INTRODUCTION
Minimal change nephropathy (MCN) is amongst the commonest causes of nephrotic syndrome worldwide accounting for up to 15% of cases of primary nephrotic syndrome in adults.(1) In children, it accounts for approximately 77% of all cases as described by the International Study of Kidney Diseases in Children.(2)
MCN is a glomerulopathy in which no significant glomerular changes are found on light microscopy. As a result, it is also known as nothing-in-light microscopy disease. Immunofluorescence studies are also negative, but electron microscopy reveals podocytopathy, specifically, fusion of the foot processes.(3) Accurate diagnosis therefore rests upon a renal biopsy. Guidelines recommend renal biopsy in all adult patients with nephrotic syndrome of uncertain cause as this aids in ascertaining diagnosis, treatment modality and prognosis.(4)
MCN may be categorised as primary or secondary in aetiology. Primary MCN remains largely idiopathic and secondary causes of MCN are diverse and account for approximately 30% of cases.(5) The clinical characteristics of patients with MCN, their disease course and response to treatment have been well described in the paediatric population. In adults, however, fewer series are available and published reports predominantly reflect European and American populations.
Available epidemiological data for adult populations suggests that MCN is more common in males and describes a geographical variation with higher prevalence in Asia as compared to North America and Europe.(6) A general trend towards a lower prevalence of MCN has been described in African countries, particularly in Black Africans. A more recent analysis of the patterns of renal disease in South Africa reported a lower incidence of MCN (affecting 3% of African and 8% of Indian children) and also found a prevalence of MCN of 10.7% in Black adults presenting with primary glomerular disease.(7) More common in Black adult patients was mesangiocapillary glomerulonephritis (35.7%) and membranous nephropathy (21.4%). In Indian patients, MCN and membranous nephropathy had an equal prevalence of 21.3% and a lower prevalence of mesangiocapillary glomerulonephritis (13.3%) was described.(7) A study in 1989, in adult Caucasian patients at a Johannesburg hospital found an incidence of MCN in 13.6% of patients with nephrotic syndrome.(3) A recent review of a single-centre renal biopsy database in Cape Town indicated a 6% prevalence of MCN in their adult predominantly mixed (coloured) and Black population.(8)
Genetic factors (human leukocyte antigen factors, including DR7, DR8, B12 and DQw3), socio-economic status and environmental pathogens have all been suggested as possible contributors to differences in the geographic prevalence of kidney diseases.(9,10) HLA DR7 is much more common in White populations than Black populations, which may explain discrepancies in MCN prevalence between racial groups.(10) Other studies, however, have failed to show similar associations.(11) A more recent case report described MCN in a patient with limb girdle muscular dystrophy type 2B, which is caused by mutations in dysferlin.(12) Whether this mutation has influence on the incidence of MCN in specific populations has not been determined.
The hygiene hypothesis suggests that good public hygiene and reduced exposure to pathogens in childhood, as assumed to be present in the majority of developed populations, leads to a persistent Th2 phenotype, thereby increasing the incidence of glomerulopathies associated with atopic causes such as MCN and IgA nephropathy.(9) African or less developed populations are more exposed to early infections and develop a Th1 response and are hence more likely to develop proliferative and crescentic forms of glomerulonephritis. However, this population is more exposed to infections such as HIV, tuberculosis and schistosomiasis, all of which are documented secondary causes of MCN.
The cardinal presenting features of MCN are those of nephrotic syndrome, specifically, proteinuria, hypoalbuminaemia, hyperlipidaemia and peripheral oedema; renal function is typically preserved in MCN. Blood pressure may be elevated in adult populations, but it is said to be normal in most cases.(1) In MCN, an acute onset, over days to 2 weeks, is usually described. In contrast, other causes of primary nephrotic syndrome such as focal segmental glomerulosclerosis and membranous nephropathy have a more gradual course, developing over weeks to months.(13) This sudden onset in presentation has thus been used as one of the clinical indicators to strengthen the suspicion of MCN as the cause of a specific case of nephrotic syndrome. This sign has been stated to be sensitive but not specific for MCN.
Available data suggests that MCN is highly responsive to therapeutic regimens consisting of glucocorticoids.(1,14) However, anecdotal evidence suggests a poorer response in adult and Black populations as compared to paediatric and Caucasian populations, requiring therapy with additional immunosuppressant therapy (cyclophosphamide, calcineurin inhibitors, azathioprine and mycophenolate mofetil, rituximab) due to glucocorticoid dependence or resistance.(15,16)
Non-immunosuppressive therapy is also part of the treatment of patients with MCN. A low-sodium diet, fluid restriction and diuresis can be considered to control oedema.(17) Hypertension can be treated with angiotensin- converting enzyme inhibitors or angiotensin receptor blockers as these have an added anti-proteinuric effect. This is mediated by lowering the systemic blood pressure and the intraglomerular pressure which then leads to a reduction in both proteinuria and secondary glomerular injury.(17) Additionally, podocytes are known to express angiotensin II receptors, type 1 (AT1) and type 2 (AT2); angiotensin blockade may therefore be beneficial in the regression of proteinuria and molecular changes in podocytes.(18)
METHODS AND MATERIALS
The histopathology records of all patients undergoing native renal biopsy between 2001 and 2010 at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and Helen Joseph Hospital (HJH) were surveyed. A total of 1618 renal biopsies were performed in the 10-year period and of these, 57 had a confirmed diagnosis of MCN. Ten patients with known secondary causes of MCN were excluded from analysis as follows: HIV (5 patients), systemic lupus erythematosus (2), autoimmune hepatitis (1), post-transplant with hypertension (2). The clinical records of these patients were obtained from their respective hospitals and retrospective review of clinical and serological parameters pertaining to MCN was conducted. Data pertaining to patient presenting features, response to treatment and outcomes was collected and analysed. The presentation of MCN was evaluated in respect of demographic factors (gender, race and age) and clinical parameters (serum creatinine, albumin, cholesterol, urine protein:creatinine ratio and presence of hypertension and renal dysfunction). Therapeutic response was evaluated in terms of remission/relapse rates, time to remission/relapse and steroid resistance; remission was defined as per the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.(16) Long-term outcomes were assessed through evaluation of the number of relapses, time to relapse and remission profiles.
Statistical analysis was conducted using STATA software version 13. Normality of distribution of variables was assessed using the Shapiro–Wilk W test and the Central Limit Theorem. Continuous variables were reported as mean ± SD or median and interquartile range as appropriate. Significance testing for normally distributed data was carried out using the Student's t-test; for non-normally distributed data, the Kruskal–Wallis test was used. The chi square test was used to assess significance in analyses of categorical binary data. The level of statistical significance was assumed at P < 0.05. In instances where a difference was noted, further analysis was performed assuming P < 0.1. Analysis of remission profiles was conducted using the Kaplan–Meier method.
RESULTS
Forty-seven (2.9% of all patients undergoing biopsy) patients with MCN were identified. The demographic features and presenting clinical characteristics of these patients are illustrated in Table 1. A predominance of Black patients (83%) was noted, with almost an equal male-to-female ratio (1.04:1) and the mean age was 31.8 ± 12.1 years. Indeed, MCN appeared to predominantly affect younger adults with 53% of the patients below the age of 30 years and 75% being younger than 40 years (Figure 1). There was an association between gender and age in that a predominance of males was diagnosed with MCN in younger patients, with females more represented amongst older patients (P = 0.057 at a 10% level of significance).
Baseline clinical characteristics of 47 patients with minimal change nephropathy.
| Characteristic | Total of study population (n = 47) |
|---|---|
| Age (years) a | 31.8 ± 12.1 |
| Range | 18–70 |
| Gender | n (%) |
| Female | 23 (48.9) |
| Male | 24 (51.1) |
| Ethnicity | n (%) |
| Black | 39 (83) |
| White | 3 (6.4) |
| Indian | 3 (6.4) |
| Mixed race | 2 (4.3) |
| Hypertension | 3 (6.4) |
| Renal dysfunction | 8 (18.1) |
| Serum creatinine (µmol/l) a | 92.5 ± 64.3 |
| eGlomerular filtration rate (ml/min/1.73 m2) a | 104.5 ± 45.2 |
| Serum cholesterol (mmol/l) a | 11.4 ± 9.1 |
| Serum albumin (g/dl) b | 21.5 (14.5–33) |
| Urine protein: Creatinine ratio (g mol/l ) b | 0.67 (0.40–0.95) |
Data are means ± SD.
Data are median (inter quartile range).
The majority of patients diagnosed with MCN presented with features of the nephrotic syndrome, with 81.4% of patients having nephrotic range proteinuria (mean protein:creatinine ratio of 0.69 ± 0.46 g mol/l ), 90% demonstrating hypoalbuminaemia (mean serum albumin level of 23.4 ± 11.4 g/dl) and 89.4% having hypercholesterolaemia (mean cholesterol of 11.4 ± 9.1 mmol/l). About 18% of patients had a presenting serum creatinine above the laboratory upper limit of normal, with the mean baseline serum creatinine level of these patients being 92.5 ± 64.3 µmol/l, and the mean eGFR 104.5 ± 45.2 ml/min/1.73 m2. Hypertension was present in 6.4% of the patients.
Of the 47 patients included in the study, 28 had complete records of treatment and outcomes, including remission and relapses. All patients received initial therapy with prednisone at a dose of 0.5–1 mg/kg with the average dose being 0.8 ± 0.19 mg/kg and the mean duration of therapy was 24.8 ± 19.0 months. Remission was achieved in 57.1% with no subsequent relapses. A total of 12 patients relapsed, of whom 7 (58.3%) had one relapse and the remaining 5 (41.7%) relapsed twice. There were no significant differences in presenting variables between patients who had relapses and those who did not.
The 12 patients with relapsing MCN received a variety of additional immunosuppressant therapy, including cyclosporine (8), cyclophosphamide (2) and tacrolimus (1). One patient received a second course of prednisone. Among those receiving cyclosporine, one patient required therapy switch to tacrolimus before achieving remission.
The mean time to first relapse was 27.8 ± 19.4 months (Figure 2). Most patients relapsed within 30 months post remission. Of these 50% relapsed within 24 months of remission and only two patients relapsed after 48 months, as seen in Figure 2.
The duration of remission was longer in males than in females. The mean time to relapse for females was 18 ± 16.9 months, whereas in male patients it was 39.3 ± 17.9 months (P = 0.09 significant at 10% level) (Figure 3).
DISCUSSION
MCN has been described as accounting for up to 15% of all causes of nephrotic syndrome in adults.(1) The prevalence is higher in Asia, North America and Europe (7.1%–15.1%) as compared to Africa.(6,9) In this series, the prevalence was 2.9%, consistent with reported lower prevalence of MCN in African countries.(7–9,19–21) It has been suggested that the lower prevalence of MCN in Africa may be underestimated due to the infrequency of renal biopsy as a diagnostic technique. A previous study from Johannesburg by Arnold reported the prevalence of MCN in adult Caucasians undergoing biopsy to be 13.6% (3) and a more recent series by Vermeulen et al. reported the prevalence of 11% in a predominately Black population;(22) both findings similar to those observed in European and North American cohorts.
Since Black patients comprise the majority of the population of the current study (83%), comparison with the report of Arnold suggests that MCN is less common in Black African patients. In support of this finding, Naicker and Okpechi have previously reported lower prevalence of MCN in Black South African adults of 10.7% and 6%, respectively.(7,8) The aetiology of the disparity of MCN between Black and Caucasian South African adults is unclear, although genetic factors, socio-economic status and environmental infectious pathogens have been proposed as possible mechanisms.
In this study, MCN was a more frequent histological diagnosis in younger patients, with 75% of patients being below the age of 40 years. This is consistent with published data indicating that MCN is more common in young individuals.(1,2,6,13) A male-to-female ratio of 1.04:1 was observed, suggesting that males and females have an almost equal risk of developing MCN. Studies of MCN in adult non-Black populations show variability in gender preference.(3,13,23) A male preponderance of 1.8–3.1:1 has been reported in paediatric populations diagnosed with MCN.(2) Interestingly, in this study, a predominance of males was observed amongst younger patients (less than 30 years), as compared to the older patients in whom more females were diagnosed with the condition.
Elevated levels of serum creatinine were found in 18% of study patients. Although MCN is typically associated with normal serum creatinine levels, some patients may present with acute kidney injury.(1) Waldman et al. in a series of 95 patients also described a prevalence of 18% of acute kidney injury in patients with MCN.(13) Mak et al. reported an even higher prevalence of acute kidney injury of 55% in their series of MCN patients.(23)
Hypertension is not an uncommon feature in adults presenting with MCN. Available data suggests that elevated blood pressure is observed in up to 47% of cases.(13,24) Hypertension, in this study, was defined as blood pressure above 140/90 mmHg, as per the South African Hypertension Society guidelines 2014, or those on antihypertensive treatment.(25) In this series, the prevalence of hypertension was found to be 6.4%. Of note, all patients found to have hypertension were already on antihypertensive therapy at diagnosis of MCN. This raises the possibility of essential hypertension occurring as a background to new onset MCN in these patients. If so, the predominance of younger patients diagnosed with MCN in this series may have contributed to the low rate of hypertension observed.
In the current study, there were no significant differences in the clinical findings (serum creatinine, albumin, cholesterol and UPCR) of patients with regard to ethnicity, gender or age groups. This suggests that the clinical severity of MCN is not affected by patient ethnicity, age or gender. MCN is highly responsive to corticosteroids and all patients included in the outcomes analysis of this study were prescribed prednisone at an average daily dose of 0.8 mg/kg as first-line therapy. The average treatment time to remission was 24.8 ± 19.0 months. No relapse after remission was found in 57.1% of patients. This is consistent with data that indicates that complete remission in adults is achieved in 51–76% within 8 weeks and in up to 96% with 16 weeks of therapy.(1,14,26)
The average duration of therapy of 2 years in this study is considerably longer than the recommended 6–8 weeks. Adult patients with MCN are believed to require a longer duration of corticosteroid therapy and are more likely to require additional therapy in order to achieve remission.(1) It has also been suggested that steroid responsiveness of MCN may vary between ethnic groups. Studies in Asia have reported excellent steroid responsiveness with up to 90% of patients achieving remission by 8 weeks of therapy.(14,26) In comparison, studies in predominantly White populations report remission rates of 75% by 13 weeks (13) and up to 92% by 21 weeks.(23) The findings in this series, in which subjects were mostly of Black race, suggest that a significantly longer period of treatment is needed to achieve remission in Black African patients. This may also partly account for the number of relapses documented in this study (12 patients, 42.9%). Single relapse was experienced in 58.3% of these patients, while 41.7% had two relapses. The average time to relapse was 27.8 ± 19.4 months with the majority of patients (83%) relapsing within 48 months after initial remission.
No significant associations were found between the likelihood of relapse and variables such as age, gender or race. The effect of age on risk of relapse in other studies is variable, with some reporting no effect,(27) and others suggesting increased frequency of relapse in those under the age of 40 years.(13,14) In the present study, there were no significant differences in the presenting characteristics of the patients who had relapses and those who did not relapse. The remission profiles of this study population show that the probability of being in remission for over 8 months is 93%. Males were found to be in remission for a longer time period (39.3 ± 17.5 months) as compared to females who relapsed within 18 ± 16.9 months. Remission profiles according to age categories indicated that 50% of older patients (30 years) maintained remission for over 12 months, while patients in the younger group remained in remission for longer, with 50% being in remission for over 16 months. Whereas Nakayama found that renal dysfunction and severity of proteinuria may predict remission induction in response to first-line therapy,(26) Mak has reported a correlation between induction of remission and serum albumin level and age.(23) Consistent with other reports, no demographic or clinical feature was shown in this study to predict remission induction.(1)
Cyclophosphamide is known to induce remission in up to 63% of MCN cases (1) and remains the recommended second-line therapeutic modality in the KDIGO clinical practice guidelines.(16) The side effect profile of this agent limits its repeated usage. Other agents such as calcineurin inhibitors, azathioprine and mycophenolate mofetil have been shown to have better side-effect profiles and may be preferred depending on risk and benefit analysis for each patient.(1,13,16) In this study, 39.2% of patients had probable steroid resistance, as evidenced by frequent relapse or relapse on steroid treatment. Of those patients, 8 were treated with cyclosporine with only 2 receiving oral cyclophosphamide and 2 receiving tacrolimus. One patient was switched from cyclosporine to tacrolimus to achieve remission. Available data shows adult steroid resistance to be present in 8% to more than 25% of cases.(13,23)
LIMITATIONS
The sample size of this study was small as MCN in Black adults has a low prevalence. This resulted in some of the data not being normally distributed. Appropriate statistical methods were employed in this study, but bias cannot conclusively be avoided.
CONCLUSION
The prevalence of MCN in Black adult patients at the Witwatersrand Academic Complex is very low but should still be considered in the differential diagnosis of nephrotic syndrome. Younger males and older females may be more likely to present with MCN. In these patients, MCN may be less responsive to corticosteroids and a longer course of therapy may be required to induce remission.