Renal disorders in rheumatoid arthritis

Renal Disorders in Rheumatoid Arthritis By Maarten Renal disorders are a frequent patients with rheumatoid less apparent

cause of death in

arthritis

(RA). but are

in living RA patients. In part, this

may be because of insensitive

screening

meth-

ods. In this review, some of the relations among renal pathology, matic therapy renal

renal function,

are clarified.

disorders

according

posed. Two categories

and antirheu-

A classification to etiology

of disorders

of

is pro-

are distin-

guished: those related to RA and its complications, and those

related to

to drug therapy.

belonging

reviewed.

Finally, a case is made for the exist-

ence of a third category, is hypothesized nephropathy

these

The

disorders

categories

are

“RA nephropathy.”

It

that this mild and nonspecific

is the result of cumulative

minor

insults caused by the disease and its therapy. The presence of such a “subclinical” thy would explain the greater patients

to other

prevalence

INDEX

insults,

and the

of RA high

of renal failure at death.

e 1999 by W.B. WORDS:

arthritis:

renal

nephropa-

sensitivity

Saunders

Company.

Kidney

diseases;

rheumatoid

renal; amyloid nephropathy.

R

HEUMATOID ARTHRITIS (RA) is a systemic disease characterized by chronic joint inflammation and a spectrum of manifestations outside the joints. These so-called extraarticular manifestations of RA include constitutional symptoms and signs, inflammation of cavity-lining cells (“serositis”) as in pleuritis and pericarditis, and vasculitis. This review deals with renal disorders seen in patients with RA. Typically, in reviews considering the clinical course of RA, two categories of renal disorders are distinguished. The first is amyloid-A (AA) or secondary amyloidosis, characterized by deposition of inert fibrillar material in the kidney and other organs, leading to dysfunction and disruption of those organs. The second is drug-induced renal disease. Both are considered to be of limited clinical importance; amyloidosis because it is viewed as a rare complication of severe RA, and drug-induced renal disease because it is usually reversible when the offending drug is withdrawn. Otherwise, renal disorders are not considered a major problem in the spectrum of extra-articular manifestations of RA; the largest Seminars in Arthrifis andRheumatism,

Vol20,

Boers textbook on rheumatological disease reserves only one paragraph for such renal disorders.’ Renal disorders are without doubt a frequent cause of death in RA patients. In the largest study of its kind, 1,000 patients with RA and 1,000 age and sex matched controls (obtained randomly from the national security register) were followed for 10 years.* In this period, 356 RA patients and 220 controls died; 20% of deaths in the RA group were related to renal disorders, contrasting with only 1% in the control group. Approximately half of the deaths in the RA group were attributed to amyloidosis, with the majority of the remaining cases suffering from “chronic nephritis” and renal infections. In other, smaller series the percentage of renal deaths in RA patients ranged from 10% to 34%,3-5 but again amyloid was not the exclusive renal lesion identified at death. These findings indicate that renal disorders in RA encompass more than amyloidosis. It is paradoxical that whereas so many RA patients die of renal complications, so little clinical attention is devoted to renal disease in living RA patients. Clearly, renal disorders are less manifest in RA patients than in patients with other rheumatological disorders, such as systemic lupus erythematosus, polyarteritis nodosa, and systemic sclerosis, but evidence is available that renal dysfunction may be quite prevalent in RA patients.’ That such dysfunction remains unnoticed or “subclinical” could be explained by a slow rate of progression, but also by the fact that the routine measure for renal function in clinical care, the serum creatinine level, may not be adequate to detect dysfunction in RA patients.6 We have recently shown that the measured creatinine clearance in these patients can be

From the Department of Internal Medicine, Division of Rheumatology, University Hospital Leiden, The Netherlands. Maarten Boers, MD, PhD: Department of Internal Medicine, Division of Rheumatology,University Hospital Leiden, The Netherlands. Address reprint requests to Maarten Boers, MD, PhD, Department of Internal Medicine, Division of Rheumatology, PO Box 1918.6201 BX Maastricht, The Netherlands. 0 1990 by W.B. Saunders Company. 0049-0172/90/2001-0006$5.0000/0

No 1 (August). 1990: pp 57-68

57

58

MAARTEN BOERS

significantly lower than expected on the basis of the serum creatinine level.’ Most likely this is due to muscle atrophy in RA patients, leading to an altered body composition and less creatinine production per kilogram of body weight. It may be reasonable to assume that a patient with active RA and a serum creatinine that is stable for several years has a slowly declining renal function. The purpose of this review is to clarify some of the relations among renal morphology, renal function, and antirheumatic therapy in patients with RA. In the following paragraphs a short historical overview of the research on renal disorders in RA will be presented, followed by a classification of these disorders into categories according to etiology. Each category will be discussed in brief. Finally, a case will be made for the existence of RA nephropathy to account for the remaining unexplained findings. HISTORICAL OVERVIEW

Studies in Patients With RA

The concept of RA as a disease entity separate from gout and rheumatic fever evolved during the 19th century; nosologic conflicts, especially on the relation between RA and rheumatic fever, continued until the 1940~.~ Thus, RA and such diseases as systemic lupus erythematosus and polyarteritis nodosa were incompletely defined, with a large area of overlap between them-even today areas of overlap persist. This has implications for the study of early reports on renal disorders in RA; on the one hand, such reports may contain patients in which another systemic disease (eg, systemic lupus erythematosus, polyarteritis nodosa) would now be considered more likely, but on the other hand, renal disorders in RA patients could erroneously be attributed to the development of a second disease. Moreover, renal diseases caused by complications unrelated to RA, especially chronic infections in series from the preantibiotic era, often cannot be ruled out completely. Classically, renal disorders in RA have been studied from either the morphological (autopsy, and later also biopsy findings) or the functional viewpoint. As early as 1856, RA and renal disease were found to coincide.’ Autopsy series dating from 1943 and later have consistently shown pathological lesions in a significant proportion of the kidneys examined-from 8% up to

90%.1°-16 As mentioned in the cause-of-death studies, amyloidosis was not the only pathological finding, but papillary necrosis and pyelonephritis were also present in substantial numbers. These studies have been extensively reviewed.5*17*18 The first study on renal function in RA was performed in 1942,19 and it was followed by several studies in the following 40 years, the largest being that of S#rensen in 1964.” In these studies, a reduced glomerular function was found in a substantial number of patients, correlated to some extent with severity and duration of the RA.2’V24Tubular dysfunction and proteinuria have also been reported, although the total number of patients studied is small.24*25-30 In a comprehensive study of 35 RA patients, we found subclinical glomerular and tubular dysfunction to be frequent.3’ Drug-Induced

Renal Disease

The recognition that drugs used in the treatment of RA could be implicated in renal disease was made in the middle of this century. The first of the so-called nonsteroidal antiinflammatory drugs (NSAIDs), acetyl salicylic acid, was marketed as Aspirin by Bayer 8~ Co in 1899. However, it was not until the 1950s that a new form of renal papillary necrosis and chronic interstitial nephritis was described in connection with prior consumption of large amounts of analgesic mixtures.32 The nephrotoxicity of (parenterally administered) gold compounds and D-penicillamine, both slow-acting or disease-modifying antirheumatic drugs, was made quite soon after their introductions in 193033 and 1960 to 1962, respectivelY*34-36None of the other slow-acting antirheumatic drugs currently in use have shown significant nephrotoxicity apart from hypersensitivity phenomena. 37However, the antirheumatic effect of cyclosporine A, a nephrotoxic immunosuppressive agent used widely in transplantation medicine, is currently being studied in several controlled trials.38-42 CLASSIFICATION OF RENAL DISORDERS IN RA

A useful classification of renal disorders in RA integrates what is known from the morphological and functional studies into an etiological framework that can be modified as new insights emerge. Thus, when chance occurrences of renal disorders are excluded, two main categories can be

59

RENAL DISORDERS IN RA

Table

1: Classification I. Renal Disorders

of Renal

Disorders

in RA

Related to RA and its

Complications A. AA amyloidosis B. Vasculitis C. So-called “rheumatoid glomerulitis” D. Sjagren’s syndrome II. Renal Disorders

Related to Drug Therapy

A. Gold compounds and o-penicillamine B.

NSAlDs 1. Analgesic nephropathy 2. Acute renal failure 3. Miscellaneous

C. Cyclosporine A 1. Acute nephrotoxicity 2. Chronic nephrotoxicity Ill. “RA Nephropathy”?

distinguished: renal disorders related to RA and its complications, and renal disorders related to drug therapy (Table 1). The third category, RA nephropathy, is purely speculative. The elements of all categories will be reviewed briefly. Renal Disorders Complications

Related

to RA and Its

AA amyioidosis. Amyloidosis is characterized by deposition of inert fibrillar material in the kidney and many other organs leading to dysfunction and disruption of those organs.43 The prefix AA differentiates this particular form of amyloid from other forms, notably the AL form related to plasma cell dyscrasia. AA amyloidosis is a complication not only of RA but also of other chronic inflammatory diseases, chronic infections and familial mediterranean fever. The prevalence of amyloidosis in cross-sectional surveys of RA patients varies with the entry criteria of the studies, from 0% to 5% in renal biopsies performed in the absence of clinical nephrological disorders,44*45to more than 50% in renal biopsies performed in the presence of such disorders, especially proteinuria.46-48 The average prevalence in the autopsy results for RA patients is 15% (range, 6% to 61%).49 The true cumulative incidence in RA is unknown, but is estimated to be around 5% over an observation period of 20 years or more.5*50 The kidney is almost invariably involved in AA amyloidosis.5 Typically, the patient presents with progressive proteinuria, although a slow decline of renal function may be the only sign of amyloidosis. 51Diagnosis is usually made by congo

red staining of tissue obtained by deep rectal biopsy. Examination of aspirated abdominal fat is rapidly gaining acceptance as a screening method.52S54Renal amyloidosis is inferred when amyloid can be demonstrated in these tissues. However, it can be argued that other potentially treatable causes of proteinuria and declining renal function in RA patients, eg, vasculitis, should be ruled out by renal biopsy before such an inference is made. Although the clinical course is one of progressive renal failure in most patients, with 50% of patients dying of uremia within 5 years and 90% within 10 years after diagnosis, the variation in the rate of progression is wide, with some patients experiencing stabilization or even improvement of renal function. 5oThe rate of progression may be related to the pattern of amyloid deposition in the kidney, with glomerular deposition predominantly responsible for proteinuria, and vascular deposition ultimately responsible for ischemic nephron loss and interstitial fibrosis.55 In the last two decades the prognosis of patients with amyloid has improved substantially because of improvement in the conservative management of end-stage renal failure and the possibilities of dialysis and transplantation. Patients with amyloidosis do not do as well on maintenance dialysis as patients with nonsystemic diseases. In a European series, the overall 2-year patient survival was 76%, compared with 50% for diabetic patients and 53% for patients with amyloidosis.56 There is limited experience with renal transplantation.57 In 21 patients with amyloid undergoing transplantation, recurrence of amyloid was noted in only 1, and rejection-not amyloid infiltration of other organs-was the main problem influencing prognosis.57 Unfortunately, no specific treatment for amyloidosis is yet available. Vasculitis. Subclinical involvement of blood vessels, ie, microangiopathy, is a common feature of RA.58,59However, the cumulative incidence of clinically manifest vasculitis during a lifetime of RA is tentatively put at no more than 5%, with major organ damage in less than 1% of all RA patients. 6oThe much higher incidence in hospital or autopsy-based series1’V61 is probably due to the selection of patients. In severe cases, a necrotizing vasculitis can be found leading to skin ulceration, mononeuritis multiplex, myositis, and patchy inflammation of smaller vessels in and

60

around many visceral organs, notably the heart and the bowels.“*62 Although not completely absent, renal lesions were not conspicuous in the early autopsy series, contrasting with the impressive renal findings in the disease bearing some morphological resemblance to polyarteritis nodosa. Possibly from this difference the conclusion was made (and has prevailed up to this day) that renal involvement is rare in rheumatoid vasculitis. However, careful examination of the evidence of original and more recent series63p64shows that this statement may not be true. In a study of renal autopsy findings in 132 RA patients, we found extensive renal involvement in the subgroup of vasculitis patients.i6 In studies of living patients the only, very indirect, evidence for renovascular involvement we found was an activated renin-angiotensin system in patients with RA vasculitis.65 However, we were otherwise unable to show that renal dysfunction was more prevalent in RA patients with vasculitis than in RA patients without this complication.31 Most likely renal involvement is a feature of severe, life-threatening, rheumatoid vasculitis. Rheumatoid glomerulitis. The existence of a glomerular lesion specific for RA, rheumatoid glomerulitis, has been debated since the publication of the first description of a low-grade, nonspecific glomerulonephritis in the autopsy findings for RA patients in 1943.” Other autopsy studies reported similar lesions in varying proportions, but in biopsy studies, including a study in which nuclei in the glomeruli were counted,66 the lesion was conspicuously absent.5*17 It is now considered likely that the first series contained patients with other unrecognized systemic diseases or infections.5*‘7 Nevertheless, more recent autopsy series, including our own, “Jo have shown an excess of specific glomerular lesions also noted in isolated cases, including membranous,67 membranoproliferative,68 and proliferative glomerulonephritis.18.69 Not all of these lesions could be attributed to antirheumatic therapy or to rheumatoid vasculitis, and therefore might be a rare complication of RA itself. On the other hand rare adverse drug reactions (especially to NSAIDs) cannot be ruled out. Even more problematic is the question whether the excess of nonspecific lesions noted in both and biopsy series45,48,70-73 (eg, chronic autopsy 15*16

MAARTEN BOERS

pyelonephritis, interstitial fibrosis, benign nephrosclerosis) can be attributed to RA. This question will be addressed later with RA nephropathy. Sjiigren’s syndrome. This syndrome is historically characterized by the triad of keratoconjunctivitis sicca or dry eyes, xerostomia or dry mouth, and the presence of a connective tissue disease, usually RA. The presence of only the first two phenomena is called the sicca complex. In newer classifications, Sjiigren’s syndrome (SS) is equal to the sicca complex, making the term “sicca” redundant. A distinction is then made between primary and secondary SS on the basis of the absence or presence of an associated connective tissue disease. Keratoconjunctivitis sicca is substantiated by the Schirmer test (to assess tear production) and slit lamp examination (to diagnose keratitis). Xerostomia is substantiated by the finding of lymphocytic infiltration in a biopsy of labial salivary glands.74 The prevalence of SS is unknown. Estimates vary widely because of disagreement on the criteria for diagnosis. Probably many patients with RA have a mild form of the syndrome; surveys have shown lymphocytic cell infiltration of salivary glands to be common in these patients.75*76However, RA patients with symptomatic SS are quite rare, as are RA patients with complications said to occur frequently in the primary syndrome (eg, pseudolymphoma, polyneuropathy, autoimmune thyroid disease). Therefore, it is unclear whether the renal complications described in patients with primary SS should also be looked for in RA patients with (secondary) SS. One study found glomerular and tubular dysfunction to be present both in RA patients with and without SS.30 In patients with primary SS, renal disorders are reported in up to 30%.77-79The majority of patients present with a mild interstitial nephritis with distal tubular acidosis.” This is manifested either by the production of alkaline urine in the face of systemic acidosis, or by the inability to acidify the urine after an acid load. Less commonly, the presenting symptom is nephrogenic diabetes insipidus or the Fanconi syndrome.81 Substantial reductions of glomerular function are common, but usually no progression to chronic renal failure is seen.80 A minority of patients develop an immune complex (membranous) glo-

61

merulonephritis, usually in the context of systemic vasculitis.80’82 In this context, hypergammaglobulinemia deserves short mention. Various hypergammaglobulinemic states have been associated with renal tubular dysfunction,83 including SS,79 systemic lupus erythematosus,84*8s primary biliary cirrhosis, and chronic active hepatitis.86 Hypergammaglobulinemia is a fairly frequent finding in patients with active RA and might also be associated with renal dysfunction. However, in a renal function study of RA patients without clinically manifest SS, we found no evidence for this association.3’ Renal Disorders Related to Drug Therapy Gold and o-penicillamine. Gold salts and D-penicillamine are widely used in the treatment of destructive RA. The short-term efficacy of these drugs has been proved in several placebocontrolled trials,87-s” but treatment is frequently discontinued prematurely because of side effects. These are most commonly renal, apart from dermatitis and bone marrow depression.” Clinically, the hallmark of renal involvement during treatment with these drugs is the development of proteinuria. This complication is seen in 1% to 10% of patients treated with parentera187,92M94 or oral gold compounds.95 The average dose given before this complication develops is 1,500 mg (range, 10 to 6,000 mg), and the average duration of treatment 1 year (range, 2 weeks to 6 years). The nephrotic syndrome develops in up to one third of patients with proteinuria. The severity of proteinuria does not correlate with the amount of gold received.94 In the case of D-penicillamine, proteinuria is more frequent, developing in up to 30% of patients. Proteinuria is also more severe, with the nephrotic syndrome developing in 16% to 70% of affected patients. Proteinuria usually develops in the first 6 months of therapy, and is seldom seen after 1 year.9”98 There is some evidence to suggest that doses lower than 500 mg/dare associated with a lower incidence of proteinuria.99*100 Discontinuing the offending drug and instituting symptomatic treatment usually suffices when proteinuria develops during treatment with gold or D-penicillamine. Recent evidence indicates that the long-term prognosis is very good, with

proteinuria eventually resolving in all cases (although this may take up to 2 years), and no evidence of progressive glomerular dysfunction 101,102 The morphological lesion most commonly associated with gold and D-pencillamine treatment is an immune complex glomerulonephritis, indistinguishable from mild idiopathic membranous glomerulonephritis (glomerulopathy). In renal biopsy material, light microscopical changes such as thickening of the basement membrane and epimembranous spikes may be absent, or seen only on thin sections. Study of the material by immunofluorescence and electron microscopy shows the characteristic granular deposits of mostly immunoglobulin G (IgG) and C3, and discrete subepithelial electron-dense deposits with obliteration of epithelial foot processes.‘7v91 Apart from membranous glomerulonephritis, nonspecific or mild mesangioproliferative lesions have been reported in several series of patients biopsied for proteinuria during gold treatment.9’,‘03*70 Proliferative extracapillary glomerulonephritis has also been described during gold therapy.lM During D-penicillamine therapy, a syndrome resembling Goodpasture syndrome has been noted with a proliferative extracapillary glomerulonephritis and pulmonary hemorrhage, but without antiglomerular basement membrane antibodies.io5 Renal vasculitis has also been noted during D-penicillamine therapy.lM Naturally, the development of these lesions during drug therapy could have been a coincidence, or caused by RA. The pathogenesis of gold and D-penicillamineinduced glomerulopathy is still poorly understood. Immunologically mediated damage is likely on morphological grounds. It has been suggested that experimental mercuric chloride-induced glomerulopathy can serve as a mode1.‘07*108 In this model, the administration of mercuric chloride to certain rat strains induces a strong polyclonal B-cell stimulation that overwhelms suppressor mechanisms, leading to the appearance of autoantibodies directed against constituents of the glomerular basement membrane, and glomerulonephritis. There is evidence in mice that D-penicillamine can also induce such a B-cell activation.“’ Apart from B-cell stimulation, direct toxicity to renal epithelium as caused by gold 11o-112 or combination of the drug with epithelial constituents could cause the formation of

62

neoantigens sufficient to trigger an autoimmune response. Once formed, the autoantibodies could react with the glomerular antigens to form immune deposits locally. This mechanism has been clearly established in experimental models of immune complex nephritis. 108~113 However, autoantibodies to renal constituents have not yet been demonstrated in patients with gold-or D-penicillamineinduced glomerulopathy. Genetic factors also play a role in the development of membranous glomerulopathy. Patients with the B-cell alloantigens HLA-DRw3 or HLA-B8 have an increased risk of developing glomerulopathy during gold and D -penicillamine treatment.11”116 This predisposition linked to histocompatibility genes supports the hypothesis of an abnormal autoimmune response. It also helps to explain why patients with a history of gold nephropathy are more likely to develop nephropathy when treated with D-penicillamine.‘17 Nonsteroidal

antiinflammatory

drugs.

NSAIDs are still the principal treatment in RA. The antiinflammatory properties of these drugs reside in their common ability to inhibit cyclooxygenase, one of the major enzymes in the biosynthesis of prostaglandins. Prostaglandins are highly unstable, unsaturated fatty acid compounds that are formed throughout the body, and act as local hormones at the site of synthesis. In humans, most prostaglandins are of the “2” series (eg, prostaglandin E,), derived from arachidonic acid. Their biological actions include regulation of vessel tone, mediation of the immune response, platelet aggregation and disaggregation, and hormone release. The kidney produces many different prostaglandins that play an important role in renal physiology. ‘18Most of the renal effects of NSAIDs are thought to be brought about by the inhibition of prostaglandin synthesis.“’ Analgesic Nephropathy

This was the first renal lesion to be associated with the use of one of the NSAIDS.~* Specifically, the consumption of large amounts of analgesic combinations containing phenacetin has been implicated in the development of this lesion. The incidence varies directly with the per capita consumption of these drug combinations.‘20~121 Although acetaminophen is usually regarded as a

safe alternative to phenacetin, a recent casecontrol study suggests that it, too, may be implicated in causing chronic renal disease.‘** Morphologically, analgesic nephropathy is a combination of papillary necrosis and interstitial nephritis. The exact cause remains controversial, both a direct toxic effect of phenacetin or its metabolites123 and an effect of ischemia produced by interference with prostaglandin synthesis have been suggested. 124The clinical picture is one of sterile pyuria, hypertension, tubular dysfunction, and moderate renal failure. Complications include recurrent urinary infections, ureteral obstruction due to necrotic papillae, and transitional cell carcinoma.‘*’ The risk of RA patients developing analgesic nephropathy is much lower than would be expected on the basis of their regular consumption of NSAIDS.‘*~ There are several possible explanations for this phenomenon: their use is under control of a physician and therefore lower doses are used, and there is less frequent use of analgesic combinations are not often used. Convincing evidence that long-term use of a single NSAID can cause chronic renal failure is not available. However, the frequency of subclinical renal disorders in patients with RA should strengthen the feeling of many physicians that NSAIDs do cause some chronic renal damage. Acute Renal Failure

Current theory, supported by observations both in experimental animals and in humans, holds that vasodilatory prostaglandins produced intrarenally mitigate systemic vasoconstrictive stimuli and thus preserve renal blood flow and especially glomerular filtration rate. Systemic vasoconstriction is a reaction to salt depletion, hypovolemia, congestive heart failure, and sequestration of extracellular fluid, as in ascites; the vasoconstriction is mediated by angiotensin II, catecholamines, and sympathetic nerve impulses. In any of these clinical situations, acute renal failure can develop when NSAIDs are administered. Other situations in which this complication can develop include anesthesia (a situation with high circulating levels of angiotensin II) and other possible stress states. In intrinsic renal disease, this complication may develop when prostaglandins serve to maximize the glomerular

RENAL DISORDERS IN RA

filtration rate, or the intrinsic ability to synthesize prostaglandins is diminished.11s~119~126 This NSAIDs effect may be more prevalent in RA patients than previously recognized; asymptomatic, reversible impairment of renal function was a common finding in two studies in RA patients, even though these patients had no clinical signs of systemic vasoconstriction.127.‘28 Reversing acute renal failure might be a promising new indication for the administration of synthetic prostaglandin analogs now being developed for another indication, ie, protection of gastric mucosa against NSAIDs. However, in an exploratory study we found no renal effect of misoprostol, a prostaglandin E, analog, in RA patients with mild-to-moderate renal failure during treatment with diclofenac.‘*’ Miscellaneous Nonsteroidal antiinflammatory drugs can induce an acute interstitial nephritis characterized by proteinuria, eosinophilia, and eosinophiluria.37,130,131This is probably an allergic phenomenon. Another form of NSAID-induced interstitial nephritis is characterized by heavy proteinuria (nephrotic syndrome) and microscopic hematuria and pyuria, but lacking eosinophilia, and eosinophiluria. 132-‘34The mechanism for this form of nephritis is uncertain, but may involve a type IV hypersensitivity reaction.37 All NSAIDs influence water and electrolyte metabolism, reflecting the myriad effects of prostaglandins in the kidney: maximal free water clearance is depressed, and sodium and potassium retention occurs.118,126 NSAIDs may aggravate hypertension and blunt the effects of antihypertensive agents. 135The combination of NSAIDs with diuretics, eg, to combat edema caused by the water retention, can cause severe hyponatremia because of water retention disproportionate to sodium retention. Combination with potassium-sparing diuretics may cause life-threatening hyperkalemia.‘lg Cycfosporine A. The introduction of cyclosporine A as an immunosuppressive agent has transformed transplantation medicine. Its selective immunosuppressive action has led to treatment trials in autoimmune diseases, including RA.136 The main side effect of cyclosporine found in almost all patients is depression of renal function. The exact mechanism is not yet clear,

63

but most evidence suggests that cyclosporine alters renal hemodynamics, possibly through interference with the balance of vasodilatory and vasoconstrictive renal prostaglandins.137 The result is tubular hypoxia and a reduced glomerular filtration rate. This depression of renal function is thought to be reversible when doses not exceeding 10 mg/kg are used for periods not exceeding 6 months.138-141 A more chronic renal failure develops when the above limits are exceeded: patients show a gradual worsening of the renal function, with interstitial fibrosis and nephron loss on biopsy.‘38,139g141 Rheumatoid arthritis patients are more susceptible to cyclosporine nephrotoxicity than patients with other autoimmune diseases, most likely because of the concurrent administration of NSAIDS.~~~~~~~~*-‘~~In 1984, we performed a placebo-controlled trial in RA patients; cyclosporine was given in an initial dose of 10 mg/kg, tapered to 5 mg/kg in the course of 6 months, Unlike the experience in the treatment of other autoimmune diseases, the serum creatinine of the RA patients remained elevated for more than 2 years after stopping the drug, indicating some degree of irreversible damage.144 A second trial compared a lower dose of cyclosporine (5 mg/kg/d) with D-penicillamine in 92 RA patients.i4’ The experience of the first trial allowed formulation of more strict guidelines for patient selection and management of nephrotoxicity. The serum creatinine level rose in all patients during cyclosporine treatment, but returned to baseline within 3 months after stopping the drug. We saw no late rises in serum creatinine level in a follow-up period of 1.6 years. These findings agree with the findings of three other recent trials,40,41,42 and demonstrate that under stringent conditions the enhanced nephrotoxicity of cyclosporine in RA has become a managable problem. CONCLUDING REMARKS: “RA NEPHROPATHY”?

Renal disorders in RA still pose problems of definition, recognition and treatment. The classification of renal disorders into the categories “disease-related” and “drug-related” is useful for specific findings. However, the majority of (nonspecific) findings are not adequately explained. It can be hypothesized that patients with

MAARTEN BOERS

64

longstanding RA suffer from a mild chronic nephropathy, unnoticed in routine clinical practice because the serum creatinine level remains constant and the nephropathy is only slowly progressive. It is uncovered only when the renal function is studied more extensively. Problems arise when other renal insults occur, either related to RA and antirheumatic therapy, or unrelated. Examples of the latter are urinary tract infection, hyper- and hypotension, etc. The renal failure then becomes manifest and may progress, explaining both the sensitivity of RA patients to nephrotoxic drugs (NSAIDS, cyclosporine) and the high proportion of RA patients with clinically evident renal dysfunction or uremia at death. The morphologic substrate for this proposed RA nephropathy would be the nonspecific nephrosclerosis and mesangial hypercellularity noted in autopsy and biopsy studies. Possibly, the glomerular mesangium is at the center of the nephropathy. Apart from a few macrophages, this interstitial space is populated by multifunctional cells capable of smooth muscle-like contractility, production of many active substances including prostaglandins, synthesis and breakdown of structural elements, and uptake of macromolecules including immune complexes. These mesangial cells are a target for both vasoconstrictor and vasodilator agents and regulate the size of the glomerular capillary bed. Many stimuli lead to proliferation of the mesangial cell, and prostaglandins have been proposed as the counterregulatory

agent (ie, inhibiting mesangial proliferation).‘46 In RA, the mesangial cell might proliferate because of increased uptake of macromolecules, notably immune complexes, combined with a chronic inhibition of counterregulation from NSAID therapy. Although this hypothesis of RA nephropathy is attractive, it is difficult to prove. The mesangium is accessible only in experimental animals, and a suitable model to study the complex interactions as described above has not been developed. In RA patients, the influences of RA itself and drug therapy, especially NSAID therapy are hard to separate. Moreover, renal biopsy studies, for example in patients with high levels of circulating immune complexes but without a clinically apparent renal disorder, would raise ethical objections. In conclusion, renal disorders in RA are a collection of diverse specific elements probably situated on a background of nonspecific nephropathy. The disorders are related to the disease itself, its complications, and antirheumatic therapy. Clinicians should realize that most RA patients have an increased risk of developing renal failure during treatment with nephrotoxic drugs or when an unassociated illness develops.

ACKNOWLEDGMENT I would like to thank Prof. A. Cats for his thoughtful comments and guidance.

REFERENCES 1. Harris ED Jr: Rheumatoid arthritis: The clinical spectrum, in Kelley WN, Harris ED Jr, Ruddy S, et al, (eds): Textbook of Rheumatology. Philadelphia, PA, Saunders, 1985, p 941 2. Laakso M, Mutru 0, Isomiiki H, et al: Mortality from amyloidosis and renal diseases in patients with rheumatoid arthritis. Ann Rheum Dis 45:663-667, 1986 3. Rasker JJ, Cosh JA: Cause and age of death in a prospective study of 100 patients with rheumatoid arthritis. AnnRheumDis40:115-120,198l 4. Scott DL, Symmons DPM, Coulton BL, et al: Longterm outcome of treating rheumatoid arthritis: Results after 20years.Lancet 1:1108-1111, 1987 5. Burry HC: Renal disorders in rheumatoid arthritis. Rheum Phys Med 11:2-9, 1971 6. Nived 0, Sturfelt G, Westling H, et al: Is serum creatinine concentration a reliable index of renal function in rheumatic diseases? Br Med J 286:684-685, 1983

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RENAL DISORDERS IN RA

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