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Glomerulonephritis
Nephritic syndromes.
These patients present with hypertension and haematuria with varying degrees of fluid overload.
In young patients, the most common cause is still post-infectious glomerulonephritis. A patient with evidence of recent infection (e.g. healing impetigo) can reasonably be expected to have a benign course and respond to blood pressure control with vasodilators and a small amount of diuretic. Serum creatinine should be only mildly elevated and should fall fast. Blood pressure control is with standard agents. There is probably little value in giving an antibiotic, and the choice of blood pressure agent (calcium antagonist or ACE inhibitor) is not critical, although some authorities are wary of the latter agents as they may contribute to a serum creatinine rise, complicating interpreting resolution, and may worsen hyperkalaemia.1
Unless another secondary cause is obvious, most other patients should be considered for renal biopsy.
Rapidly progressive glomerulonephritis
This is a medical emergency, and needs to be recognised as such. Watching progressive deterioration in renal function to a stage of irreversible kidney failure is very avoidable.
Consider this condition in any euvolaemic or overhydrated patient with haematuria and a serum creatinine rising over days. The diagnostic clue is an active urinary sediment, usually with red cell casts. Ideally, all such patients should be referred promptly for consideration for renal biopsy, and therapy tailored to the results of the biopsy. If any delay is envisaged, serious consideration should be given to starting therapy before the biopsy is performed. Such decisions should ideally be made in consultation with a nephrologist.
- Methylprednisolone 500mg – 1g slowly (3 – 4 hours) IV daily for three days
- AND cyclophosphamide 100 mg daily PO.
Sudden hypotension and collapse while methylprednisolone is infused has been described, but is rare. Management is supportive after stopping the infusion. Once the patient responds, the infusion can be cautiously recommenced at a much slower rate. The choice of 500mg or 1 g of methylprednisolone is largely one of preference in the absence of a comparative efficacy trial. Weak observational information from the literature on the use of pulse corticosteroids in SLE suggests little extra benefit of 1 g over 500 mg, and possibly more infections, although multiple confounders make this data difficult to interpret.2
Even if the immunosuppressive therapy has been given, and the patient appears to be responding, consideration should be given to referral for biopsy.
Interpreting renal biopsies
|
Histology |
Clinical |
Management |
|
Minimal change |
Nephrotic; 25% can have haematuria and a third are hypertensive as well |
Prednisone 60 mg/day – 80% response. Only about 1% progress to ESRF |
|
Membranous |
Nephrotic. Microscopic haematuria in 50% |
After a 3 day IV methylprednisolone pulse giving alternating monthly prednisone (0.4 mg/kg/d) and chlorambucil (0.2 mg/kg/d) for 6 months (Ponticelli regimen) followed to 10 yrs yields probability of surviving without ESRF of 92% vs. 60%[5]. NNT 4 (2-7) – still controversial. |
|
Mesangiocapillary (= membranoproliferative) |
Can present as nephrotic or nephritic or just haematuria or proteinuria |
No effective Rx. ESRF in 50% at 10 years |
|
Focal glomerulosclerosis |
Nephrotic. Strong association with HIV infection |
Only about 10% respond to steroids. 50% to ESRF in 5 years |
|
Mesangioproliferative |
Nephrotic |
50% steroid responsive 36% ESRF at 10 years |
|
SLE |
Renal survival at 10 years[6] | |
|
I – normal histology |
(Good) |
No specific treatment needed |
|
II – mesangial |
(Good) | |
|
III – focal |
52% |
Pulse methylprednisolone 1g daily IVI for three days, then oral cyclophosphamide 1-3 mg/kg/d for three months After induction, maintenance with low dose steroids (e.g. 10mg per day) or steroids plus azathioprine. |
|
IV- diffuse |
75% | |
|
V – membranous |
47% | |
|
Diabetes |
Most sensitive indicator of early damage is increased urinary albumin excretion (special dipsticks or spot specimen to lab) |
Control the BP, ideally using an ACE inhibitor. |
|
Control the sugar | ||
|
Control dyslipidaemia | ||
|
Avoid excessive dietary protein | ||
|
Amyloidosis |
Chemotherapy for myeloma if this is the cause |
Perspective – therapies for glomerulonephritis
Glomerulonephritis is a serious condition, and lupus nephritis particularly so. A follow up study3 of aggressively treated patients (steroids, cyclophosphamide, plasmapheresis) with lupus nephritis found a 5% five year mortality in 37 patients who responded compared with 31% in 49 patients who did not respond to treatment. Five year progression to end stage kidney disease was 6% and 54% respectively.
Many clinicians seem to find renal therapeutics quite bewildering. This is partially explained by the ‘closed shop’ situation where nephrologists interpret arcane histology before recommending therapy, although when you think about this, it applies to most disciplines.
Another part of the explanation may be provided by a review4 of the evidence base in nephrology, which found that 2779 RCTs were published in nephrology from 1966 to 2002 as opposed to the next highest discipline, haematology (5335 over the same time period). Cardiologists have managed to produce ten times as many RCTs (27109) as nephrologists over this 37 year period. Of equal concern, the trials were often of poor methodological quality – 50% failed to perform intention to treat analysis, 92% failed to report on the blinding of outcome assessors, and in 89% allocation concealment was unclear.
A few general principles are emerging:
In lupus nephritis, pulsing patients with 500mg methylprednisolone daily for 3 days may be safer and as effective as the previous conventional 1 g /d for three days5 ,6 (although the evidence from the second reference is fairly weak – retrospective cohort). For lupus nephritis maintenance therapy, azathioprine and steroids may be as effective as cyclophosphamide and steroids.
Pulse cyclophosphamide and pulse steroids are probably still gold standard for eliciting remission in diffuse proliferative lupus nephritis7 ,8 .
Early renal biopsy is worthwhile in SLE patients with raised creatinine or abnormal urinalysis9 unless a decision to institute profound immunosuppression has already been made based on other lupus criteria. Even in that situation, a biopsy may provide prognostic information and can assist in planning maintenance therapy.
In patients with membranous nephropathy, the Ponticelli trials are still regarded as providing some of the best evidence. They were underpowered to detect a mortality advantage of immunosuppression, and treated patients with relatively early disease (0.5-0.6g protein/mmol creatinine, versus 7-8 in some other trials) but showed convincing evidence of benefit on renal survival (92% vs. 60% at 10 years, ARR 32%, NNT = 4; 95% CI 2% – 7%).
Another group10 have adopted a more restrictive approach to immunosuppression in this patient group, confining its use to patients with a creatinine of > 135 micromol/l, or an increase of creatinine of more than 50% above baseline, or severe nephrotic syndrome with proteinuria of more than 8g/day. In a prospectively studied cohort of 69 patients they ended up only treating half the patients (48%) and achieved complete remission in 32%, partial remission in 35% and progression to end stage renal failure or death in 10%. The remaining 23% remained with severe nephrotic syndrome or renal dysfunction, which compared favourably with the same group in the Ponticelli trials (36% of controls, 31% of those immunosuppressed). The treatment used by this group after 1991 was cyclophosphamide 1.5-2 mg/kg/day for 12 months and ‘3 consecutive pulses’ of 1g methylprednisolone at the beginning of months 1, 3 and 5 and then prednisone 0.5 mg/kg on alternate days for six months. This was felt to be less toxic than the chlorambucil regimen although they had one death from cyclophosphamide related bladder cancer, giving a treatment-related mortality rate of 3% (95% CI 0.5 – 15%)…
Ong LT. Management and outcomes of acute post-streptococcal glomerulonephritis in children. World J Nephrol. 2022 Sep 25;11(5):139-145. doi: 10.5527/wjn.v11.i5.139. PMID: 36187464; PMCID: PMC9521512. ↩
Mejía-Vilet JM, Ayoub I. The Use of Glucocorticoids in Lupus Nephritis: New Pathways for an Old Drug. Front Med (Lausanne). 2021 Feb 16;8:622225. doi: 10.3389/fmed.2021.622225. PMID: 33665199; PMCID: PMC7921306. ↩
Korbet SM, Lewis EJ, Schwartz MM, et al. Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis. 2000;35:904-14 ↩
Strippoli GF, Craig JC, Schena FP. The number, quality, and coverage of randomized controlled trials in nephrology. J Am Soc Nephrol. 2004;15:411-9 ↩
[1] Badsha H, Edwards CJ. Intravenous pulses of methylprednisolone for systemic lupus. Semin Arthritis Rheum. 2003;32:370-7 ↩
Badsha H, Kong KO, Lian TY, et al. Low-dose pulse methylprednisolone for systemic lupus erythematosus flares is efficacious and has a decreased risk of infectious complications. Lupus. 2002;11:508-13 ↩
[1] Flanc RS, Roberts MA, Strippoli GF. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis. 2004;43:197-208 ↩
[1] Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med. 2001;135:248-57 ↩
Contreras G, Roth D, Pardo V, et al. Lupus nephritis: a clinical review for practicing nephrologists. Clin Nephrol. 2002;57:95-107 ↩
Du Buf-Vereijken PW, Feith GW, Hollander d, et al. Restrictive use of immunosuppressive treatment in patients with idiopathic membranous nephropathy: high renal survival in a large patient cohort. Q J Med. 2004;97:353-360 ↩