What is new in the treatment of dense deposit disease (DDD) & C3 G.N.

 

CLINICAL NEPHROLOGY

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Q. What are the long-term implications of COVID-19 -related AKI?

After COVID-19 infection recovery, patients who developed an AKI should be followed by a nephrologist, as a risk of CKD (chronic kidney disease) development still high. Other groups of COVID-19 patients with no AKI development, but showing RBCs and/or albumin should be closely monitored to guard against CKD or ESRD evolution.

 

Q116. What is new in the treatment of dense deposit disease (DDD) & C3 G.N.?

A. Eculizumab(Ecz.)=a humanized monoclonal A.B. tht binds é high affinity to C5. It prevents cleavage of C5, So, prevents C5a & terminal C. cx (C5b-9) formation, wch hv bn implicated in pathogenesis of both (DDD) & C3 G.N.. Three case rep. & one phase I open-label trial hv experienced Ecz. (total 9 ptn.). S. membrane attack cx were normalized in 7 ptn.. S. cr. improved in 4 ptn., worsened in 3 ptn. & remained unchanged in 2. Prot. dcr. in 6 ptns, many of whom hd NRP prior to beginning ttt. but worsened in one ptn. & remained unchanged in 2 ptn.. Based upon these data, Ecz. cn be used in DDD or C3 G.N. ptns. who have deteriorating R. function or sev. N.S. despite ttt. é Pph.

Q.117. What is the C.P. & diagnosis of post-streptococcal G.N.(PSGN)?

A. PSGN is the most common cause of Ac. nephritis worldwide. It occur mainly é developing world. Risk is greatest in children (5-12 y.) & elderly>60 y.. PSGN is caused by G. immune cx. dis. induced by specific nephritogenic  strains of G. A beta-hemolytic strept. (GAS).Two leading candidate nephritogenic Ag.:

v  Nephritis-ass. plasmin receptor     &

v  streptococcus pyrogenic exotoxin B.

Ch.Ch. pth. features: E/M: (dome-shaped🛎subepith. deposits) & I.F.: (deposition of IgG & C3 in a diffuse granular pattern é msng. & G. cpll. walls. L.M.: cellular infiltration & G. proliferation are nonsp..

The Most comm. “C.P.”.:[edema, gross hematuria & H.T.], presentation varies fr. a.Sm.tic microscopic hematuria to full-blown Ac. N.S.(gross hematuria, Prot., edema, H.T. & AKI.).Lab.: [abn. urinalysis (dysmorphic RBCs, Prot., RBCs casts & pyuria), +ve serology for A.B. to strept. Ag. & hypoC.].                                                  

PSGN typically Dgx.🠞[ Ac. nephritis + recent GAS infection.]. Although severe G.N. (eg, M.P. & IgA Np.) have similar present. to PSGN, sp. clinical differences can D.D. them. If Dgx is uncertain🠞R. biopsy may be needed to identify sp. R. disease.

Q.118. How to treat PSGN.?  There is no sp. therapy to treat PSGN. Management is supportive & focused upon ttt volume overload that causes clinical complic. of PSGN. General measures incl.: sodium & water restriction &diuretic therapy.

Ptn. é ARF.:DX. may be required. H.T. ptn.🠞lasix for prompt diuresis &🠟B.P.. H.T. encephalopathy due to severe H.T., will require emergent therapy to 🠟B.P.

Most ptns, esp. children🠞complete clinical recovery & resol. of dis. process begins é 1^st 2 w.. Small No. have late  complication (i.e, H.T.,🠝proteinuria & R.I.).

Q. 119. What biological agents associated with post-infectious G.N.?

A. Bacterial infections:

1. Skin or throat (Strept. G. A).
2. Endocarditis (Staph. aureus, Strept. viridans).
3. Visceral abcess   (Staph. aureus, E. coli, Pseud., Proteus mirabilis).
4. Shunt nephritis.(Staph. aureus, Staph. albus, Strept. viridans).
5. Pneummonia. (Diplococcus pn., Mycoplasma).
6. Thyphoid fever.  (Salmonella typhi).

B. Viral  infection:

1)   Mumps.

2)   Hepatitis B.

3)   Epstein Barr virus.

4)   Parvovirus B19 .

5)   Varicella .

6)   CMV infection.

7)   Coxsackie.

8)   Rubella.

 

C. Parasitic infections.

1)   Shistosoma mansoni.

2)   Plasmodium falciparum.

3)   Toxoplasma gondii.

4)   Filaria.    

 

Q.120. How to distinguish different forms of FSGS?

A. DD. I.ry & II.ry FSGS has important theraputic implications. I.ry FSGS may resp. to im/m. ag. e.g. steroids, while II.ry us. fails to do & may be best ttt é modalities tht.🠟intraG. pressure, e.g ACEI. Distinction can usually be made fr. P.H. (e.g. diso. ass. é  I.ry dis.), ch.ch. of onset, find. on E/M & degree of Prot.

In contrast to II.ry FSGS who present é slowly incr. Prot. & R.I. over time, Iry FSGS typically present é Ac. onset of N.S. & us. ass. é periph. edema, hypo-alb. & NRP. By comp., Prot in IIry FSGS is often nonnephrotic & both low s. albumin & edema are unusual even when protein excr. >3-4  g/d.👍

E/M. find. also diff. in Iry & IIry FSGS. Iry is ass. é diffuse foot process fusion; in comp., it’s focal in IIry dis. & largely limited to sclerotic areas .

To D.D.: (healed vasculitis) fr. (Idiopathic FSGS) or tht due to (nephron loss). É healed vasculitis, the obsolescent segment of cpll. tuft is us. incorporated into scar tissue tht is us. composed of collagens type I & III & tht may fragment the tuft. On PAS st., this scar tissue stains less intensely thn the strongly PAS-+ve segm. of collapsed cpll.  B.M. material in Iry FSGS.

Familial & idiop. FSGS: DD.: extremely difficult since familialdis. hs high % of steroid-resistant🔒ptn. (at least in children). Familial disorder🠞wide range of clinical dis., ranging from M.C. to adult onset FSGS . Find. sugg. (but not diagnostic) familial dis.:[F.H. of dis. & onset in infancy or childhood.]. Steroid-resist. is a consistent finding in Iry FSGS. Steroid-resistant FSGS is due to familial dis. in many children; its predictive value in adults is uncertain. Genetic screening may identify famil. disease.

Q.121. How to treat primary FSGS?

A. Unttt ptns é N.S. (Prot>3.5 g/d.+ hypoalb.) due to Iry FSGS typically progress to ESRD. Steroids & other im/m.🠞partial & complete Prot resp. of almost 70 %. Ptns without N.S. are more likely to remit spontaneously, or hv slowly progr. dis.. The most important “predictor of outcome” in Iry FSGS is➳ Response to initial thpy.

v  A complete response = 🠟in Prot to < 200-300  mg/d.                       

v  Partial resp. in NRP: 🠟 in Prot by ≥50 % & ideally to <3.5 g/d.

v  Relapse= return of Prot to ≥ 3.5 g/d. after complete/partial remission.

v  Steroid-depend = relapse while on steroids or shortly after stop of steroids, or need for continuation of steroids to maintain remission.

v  Steroid-resistance= little or no 🠟 in Prot, 12-16 w. after prdn., or some🠟 in Prot é prolonged thp. tht cannot be considered partial remission.

On long-term: much lower rate of R.F.é complete or partial remmission, compared to steroid-resistant ptns. Ptns é complete remission shd not progress to R.F. if they don’t relapse.

Ttt. of primary FSGS: Initial im/m.: Im/m. thpy for nephrotic Iry FSGS. Decision to provide im/m. é signif.🠟 Kid. function. (e.g, GFR<25-35 mL/min/1.73 m2) should consider: acuity of R.F.(= more reversible dis.), biopsy find.( sev. interst-itial fibrosis & G.sclerosis = less reversible dis.) & adverse effects é im/m.

      Prednisone:1mg/kg/d. (max. 60-80 mg), if no C.I. to steroid use. Duration of initial dose & tapering rapidity deped upon remission rapidity.

      Csp: initial thp. in ptns cannot tolerate high dose steroids (e.g, poorly con-troll. D.M., sev. osteoporosis)🠞3-4 mg/kg/d. (2 divided doses) or=100 mg twice/ d. + low dose prdn. (0.15 mg/kg/d., max. 15 mg/d.). Monitor Csp lev. to ascertain absorption & avoid nephrotoxic lev.(e.g,F100-175 ng/mL).

      Continue Csp for at least 6 m. after complete remission & one y. after partial remission, but at lowest dose required to keep remission (≤3 mg/ kg/d.). Prednisone is tapered after 6 m. & continued é lower dose for Csp thp.. Avoid Csp or other CNI. é👉(1) Significant vascular or (2) inter-stitial dis. on R biopsy, or (3) é GFR <40 mL/min per 1.73 m2.                        

                  Don’t 👆provide im/m. in non-NRP . Ptn.é preserved R. function have a relatively good prognosis, others é  R.I. may be IIry or unrecognized disease .

Q.122. How to treat relapsing disease?

Defin.:[Return of Prot. to ≥ 3.5 g/d. after complete or partial remission.].

If ptn hs recurrent N.S. after a complete resp. to steroids & has not hd signif. S.E. rel. to steroids 🠞 a second course of prednisone is suggested.                             Signif. steroid toxicity or subsequent relapses ⮚[ Csp + low dose prdn.], é same consideration for its use in initial thp.: cautions, dose & dur. of thp. apply. Steroid-resistant or steroid-dependent dis.:🠞Csp for ttt of resistant to or steroid dependent , é same previous considerations .

MMF: 750-1000 mg twice d./6 m.for resistant to or steroid dependent & not resp. or C.I. to Csp, or é partial resp. to prednisone and/or Csp but hv Sn of steroid or Csp toxicity. Only in these circumstances above 🠞[Pph.+ im/m.] can be tried. Monitoring: routine chemistries: pl. Cr. for GFR & ur. protein-to-cr. ratio at 2-4 w. intervals é initial 2-3 m. Prior im/m. tapering, confirm level of Prot. é two 24-h. ur. collections. Once thpy stabilized and/or tapered⮚ Monitor é 1-2 m.

Nonim/m:  ACEI/ARB, principal thp. for nonnephrotics & ptns not eligible for im/m., and may be partic. beneficial for nephrotic ptns who don’t go into prompt remission foll. im/m. thp. or who have persistently 🠟Kidney function. Ptn. é persistent NS and/or CKD🠞lipid lowering (statin) é goal of reducing the risk of CVS dis..Ptns ttted é Csp & statin shd be monitored for Rbdlsis.

Q.123. What is the classification & treatment of RPGN (crescentic G.N.)?

A. RPGN: ch.ch. morphologically by extensive crescents & clinically by prog-ress to ESRD in unttt ptns é wk.s to m.s. Types: one of 3 mech.: of “G. inj.”:

Type 1: Anti-GBM : refers to anti-GBM AB. disease.

Type 2: Immune cx.: serology & hist. finding point to an underlying dis., e.g. Msng. IgA depos. in (IgA Np), antistrept. AB. & subepith. humps in (postinfec. GN), ANA & subendoth. deposits in (L.N.), cryoglobulins & intraluminal "thrombi" in (M. Cryg.).

Type 3: Pauci-immune RPGN : necrotizing GN. but few or no immune deposits by IF. or E/M. Mj. of ptns é renal-limited vasculitis are ANCA+ve, é 75-80 % have (MPO)-ANCA & many hv or will dev. Sm of  vasculitis.   

C.P.: C/O may be similar to those in sev. postinfc. GN: Ac. macroscopic hem-aturia,🠋urine output & edema. More commonly, RPGN hs insidious onset é initial Sm. of fatigue or edema. R.I. occ. at Dgx. in almost all cases. urinalysis: hem-aturia, RBCs  & other casts & variable degree of proteinuria. Ptns é anti-GBM A.B. dis. may hv pulm. hge & hemoptysis due to A.B. directed against alveolar B.M.. Similar finding cn be sn in W.G. (direct lung involv.) & any G. dis. complic-ated by marked fluid overload & pulm. edema. Systemic C/O :extra-R. organ involvment, are common é pauci-immune RPGN, with or without ANCA positivity.

Evaluation & Dgx : Accurate & urgent Dgx is essential in ptn presenting é clinical finding sugg.: RPGN. Ptns should undergo R. biopsy & appropriate serology. These incl.: ANCA, anti-GBM A.B, antinuclear A.B, and others.

Therapy: Early Dgx é R. biopsy & serology & early initiation of thp. is essential to🠋irreversible R. inj. Empiric thp shd begin é sev. dis., esp. if R. biopsy or interpretttation will be delayed. Empiric thp consists of i.v. pulse Mprd. (500-1000 mg/d ./3d.), oral/i.v. Cph. & Pph., é hemoptysis or anti-GBM AB. disease.

Q124. What is the classification of Schistosomal G.N.?

A. Schistosomal G.N.:

 I.        MesPGN: {S. Mansoni, Hematob. & Japonicum⮚Ig. M, C3 & Sch. gut Ag, mostly A.Sm.tc⮚ Prot/hematuria⮚ may respond to anti-bilharzial ttt.}.

II.        Diffuse proliferative exudative G.N.: {S. Mansoni, Hematob. & Jap. & Sal-monella sp.⮚C3 & Salmonella Ag⮚Low C3 é Salmonella infc.⮚Ac. Nephritic synd. & toxemia⮚may respond to to anti-bilharzial & Salmonella ttt.}.

III.        MPGN.: {S. mansoni⮚Ig. G, A., M.,C3 ⮚N.S., H.T., HSM, R.F.⮚No ttt.

IV.        FSGS.: {S. mansoni ⮚Ig. G,M, ⮚N.S., H.T., HSM, R.F. ⮚ No ttt.

V.        Amyloid: {S. mansoni, Hematob.⮚AA protein.⮚N.S., H.T., HSM, R.F.⮚ No ttt.

VI.        Cryoglobulinemic G.N.: {S. mansoni+HCV. ⮚Ig. G.M. C3⮚N.S., H.T., HSM, R.F., purpura, vasculitis, arthritis.⮚ttt.: Interferon + Ribavirin, ster-oids, im/m., Pph.

Q125. What are the renal syndromes associated with infection? 

A. “Renal syndrome” associated with infection:

I.        Subclinical microhemturia, non-nephrotic Prot: Ac. MesPGN, due: e.g. [Typhoid fever, Pl. falciparum, PSGN.].

II.        Ac. Nephritic synd.: Ac diffuse proliferative GN, due to🠞e.g. PSGN.

III.        ARF, NS: Ac &  ch.🠞diffuse proliferative GN🠞e.g. PSGN., Endocarditis, Methicillin resistant S. aureus.

IV.        N.S. & êGFR: 🠞[ch. FSGS, MPGN I ± cryog.] 🠞e.g. HCV, HIV, infected A/V shunts, Parvovirus.

V.        N.S.: ch. MN, Amyloid🠞e.g. HBV, Leprosy, Kala azar, Schistosoma.

VI.        ARF + Systemic Sm + arthralgia, skin ulcer: Ac. & ch.: vasculitis tub-ulointerstitial inflmm., atrophy & fibrosis🠞e.g. HBV, HIV.

VII.        HUS: AC.: Arteriolar thickening & occlusion, microthrombi, cpll. wall thickening🠞e.g. E. Coli O157-H7.

VIII.        Azotemia, Non-nephrotic Prot, eosinophilia: Ac. & ch. interstitial nephritis🠞e.g. Ebstein Barr virus, Legionnaire’s dis., Hantavirus, Kala-azar.

Q126. What are the expected renal lesions with parasitic manifestation?

A. Renal lesions with parasitic manifestation:

I.        Schistosomiasis:

1.    Hematobium⮞MesPGN- T/I. dis. - Amyloidosis- Granuloma- Post Tx. dis.

2.    Mansoni:⮞MesPGN- FSGS- DPGN- MPGN-Amyloidosis- Granuloma- Post Tx. dis.

3.    Jabonicum: ⮞MesPGN.

4.    Mekongi: ⮞T/I. disease.

II.        Malaria:

1.    Malariae: ⮞MPGN.

2.    P. Falciparum:⮞ DPGN-MPGN- AKI- Post Tx. dis.

III.        Filariasis:

1.    Onchocerciasis:⮞MesPGN- MCD- MPGN- Post Tx. dis.

2.    Loiasis:⮞MN- MesPGN- Post Tx. dis.

3.    Bancroftiasis:⮞MesPGN-MPGN-DPGN-Chyluria.

4.    Dirofilariasis:⮞MPGN. (dogs)-MN. (Dogs & Cats).

5.    Brugia malayi:⮞MesPGN- DPGN- MPGN.

IV.        Kala-Azar:⮞DPGN (human)-MPGN(dogs)-T/I. dis.- Amyloidosis- Post Tx. dis.

V.        Trichinosis:⮞MesPGN

VI.        Strongyloidiasis:⮞MesPGN

VII.        Echinococcosis: MPGN.-Hydatid cyst infestation.

VIII.        Opisthorchiasis:⮞MesPGN- T/I. dis.- AKI-

IX.        Chagas dis.:⮞MesPGN (Mice).

X.        Babesiosis:⮞MesPGN- AKI- Post Tx. dis.

XI.        African Trypanosomiasis:⮞MesPGN (Monkey & mice).

XII.        Toxoplasmosis:⮞MesPGN.