Management practice and treatment outcomes of adult patients with Lupus Nephritis at the Renal Clinic of St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia

Systemic lupus erythematosus (SLE) is a severe autoimmune disorder characterized by the involvement of multiple organs. It is an autoimmune disorder in which the immune system attacks its own tissues, causing widespread inflammation and tissue damage within the affected organs. It affects the joints, skin, brain, lungs, kidneys, and blood vessels. The degree or severity of the complications mainly depends on the area affected ranging from skin to various internal organs with a variety of symptoms. Lupus nephritis (LN) denotes a common and severe manifestation of SLE and could be a major factor exerting a negative impact on long-term renal and patient survival [1‐3]. Renal involvement occurs in up to 60% of adult patients with SLE and is a major determinant for morbidity and mortality in these patients. Renal involvement in SLE carries a significant risk of morbidity and mortality, which is related to both disease and treatment-related complications [4, 5]. SLE is a potentially severe autoimmune disorder that shows variations in incidence, prevalence, disease activity and prognosis according to race and ethnicity [6]. LN appears to be more prevalent in certain ethnic groups such as Asians, African Americans and Hispanics [7, 8].

As evidence showed that the onset of SLE and lupus flares may trigger by certain environment factors. Among these identifying the environmental risk factors associated with SLE is exposure to ultraviolet radiation, certain medication and hormonal preparations that may result in induce inflammatory response, damage cells and appear clinical symptoms by activating the innate and adaptive immune system [9, 10].

Photosensitivity is well known characteristic in both cutaneous and SLE and has been observed in more than 90% of lupus erythematosus patients following ultraviolet radiation. But, sun-induced organ involvement is rarely reported in lupus erythematosus. It’s believed that sunburn-induced keratinocyte necrosis/apoptosis exposed intracellular antigens as trigger for the generation of autoantibodies that finally mediated immune-complex nephritis [11, 12].

In Africa, an increase in the incidence and prevalence of SLE has been observed currently. Few studies indicate that this high frequency in the African population may be related to the high sun-exposure [13, 14].

Immune complex-mediated LN is the most common cause of kidney disease in SLE. Due to an accumulation of autoantibody-containing immune complexes, the kidney becomes modestly or severely inflamed. Thrombotic microangiopathy, lupus podocytopathy, antiphospholipid antibody-induced vascular lesions and tubule interstitial nephritis are other mechanisms that lead to kidney damage. Renal biopsy is the ‘gold standard’ for diagnosis and classification of LN [15, 16]. The clinical course of LN is heterogeneous and varies from mild subclinical disease to an aggressive course that may rapidly progress to end-stage renal disease (ESRD). The nature and severity of the clinical features of LN do not always predict the underlying histological severity. LN is the most common secondary glomerulonephritis leading to ESRD reported in many countries worldwide [17]. The prognosis of LN could be affected by several demographic, clinical, laboratory, and histological variables at disease presentation, as well as the therapeutic modalities used [18].

The overall goal of LN treatment is prevention of ESRD. To prevent ESRD, short-term treatment strategies have focused on complete or partial reversal of the clinical signs of kidney injury [19]. For this purpose, patients should be treated with an induction therapy with cyclophosphamide (CYC), in combination with corticosteroids, has been used effectively to induce remission in LN, but it has considerable adverse effects. Thus, there has been growing interest in the use of mycophenolate mofetil (MMF) as induction therapy, maintenance therapy, or both for patients with LN. Moreover, other immunosuppressive drugs such as tacrolimus or azathioprine (AZA) are now widely used for maintenance treatment of LN [20‐22]. The use of immunosuppressive drugs, such as MMF, CYC, AZA, improves LN outcomes. These drugs are frequently used with corticosteroids. Because of their effectiveness in LN, immunosuppressive drugs reduce the cumulative corticosteroids dose and associated side effects. Immunosuppressive drugs differ from each other with respect to safety during pregnancy, administration route, frequency of dosing, and cost [17, 23].

Even if there has been significant improvement in patients and renal survival over the past years, the current immunosuppressive regimens still achieve suboptimal results, with unacceptable high rates of progression to ESRD, disease relapse rate and treatment related complications. Long-term use of high dose immunosuppressive agents has also resulted in significant toxicity [15, 24]. Since immunosuppressive drugs are related to significant adverse events, special care should be tended to prevent infection like pneumocystis jirovecci pneumonia, and to prevent steroid-induced osteoporosis, gastrointestinal bleeding, dyslipidemia and hypertension [25‐28].

Moreover, there is a major difference in prevalence, disease severity, treatment response and clinical outcomes between LN patients from different racial and ethnic backgrounds [2]. The severity of disease has been also described to be increased in Africans and therefore the treatment and outcome of African patients with LN has not been rigorously assessed [29].

Treatment of SLE or LN patients in Africa is also restricted by the availability and cost of immunosuppressive drugs, and by the shortage of facilities for laboratory monitoring of patients like some serological tests and kidney biopsy. Thus, in resource limited countries, clinicians treating LN patients have limited choices of therapy and this may result in poor treatment outcomes [30].

In addition to the high cost and limited availability of drugs, adherence to treatment is a problem among SLE or LN patients worldwide. Moreover, low levels of formal education and long distances to travel for specialist care, contribute to low follow-up rates and poor treatment outcomes [31].

Reducing morbidity and mortality associated with LN patients will require more rapid and complete control of inflammatory kidney injury and minimization of LN flares. To improve the outcome of treatment in such patients, earlier diagnosis and treatment, identifying effective/safe drugs and improving patient compliance are important strategies. Thus, the present study aimed to assess the pattern of response to treatment in adult LN patients and to identify the associated factors for poor renal outcome at the renal clinic of St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia. The results and identified gaps of this study will be used as an input for clinicians to improve the management of LN in Ethiopian health care settings.

In this study, medical records of 114 LN patients were retrospectively evaluated to assess the management practice and treatment outcome of LN. All the patients were evaluated using the KDIGO criteria for the treatment outcome and associated factors. Based on these criteria 78.9% of the LN patients had good prognosis and 21.1% patients were found to have poor prognosis. According to the results of this study females were found dominant in number with a female-to-male ratio of 6.6:1 and the mean (± SD) age at onset of LN was 29.10 ± 9.67 years. The age range in this study was from 18 – 63 years and 56.1% of the patients were found below 30 years. The gender ratio is lower compared to studies done in Morocco, 7.8:1 [35], South Africa, 7.4:1 [36], Southern India, 8:1 [37] and Saudi Arabia, 8.3:1 [38] but higher compared to Egypt, 5.4:1 [39], Tunisia, 5.8:1 [40], Senegal, 4.3:1 [41] and Jordan, 6.2:1 [42]. The age distribution is comparable and slightly lower compared to studies from Morocco [35], Jordan [42], South Africa [43], Kenya [44], Saudi Arabia [38] and Senegal [41]. But the mean age in this study is slightly higher than the results of a study in Tunisia [40] and Southern India [37]. This gender and age distribution difference may be due to variation in study participants, study design, socioeconomic status and health care practice in screening and diagnosing of SLE patients for renal involvement follow up. The reason why LN is more dominant in females during childbearing age is that due to the exposure to high endogenous estrogen level which may increase the risk for the development of the disease. This is also supported by other study [45].

Edema at onset 97(85.1%), nephrotic syndrome 76(66.7%), hypertension 53(46.5%), hematuria 86(75.4%) and AKI 48(42.1%) were found the common initial clinical presentation in LN patients in this study. At the time of diagnosis of LN, mean SBP and DBP were 129.52 ± 19.96 and 82.59 ± 14.32 mmHg, respectively. This finding is similar to the results of a study done in Morocco where nephrotic syndrome (52.6%), hypertension (33.3%) and hematuria (76.3%) were the initial manifestations [35]. Another study from South Africa reported that 54.8 and 31.0% of all patients had edema and hypertension, respectively, at onset of LN [36]. The study done in India reported 33.3% of the patients had hypertension and 34% nephrotic range proteinuria at the initial presentation [37]. Edema, nephrotic syndrome, hypertension and hematuria, the most common initial clinical presentations in LN patients, were found similar with other studies [40‐43, 46].

In this study, leucopenia 29(25.4%) and thrombocytopenia 19(16.7%) were found the common hematologic manifestations/disorders in LN patients. A study done by Shivaprasad et al.,in India reported similar findings [37]. But this hematological manifestations is higher than the results of a study from Egypt [47]. The possible reason for this variation may be due to the difference in ethnicity, presence of comorbidities or complications at diagnosis and the type of medication taken.

The mean baselines of SCr, serum albumin and 24-h urine protein were 2.45 ± 2.167 mg/dL, 2.77 ± 0.64 mg/dL and 4.47 ± 2.24 g/24 h, respectively. At the initial presentation, the mean eGFR calculated using the CKD-EPI was 58.36 ± 42.31 ml/min and majority of the patients (29.8%) were classified as stage 3 CKD. These findings are comparable to the results of a study done in India [37]. A study by Okpechi et al., in South Africa reported that the mean baseline eGFR is higher [36] compared to the present study. In addition, a similar study from Senegal, 2020 [48] reported that the baseline eGFR is slightly higher. This discrepancy could be due to the difference in the study participants, the type of medication used and the formula used to calculate eGFR using MDRD and CKD-EPI.

Kidney biopsy was done for 71(62.3%) patients at initial presentation and most of them were classified as class IV 28(39.4%) followed by class III 20(28.2%). This is similar to the findings in India [37], Egypt [47], South Africa [43], Tunisia [40] and Senegal [41] as class IV and class III were the commonest kidney biopsy in LN patients at the initial presentation.

A study in Jordan class IV and V were the most common pathological class of LN but class III are lower than [42] to this study. A study by Niang et al., in Senegal indicates that class IV and V were found the commonest [46]. In the present study class V were lower compared to studies done in South Africa [36], Egypt [39], Senegal [48] and London [49]. This variation could be due to the availability and affordability of kidney biopsy in the study setting is limited.

In this study immunologic tests done at disease onset includes; 85(74.6%) were ANA positive, 31(27.2%) were Anti-dsDNA positive and 11(9.6%) were LA positive. Complement level determinations were also done for C3 (low) and C4 (low) in 44(38.6%) and 38(33.3%) respectively. These serologic tests were lower compared to other studies conducted [35‐37, 40, 43, 49]. The possible reason for this variation could be due to the difference on the availability and physicians’ choice of diagnostic tests. In addition, it may be due to variation in study design and study participants.

The treatment regimen used for the different classes of LN for induction and maintenance therapies as well as other adjuvant drugs used were assessed in this study. According to this CYC and MMF were given as induction treatment and maintenance therapy coupled with 67(58.7%) and 34(29.8%) patients, then 76(66.7%) and 32(28.1%) patients, respectively. AZA was given in 14(12.2%) as a maintenance therapy. In addition, rituximab and tacrolimus were given in refractory LN patients. Prednisolone was used in all patients. This is similar to the finding in Texas, 2011 most patients received IV CYC for induction, few use MMF but most patients use MMF as maintenance therapy and few use IV CYC for maintenance therapy [24].

In the present study the use of MMF as induction and maintenance therapy is higher compared to previous studies done in Africa; most of them used CYC as induction treatment [29]. This may indicate good adherence to recent clinical practice guidelines in the study setting. The present study findings in line with study done in South Africa on 87 LN patients [50].

A study from Senegal in 2020 reports that at the induction phase most patients received steroids (with pulse methylprednisolone for 3 days followed by an oral prednisone) for a total of 99 LN patients [48]. This is similar to the present study on the choice of immunosuppressive drugs for the induction and maintenance therapy. On the other hand, study in South Africa for outcome of patients with membranous LN indicates that prednisolone plus CYC used commonly as induction. Also, more patients received prednisone and azathioprine for maintenance therapy. Few patients received prednisolone plus CYC as maintenance and MMF or prednisolone alone as maintenance [36]. This is also supported by a study done in Eastern India for short-term outcomes of LN patients uses CYC and MMF as induction agent [51].

In this study, most LN patients receive chloroquine, ACEI/ARB, anti-platelet agents and lipid lowering drugs as adjuvant therapy as supported by a study in South Africa [36]. This is also in line with the KDIGO 2021 guideline recommends that patients with LN should be treated with hydroxychloroquine or an equivalent antimalarial (chloroquine) unless contraindicated. It also recommends kidney protective therapy using RAAS blockage in LN patients is the key principle of patients to prevent progression to ESRD [27].

GI intolerance presented as abdominal pain, nausea or diarrhea was the most common 27(31.2%) adverse event reported from the use of MMF in this study. Diarrhea was reported as the frequent adverse event of MMF supported by other studies [52, 53]. A study by Lu et al., done in active LN patients reports that 4.2% suffered from gastrointestinal upset as a side effect of MMF which resolved without discontinuation [54]. In addition, in this study, according to the treating physicians’ the following adverse events were reported: peptic ulcer, cushingoid appearance, diabetes mellitus, leucopenia, psychosis, cataract/glaucoma, infection (candidiasis, herpes, urinary tract infection) and pleural effusion. Such adverse events also reported somewhere else [36, 55] with different magnitude This adverse event variation could be due to difference in sample size and race of study participants, choice of immunosuppression and follow up period.

In the present study 40(35.1%) patients achieved complete remission, 51(44.7%) patients attained partial remission and 23(20.2%) patients had no remission to treatment at the end of the study. In addition, 7(6.14%) patients progressed/reached to ESRD and death occurred in 4(3.51%) patients. This is comparable to the findings of South Africa [50], India [37], Morocco [35], Senegal [41, 48] and Eastern India [51]. However, there are slight variations due to different study design, sample size, race of study participants, type of regimen, outcome criteria and diagnostic tests used.

Exacerbation or worsening of edema and relapse were found the common hospitalization events and reason for admission in LN patients during the study period in this study setting but the cause of death was not reported. A study by Ameh et al., reports that increased disease activity, kidney failure and infections were the common causes of mortality in LN patients [29]. This is also supported by other similar studies [35, 41].

There are different factors affecting the treatment outcome of LN patients depending on their race. In this study, AKI at onset, high SCr at six-months, no response at six-months to achieve complete remission and presence of flare were found the independent risk factors of poor treatment outcomes. The findings of this study comparable with other study [37]. However, a study by Momtaz et al., in Egypt reported that high baseline SCr, failure to achieve remission, hypertension, and nephritic flare were found the main risk factors for poor renal outcome [56]. Studies done in South Africa indicates that the factors associated with poor renal outcome in LN patients were elevated blood pressure, lack of complete remission at 6 months, nephrotic range proteinuria, low complement levels (C3 & C4) and positive double-stranded DNA [36, 43, 57]. Moreover, hypertension and nephrotic syndrome were factors of poor renal prognosis in many studies [40, 41, 51]. There may be slightly variations due to differences in the composite end points used such as drug choice, availability of diagnostic tests for histological identification, referral and follow up practice, racial variation which basically affects the treatment response and associated complications.

In this finding indicates that patients who develop AKI (p = 0.026) were found to be 4.8 times higher odds of poor prognosis than those without. This is similar to the finding of Senegal and South Africa reports [41, 43].LN patients who did not attain complete remission at six-months (p = 0.041) have 5% higher risk of poor renal prognosis. This is supported by a study in South Africa [36, 57] in which failure to achieve remission following induction therapy or lack of complete remission at 6 months results in poor renal prognosis.

Any history of relapse or flares (p = 0.004) during treatment of LN patients results in poor prognosis and to this effect needs additional immunosuppressive treatment. This is supported by a study done by Kammoun et al., and Sircar et al., in which high activity index score of LN was associated with poor renal prognosis [40, 51]. A study in Texas a high chronicity index is associated with poor response and MMF as a maintenance agent may improve the response to treatment [24]. But the use of MMF as maintenance therapy does not result any significant association in the present study. This may be affected by the sample size and availability of the medication.

The treatment outcome of LN patients in this study was found comparable to other study findings, but relapse, treatment-related complications and adverse events of steroids and other immunosuppressive regimens needs close monitoring. AKI at onset, increased SCr at six-months, no response at six-months to achieve complete remission and presence of flares were predictors of poor treatment outcome.