Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis

INTRODUCTION — The pathologic hallmarks of systemic sclerosis (SSc; scleroderma) are diffuse fibrosis (uncontrolled accumulation of collagen) and widespread sclerosis (thickening and narrowing) of small- and medium-sized vessels. (See "Pathogenesis of systemic sclerosis (scleroderma)".)

SSc may affect only the skin and subjacent tissues but is generally associated with systemic involvement. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Clinical features'.)

The most serious kidney manifestation of SSc is scleroderma renal crisis (SRC), which occurs in a minority of patients. A review of SSc-associated kidney disease will be presented here, with the emphasis on SRC. Extrarenal manifestations of SSc are discussed separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Major organ involvement'.)

PREVALENCE — Autopsy studies reveal kidney pathology in approximately 60 percent of patients with SSc [1]. In addition, as many as 50 percent of patients with SSc have markers of kidney disease, as manifested by mild proteinuria, elevated serum creatinine concentration, and/or hypertension [2,3]. However, many of these findings can be attributed to causes other than SSc.

The most serious kidney manifestation of SSc, SRC, occurs in as many as 5 to 20 percent of patients with diffuse cutaneous SSc [3-10]. SRC occurs in only 1 to 2 percent of patients with limited cutaneous SSc [8]. However, since limited cutaneous SSc is the more common form of the disease, a substantial proportion of patients with SRC (approximately 20 percent) have limited cutaneous SSc [8,9].

Antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis develops rarely, in less than 1 percent of patients with SSc [11,12]. (See 'Other types of kidney disease' below.)

SCLERODERMA RENAL CRISIS — SRC is a life-threatening complication of SSc. Prior to the widespread use of angiotensin-converting enzyme (ACE) inhibitors, almost all patients with SSc who had significant kidney involvement died within one year [13,14].

Risk factors — A number of risk factors for SRC have been identified:

●Diffuse skin involvement – The most important risk factor for SRC is diffuse skin involvement, particularly if it is rapidly progressive [5,7-9,15]. A study of 826 patients with diffuse cutaneous SSc found that rapid progression of skin thickness was an independent predictor of early SRC (odds ratio [OR] 2.05, 95% CI 1.10-3.85) [16]. The presence of palpable tendon friction rubs, common in patients with SSc who have diffuse skin involvement, is associated with a greater than twofold increase in the risk for SRC [17]. SRC occurs infrequently in patients with limited cutaneous SSc and only rarely in patients with SSc who lack skin involvement (ie, systemic sclerosis sine scleroderma) [18].

●Glucocorticoid use – The use of glucocorticoids, particularly in high doses, is associated with the development of SRC [8,9,15,19-22]. In a case-control study of 110 patients with SSc, moderate- to high-dose glucocorticoid therapy (≥15 mg/day of prednisone or equivalent) in the preceding six months was associated with a markedly increased risk of SRC (OR 4.37, 95% CI 2.03-9.43) [21]. Other studies have found similar results, with approximately 60 percent of patients with SRC having had prior recent exposure to glucocorticoids [8,9,23].

The use of higher doses of glucocorticoids might result in salt and volume retention, the initiation or worsening of hypertension, and the triggering of SRC in a subset of these patients. Glucocorticoids may also stimulate increased expression of the endothelin receptors in the kidney.

●Serum autoantibodies – The presence or absence of certain serum autoantibodies appears to predict the risk for SRC:

•Autoantibodies directed against ribonucleic acid (RNA) polymerase III are associated with a higher risk of SRC [8,24-26]. In a study of patients with SSc, anti-RNA polymerase III autoantibodies were detected in the serum of 59 percent of 96 patients who developed SRC compared with only 12 percent of 735 patients who did not develop SRC [8]. Another analysis of 1029 patients with SSc reported anti-RNA polymerase III autoantibodies in 52 percent of those who developed SRC [26].

•By contrast, anticentromere antibodies are associated with lower risk of SRC [8]. Anticentromere autoantibodies were observed in 1.8 percent of patients who developed SRC versus 29 percent in patients who did not.

●Cyclosporine – There is anecdotal evidence that cyclosporine, a renal vasoconstrictor, may accelerate kidney disease in patients with SSc. In one report, acute kidney injury (AKI) developed in three of eight patients treated with cyclosporine [27]. However, a causal relation to the drug, rather than to SSc itself, could not be determined. (See "Cyclosporine and tacrolimus nephrotoxicity".)

●Other risk factors – Additional factors that may identify patients with SSc who are at increased risk for SRC include contractures at the large joints, new-onset anemia, and new cardiac events such as heart failure or pericardial effusion [5,15,24,28].

Clinical presentation — SRC is a relatively early complication of SSc that almost invariably occurs within the first five years after the onset of the disease. In a series of 110 cases of SRC, SRC occurred at a median duration of 7.5 months from the first non-Raynaud clinical manifestation of SSc [8]. In some cases, SRC may even be the initial manifestation of SSc [29,30].

As described above, rapidly advancing skin induration is a major risk factor for SRC. However, SRC can occur in the absence of warning signs. (See 'Risk factors' above.)

SRC is characterized by the following features [4,5,7,23]:

●Abrupt onset of moderate to marked hypertension, sometimes accompanied by manifestations of malignant hypertension such as hypertensive retinopathy (hemorrhages and exudates) and hypertensive encephalopathy [23,31]. In a review of 145 patients with SRC, 85 percent had new diastolic hypertension, with a mean peak blood pressure of 178/102 mmHg [31]. The acute blood pressure elevation in SRC is typically associated with an increase in plasma renin activity.

In approximately 10 percent of patients, SRC occurs in the absence of hypertension [19]. However, some of these patients have blood pressures that are higher than their baseline values (eg, 130/80 mmHg in a young, thin woman whose baseline value was 100/60 mmHg).

●Acute kidney injury.

●A normal urine sediment. Glomerulonephritis is not a feature of SRC, and, accordingly, microscopic hematuria or cellular casts are uncommon. Heavy proteinuria is not a typical finding in SRC.

Other findings that may be associated with SRC reflect both the underlying vasculopathy and the marked hypertension. Laboratory parameters indicative of a thrombotic microangiopathy may be present, such as thrombocytopenia, anemia, elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear (picture 1). Additional clinical manifestations of malignant hypertension may include heart failure, pericardial effusion, headache, and seizures.

Pathology — The primary histopathologic changes in the kidney are localized in the small arcuate and interlobular arteries and the glomeruli [5,32]. The characteristic finding is intimal proliferation and thickening that leads to narrowing and obliteration of the vascular lumen, with concentric "onion-skin" hypertrophy. These histopathologic findings are similar to SSc-associated vascular lesions found in other organs (picture 2A-E).

SRC is a thrombotic microangiopathy similar to malignant hypertension (formerly called malignant nephrosclerosis), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), radiation nephritis, chronic kidney transplant rejection, and the antiphospholipid antibody syndrome. Because of the nonspecific kidney histologic findings common to all these entities, a kidney biopsy does not definitively establish the diagnosis of SRC.

Diagnosis

Initial evaluation — The diagnosis of SRC should be considered in all patients with SSc who present with acute kidney injury, particularly if the patient has a concomitant sudden increase in blood pressure. Because acute kidney injury in patients with SSc is not always due to SRC, patients should be evaluated thoroughly for other causes of acute kidney injury using the same approach as that for patients without SSc. This is discussed in more detail elsewhere. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

In addition, patients suspected of SRC should be evaluated for the presence of a thrombotic microangiopathy with a complete blood count, a peripheral blood smear, and measurement of serum LDH and haptoglobin. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Establishing the diagnosis — SRC is a clinical diagnosis based upon the presence of characteristic features in patients with SSc. Kidney biopsy is generally not required to diagnose SRC, but sometimes may be helpful by ruling out other diagnoses and/or by providing useful prognostic information. (See 'Pathology' above.)

Although there is no generally accepted or validated definition of SRC, diagnostic and classification criteria have been proposed [33,34]. We take the following approach to the diagnosis of SRC:

●In patients with SSc who have any high-risk features (ie, acute kidney injury early in the disease course [within five years of diagnosis], presence of skin involvement, autoantibodies to RNA polymerase III, or moderate- to high-dose glucocorticoid therapy [≥15 mg/day of prednisone or equivalent] in the preceding six months), we make the diagnosis of SRC if the patient meets the following two criteria:

•Acute increase in blood pressure defined as any of the following: new onset of elevated systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg in a patient with previously normal blood pressure, an increase in systolic blood pressure of ≥30 mmHg above baseline, or an increase in diastolic blood pressure ≥20 mmHg above baseline. Blood pressure should be checked at least twice, with measurements separated by at least five minutes.

•Acute kidney injury, as defined by Kidney Disease Improving Global Outcomes (KDIGO) guidelines (table 1), not explained by other causes.

●In patients with SSc who do not have any high-risk features, we make the diagnosis of SRC if the patient meets the two criteria above plus at least one of the additional supportive findings below:

•Evidence of microangiopathic hemolytic anemia and thrombocytopenia, as suggested by the following: new or worsening anemia not due to other causes, the presence of schistocytes on a peripheral blood smear, thrombocytopenia, elevated LDH, and/or low haptoglobin.

•Evidence of target organ dysfunction, such as:

-Hypertensive retinopathy (see "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults", section on 'Clinical manifestations and diagnosis')

-Hypertensive encephalopathy (see "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults", section on 'Clinical manifestations and diagnosis')

-Acute heart failure

•Characteristic changes on kidney biopsy (see 'Pathology' above)

●Rarely, patients with SRC may present without characteristic increases in blood pressure [19]. In patients with SSc who do not meet the blood pressure criteria above, we make the diagnosis of SRC only if the patient has a high-risk feature, acute kidney injury not explained by other causes, and at least one of the following additional findings: evidence of microangiopathic hemolytic anemia and thrombocytopenia, and/or characteristic changes on kidney biopsy.

Differential diagnosis — SRC must be distinguished from other forms of thrombotic microangiopathy, particularly TTP and HUS. Patients with TTP/HUS characteristically present with thrombocytopenia, purpura, and prominent microangiopathic hemolysis and may have rapidly progressive kidney failure. The clinical manifestations may mimic SRC, but patients with TTP/HUS have no clinical or serologic signs of SSc.

Distinguishing TTP/HUS from SRC at presentation may present a considerable and urgent diagnostic challenge. The diagnosis of TTP/HUS is sometimes suggested by the presence of a potential inciting event, such as diarrhea in children or certain forms of chemotherapy in adults. In addition, TTP, but not SRC, is characterized by an absence or marked reduction (ie, <10 percent) in the serum activity of the metalloprotease ADAMTS13. Kidney biopsy does not distinguish between these disorders. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Diagnosis of immune TTP".)

Surveillance — SRC is a life-threatening complication of SSc. Patients with the diffuse cutaneous form of SSc, autoantibodies to RNA polymerase III, and early-stage disease are at greatest risk for SRC, particularly if skin involvement is advancing and/or tendon friction rubs are present. Close monitoring is most important during the first four to five years of SSc since SRC most frequently occurs during this phase of the disease. (See 'Clinical presentation' above.)

The primary rationale for monitoring for SRC is that treatment is more likely to be effective when initiated early, before irreversible kidney injury has occurred. However, no studies to date have evaluated the effectiveness of monitoring patients with SSc for the development of SRC in terms of reducing morbidity and mortality.

We use the following surveillance regimen:

●Blood pressure should be measured on a regular basis in all patients with SSc. For patients at high risk for SRC (such as those with early-stage diffuse cutaneous disease, rapidly progressive cutaneous involvement with tendon friction rubs, or the presence of autoantibodies to RNA polymerase III), we advocate daily home blood pressure measurements and, for others, twice-weekly measurements.

In patients with SSc, a persistent rise of 15 mmHg in the systolic blood pressure or a 10 mmHg rise in the diastolic blood pressure raises concern and the need for further evaluation, including determination of the serum creatinine. In patients with SSc taking antihypertensive medications, sustained hypertension >140/90 mmHg, which is not readily corrected with dose adjustment and dietary salt restriction, would trigger further evaluation [8].

●We measure serum creatinine at every clinic visit (eg, every three months) in all patients with SSc. An increase in the serum creatinine from baseline may be a warning sign of impending SRC.

Prevention — There are no prospective studies that demonstrate that the avoidance and/or administration of any agent lowers the incidence or severity of SRC.

●Avoidance of glucocorticoids – As previously mentioned, the use of high-dose glucocorticoids is associated with a marked increase in the risk of SRC (see 'Risk factors' above). When glucocorticoid use is unavoidable in patients with SSc (eg, when there is concomitant myositis), we limit the dose of prednisone to <15 mg/day and use it for the shortest possible period.

●No role for ACE inhibitors, ARBs, or calcium channel blockers – We do not use ACE inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers (CCBs) for prevention of SRC. The crucial role of ACE inhibitors in the treatment of SRC is discussed below. (See 'ACE inhibitors in all patients' below.)

Observational studies suggest the counterintuitive possibility that ACE inhibitors may increase the risk of developing SRC. In a cohort of over 14,000 patients with SSc who were followed for approximately five years, the use of ACE inhibitors was associated with an increased risk of developing SRC (hazard ratio [HR] 2.6, 95% CI 1.7-4.0) [35]. By contrast, the use of ARBs or CCBs was not associated with the development of SRC. In another study of 87 patients with SRC, prior exposure to ACE inhibitors (ie, before the diagnosis of SRC) was associated with an increased risk of death (HR 2.4, 95% CI 1.02-5.75) [36]. It is possible these data indicate that ACE inhibitors delay recognition and/or aggressive treatment of serious kidney complications in patients with SSc.

There are no trial data evaluating the impact of ACE inhibition specifically on the risk of SRC. However, one trial compared the effect of quinapril versus placebo on the progression of cutaneous and visceral disease among approximately 200 patients with SSc [37]. Mean baseline creatinine in both groups was 0.9 mg/dL. At a follow-up of approximately three years, compared with placebo, there was a relative increase in creatinine in the quinapril group (OR 3.2, 95% CI 0.9 to 5.5). However, the episodes of increase in creatinine were not diagnosed as SRC.

CCBs were found to be associated with a lower risk of SRC (HR 0.09, 95% CI 0.04 to 0.24) in one observational study of over 400 patients [22]. However, the overall number of SRC events was low. In addition, this association has not been replicated in other studies [21,35,38].

●Choice of blood pressure medications – Among patients who are already on an ACE inhibitor for treatment of hypertension, our approach varies depending upon their risk for SRC. We replace the ACE inhibitor with another antihypertensive agent only among patients at high risk (ie, those with early-stage diffuse cutaneous disease or the presence of RNA polymerase III antibodies). We do not modify antihypertensive therapy among patients previously on an ARB or a CCB, regardless of their risk for SRC. (See 'Risk factors' above.)

Treatment — SRC is a medical emergency that requires hospital admission for prompt and aggressive treatment. Without intervention, SRC can progress to end-stage kidney disease (ESKD) over a period of one to two months, with death usually occurring within one year [4]. Successful treatment of SRC is dependent upon its initiation before irreversible kidney damage has occurred.

Goals of therapy — The mainstay of therapy in SRC is effective and prompt blood pressure control. The principal goal is to return the patient to their previous baseline blood pressure within 72 hours. The optimal antihypertensive agent is an ACE inhibitor. If this blood pressure goal cannot be achieved with ACE inhibitor therapy alone, other antihypertensive agents should be added. (See 'ACE inhibitors in all patients' below and 'Other antihypertensive agents' below.)

For patients with SRC and hypertension who present with evidence of central nervous system (CNS) involvement, additional goals for immediate blood pressure lowering are the same as for any patient with hypertensive retinopathy and/or encephalopathy. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults", section on 'Goal of therapy'.)

Since the development of hypertension is usually acute in SRC, rapid blood pressure reduction to baseline does not usually carry the risks seen with rapid blood pressure lowering in patients with longstanding hypertension.

ACE inhibitors in all patients — For all patients with SRC, we recommend blood pressure control with an angiotensin-converting enzyme (ACE) inhibitor rather than other antihypertensive agents. We use captopril as initial therapy rather than other ACE inhibitors because of greater clinical experience with this agent and because its rapid onset (peak effect at 60 to 90 minutes) and short duration of action permit rapid dose escalation. Other ACE inhibitors (such as enalapril or ramipril) may provide comparable benefit although data are limited. For patients who are unable to take oral medications, we administer a single dose of intravenous (IV) enalaprilat, followed by oral captopril administered through a nasogastric tube. We avoid additional doses of IV enalaprilat due to its longer duration of action. Initial dosing of captopril is discussed below. (See 'Initial captopril regimen' below.)

For patients who are unable to take an ACE inhibitor (eg, due to allergy), an ARB is an alternative option. However, it is not known whether ARBs are as effective as ACE inhibitors, since these agents have not been adequately evaluated in the treatment of SRC.

Observational data have shown that ACE inhibitors are associated with greater antihypertensive efficacy, better preservation of kidney function, and lower mortality in patients with SRC [8,31,39-41]. Prior to the widespread use of ACE inhibitors, almost no patients with SRC had recovery of kidney function, and almost all died within one year [13,14,21,39]. The benefits of ACE inhibitor therapy are illustrated by the following studies:

●In a prospective cohort study of 108 patients with SRC conducted before and after the availability of ACE inhibitors, treatment with an ACE inhibitor (mostly captopril) was associated with a significantly higher rate of recovery of kidney function [39]. Among patients who survived dialysis for more than three months, 11 of 20 patients who continued ACE inhibitor therapy were able to discontinue dialysis after 3 to 15 months compared with 0 of 15 patients who were not treated with ACE inhibitors (55 versus 0 percent). One-year survival for SRC was 76 percent in patients treated with ACE inhibitors compared with 15 percent in patients treated with other drugs.

●In a retrospective case series of 110 patients with SRC, all but two of whom were treated with ACE inhibitors, 24 of the 72 patients (33 percent) who started dialysis successfully discontinued it [8]. One- and five-year survival rates were 82 and 59 percent, respectively.

●A prospective cohort study of 145 patients with SRC who were continuously treated with ACE inhibitors and followed for 5 to 10 years reported that 55 patients (38 percent) did not require dialysis, and 34 patients (23 percent) who started dialysis successfully discontinued it after 2 to 18 months (mean 8 months) [31].

Initial captopril regimen — Our initial approach to treatment varies with the patient's blood pressure and whether the patient has SRC alone or in combination with CNS involvement (ie, hypertensive encephalopathy and/or retinopathy).

●Hypertension without CNS involvement – For patients with SRC and hypertension who lack evidence of CNS involvement, we begin captopril at a dose of 6.25 to 12.5 mg. We progressively escalate the dose in 12.5 to 25 mg increments at four- to eight-hour intervals until the goal blood pressure is reached (see 'Goals of therapy' above). The maximum captopril dose is 300 to 450 mg/day, usually divided in three daily doses.

●Hypertension with CNS involvement – For patients with SRC and hypertension who have evidence of central nervous system involvement (eg, encephalopathy, papilledema), we administer the same captopril dose escalation regimen as above and, for acute blood pressure control, add a very short-acting parenteral antihypertensive drug such as nitroprusside (see 'Goals of therapy' above). To allow for rapid up-titration of captopril, parenteral antihypertensive agents should be discontinued as soon as possible. We avoid the use of intravenous labetalol (and other beta blockers) in SRC because of the theoretical risk of worsening vasospasm.

●Normotension – For patients with SRC who are normotensive, we begin captopril at a dose of 6.25 mg and, if tolerated, increase the dose to 12.5 mg at the second dose. Further dose escalation should be pursued as needed to lower the patient's blood pressure to baseline and must be done carefully to prevent the development of hypotension. (See 'Goals of therapy' above.)

Long-term therapy — We continue ACE inhibitor therapy indefinitely, even if no longer needed for blood pressure control and even if only low doses are tolerated. For long-term therapy, longer acting ACE inhibitors (such as enalapril or ramipril) may be used rather than captopril to improve patient adherence. We do not stop ACE inhibitors in patients who progress to dialysis, since an appreciable proportion will recover sufficient kidney function to discontinue kidney replacement therapy [8,31,42].

The benefits of indefinite ACE inhibitor therapy are unclear. There are no studies examining ACE inhibitor withdrawal in patients with a history of SRC.

Other antihypertensive agents — For patients without sufficient blood pressure control despite maximum dose of an ACE inhibitor, we add a dihydropyridine calcium channel blocker such as amlodipine. In addition to their blood pressure lowering efficacy, dihydropyridine calcium channel blockers are first-line pharmacologic therapy for Raynaud phenomenon. Other antihypertensive drugs that can be added, if necessary, include diuretics and alpha blockers. Beta blockers are usually avoided in patients with SSc because of the theoretical risk of worsening vasospasm.

We avoid combination therapy with ARBs and ACE inhibitors for SRC since multiple studies of patients with other diseases have suggested that patients treated with both an ACE inhibitor and ARB are at higher risk for adverse events compared with those treated with only one agent. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Increased adverse effects'.)

However, there are no studies that specifically address the role of second-line blood pressure therapy in patients with SRC.

Monitoring response to therapy — In addition to close monitoring of blood pressure, we assess kidney function, electrolytes, and hemolysis parameters during therapy. Our approach is as follows:

●We measure the serum creatinine concentration daily after initiating an ACE inhibitor. Patients starting therapy commonly show an initial, transient rise in serum creatinine concentration because of the ACE inhibitor-induced fall in efferent arteriolar resistance and intraglomerular pressure (see "Renal effects of ACE inhibitors in hypertension", section on 'Renovascular hypertension'). However, because of the importance of ACE inhibitor therapy for survival and eventual kidney recovery, we do not stop ACE inhibitors even for a progressive rise of serum creatinine.

●We measure serum electrolytes daily after initiating an ACE inhibitor. Patients with acute kidney injury who are treated with an ACE inhibitor are at risk of hyperkalemia. Despite aggressive medical therapy to control hyperkalemia, some patients may require dialysis initiation to tolerate ongoing therapy with an ACE inhibitor or ACE inhibitor dose escalation. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Hyperkalemia' and "Treatment and prevention of hyperkalemia in adults".)

●After the initial assessment of hemoglobin, platelet count, serum levels of LDH and haptoglobin, and the peripheral blood smear, we recheck these laboratories daily until the hemoglobin stabilizes and the other parameters normalize. Because the degree of microangiopathic hemolysis often reflects the activity of the disease process, laboratory evidence of ongoing hemolysis is an indication to intensify ACE inhibitor therapy, regardless of blood pressure control.

Experimental therapies — Some centers have anecdotally reported the use of other therapies in patients with SRC, but we do not use any of these agents as initial therapy:

●In a single-center retrospective chart review of 20 patients with SRC, 10 with associated microangiopathic hemolytic anemia were treated with plasma exchange therapy in combination with ACE inhibitors [43]. Patients treated with the combination therapy had a better kidney survival rate at one year (80 percent) compared with those who were treated with ACE inhibitors only (45 percent). A randomized trial is needed to confirm these observations.

●The nonselective endothelin-1 receptor antagonist bosentan was studied in six patients with SRC [44]. When used in combination with ACE inhibitors for six months, bosentan was associated with a trend toward improved blood pressure control and preserved kidney function.

●Intravenous prostacyclin (iloprost or epoprostenol), which is believed to help the microvascular lesion without precipitating hypotension, has been administered for SRC based upon anecdotal observations of benefit.

●Limited evidence has been presented for the use of the complement inhibitor eculizumab as a rescue therapy in SRC [45]. However, there are no controlled studies examining the safety and efficacy of complement inhibitors in patients with SRC.

Prognosis — Despite the improved prognosis associated with long-term ACE inhibitor therapy, outcomes in SRC remain poor. As an example, approximately 20 to 50 percent of patients with SRC will require dialysis [8,21,31]. The prognosis of SRC may be worse for patients with the following characteristics:

●End-stage kidney disease – Mortality is higher for patients who progress to ESKD. In a prospective cohort study of 145 patients with SRC treated with ACE inhibitors, patients who did not require dialysis or required only temporary dialysis had long-term outcomes similar to patients with diffuse SSc who did not have SRC, with mortality rates of 10 percent at five years and 15 to 20 percent at eight years [31]. By contrast, the mortality rates in patients who required permanent dialysis were approximately 60 percent at five years and 75 percent at eight years.

Survival on dialysis in patients with SRC is worse than in other forms of ESKD, as illustrated in a study from the United States Renal Data System that included 364,000 patients with ESKD on maintenance dialysis, 820 of whom had SSc [46]. Two-year survival was significantly lower in patients with SSc (49 percent versus 64 percent in all other patients), even though the patients with SSc were younger. Similar findings have been reported in a study of 342 patients with SSc in Europe [42]. Since vascular access is particularly troublesome in patients with SSc, complications with vascular access may have contributed to the higher mortality.

●Normotensive SRC – Patients with normotensive SRC have worse kidney outcomes and higher mortality than patients with SRC who are hypertensive [19,23]. Worse outcomes in normotensive renal crisis have been attributed to several factors, including delayed recognition of SRC and the possibility that normotensive SRC might indicate cardiac failure in these patients.

●Specific findings on kidney biopsy – Greater numbers of thrombosed vessels, the severity of ischemic glomerular collapse, and peritubular C4 staining observed on kidney biopsy may correlate with poor outcomes [47].

Kidney transplantation — There is limited experience with kidney transplantation in patients with SRC, in part because transplantation is sometimes precluded by the severity of the extrarenal manifestations of SSc [48,49]. The United Network for Organ Sharing (UNOS) database included 260 transplants performed between 1987 and 2004 for the kidney diagnosis of SSc [50].

Minimum wait time for transplantation — We generally do not perform kidney transplantation for at least six months after the initiation of dialysis. Recovery of kidney function can occur in SRC, permitting discontinuation of dialysis in many patients. Since the improvement in kidney function can continue for up to 18 months, decisions regarding kidney transplantation do not have to be made during or immediately following an episode of SRC.

Graft and patient outcomes — Kidney allograft survival in patients with SRC is reduced compared with that of transplant recipients with ESKD due to other kidney disorders; however, this difference has diminished as more successful immunosuppression protocols have been utilized [28,42,50-52]. Reported graft survival rates in the United States from the UNOS registry were 68 to 79 percent at one year, 60 to 70 percent at three years, and 57 percent at five years [28,51]. However, these data included some patients who were treated in the pre-cyclosporine era and therefore likely had more episodes of rejection and worse outcomes. A European database of patients transplanted from 2002 to 2013 reported much better one- and five-year graft survival rates (90 and 72 percent, respectively), likely reflecting the use of more effective immunosuppressive strategies [42].

Despite these relatively low allograft survival rates, patient survival after kidney transplantation is superior to that of patients with SRC on dialysis who remain on the waitlist. This was shown in a study of 258 patients with SRC who were listed for kidney transplantation between the years 1985 to 2002 [51]. The one- and three-year patient survival with transplantation was 90 and 80 percent, respectively, compared with 81 and 55 percent in those who remained on the waitlist.

Recurrent disease — The incidence of recurrent SRC in the transplanted kidney is difficult to ascertain with certainty because the primary kidney histopathologic changes associated with SRC (mucoid intimal thickening of the interlobular arteries and fibrinoid necrosis in the glomeruli) may be difficult to differentiate from acute or chronic kidney allograft rejection. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection" and "Kidney transplantation in adults: Chronic allograft nephropathy".)

However, recurrence rates in transplanted kidneys are low (fewer than 5 percent) [28,51,52]. As an example, in a review from the UNOS database of 260 transplants for SRC performed between 1987 and 2004, recurrent disease developed in five (1.9 percent) [28]. Most recurrences occurred within the first one to two years after transplantation, with many occurring within a few months.

Early loss of native kidney function due to SRC appears to be a risk factor for recurrence in the transplanted kidney [28]. In addition, recurrent SRC may be preceded by one or more clinical markers that are predictive of severe SSc, such as progressive skin thickening, new-onset anemia, and cardiac complications such as pericardial effusion or congestive heart failure [28].

The optimal immunosuppressive regimen to avoid recurrent SRC in patients who undergo kidney transplantation is unknown [52]. Transplant centers have successfully used calcineurin inhibitors for maintenance immunosuppression and high-dose glucocorticoids for induction therapy in patients with a history of SRC [53]. However, because of the potential association between cyclosporine and risk of developing SRC, it is possible that noncalcineurin inhibitor-based immunosuppressive regimens (eg, belatacept) may be superior for allograft patients with SSc. Because glucocorticoids are an established risk factor for SRC, we avoid high-dose glucocorticoids (>20 mg prednisone per day) in transplant patients with SSc whenever feasible. (See 'Risk factors' above.)

We continue ACE inhibitors indefinitely after transplantation.

Recurrent SRC in the transplant may follow a similar course as the primary disease. The treatment of recurrent SRC is the same as that for disease in the native kidney. (See 'Treatment' above.)

OTHER TYPES OF KIDNEY DISEASE — Kidney disease in patients with SSc is not always due to SRC. This is particularly true in patients with few risk factors for SRC. (See 'Risk factors' above.)

Acute kidney injury in SSc may reflect prerenal disease associated with heart failure, pulmonary hypertension, nonsteroidal antiinflammatory drugs, diuretics, or hypovolemia due to gastrointestinal involvement and/or malabsorption [3].

Rarely, patients with SSc present with antineutrophil cytoplasmic antibody (ANCA)-related crescentic glomerulonephritis [54,55]. The diagnosis is confirmed by kidney biopsy showing a pauci-immune crescentic glomerulonephritis. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Disease associations'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Prevalence – As many as 50 percent of patients with systemic sclerosis (SSc; scleroderma) have mild proteinuria, elevated serum creatinine concentration, and/or hypertension. However, many of these findings can be attributed to causes other than SSc. Scleroderma renal crisis (SRC) occurs in 5 to 20 percent of patients with diffuse cutaneous SSc and in 1 to 2 percent of patients with limited cutaneous SSc. (See 'Prevalence' above.)

●Scleroderma renal crisis – SRC is a life-threatening complication of SSc that almost always occurs within the first five years of disease onset.

•Risk factors – The most important risk factor for SRC is diffuse skin involvement, particularly if it is rapidly progressive. Other risk factors include glucocorticoid use and autoantibodies directed against RNA polymerase III. (See 'Risk factors' above.)

•Clinical presentation – SRC is characterized by acute kidney injury (AKI), abrupt onset of moderate to marked hypertension, and a normal urine sediment without heavy proteinuria. Evidence of a microangiopathic hemolytic anemia may be present (picture 1). Although approximately 10 percent of patients with SRC are normotensive, some of these patients have a substantial increase in blood pressure from baseline. (See 'Clinical presentation' above.)

•Diagnosis – SRC is a clinical diagnosis based upon characteristic features in patients with SSc and the exclusion of other causes of AKI. Kidney biopsy is generally not required. Our approach to diagnosis incorporates the presence or absence of specific high-risk features, blood pressure criteria, and, as necessary, additional supportive findings. SRC must be distinguished from other forms of thrombotic microangiopathy, particularly thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. (See 'Diagnosis' above.)

•Surveillance and prevention – We advocate monitoring for SRC with regular assessments of home blood pressure and serum creatinine. We avoid glucocorticoid use in patients with SSc whenever possible. We do not use angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers (CCBs) to prevent SRC. Among patients previously taking an ACE inhibitor for hypertension, we replace it with an alternative agent only if they are at high risk for SRC. (See 'Surveillance' above and 'Prevention' above.)

•Treatment – SRC is a medical emergency that requires hospital admission. We use the treatment approach below:

-Goals of therapy – The principal goal is to return the patient to their previous baseline blood pressure within 72 hours. For patients with SRC and hypertension who present with evidence of central nervous system (CNS) involvement, additional goals for immediate blood pressure lowering are the same as for any patient with hypertensive retinopathy and/or encephalopathy. (See 'Goals of therapy' above.)

-ACE inhibitors – For all patients with SRC, we recommend blood pressure control with an ACE inhibitor rather than other antihypertensive agents (Grade 1B). We use captopril because its rapid onset and short duration of action permit rapid dose escalation. For patients who are unable to take an ACE inhibitor, an ARB is an alternative option. Initial dosing and duration of ACE inhibitor therapy are discussed above. (See 'ACE inhibitors in all patients' above.)

-Additional antihypertensive agents – For patients without sufficient blood pressure control despite maximum dose of an ACE inhibitor, we add a dihydropyridine calcium channel blocker such as amlodipine. Beta blockers are usually avoided in patients with SSc because of the theoretical risk of worsening vasospasm. (See 'Other antihypertensive agents' above.)

-Monitoring response to therapy – We follow kidney function, electrolytes, and laboratory markers of microangiopathic hemolysis during treatment. Because of the importance of ACE inhibitor therapy for survival and eventual kidney recovery, we do not stop ACE inhibitors even for a progressive rise of serum creatinine. (See 'Monitoring response to therapy' above.)

•Kidney transplantation – Kidney transplantation is an option for patients with SRC who progress to end-stage kidney disease. We do not perform kidney transplantation for at least six months after the initiation of dialysis, given the chance of recovery of kidney function. (See 'Kidney transplantation' above.)