The Implication of the KDIGO Clinical Practice Guidelines on Management of IgA Nephropathy

Published on 02/05/2016 by admin

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Last modified 03/05/2016

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Recommendation
 Long-term ACEI or ARB or ARB treatment when proteinuria is >1 g/day, with up-titration of the drug depending on blood pressure (1B)
Suggestions
Proteinuria
 ACEI or ARB if proteinuria is between 0.5 and 1 g/day (in children, between 0.5 and 1 g/day per 1.73 m2) (2D)
 ACEI or ARB be titrated upward as far as tolerated to achieve proteinuria <1 g/day (2C)
 6-month course of corticosteroid therapy in patients with persistent proteinuria ≥1 g/day despite 3–6 months of optimized supportive care (including ACEI or ARB and blood pressure control) and GFR >50 ml/min per 1.73 m2 (2C)
 Fish oil if persistent proteinuria ≥1 g/day despite 3–6 months of optimized supportive care (including ACEI or ARB and blood pressure control) (2D)
Blood pressure
 Treatment goal of <130/80 mmHg in patients with proteinuria <1 g/day (not graded)
 Treatment goal of <125/75 mmHg when initial proteinuria is >1 g/day (not graded)
Rapidly declining GFR
 Supportive care for AKI in IgA nephropathy, with a kidney biopsy performed during an episode of macroscopic hematuria showing only ATN and intratubular erythrocyte casts (2C)
 Steroids and cyclophosphamide in patients with IgA nephropathy and rapidly progressive crescentic IgA nephropathy, analogous to the treatment of ANCA vasculitis (2D)
 Treatment as for MCD in nephrotic patients showing pathological findings of MCD with mesangial IgA deposits on kidney biopsy (2B)
Treatments not suggested
 Immunosuppressive therapy in patients with GFR <30 ml/min per 1.73 m2 unless there is crescentic IgA nephropathy with rapidly deteriorating kidney function (2C)
 Mycophenolate mofetil (2C)
 Antiplatelet agents (2C)
 Tonsillectomy (2C)
Abbreviation: ACEI angiotensin-converting enzyme inhibitor, AKI acute kidney injury, ANCA anti-neutrophil cytoplasmic antibody, ARB angiotensin receptor blocker, ATN acute tubular necrosis, GFR glomerular filtration rate, MCD minimal change disease
The rationale of the KDIGO guidelines is based on moderate-quality evidence to suggest that proteinuria more than 1 g/day is associated with an accelerated decline in kidney function, in a dose-dependent fashion and independent of other risk factors. The strongest evidence (“We recommend”) points to a proteinuria (in adults) cutoff of 1 g/day (Table 14.1), below which (and sustained) a favorable outcome is achieved. There is valid concern that an increased risk starts with proteinuria above 0.5 g/day (“We suggest”).
Noting the less controversial proteinuria cutoff of 1 g/day in adults, the KDIGO guidelines suggest additional treatment when the proteinuria is persistently more than 1 g/day despite 3–6 months of optimized supportive care (including ACEI or angiotensin II receptor blocker and blood pressure control). Choices (“we suggest”) include fish oil, a 6-month course of corticosteroid therapy, or both. The guidelines do not address how to choose between fish oil and corticosteroid, but the corticosteroid therapy should be restricted to patients with glomerular filtration rate of more than 50 ml/min per 1.73 m2 of body surface area according to the KDIGO guidelines (Table 14.1). Furthermore, the preferred dosage regimen for corticosteroids (combined pulse and oral steroids versus purely oral regimen) cannot be commented. The guidelines also draw attention to the potential of more side effects with high-dose pulse corticosteroids, as reported in non-IgA nephropathy patients [1].
It is important to take precaution and keep in mind that the KDIGO guidelines include mostly Level 2 evidence (“We suggest”) and much less Level 1 recommendation (“We recommend”). This is partly because of the considerable lack of randomized controlled trials, among which patient numbers seldom exceed 200. Another important purpose of the KDIGO guidelines is the opportunity to prioritize areas in need of research. For example, there is no randomized controlled trial of treatment in crescentic IgA nephropathy.

14.3 Published Commentaries of KDIGO Guidelines

Since the publication of KDIGO guidelines, a few reviews had been published on the topic of IgA nephropathy [6, 7] and evaluation of the guidelines [8]. In particular, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) [9] and the Canadian Society of Nephrology [10] made specific comments on the chapter of IgA nephropathy.
Much insight can be gleaned from the discussion from these two documents [9, 10]. Their focuses were summarized in Table 14.2. A few points deserve mentioning. First, both commentaries highlighted the corticosteroid treatment threshold for IgA nephropathy: trial of corticosteroids should only be considered in patients with preserved renal function or glomerular filtration rate above 50 ml/min per 1.73 m2. Admittedly, this is reasonable to draw such conclusion based on the inclusion criteria and subject profiles of the three major trials of corticosteroids [1113]. Nonetheless, concern about corticosteroid side effects explains the need to emphasize the treatment criteria. The Canadian commentary advises the consideration of corticosteroids at the level of the individual patients, taking into account of their relative contraindications to steroid therapy [10]. And, as highlighted by the US commentary [9], a meta-analysis of corticosteroid treatment in IgA nephropathy suggested an increased efficacy with shorter-term high-dose therapy compared to longer-term low-dose therapy [14]. Second, the controversy of using mycophenolate mofetil can be demonstrated by the different views from the two commentaries. The US commentary generally agreed with the recommendation not to use mycophenolate mofetil in patients with IgA nephropathy, but hinted on the racial differences in the response to mycophenolate mofetil [9]. The benefit of mycophenolate mofetil in Asian patients, as shown in the reduction of proteinuria, a decrease in rate of decline in glomerular filtration rate and end-stage renal disease risk after 6 years of follow-up [15, 16], was acknowledged in the commentary. On the other hand, the Canadian commentary argued against the use of mycophenolate mofetil and reminded us the potential toxicity (including severe pneumonia such as Pneumocystis pneumonia) as observed in observational studies, in line with what were recommended by the KDIGO guidelines.

Table 14.2

Published comments on KDIGO clinical practice guideline concerning IgA nephropathy
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Commentary source
Critiques, remarks, and rationale
Implication and suggestion
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) US commentary [9]
No trials showing ACEI or ARB decrease the risk for ESRD from IgA nephropathy
No need to decrease proteinuria to <0.5 g/day/1.73 m2 in children
No objective evidence for superiority of proteinuria goal <0.5 g/day per 1.73 m2 to <1.0 g/day per 1.73 m2 in children
Target blood pressure goals in children based on gender and age norms outlined by the National Institutes of Health (NIH) Task Force on Blood Pressure Control in Children, aiming for blood pressure below the 95th percentile
Agree with the additional benefit of corticosteroids
Agree with not treating with cyclophosphamide or azathioprine
Trial of corticosteroids restricted to patients with preserved renal function (concept about “point of no return”)
Generally agree with not using mycophenolate mofetil, but there may be some benefit in patients of Asian ancestry
Reasonable to use mycophenolate mofetil as an alternative agent if corticosteroids fail or are poorly tolerated in patients of Asian ancestry
Conflicting evidence on efficacy of fish oil supplements but there is little risk
Suggest future research comparing racial differences in response to immunosuppressive agents