischemia that triggers renin secretion and the production of angiotensin II, which causes severe hypertension.

The effect is similar to that found in malignant hypertension.

Intraglomerular thrombosis may be responsible for permanent loss of filtration and glomerular function without obvious proteinuria or other urinary abnormalities. Some degree of intraglomerular thrombosis often coexists during systemic lupus erythematosus with focal or diffuse proliferative glomerulonephritis. Small vessel thrombosis may occur in the absence of detectable antiphospholipid antibodies, but sometimes thrombocytopenia and often complement glomerular deposition and immune complexes occur.


Renal impairment of systemic lupus erythematosus can cause a range of abnormalities, ranging from asymptomatic proteinuria or microscopic hematuria with normal renal function to severe nephrotic syndrome or renal failure. acute.Moderate alterations may occur intermittently. Several clinical pictures can be described.

Asymptomatic forms:

Asymptomatic renal impairment is usually detectable in the form of moderate proteinuria or microscopic hematuria.

The possibility of clinically silent kidney disease is well established; when biopsies are performed, diffuse proliferative glomerular lesions are observed in a proportion of cases that can be up to 45%. Typically, kidney damage fluctuates with other systemic manifestations of the disease and can become more severe at any time.

Severe nephrotic syndrome:

A nephrotic syndrome may develop in a context of hypertension and hematuria with fairly rapid development of significant renal damage. These situations are typically associated with significant extrarenal disease activity and the alternation of relapses and remissions is the same for kidney disease as for extrarenal disease. In the absence of treatment, the evolution is in rule towards the final renal insufficiency or the death in the space of 2 years approximately.

Isolated nephrotic syndrome:

The nephrotic syndrome may be accompanied only by discrete renal lesions, with hematuria simply microscopic and sometimes moderate hypertension. Evolution is usually slowly progressive and associated with mild systemic manifestations. For about half of these patients, the ultimate course will be towards end-stage renal failure, but only after many years.

Rapidly progressive nephropathy:

A minority of patients present themselves immediately with a serious and rapidly progressive disease, leading in the short term to end-stage renal failure, despite most often aggressive therapy. There are usually serious extrarenal manifestations, severe hypertension and often encephalopathy with papilledema. Scattered capillary thrombi and sometimes croissants can be observed histologically. In rare cases, acute oligoanuric renal failure occurs, related to the activity of the disease itself or the administration of nonsteroidal anti-inflammatory drugs. The clinical picture may be very similar to that of thrombotic thrombocytopenic purpura, with microangiopathic haemolytic anemia, seizures and acute renal failure. This is especially true during pregnancy and in patients with lupus anticoagulants.

Distal tubular acidosis:

Distal tubular acidosis may develop in systemic lupus erythematosus, but its clinical consequences are usually minimal, with the possible exception of nephrocalcinosis and stone formation.


It is difficult to develop a kidney disease management program without having a biopsy. However, when active therapy with cyclophosphamide or plasma exchange is indicated anyway because of the severity of extrarenal disease, it must be taken into account that the results of the renal biopsy are unlikely to alter the treatment regimen. that this gesture is not without risks.

Minor renal abnormalities:

When blood pressure and renal function are normal, urinary sediment does not contain red blood cells and proteinuria is less than 1 gd -1 , no specific treatment is required for minimal abnormalities or pure mesangettes.

Nonsteroidal anti-inflammatory drugs should be used with caution as they may reduce the rate of glomerular filtration.

Moderate renal abnormalities:

Focal proliferative glomerular abnormalities do not necessarily imply treatment, although the use of low doses of corticosteroids and cytotoxic agents has had its supporters. In cases of marked segmental proliferation with significant proteinuria, renal failure and nephrotic syndrome, it is usual to treat patients as if they had diffuse proliferative glomerulonephritis.

Membranous nephropathy:

Usually, no specific treatment is indicated for membranous nephropathies with asymptomatic hematuria and stable renal function. Corticosteroids do not seem able to control proteinuria and the role of cytotoxic agents is unclear. In case of sudden deterioration of renal function, a new biopsy is necessary to eliminate a more active aspect of the disease. In a small study, ciclosporin was used in systemic lupus erythematosus (SLE) membranous nephropathy and proteinuria decreased in all treated patients.

Serious proliferative abnormalities:

Diffuse proliferative glomerulonephritis and severe forms of focal proliferative glomerulonephritis are usually aggressively treated when there is a nephrotic syndrome, abnormalities of urinary sediment indicating activity or renal failure. However, the evolution is very variable from one patient to another and the rigid application of protocols from clinical trials may expose patients whose disease is not severe or respond very well to excessive immunosuppression.Corticosteroids are effective but have a high dose, a significant morbidity. Oral prednisolone has been recommended at a dose of 1 to 2 mg kg -1 d -1 , but the current rule is not to exceed 60 mg d -1 approximately. The use of intravenous methylprednisolone bolus (0.5 to 1 gd -1 for 3 days) may reduce the long-term side effects of corticosteroids without losing effectiveness. Following boluses, prednisolone is usually maintained until the disease goes into remission and then gradually disappears.

It is usual to add a cytotoxic agent; this attitude is largely based on the results of a National Institutes of Health study in which patients with kidney disease were randomized to one of five treatment regimens: high-dose prednisolone (1 mg kg -1 d -1 as a loading dose), azathioprine (up to 4 mg kg -1 d -1 ), oral cyclophosphamide (up to 4 mg kg -1 d -1 ), cyclophosphamide and azathioprine combined orally (up to 1 mg kg -1 d -1 ) or intravenous cyclophosphamide (0.75 gm -2 every 3 months, with increases up to 1 gm -2 if nadir leukocytes were not less than 4 Å ~ 10 9 l -1 ). Low doses of prednisolone (0.5 mg kg -1 d -1 ) were added to all cytotoxic treatments.

The risk of developing renal failure was greater in patients treated with corticosteroids alone than in all other groups.However, only the difference between intravenous bolus cyclophosphamide and high-dose prednisolone was statistically significant. In patients receiving cytotoxic drugs, the incidence of malignancies was lowest in the cyclophosphamide group. The highest risk of infection occurred in the high-dose corticosteroid group. Haemorrhagic cystitis, myelosuppression and gonadal toxicity were only observed with oral cyclophosphamide.

Intravenous methylprednisolone monthly for 6 months was compared to monthly intravenous cyclophosphamide for 6 months, with or without maintenance infusion every 3 months for the next 2 years. Only patients in the latter group had a significant advantage in terms of renal disease progression, and the addition of quarterly doses of cyclophosphamide reduced the frequency of recurrence by 50 to 10% over 5 years. The risks of this long-term cytotoxic treatment are, however, significant. Other groups performed well using induction therapy with methylprednisolone followed by oral maintenance therapy with prednisolone and a cytotoxic agent. A study of 65 cases of severe diffuse proliferative disease showed a remission rate of 29% with monthly intravenous injections of methylprednisolone, 65% with cyclophosphamide monthly and 85% with the combination of both. Despite the lack of a controlled study of a large number of cases demonstrating that cyclophosphamide is superior to azathioprine, there is consensus that this is the case. There appears to be a slight advantage in using intravenous cyclophosphamide rather than oral cyclophosphamide.

Relapse of lupus nephritis and long-term monitoring:

Patients who have had kidney disease should have lifetime monitoring of blood pressure, creatinine (or creatinine clearance) and urine strip every 3 to 6 months. When there is deterioration of renal function, significant proteinuria or hematuria, renal biopsy should be considered and nephrologist consulted.

Lupus nephropathies often relapse after treatment; if the clinical characteristics have changed or if a significant period of time has elapsed since the last renal biopsy, the latter must be repeated. In case of active disease without major chronic lesions, it is usual to resume immunosuppression, as above. In some patients, relapses are early and frequent, which may warrant testing of a more experimental treatment, such as mycophenolate.

Other therapeutic agents:

Several publications suggest that mycophenolate can reduce proteinuria and improve kidney function. In a series of 13 subjects who did not respond to conventional therapy or who had relapsed, mycophenolate was associated with a significant decrease in creatinine and proteinuria, as well as a normalization of urinary sedimentation. In a small randomized study, 42 patients with diffuse proliferative nephropathy were randomly assigned to the combination of prednisolone and mycophenolate for 12 months, or prednisolone and cyclophosphamide for 6 months, followed by prednisolone and azathioprine. 6 more months. The response to treatment was similar in both groups. However, the trial excluded patients with serum creatinine greater than 300 μmol l -1 , those with life-threatening comorbidities such as cerebral involvement, and those whose history suggested a lack of compliance. , those who had received cyclophosphamide in the past six months, and those who had taken moderate doses of oral prednisolone for more than 2 weeks.

A recent publication reported total or partial remission in 12 cases of proliferative disease treated with mycophenolate.

In contrast, only two responses were observed in six cases of lupus membranous nephritis and the mean follow-up was only 15.3 months. Mycophenolate is widely used in kidney transplants and the reference dosage would be 1 g twice daily for an individual weighing 70 kg. The drug is well tolerated and there is no need to routinely monitor serum concentrations.

The addition of corticosteroids to ciclosporin at a dose of 5 mg kg -1 d -1 has been associated with an improvement in renal function. Plasma exchanges showed no significant benefit in diffuse proliferative lupus glomerulonephritis. From the results obtained in a small series of patients, intravenous immunoglobulins could provide some benefit in membranous or membranoproliferative lupus glomerulonephritis resistant to conventional treatment.

In 14 randomized patients, monthly intravenous immunoglobulin infusions were comparable in efficacy to intravenous cyclophosphamide as maintenance therapy, but all patients had previously been remitted with cyclophosphamide.

In the general case, the treatment regimen for severe proliferative diffuse glomerulonephritis in the context of systemic lupus erythematosus can be stated as follows. Corticosteroid therapy involves intravenous administration of methylprednisolone at a dose of 0.5-1 gd -1 for 3 days followed by oral prednisolone at a dose of 0.5-1 g kg -1 d -1 . is then gradually decreased to reach a minimum dose, if possible zero. Cyclophosphamide is usually added at a dose of 1-2 mg kg -1 d -1 for 2-6 months, followed by azathioprine at 1-2 mg kg d -1 . Intravenous boluses of cyclophosphamide may also be used in some cases. In the event of a contraindication to previous treatments or in the absence of a response, ciclosporin can be tested at a dose of 5 mg kg -1 d -1 . According to the findings of a recent meta-analysis, the combination of cyclophosphamide and corticosteroids remains the best option for preserving renal function in patients with diffuse proliferative lupus glomerulonephritis.

End-stage renal failure:

Patients who have lost renal function require substitution therapy. In the event of rapidly progressive renal deterioration, regular nephrology follow-up is required to plan the locum. If the disease was previously slowly progressive, it usually remains relatively silent on dialysis. On the other hand, if the disease was aggressive and rapidly progressive, it can remain active and symptomatic. For a significant proportion of patients, death occurs within a few months after the onset of dialysis; however, 10 to 28% of them, according to the series, can find a renal function sufficient to interrupt the dialysis. The presence of an active lupus anticoagulant may be responsible for thrombosis of the fistula.

Transplantation is often postponed for 1 year after the onset of dialysis to await maximal renal functional recovery and, in some cases, to give the patient time to recover from previous immunosuppression. Lupus nephritis recurs in approximately 3 to 4% of transplant patients.

General aspects of the treatment:

Patients with lupus nephritis may have to deal with the many problems that affect any patient with kidney disease.Hypertension can promote worsening of kidney damage and is a cardiovascular risk factor, which may require the prescription of several antihypertensive drugs. In black skin patients, calcium channel blockers or diuretics may be indicated. Diuretics are usually the appropriate treatment in all hypertensive patients with water-soluble retention, especially in cases of nephrotic syndrome. In the absence of water-soluble retention, the first choice is usually an angiotensin converting enzyme inhibitor, which can reduce proteinuria.

When kidney function is severely compromised, blood pressure can be difficult to control until dialysis or haemofiltration is instituted.

All patients with chronic kidney disease have a high risk of vascular disease and are often hyperlipidemic, so a lipid-lowering treatment is a priori beneficial.

Unfortunately, renal failure has often been an exclusion criterion for therapeutic trials with lipid-lowering agents, so no randomized trial has provided any formal evidence of benefit in this group. The rule is none the less to monitor the lipid profile and to treat with an appropriate statin when the levels of total cholesterol or cholesterol associated with low density lipoproteins are increased.


Toleragene B cells LJP 394 (abetimus sodium) is a synthetic compound that binds to native deoxyribonucleic acid (DNA) antibodies attached to B cells or present in solution. It reduces the level of circulating anti-native DNA antibodies in the short term, presumably by forming soluble complexes, which do not seem to activate the complement significantly. In rodents, LJP 394 induces B-cell tolerance by bridging anti-native B cell immunoglobulin immunoglobulins and initiating anergy or apoptosis of B cells. In a randomized trial, LJP 394 in patients whose antibodies had a high affinity for its DNA epitope was associated, compared with placebo, in an increase in the delay before the next renal inflammatory attack, in a decrease in the number of relapses and in a reduction in the number of conventional treatment periods. The drug was well tolerated but, based on the results of the intent-to-treat analysis, the time to onset and the number of renal inflammatory attacks were not different in the two groups.

In organ transplants, a potent immunosuppressive agent, CTLA4-Ig, is in the experimental stage. It binds to CD80 and CD86 and is thought to interrupt costimulatory signals to T cells; it has been shown to have some efficacy in animal models of lupus nephritis.

Systemic vasculitis:

Estimates of the incidence of primary vasculitis range between 7 and 15 new cases per million per year. The vasculitis of the small vessels are the most frequent. According to a European report, Wegener’s granulomatosis and microscopic polyangiitis represent 0.5% of patients who receive a kidney transplant. Most patients have a white Caucasian phenotype, and the peak incidence appears to be in the fifth and sixth decades. In a recent study, the cumulative survival rate of patients with systemic vasculitis with renal involvement was 82% at 1 year and 76% at 5 years. End-stage renal disease developed in 28% of cases and at least one relapse was observed in 34% of cases, within a median time of 13 months after diagnosis. The most commonly used classification for vasculitis is the Chapel Hill consensus, based on the size of the smaller vessels involved.

The term kidney-limited vasculitis or rapidly progressive idiopathic glomerulonephritis refers to isolated focal necrotizing glomerulonephritis resulting from vasculitis affecting only the small vessels of the kidney. Secondary causes of vasculitis and glomerulonephritis include rheumatoid arthritis and systemic lupus erythematosus.


According to the Chapel Hill consensus, Wegener granulomatosis is a granulomatous inflammation affecting the airways, with necrotizing vasculitis of small or medium-sized vessels. Microscopic polyangiitis is a necrotizing vasculitis affecting small vessels without granulomatous inflammation and with little or no immune deposition. All signs of microscopic polyangiitis may appear in Wegener’s granulomatosis, but the reverse is not true.

Renal involvement in vasculitis of small vessels:

Renal involvement is variable but is rarely at the forefront of the initial clinical picture. The first symptoms may be, in some cases, gross hematuria or massive proteinuria causing foamy urine. Hypertension is not a major sign; it is present in about half or less than half of all patients. If there is a clinical suspicion of vasculitis, it is important to check the renal function and to check the presence of blood and protein with the urine strip and, by microscopic examination, for the presence of leukocyte or erythrocyte cylinders. Kidney imaging is rarely useful, except for the collection of anatomical data before a biopsy, although it may show increased renal echogenicity.


When kidney disease is suspected, it is usually confirmed by renal biopsy, unless the therapeutic attitude has already been dictated by other data, particularly the histological appearance of other biopsy specimens. The dominant image is usually segmental and focal necrotizing glomerulonephritis. In advanced active forms, lesions may become diffuse, affecting all glomeruli. Extracapillary proliferation and the formation of croissants in Bowman’s capsules may be added.Lesions of different ages can be observed, with coexistence of recent inflammatory changes and chronic lesions. An inflammatory infiltrate of the interstitial tissue may also be present. The search for immunoglobulin deposits and complement components by immunofluorescence is typically negative, although they may be present in small amounts.


Two major profiles of neutrophil anti-cytoplasmic antibody (ANCA) specificity have been identified and are of clinical interest. ANCAs with cytoplasmic distribution in immunofluorescence are called c-ANCA; they are usually directed against the proteinase 3 neutrophil granules. They are typically present during Wegener’s granulomatosis. The other major type of ANCA, perinuclear immunofluorescence distribution, is called p-ANCA and is usually directed against granular myeloperoxidase. This type of ANCA is typically associated with microscopic polyangiitis, rapidly progressive idiopathic glomerulonephritis, and Churg and Strauss disease. The relapse rate is approximately four times higher in patients with c-ANCA than in those with p-ANCA. Distributional antibodies similar to p-ANCA but lacking antimyeloperoxidase specificity are present in a wide variety of conditions, such as inflammatory bowel disease and infectious endocarditis. The presence of affinity-free p-ANCA for myeloperoxidase has little specificity for the diagnosis of vasculitis.


The definitive diagnosis is usually based on the histological features of the tissue involved. The histological discovery of focal necrotizing glomerulonephritis in an evocative clinical picture and the presence of ANCA are indisputably sufficient to initiate treatment. Vasculitis is sometimes seen on a renal biopsy specimen, but this is not often the case.In an evocative clinical context, the discovery of ANCA will often be a sufficient argument to initiate treatment, especially when the biopsy can not be performed.

Various other investigations can support the diagnosis.

The hemogram may show normochromic normocytic anemia (or hypochromic microcytic anemia in haemorrhage), leukocytosis and thrombocytosis. The rate of globular sedimentation and the level of C-reactive protein are usually increased. A decrease in albumin and an increase in alkaline phosphatase are possible, in connection with the acute phase of the inflammatory response.

Immunoglobulins can be increased. The levels of complement fractions are usually normal, but the search for rheumatoid factor may be positive. In cases of renal impairment, blood levels of urea and creatinine may be elevated and microscopic hematuria or proteinuria with leucocytic or haemorrhagic cylindruria may be observed.

Diagnostic imaging can be helpful, including high-resolution pulmonary computed tomography. Significant differential diagnoses include Goodpasture disease (or glomerular basal antimembrane antibody disease), cryoglobulinemia, rheumatoid purpura, and systemic lupus erythematosus. In all these cases, immune deposits are clearly visible on the renal biopsy specimen.


A study by the National Institutes of Health clearly demonstrated the benefit of the combined use of cyclophosphamide and corticosteroids in Wegener’s granulomatosis. However, the proposed regimen included high doses of cyclophosphamide for at least one year after remission and high doses of corticosteroids, which caused a high rate of complications: 8% diabetes, 21% cataracts, 17% d alopecia, 46% serious infections, 43% haemorrhagic cystitis (2.5% bladder cancer) and 3% vascular osteonecrosis. After 1 year of cyclophosphamide, 57% of women of childbearing age had biochemical ovarian failure, amenorrhea or infertility. A significant increase in the number of hematological malignancies was also noted.

The treatment regimen developed at Hammersmith Hospital in the UK has been shown to reduce the rate of complications while maintaining efficacy. Cyclophosphamide is used only at the beginning of treatment and the complementary treatments are reserved for severe and rapidly progressive forms. Cyclophosphamide is used for 3 months, then the relay is taken by azathioprine. The dose of cyclophosphamide is reduced in elderly patients, who are particularly vulnerable to side effects. The fulminant forms are further treated by plasma exchange or bolus methylprednisolone. After induction therapy, maintenance therapy is usually based on azathioprine, typically at a maximum dose of 1 mg kg -1 d -1 . Corticosteroids are gradually decreased to about 5 mg j -1 , then more slowly until complete arrest if possible. In case of relapse, cyclophosphamide is resumed.

Cyclophosphamide can be administered as an intravenous bolus, which reduces the total dose and allows the coadministration of mesna to protect against haemorrhagic cystitis.

In a randomized, controlled multicentre study of patients with renal impairment, intravenous bolus use reduced the cumulative dose of cyclophosphamide by 57% compared with oral therapy. Survival, remission rate, recurrence rate, and renal outcome did not differ between the two groups, but the incidence of severe leukopenia, severe infection, or gonadal toxicity was reduced in the group. treated by intravenous injection. Intravenous boluses may, however, be less effective in controlling the disease, particularly granulomatosis. Cyclophosphamide appears to be superior to azathioprine in Wegener granulomatosis but this has not been established in microscopic polyangiitis.

However, some patients do not respond well to azathioprine. After 3 months of induction therapy, the European Vasculitis Study Group randomly compared maintenance therapy with cyclophosphamide (1.5 mg kg -1 d -1 ) and azathioprine. (2 mg kg -1 d -1 ). The relapse rate was the same in both groups and was approximately 15% over 18 months.

Complementary treatment of serious forms:

Plasma exchanges have been used with good results in patients with focal necrotizing glomerulonephritis.

In cases severe enough to warrant hemodialysis, 10 of the 11 treated patients were able to discontinue hemodialysis, compared to only three out of eight patients who had not benefited from plasma exchange. There was no significant benefit in the less severe forms. Intravenous boluses of methylprednisolone have also been shown to be useful as adjunctive therapy. Of 23 patients treated, 16 were able to discontinue dialysis, compared to none of the nine patients who had not received a bolus. Plasma exchanges have the disadvantage of a high cost; they can cause bleeding and allergic reactions and require the establishment of central vascular access. In contrast, methylprednisolone may be associated with an increased risk of infection and increases the likelihood of diabetes, avascular osteonecrosis, cataracts and hypertension.

Other therapeutic approaches:

Methotrexate at a dose of 0.3 mg kg -1 week -1 was associated with a response rate of 75%. Cotrimoxazole provides some benefit in localized Wegener granulomatosis, but there is no strong evidence to support its use in renal impairment. Cyclosporin does not appear to be widely used, despite some anecdotal reports of its use as adjuvant. In contrast, intravenous immunoglobulin at a dose of 0.5 g kg -1 day -1 for 5 days gave good results, without major difficulties, when used in combination with corticosteroids and cytotoxic agents. In a randomized trial, intravenous immunoglobulins were compared to placebo in previously treated cases of vasculitis, for which therapeutic intensification was considered. Immunoglobulins reduced the activity of the disease compared to placebo, but this effect was not maintained at 3 months. In refractory forms of very high severity, antibodies directed against immune cells such as anti-CD52 or anti-CD4 have been found to be useful, as well as polyclonal antithymocyte antibodies.

End stage renal disease:

Patients with systemic vasculitis who reach the end stage of renal disease require locum therapy. Hemodialysis and peritoneal dialysis are generally well tolerated. Renal transplantation is considered when the disease has been in remission for at least 6 months, but recurrence may occur and affect the graft. There is no compelling argument for modifying standard immunosuppression regimens for transplantation in patients with systemic vasculitis.


Renal involvement of scleroderma can be acute and life threatening, or insidious and benign. The most dramatic clinical picture is that of acute renal crisis. Constant vigilance against this risk is required during routine surveillance of patients with scleroderma. There are often minor renal abnormalities, the clinical impact of which is usually minimal. In a series from the United Kingdom, the overall incidence of major renal complications was 5.3%. It was 1.6% in limited skin scleroderma and 12% in systemic scleroderma. A major risk factor appears to be extensive skin involvement.Other risk factors include African origin, pregnancy, and rapid progression of the skin disease. In one series, the incidence of acute scleroderma seizures was 21% in patients of African origin compared to 7% in subjects with Caucasian phenotype. A scleroderma kidney crisis during the third trimester of pregnancy may be misinterpreted as preeclampsia. However, unlike preeclampsia, a scleroderma kidney crisis can also occur in the postpartum period.Kidney crisis is more common in winter and usually occurs within 5 years of diagnosis.


The cause of scleroderma remains unknown. Pathological abnormalities, however, include connective tissue proliferation and vascular injury, which can decrease tissue vascularization and lead to organ dysfunction. Vascular alterations of the kidney may include intimal hyperplasia and fibrinoid necrosis; plasma renin levels are high. Vascular narrowing, which may be due to structural alterations or vasoconstriction, is responsible for a decrease in renal blood flow, which in turn stimulates renin production from the juxtaglomerular apparatus in each nephron.

Renin triggers the formation of angiotensin II, a vasoconstrictor, which causes additional renal vasoconstriction and worsens renal ischemia. This creates a vicious circle that rapidly reduces renal blood flow and glomerular filtration and, in addition, causes hypertension.

Angiotensin II acts directly on the receptors of the proximal tube to trigger the reabsorption of sodium; it also acts on the adrenal cortex to promote the production of aldosterone, which increases the distal tubular reabsorption of sodium.Sodium retention and concomitant retention of water further aggravate hypertension and may contribute to the formation of pulmonary edema.


Insidious minor kidney damage is probably more common than is usually accepted. In a series of autopsies, vascular abnormalities were found in 60-80% of cases.

However, it must be taken into account that kidney disease is a leading cause of hospital death, where autopsies are usually performed. Radioisotopic explorations showed that renal blood flow could be decreased in the absence of any other element in favor of renal impairment. The same study also found that 36% of patients with scleroderma had proteinuria of at least 1 + , 24% had blood pressure above 140/90 mmHg, and 19% had elevated blood urea. These various abnormalities are thought to be the counterpart of autopsy findings and are not usually sufficient reason for renal biopsy in the context of scleroderma.


A major renal crisis may occur, marked by the sudden onset of severe hypertension and acute deterioration of renal function. The clinical picture is that of severe hypertension, with headaches, visual disturbances and seizures. On examination, the blood pressure is high and there are often acute abnormalities of the fundus. Proteinuria is common, but is usually not nephrotic and may precede acute access. Microscopic hematuria may be present, accompanied by leukocyte cylinders. When hypertension is severe and accompanied by significant fluid retention, pulmonary edema may occur. Blood tests show high levels of urea and creatinine. Morphological examination of red blood cells on the blood smear may be suggestive of a microangiopathic haemolytic process when hypertension is severe. The presence of antinuclear, anti-scl 70, anticentromeric and ribonucleic acid (RNA) polymerase antibodies is possible, but there is no specific serological marker for renal impairment.


A renal biopsy is usually performed to rule out other possible diagnoses such as acute glomerulonephritis.

The blood pressure should be well balanced before the biopsy to reduce the risk of bleeding. A biopsy is useful when renal replacement therapy is considered as it excludes other possible causes and may influence subsequent decisions about transplantation. Sometimes, unexpectedly, the acute scleroderma kidney crisis can be followed by a slow but true remission, which justifies postponing the kidney transplant decision by at least 2 years after the crisis.

The characteristic histological features of the acute renal crisis of scleroderma are well known. The proliferation of the intima can reach the walls of the renal arteries; when it is severe, it achieves the so-called “bulb of onion” aspect. This process is particularly marked in the arterial and interlobular arteries and may be responsible for narrowing of the lumen of the vessels resulting in renal ischemia.

It can also be noted an accumulation of glycoproteins and mucopolysaccharides in the vascular walls. Areas of fibrinoid necrosis are observed in small arteries and arterioles. There may be focal or diffuse glomerular basement membrane thickening, glomerular thrombosis and, ultimately, glomerular sclerosis. Tubulointerstitial alterations appear in the long run.


A key aspect of managing scleroderma is the monitoring and prevention of acute renal crisis. Black and Denton recommend that for all patients with diffuse scleroderma, monitoring include once a month a blood pressure measurement and every 3 to 6 months a measurement of creatinine clearance and proteinuria. These monitoring procedures must be maintained for the first five years and then spaced if there are no alarming elements. In localized scleroderma, the risk of acute renal crisis is lower and monitoring can be spaced out from time to time, with an annual estimate of the glomerular filtration rate. If there is any sign of kidney damage or hypertension, an angiotensin converting enzyme inhibitor should be prescribed. Some data suggest that this class of drugs may contribute to the prevention of kidney attacks. More generally, antihypertensive treatment is probably useful for Raynaud’s syndrome. It has been suggested that high dose corticosteroid therapy and ciclosporin may be predisposing to renal crisis.

In a renal crisis, the main goal of treatment is the very rigorous control of blood pressure by the angiotensin converting enzyme inhibitors. Treatment is usually performed in a hospital setting. The blood pressure is reduced by about 10-15 mmHg per day until reaching 120-130 / 70-80 mmHg. Too fast a reduction in blood pressure would put the risk of an undesirable aggravation of renal ischemia. Calcium inhibitors and other classes of drugs may also be used. Low dose prostacyclin may be used although there is no clear evidence that it is beneficial; it can help reduce blood pressure and may have a potentially useful effect on renal blood flow. Renal function should be monitored daily. In addition, regular monitoring of the blood count, red cell morphology, coagulation factors, and fibrin degradation products is important to look for signs of microangiopathic haemolytic anemia. Nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs and contrast agents, should be avoided. When blood pressure is under control and hemostasis is normal, a renal biopsy can be performed to confirm the diagnosis.


Dialysis may be necessary when kidney damage is severe, but transplantation should be delayed for at least 2 years to allow maximum renal recovery. Angiotensin-converting enzyme inhibitors should be continued during this period and blood pressure should be very carefully controlled to optimize the chances of renal recovery.

The life expectancy of scleroderma patients with end-stage renal disease is significantly shorter than that of other patients with end-stage nephropathy.


There are various reasons for kidney disease to develop in the conditions discussed here, but common themes emerge. Whatever the diagnosis, the strict normalization of blood pressure figures is essential and can influence evolution. Kidney disease may be silent, warranting active surveillance of patients with conditions that may affect the kidney. Identification and early treatment of renal damage may allow better preservation of renal function than if the disease is allowed to progress.

In some clinical situations, well validated regimens are available, but in others optimal immunosuppressive regimens are not yet established. It may be necessary to individually adjust the immunosuppression according to the age of the patient and the general condition, as well as the response to treatment. The diversity of clinical aspects and the rarity of some forms of systemic autoimmune disease make it difficult to build large-scale clinical trials, although progress is being made in this direction.