Q.274. How can you suspect a hereditary form of G. nephritis?

HEREDITARY DISORDERS

Revise please the abbreviation list on:

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Q.274. How can you suspect a hereditary form of G. nephritis?

A. Pres. of Gross hematuria + F.H. of R.F. + Sensorineural deafness + ocular mnf. (anterior lenticonus), in a male (x-linked) = Suug.: Alport’s Synd. (hered-itary nephritis).

Q.275. How to confirm diagnosis of Alport’s syndrome?

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A. Laminated appearance of G.B.M. due to longitudinal splitting of the “Lamina Densa” is diagnostic of Alport’s in immunostain of R. biopsy.

v A less invasive test: “Skin Biopsy”: incubated + monoclonal A.B., anti a-5-type IV. Collagen 🠊No staining in X-linked Alport’s, but:👉discontinued staining in female carriers. Normal staining occ. é [autosomal dominant Alport’s-thin B.M. dis. & other G.pthies].

Q.276. How can you D.D. Alport’s fr. other common causes of Glomerular hematuria?

A. Other common causes incl.: IgA. Np. (Gross hematuria + No F.H. + post respiratory infc.) & Thin B.M. dis.:” Benign familial hematuria” (microscopic hematuria + F.H. + benign course i.e. No R.F.).

Q.277. What are the clinical manifestations & diagnosis of hereditary nephritis (Alport’s syndrome)?

A. Alport ‘s is a genetic heterog. dis. results fr. mutations in genes encoding a-3, a-4 & a-5(IV) chains of type IV collagen. X-linked, autos. recessive & autos. dominant forms of the dis. account for 80, 15 & 5 % of cases, resp.. Abn. of a-3, a-4, or a-5 (IV) cha-ins of type IV collagen cause: B.M. impairment in the glomerulus, eye & inner ear. C.P. us. based upon clinical manif. of affected males é X-linked dis..: G. dis. progress to ESRD, ocular abn. (ant. lenticonus), sensorineural hearing loss &+ve F.H. of R.F. & hearing loss. Auto. recess. disease hv similar C.P. & course, while autos. dom. disease hv a slower deterioration of R. function.

Initial R. manif. aSm.tic microscopic hematuria. S. cr. & B.P.: normal in early childhood, but progressive R.I., H.T. & proteinuria dev. é time. ESRD us. occ. between 16 & 35 y., but course is more indolent in some families. Dgx. us. susp. fr. F.H. of R.F. & deafness. Confirm. of Dgx. is made by either skin or R. biopsy. EM: Classical Alport's syndrome due to X-linked hereditary nephritis. There’s prominent lamination and fraying of the GBM.

Classical Alport's synd. due to X-linked hereditary nephritis. Interstitial foam cells are often a clue for dgx. in patients without hyperlipidemia.

Q.278. How to treat hereditary nephritis (Alport ‘s syndrome)?

A. There’s no sp. ttt for Alport ‘s . Ptns é H.T.: Anti-H.T. agents directed towards angiotensin blockade . This cn be accompl. by ACEI/ARB. Such thpy may be used in normotensive ptns é evid. of progressive dis., such as overt proteinuria. We don’t recommend Csp in Alport ‘s. Csp hs not bn shown to regress rate of R. dis. Progression & hs significant S.E. incl. Csp R. toxicity. Either DX. or R.TX. cn be used é Alport ‘s ptn. dev. ESRD. The pre-ferred modality of RRT is R.Tx. Recurrent dis. does not occ. in Tx. (since donor GBM is normal); however, 3 % of Tx males dev. de novo anti-GBM AB dis..

Q.279. What is “Fabry dis”?

A. (Angiokeratoma Corporis Diffusum Universale) is an X-linked error é “glycosphingolipid” metabolism🠊a-galactocidase deficiency 🠊“Ceramide” accumulation. Multi-system derangement: episodic pain & acroparaesthesia + renal mnf. (proteinuria/ hematuria, N.S., R.F. é 5^th decade), Skin Reddish-purple macule (Angiokeratoma) é abdomen & upper thigh. Autonomic Neuropathy- prem-ature CAD- M.I.- C.V.S. & hypertrophic CMP cn also be sn.

Q.280. What is the management?

A. Dg.x.: Dcr. level of “a. galactosidase A”. – “Urinary ceramide” for carriers.

E/M.: “Zebra bodies” = Myelin figures é cytoplasm of “bodocytes”.

ttt.:[R.H. a-G.S.A]= {Recombinant human “a. galactosidase A”. replacement thpy}.

Q.281. What is the role of hereditary complement deficiencies?

A. In addition to incr. consumption, two other mech. account for H.C.: hereditary complement def. & pres. of circulating F. complement activity.

H.C.D., e.g. C2 def. predispose to dev. of autoimmune dis. e.g., lupus % as high as 50 % in ptn. e`C2 def.. low CH50 (wch reflects activity of whole complement cascade), low to absent C2, but normal level of other C. components. In contrast, conc. of multiple C. comp. (e.g. C4 & C3) is reduced in idiopathic lupus due to incr. utilization.

Relationship between C. def. & immune c.x. dis. reflects loss of a mj. func. of C. system. C. activity normally plays an important role in clearing immune c.x. (via attachment to C3b receptors on RBCs) and in limiting growth of Ag-AB lattice, both of wch prevent formation of insoluble im/m. ppt responsible for G. dis..

Q.282.What is the C3 nephritic factor?

A. Some G. dis. are ch.ch. by pres. of circul. factor tht promote C. breakdown ind-ependent of activation by im/m. complex., described in type 2 MPGN in which an IgG auto-AB (C3 nephritic f.) enhance C. breakdown by binding to C3 convertase (C3 c) (alternate pathway). This reaction prevents inactivation of (C3 c) allow continued C3 breakdown. Both a similar nephritic f. & a diff. one directed agnst (C3 c) of the classic pathway hv bn described in isolated cases of PSGN.

Q.283.Define Primary hyperoxaluria (PHx)?

A. PHx: [a rare inborn error of glyoxylate metabolism ch.ch. by overproduction of oxalate Ø Ca oxalate deposition in various organs, esp., kidney ESRD].

Etiology: Autosomal recessive enz. defects of glyoxylate mtb.🠊🠉 oxalate production. PHx type1 (PHx1) (80%) hepatic peroxisomal enz. alanine mutations : glyoxylate aminotransferase (AGT). PHx2 (10%) mutations of glyoxylate reductase/hydroxypyruvate reductase (GRHPR).🠊 urinery excretion of oxalate oversaturation🠊 Urolithiasis & Nephrocalcinosis (NC). Recurrent stones & progressive N.C. 🠊 Renal parenchymal inflmmation & fibrosis 🠊 ESRD. As R. function declines, pl. oxalate > 30 µmol/L (supersaturation threshold for Ca oxalate), ur. oxalate excretion🠊Ca oxalate deposition é non-renal tissues: [retina, myocardium, vessels, skin, bone & C.N.S]. (Systemic Oxalosis).

C.P.: PHx1: depends on age bec. of marked heterogeneity of dis. expression. Affected children present é Sm. of N.C., urolithiasis, and/or CKD. ESRD: ½ of ptns by young adulthood. As R. func. declines, comp. of systemic oxalosis develop cardiac conduction defects, bony pain & risk of fractures, dcr. visual acuity. PHx2 : hv less severe dis. recurrent urolithiasis, but less likely to hv N.C. & rarely progress to ESRD. Dgx. of both PHx 1 & 2 are based on C.P. (recurrent urolithiasis or N.C.), markedly ur. oxalate excr. & confirmed by molecular genetic testing. liver biopsy dcr. or absent AGT activity for PHx1 & GRHPR for PHx2 is used to confirm Dgx.. Prior genetic & mtb. testing is useful in D.D. between the two forms , as ur. excretion of glycolate is strongly suggestive, but not diagnostic,

of PHx1 & PHx2 typically hv L-glyceric a.

Q.284. What is the differential diagnosis of PHx?

A. D.D. of both types of PH: fr. 2^ndry oxalosis due to incr. oxalate intake or 🠉 oxalate reabsorption due to small bowel dis.. The two types cn be distinguished fr. each other & other inborn error of oxalate & secondary causes of oxaluria by [metabolic screening & molecular testing]. (see above).

Q.285. What are the treatment options?

A. PHx shd initiate the foll. medical thpy to Ca oxalate deposition & R.I..

💢 High fluid intake (>3 L/d./1.73 m2) to 🠋 tub. fluid oxalate & intratub. oxalate deposition é goal of ur. oxalate < 0.4 micromol/L thr. 24-h/d..

💢 Neutral phosphate (OrthoPo4: 30-40 mg/kg), but (higher é skeletal gro-wth), K. citrate (0.15 g/kg), and/or Mg. oxide (500 mg/d./m2) to 🠋 ur. Ca oxalate ppt..

💢 PHx1: 3-6 m. trial of pyridoxine, 30 % of PHx1: pyridoxine 🠋 ur. Oxalate.

💢 PHx1: alth. 3 T.x. options are available, it remains unclear what is optimal. Until more data are available: combination of liver/R.Tx. in ptn é R.I.

💢 PHx2 & ESRD: R.Tx. alone as because it’s unknown whether liver Tx. corrects the inborn error of glyoxylate metabolism.

Q.286. Which are the common complications of nephropathic cystinosis in the first decade of life? What is the culprit gene & common clinical features?

A. Common complications of nephropathic cystinosis in the first decade of life:

Corneal clouding due to cystine crystal deposition.